BACKGROUNDS: The AFIRE (Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease) trial demonstrated that rivaroxaban monotherapy was non-inferior in efficacy and superior in safety compared to rivaroxaban plus single antiplatelet therapy in patients with atrial fibrillation (AF) and stable coronary artery disease (CAD). This study examined whether systolic blood pressure (SBP) affects clinical outcomes and modifies the impact of antithrombotic therapy. METHODS: In this post hoc analysis, participants were stratified based on median SBP at baseline: >126 mmHg (High SBP group, n = 1042) and ≤126 mmHg (Low SBP group, n = 1093). The primary efficacy endpoint was a composite of cardiovascular events and all-cause death. The primary safety endpoint was major bleeding. RESULTS: The mean SBP was 139 mmHg and 114 mmHg in the High and Low SBP groups, respectively. In the propensity score-matched cohort (n = 1684), the Low SBP group had a significantly higher incidence of the primary efficacy endpoint (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.01-1.88; p = 0.039), while the primary safety endpoint was comparable between groups. In the Low SBP group, rivaroxaban monotherapy was associated with lower risks of both the primary efficacy (HR, 0.60; 95% CI, 0.41-0.86; p = 0.006) and safety endpoints (HR, 0.40; 95% CI, 0.22-0.74; p = 0.003) compared with combination therapy, whereas no significant differences were observed in the High SBP group. CONCLUSIONS: Lower SBP was associated with increased risk of cardiovascular events and all-cause death. Rivaroxaban monotherapy demonstrated more favorable efficacy and safety outcomes particularly patients with lower SBP.

BACKGROUND: Vericiguat, a soluble guanylate cyclase stimulator, is recommended for patients with chronic heart failure (HF) who recently worsened despite guideline-directed medical therapy. However, there is limited data on its real-world utilization and outcomes. The ROVER-Japan study examined prescribing patterns and prognosis among Japanese patients who initiated vericiguat in routine practice. METHODS AND RESULTS: This retrospective cohort study analyzed secondary data from a Japanese hospital administrative database. Among adult patients diagnosed with HF, 4936 patients who initiated a starting dose of vericiguat (2.5 mg/day) on top of any fundamental HF therapy between September 15, 2021, and July 31, 2024, were included. Patients were followed for up to one year or until death, loss to follow-up, or the end of the study period. The mean age of the included patients was 75.4 (standard deviation 12.4) years. At vericiguat initiation, 60.4% of the patients had a recent worsening HF event, defined as HF hospitalization (HFH) in the previous six months or outpatient intravenous diuretics in the previous three months. Quadruple guideline-directed therapy was administered to 29.6% of patients at baseline. One year after treatment initiation, 95.7% of patients had a medication possession ratio ≥ 80%, and 66.6% continued vericiguat treatment. Natriuretic peptide levels and diuretic use decreased, while eGFR remained stable after vericiguat initiation. The one-year cumulative incidence of composite of cardiovascular death or HFH was 29.8%. CONCLUSIONS: This study provides real-world insights into the contemporary use and outcomes of vericiguat in a large, diverse HF population.

BACKGROUND: In order to collect information on the onset of cardiovascular disease (CVD) events for participants, the Tohoku Medical Megabank Organization (ToMMo) constructed a system to identify CVD events using a self-administered questionnaire regarding CVD onset. The association between traditional cardiovascular risk factors and CVD onset was also examined. METHODS AND RESULTS: This study included participants from the ToMMo's Community-based Cohort Study and the Birth and Three-Generation Cohort Study. To identify CVD onset, the participants were first asked about stroke, myocardial infarction, and angina pectoris using self-administered questionnaires. Next, for those reporting onset, the ToMMo mailed structured CVD registration forms to their medical institutions. These institutions used medical records to complete and return the forms. CVD onset was then determined at event adjudication meetings involving multiple physicians and epidemiologists, based on the information from these registration forms. A nested case-control study with 602 CVD cases and 1,204 matched controls using data from a Community-based Cohort Study of the ToMMo was conducted. Using conditional logistic regression models, we found significant association between traditional CVD risk factors, such as hypertension and dyslipidemia, and CVD onset. CONCLUSIONS: The ToMMo establishes a system for identifying CVD onset in cohort study participants. In the future, combining participants' lifestyles and genomic information with CVD onset may help build evidence for personalized prevention and medicine.

BACKGROUND: Pulmonary hypertension (PH) due to left heart disease (group 2 PH) is associated with a worse prognosis than isolated heart failure. Both pulmonary arterial hypertension (group 1 PH) and group 2 PH are involved in pulmonary artery (PA) remodeling, which is potentially driven by shared molecular mechanisms. The aim of this study was to investigate the underlying processes contributing to PA remodeling in group 2 PH. METHODS: To mimic the response to a left-sided pressure load, pulmonary arterial smooth muscle cells (PASMCs) were subjected to mechanical stretch. RNA sequencing of PAs from patients with group 2 PH was performed using the Gene Expression Omnibus database. Mice with transverse aortic constriction and spontaneously hypertensive rats were used as group 2 PH models, and they were treated with adeno-associated virus via intratracheal instillation. RESULTS: RNA sequencing of PASMCs after the stretch stress identified 1585 genes specifically upregulated in PASMCs from patients with group 1 PH. Further PA and plasma analyses from patients with group 2 PH, integrated with group 1 PH findings, identified enhancement of TGF-β (transforming growth factor-beta) signaling by the INHBA (inhibin subunit beta A) as a key feature. Metabolomics revealed that stretch-induced mitochondrial dysfunction in PASMCs caused lactic acidosis via enhancement of PDK1 (pyruvate dehydrogenase kinase 1) and c-MYC, leading to increased INHBA expression. Mice with transverse aortic constriction exhibited increased INHBA expression, decreased PDH (pyruvate dehydrogenase) expression, and acidic alterations in PAs. Targeted silencing of INHBA or PDK1 using adeno-associated virus in mice with transverse aortic constriction attenuated PA remodeling, improved right ventricular function, and reduced PH. CONCLUSIONS: Integrated RNA sequencing and metabolomics with stretched PASMCs and animal models identified mitochondrial dysfunction and subsequent acidic alterations as stimulators of increased INHBA expression and TGF-β signaling. These mechanisms contributed to PA remodeling in group 2 PH and provided potential therapeutic strategies.

OBJECTIVES: The association between blood pressure (BP) and the mortality risk may vary depending on the comorbidities. This study was conducted to investigate the subgroup-specific correlation between systolic BP (SBP) and mortality in patients with coronary artery disease undergoing percutaneous coronary intervention (PCI). METHODS: The Clinical Deep Data Accumulation System for PCI (CLIDAS-PCI), a nation-wide multicenter database with seven tertiary medical hospitals in Japan, retrospectively collected data on patients undergoing PCI for acute coronary syndrome or stable coronary artery disease. Cubic spline curves modeled the relationship between SBP and all-cause death in the entire cohort and subgroups stratified by age, sex, diabetes, left ventricular (LV) hypertrophy, renal function and LV systolic function. We assessed the SBP, which minimizes mortality risk. RESULTS: A total of 8384 patients [71 [IQR 64, 78] years, 6494 (77%) male] with SBP at hospital discharge were analyzed. During 2.7 years of median follow-up, 695 deaths occurred. In the overall population, spline analysis demonstrated a nadir range of mortality risk around an SBP of 110-130 mmHg. Subgroup analyses revealed that elderly (age ≥ 80 years), those with renal dysfunction, and those with preserved LV systolic function had higher SBP levels associated with lowest risk. Conversely, patients <80 years, those with better renal function, and those with LV systolic dysfunction exhibited lower SBP levels at lowest risk. CONCLUSION: This study demonstrated differential association between SBP and mortality risk in various subgroups, highlighting the need for personalized BP management in multimorbid patients with coronary artery disease.

BACKGROUND: The AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial demonstrated that rivaroxaban monotherapy has noninferior efficacy and superior safety compared with combination therapy (rivaroxaban plus a single antiplatelet) in patients with atrial fibrillation and stable coronary artery disease. OBJECTIVES: This post hoc analysis aimed to explore the impact of medication adherence on the AFIRE trial results. METHODS: A total of 2,120 patients were categorized into adherent and nonadherent groups based on self-reported assessments, which were further validated through on-site visits to the facilities. Adherence was defined as continuous medication use as prescribed. The primary efficacy endpoint was a composite of stroke, systemic embolism, myocardial infarction, revascularization requiring unstable angina, or all-cause death. The primary safety endpoint was major bleeding events. RESULTS: Among the 2,012 (94.9%) adherent patients, rivaroxaban monotherapy showed significantly better outcomes compared with combination therapy regarding both efficacy (HR: 0.72; 95% CI: 0.53-0.96; P = 0.028) and safety (HR: 0.63; 95% CI: 0.41-0.97; P = 0.034). However, no significant differences in outcomes were shown in nonadherent patients (n = 108). There was no interaction between medication adherence and the randomized treatment group. In clinically high-risk patients with a history of angina pectoris, compared with nonadherent patients (n = 68), those who demonstrated medication adherence (n = 1,281) exhibited significantly better efficacy outcomes (HR: 0.52; 95% CI: 0.30-0.97; P = 0.041). CONCLUSIONS: High adherence to rivaroxaban monotherapy was associated with improved outcomes, underscoring the importance of adherence in achieving optimal therapeutic effects (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease [AFIRE], NCT02642419; AFIRE Study: Atrial Fibrillation and Ischemic events with Rivaroxaban in patiEnts with stable coronary artery disease Study, UMIN000016612).

The progressive nature of heart failure (HF) is influenced by underlying pathophysiological mechanisms, including nutrition and metabolism. Previous studies have highlighted the prognostic importance of body mass index (BMI) in patients with stage C/D HF patients; however, limited data exist on the asymptomatic HF stages (stage A/B) METHODS: We prospectively evaluated consecutive HF patients in stage A/B (n = 501/4767, respectively, mean age 67.6 ± 12.0 years, male 71.1 %) from the multicenter observational CHART-2 (chronic HF registry and analysis in the Tohoku District-2) study. Patients were stratified into four groups based on BMI (<18.5, 18.5-24.9, 25-29.9, ≥30 kg/m2) according to the WHO criteria. We assessed 10-year survival and hospitalization rates, using a composite endpoint of all-cause death or HF hospitalization RESULTS: The lowest BMI (<18.5 kg/m2) was significantly associated with the composite endpoints and the incidence of HF (both P < 0.05). This association was particularly pronounced in older patients (above median age: 70 years), but was not evident in younger patients (below median age). Additionally, the lowest BMI group was characterized by older age and lower albumin levels (P < 0.05). There were variations in the correlation between BMI and composite endpoints among age groups; in the elderly, a lower BMI was consistently associated with worse prognosis; in younger patients, the association was not evident CONCLUSION: These results provide the first evidence that a lower BMI significantly impacts all-cause death or HF hospitalization in the older population, even in the early stages preceding HF.

BACKGROUND: Patients with heart failure (HF) often present with a relative deficiency of cyclic guanosine monophosphate (cGMP) despite elevated B-type natriuretic peptide (BNP) levels. Sacubitril/valsartan and vericiguat target the cGMP pathway, but the relative contribution of cardiac versus systemic cGMP production remains uncertain. This study evaluated the association between cGMP changes and hemodynamic changes in patients with HF with reduced ejection fraction (HFrEF) receiving these agents. METHODS: Fourteen symptomatic HFrEF patients (median age 65.0 [IQR: 56.0-72.3]years, EF 25.5 [24.0-33.3]%) and 20 control patients without HF (66.0 years, EF 66.5 %) were enrolled. Of the HFrEF patients, five received sacubitril/valsartan alone and nine received vericiguat (newly initiated or added to sacubitril/valsartan). All HFrEF patients underwent right heart catheterization before the treatment and two months after treatment. Blood samples were collected from the coronary sinus, arteries, and veins. RESULTS: HFrEF patients showed higher coronary sinus cGMP levels compared with controls (15.8 ± 1.7 vs. 10.9 ± 1.2 nM, p < 0.05) but a markedly lower cGMP/BNP ratio (0.09 ± 0.02 vs. 1.71 ± 0.63, p < 0.05), suggesting a relative cGMP deficiency. After the therapy, the cGMP/BNP ratio significantly increased (0.278, p < 0.05). The change in coronary sinus cGMP correlated with improvement in cardiac index (r = 0.57, p = 0.039). cGMP levels rose consistently across all sampling sites, indicating a systemic augmentation of the cGMP pathway. CONCLUSION: Elevation of cGMP levels were associated with hemodynamic improvement in HFrEF patients treated with sacubitril/valsartan and vericiguat. These findings highlight the therapeutic relevance of cGMP pathway augmentation and provide mechanistic insights aligned with the known clinical effects of these agents in HFrEF.

BACKGROUND: Early detection and treatment of cardiotoxicity are essential for reducing cardiac events. However, a reliable predictive model for cardiotoxicity in patients with breast cancer receiving chemotherapy is lacking. OBJECTIVES: In this study, we aimed to develop a risk prediction model and establish effective surveillance for cardiotoxicity in patients with breast cancer undergoing chemotherapy. METHODS: Patients with breast cancer scheduled for neoadjuvant and/or adjuvant chemotherapy were prospectively screened at 25 participating institutions between August 2017 and March 2020. Cardiotoxicity was defined as a reduction in left ventricular ejection fraction of >10% from baseline to a value <53%. RESULTS: The study included 559 chemotherapy-naïve female patients. Cardiotoxicity was observed in 46 of 559 patients (8.2%) during a median follow-up period of 366 days (Q1-Q3: 365-367 days). The CHECK HEART (Comprehensive Heart Imaging to Evaluate Cardiac Damage Linked With Chemotherapy in Breast Cancer Patients) score consisted of 6 variables: heart rate, left ventricular global longitudinal strain, left ventricular end-systolic and end-diastolic diameters, right ventricular fractional area change, and treatment with anthracycline and trastuzumab. The time-dependent area under the receiver operating characteristic curve (AUC) at 12 months based on pretreatment data showed acceptable accuracy (AUC: 0.82; 95% CI: 0.76-0.89). CONCLUSIONS: The developed multivariable risk prediction models can accurately predict cardiotoxicity and support effective surveillance in patients with breast cancer receiving chemotherapy.

BACKGROUND: Some patients of heart failure with improved ejection fraction (HFimpEF) have subsequent decline in left ventricular ejection fraction (LVEF) after improvement, and their prognosis is uncertain. AIMS: We aimed to examine the clinical characteristics and long-term prognosis of this sub-population of HFimpEF. METHODS: We examined 399 consecutive patients with HF with reduced ejection fraction (HFrEF, LVEF ≤ 40 %) with LVEF data at both baseline and follow-up in the CHART-2 Study. We classified them as follows; persistent HFrEF group (LVEF ≤ 40 % at 1-year and 2-year follow-up, n = 238), temporary HFimpEF group (≥10 % increase from baseline with LVEF > 40 % at 1-year follow-up but LVEF ≤ 40 % at 2-year follow-up, n = 22), and persistent HFimpEF group (≥10 % increase from baseline with LVEF > 40 % at 1-year follow-up, and LVEF > 40 % at 2-year follow-up, n = 139). RESULTS: The temporary HFimpEF group (adjusted hazard ratio: 2.95; 95 % CI: 1.55-5.63) and the persistent HFrEF group (2.53; 1.75-3.67) were associated with increased risks for the composite of cardiovascular death and HF hospitalization. The risk factors for decline in LVEF included LVEF (adjusted odds ratio: 0.80; 95 %CI: 0.69-0.90), LV end-diastolic dimension (LVDd) (1.14; 1.05-1.25), B-type natriuretic peptide (BNP) levels (1.04 per 10 pg/mL increase; 1.00-1.08), estimated glomerular filtration rate (eGFR) levels (0.95; 0.92-0.99) and serum sodium levels (0.70; 0.50-0.91) at 1-year follow-up. CONCLUSIONS: These results indicate that patients with HFrecEF account for 23% of those with HFrEF and that 12% of them have subsequent decline in LVEF associated with similar worse prognosis as in those with persistent HFrEF.

BACKGROUND: Accurately predicting left ventricular ejection fraction (LVEF) recovery after percutaneous coronary intervention (PCI) in patients with chronic coronary syndrome (CCS) is crucial for clinical decision-making. OBJECTIVE: This study aimed to develop and compare multiple machine learning (ML) models to predict LVEF recovery and identify key contributing features. METHODS: We retrospectively analyzed 520 patients with CCS from the Clinical Deep Data Accumulation System database. Patients were categorized into 4 binary classification tasks based on baseline LVEF (≥50% or <50%) and degree of recovery: (1) good recovery, defined as an LVEF increase of >10% compared with ≤0%; and (2) normal recovery, defined as an LVEF increase of 0% to 10% compared with ≤0%. For each task, 3 feature selection strategies (all features, least absolute shrinkage and selection operator [LASSO] regression, and recursive feature elimination [RFE]) were combined with 4 ML algorithms (extreme gradient boosting [XGBoost], categorical boosting, light gradient boosting machine, and random forest), resulting in 48 models. Models were evaluated using 10-fold cross-validation and assessed by the area under the curve (AUC), decision curve analysis, and calibration plots. RESULTS: The highest AUCs were achieved by RFE combined with XGBoost (AUC=0.93) for preserved LVEF with good recovery, LASSO combined with XGBoost (AUC=0.79) for preserved LVEF with normal recovery, LASSO combined with XGBoost (AUC=0.88) for reduced LVEF with good recovery, and RFE combined with XGBoost (AUC=0.84) for reduced LVEF with normal recovery. Shapley Additive Explanation analysis identified uric acid, platelets, hematocrit, brain natriuretic peptide, glycated hemoglobin, glucose, creatinine, baseline LVEF, left ventricular end-diastolic internal diameter, heart rate, R wave amplitude in V5, and R wave amplitude in V6 as important predictive factors of LVEF recovery. CONCLUSIONS: ML models incorporating feature selection strategies demonstrated strong predictive performance for LVEF recovery after PCI. These interpretable models may support clinical decision-making and can improve the management of patients with CCS after PCI.

BACKGROUND: Avoiding potentially inappropriate medications (PIMs) that can worsen heart failure (HF) is a clinical priority. Yet, the prevalence and determinants of PIM use in this population are not well characterized. The Japanese Registry of All Cardiac and Vascular Diseases and the Diagnosis Procedure Combination (JROAD-DPC) database is a nationwide claims-based registry that captures detailed information on hospitalizations for cardiovascular disease across Japan, providing a unique opportunity to examine prescribing patterns in real-world practice. METHODS: We analyzed JROAD-DPC data on hospitalizations for HF among patients aged ≥ 60 years between 2012 and 2020, in a study supported by the Japan Agency for Medical Research and Development. The temporal trend in the utilization of HF-exacerbating PIMs listed in the American Geriatrics Society Beers Criteria®, non-steroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) inhibitors, non-dihydropyridine calcium-channel blockers (CCBs), cilostazol, and thiazolidinediones, was assessed using Cochran-Armitage trend tests. Factors associated with PIM use were evaluated using multivariate mixed-effects Poisson regression models, with hospitals treated as random intercepts. RESULTS: A total of 1,232,368 HF hospitalizations were analyzed. The overall prevalence of PIM use declined over time: NSAIDs and COX-2 inhibitors decreased from 15.7 % in 2012 to 9.2 % in 2020, and non-dihydropyridine CCBs from 14.5 % to 9.7 %. Despite this decline, these medications continued to be prescribed for a substantial proportion of patients. Utilization patterns differed by patient characteristics; notably, women were more likely than men to receive NSAIDs, COX-2 inhibitors, and non-dihydropyridine CCBs. CONCLUSIONS: Although the use of HF-exacerbating PIMs has decreased over time, NSAIDs, COX-2 inhibitors, and non-dihydropyridine CCBs remain commonly prescribed. Given their potential to worsen HF outcomes, raising clinical awareness of PIMs and addressing patient-specific prescribing patterns are essential steps toward safer pharmacological management in older adults with HF. Findings from JROAD-DPC highlight the ongoing need for strategies to further minimize PIM-related risks.

BACKGROUND: Anemia is a common comorbidity associated with adverse outcomes in patients with heart failure with preserved ejection fraction (HFpEF). However, the clinical relevance of new-onset anemia to sudden cardiac death (SCD) in patients with HFpEF remains unclear. This study investigated the association between new-onset anemia with ventricular arrhythmias (VAs) and SCD. METHODS: Anemia was defined as a hemoglobin (Hb) level of <13 g/dL in men and <12 g/dL in women. Patients with Hb levels above these thresholds were categorized as without anemia. We analyzed data of 686 patients with symptomatic HFpEF (ejection fraction ≥ 50 %, New York Heart Association class II-IV) without anemia at baseline from a multicenter prospective observational CHART-2 study. The primary endpoint was a composite of ventricular tachycardia, ventricular fibrillation, and SCD. RESULTS: At the 1-year follow-up, 109 patients developed new-onset anemia (median Hb, 11.9 g/dL), whereas 577 remained without anemia (median Hb, 14.0 g/dL). Over a median follow-up of 9.2 years, patients with new-onset anemia had a significantly higher incidence of composite outcomes (12.8 % vs. 5.2 %, P = 0.008). After adjusting for potential confounders, new-onset anemia was associated with an elevated risk of the composite outcome (adjusted hazard ratio 2.20, 95 % confidence interval 1.10-4.42, P = 0.027). The association between new-onset anemia and lethal arrhythmias was independent of heart failure hospitalization or myocardial infarction occurring before the primary endpoint. CONCLUSIONS: New-onset anemia was significantly associated with an increased risk of VAs and SCD in patients with HFpEF, underscoring the importance of monitoring Hb levels for risk stratification.Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00418041.

BACKGROUND: Recent heart failure (HF) guidelines emphasize the importance of recognizing patients with mild elevations in NT-proBNP (N-terminal pro-B-type natriuretic peptide). While NT-proBNP is a key biomarker for diagnosing HF and predicting outcomes, its levels are often lower than expected in HF with preserved ejection fraction. METHODS: Using data from the SUPPORT (Supplemental Benefit of an Angiotensin Receptor Blocker in Hypertensive Patients With Stable Heart Failure Using Olmesartan) trial, we examined the temporal changes in NT-proBNP and long-term outcomes in patients with HF with preserved ejection fraction (left ventricular ejection fraction ≥50%) categorized by NT-proBNP levels (≤55, 55-125, 125-300, and ≥300 pg/mL). RESULTS: Among 602 patients with HF with preserved ejection fraction, 335 (55.6%) had NT-proBNP <300 pg/mL (12.5% with ≤55, 18.1% with 55-125, and 25% with 125-300 pg/mL). Patients with NT-proBNP <300 pg/mL were younger and had higher body mass index, more ischemic heart disease, less cardiac remodeling, and lower risks of HF hospitalization or all-cause death compared with those with NT-proBNP ≥300 pg/mL. Over 3 years, 52 (15.5%) patients with NT-proBNP <300 pg/mL, including 40 with 125 to 300 pg/mL, experienced NT-proBNP increase to ≥300 pg/mL, accompanied by left ventricular end-systolic enlargement and left ventricular ejection fraction decline. Importantly, these patients had comparable risks of HF hospitalization or all-cause death as compared with those with persistently elevated NT-proBNP ≥300 pg/mL (adjusted hazard ratio, 1.08 [95% CI, 0.69-1.69]). CONCLUSIONS: More than half of patients with HF with preserved ejection fraction had NT-proBNP <300 pg/mL at baseline. Patients with mild elevations in NT-proBNP may progress to overt elevations over time, accompanied by cardiac deterioration and adverse outcomes.

BACKGROUND: There are few data verifying the utility of the CHADS-P2A2RC score in comparison with the CHADS2 score for estimating net adverse clinical events (NACE) in chronic coronary syndrome (CCS) patients without atrial fibrillation (AF) in real-world settings. METHODS: We performed analysis for a total of 3985 CCS patients without AF who underwent percutaneous coronary intervention (PCI) between April 2013 and March 2019 for whom information was obtained from the CLIDAS (Clinical Deep Data Accumulation System)-PCI database. The primary endpoint was NACE defined as the composite of 3-point major adverse cardiovascular events (3P-MACE) (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) and GUSTO moderate/severe bleeding events. RESULTS: Kaplan-Meier analysis showed that both the CHADS-P2A2RC and CHADS2 scores stratified the risks. The incidences of NACE were stratified well by the very-high-risk category, which was uniquely defined as a CHADS-P2A2RC score of ≥6 (hazard ratio: 2.38, 95 % CI = 1.91-2.97, p-value <0.001). The area under the curve (AUC) in estimating NACE within 3 years was higher when the CHADS-P2A2RC score was used than when the CHADS2 score was used (0.67 vs. 0.62, p = 0.003). This was mainly due to the accuracy in estimating bleeding events (0.66 vs. 0.60, p = 0.006). CONCLUSIONS: The accuracy in estimating NACE after PCI for CCS patients without AF was higher when the CHADS-P2A2RC score was used than when the CHADS2 score was used, mainly due to the accuracy in predicting bleeding risk. Higher incidences of endpoints were well-stratified by a very-high-risk category defined as a CHADS-P2A2RC score of ≥6.

A 69-year-old woman presented with heart failure and progressive muscle weakness and was diagnosed as anti-mitochondrial antibody (AMA) myositis with cardiac involvement. Immunosuppressive therapy with prednisolone and intravenous cyclophosphamide significantly improved the symptoms, hemodynamics, and cardiac function. Cardiac magnetic resonance (CMR) T1 and T2 mapping showed elevated native T1, T2, and extracellular volume fractions during heart failure exacerbation (day 37) compared to pre-hospitalization values (10 months before admission) and follow-up conducted 6 and 12 months after admission. This case underscores the importance of comprehensive evaluation, such as serial CMR imaging and immunosuppressive therapy, in managing myocardial involvement in AMA-positive myositis.

Proton pump inhibitors (PPI) reduce gastrointestinal bleeding (GIB) after percutaneous coronary intervention (PCI), but their impact on mortality and major adverse cardiovascular events (MACE) remains unclear. This study investigated the association between PPI-related GIB reduction and MACE and mortality using a real-world database. We analyzed 6,457 patients undergoing PCI (2013 to 2019), using the Clinical Deep Data Accumulation System including electronic medical records from 7 Japanese hospitals. Patients were grouped by PPI use. The primary outcome was GIB and secondary outcomes were all-cause mortality and MACE. Propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and Cox regression were used to estimate hazard ratios. To estimate causal inference, mediation analysis was conducted to assess the indirect effects of PPI use via GIB reduction. PSM and IPTW analyses revealed a lower GIB incidence in the PPI group (PSM: <0.1%, IPTW: 1.6%) than in the non-PPI group (PSM: 2.3%, IPTW: 2.7%). No significant association was found between PPI use and all-cause death or MACE. However, in patients with acute coronary syndrome (ACS), IPTW analysis indicated that PPI use was associated with lower all-cause death (HR: 0.582, 95% CI: 0.364 to 0.931) and MACE (HR: 0.570, 95% CI: 0.344 to 0.946). Importantly, mediation analysis suggested that GIB reduction partially mediated the association between PPI use and lower mortality. In conclusion, PPI use after PCI was associated with lower GIB risk. In ACS patients, it may be associated with a reduction in all-cause mortality, partially mediated by GIB reduction.

The prevalence of malignancies in patients undergoing percutaneous coronary intervention (PCI) is increasing with aging. Active malignancy is a significant contributor to high bleeding risk. For cancer patients requiring oral anticoagulant (OAC) therapy, the choice between direct oral anticoagulants (DOAC) and warfarin is critical. The aim of this study was to investigate long-term bleeding events in patients with malignancy undergoing PCI. The CLIDAS (Clinical Deep Data Accumulation System) multicenter database includes data from seven tertiary medical hospitals in Japan. This retrospective analysis included 6451 patients who underwent PCI between April 2013 and March 2019 and completed 3-year follow-up. The patients were divided into two groups; No malignancy (n = 5787) and Malignancy group (n = 664). Malignancy was defined by a history of cancer treatment. These groups were further subcategorized based on OAC therapy; (1) No malignancy without OAC (n = 5134), (2) No malignancy with DOAC (n = 261), (3) No malignancy with warfarin (n = 392), (4) Malignancy without OAC (n = 589), (5) Malignancy with DOAC (n = 38), and (6) Malignancy with warfarin (n = 37). The primary outcome was the incidence of bleeding events, defined according to the Global Use of Streptokinase and t-PA for Occluded Coronary Arteries classification of moderate and severe bleeding. The secondary outcomes were major adverse cardiac events (MACE) and net adverse clinical events (NACE). Multivariable Cox regression analysis showed that the malignancy with warfarin group had a significantly higher risk of bleeding events compared to the malignancy without OAC group (hazard ratio [HR], 3.64; 95% confidence interval [CI], 1.38-9.61, p value = 0.009). No significant differences were observed for MACE (HR, 1.39; 95% CI 0.59-3.25, p value = 0.454) or NACE (HR, 1.62; 95% CI, 0.80-3.29; p value = 0.184). Malignancy patients receiving warfarin were associated with a higher risk of bleeding events. DOACs may represent a preferable alternative to warfarin with regard to bleeding risk in patients with malignancy undergoing PCI.

Family history of hypertension may reflect genetic and lifestyle factors. Genetic risk can be assessed using polygenic risk score (PRS); however, whether PRS can stratify hypertension risk when combined with family history and lifestyle information is unclear. This prospective cohort study included 9,001 hypertension-free individuals aged ≥20 years from the Tohoku Medical Megabank Community-Based Cohort Study. Participants were scored on lifestyle factors, including body mass index, urinary sodium-to-potassium ratio, physical activity, alcohol consumption, and smoking at recruitment. During the mean follow-up of 4.3 years, 2822 (31.4%) cases of hypertension occurred. High genetic risk and poor lifestyle were associated with increased hypertension risk. Compared with participants with low genetic risk, ideal lifestyle, and no family history, high genetic risk significantly increased hypertension risk, even among those with ideal lifestyle and no family history (relative risk [RR] 1.28 [95% confidence interval [CI] 1.11-1.46]). Participants with low PRS, ideal lifestyle, but with family history had increased hypertension risk (RR 1.32 [95%CI 1.11-1.57]). Poor lifestyle increased hypertension risk across most genetic risk groups, regardless of family history. Integrating PRS into models with family history and lifestyle risk significantly improved predictive accuracy (area under the curve: 0.671 for family history and lifestyle risk and 0.674 for PRS integrated; P for difference <0.05). Integrating PRS with lifestyle and family history enhances the stratification of individuals at high risk for hypertension.

BACKGROUND: Intensive immunosuppressive therapy (IIT) is recommended for PAH associated with connective tissue disease (CTD-PAH). However, the long-term effects of IIT on pulmonary hemodynamics in this population remain unexplored. Additionally, its effectiveness in patients with systemic sclerosis (SSc)-associated PAH (SSc-PAH) is poorly understood. METHODS AND RESULTS: This retrospective analysis included 69 consecutive patients with CTD-PAH treated at our institution (men/women: 9/60, mean age 55.3 ± 14.0 years). Patients were divided into two groups, wherein 41 patients received IIT (IIT group) and 28 did not (non-IIT group). Both groups received conventional vasodilator therapy. The prognosis and pulmonary hemodynamics were evaluated in all patients. The IIT group exhibited significantly lower rates of PAH-related mortality (p < 0.001) compared with the non-IIT group. The mean PAP (mPAP) improved significantly in the IIT group during the follow-up (baseline: 38.7 ± 12.2 mmHg; 1 year: 27.0 ± 8.2 mmHg; 5 years: 26.8 ± 7.3 mmHg, p < 0.05), while it remained unchanged in the non-IIT group. None of the patients with CTD-PAH required IIT retreatment. Among the 27 patients with SSc-PAH, the IIT group (n = 9) showed a significantly greater improvement in mPAP compared with the non-IIT group (n = 18) (ΔmPAP at 1 year: -13.4 ± 6.5 mmHg in IIT group vs. -3.0 ± 6.2 mmHg in non-IIT group, p < 0.001). CONCLUSIONS: This study's findings suggest that IIT may lead to sustained improvements in pulmonary hemodynamics and better long-term outcomes in patients with CTD-PAH, including potential benefits in those with SSc-PAH.

BACKGROUND: Whether adherence to a healthy lifestyle can mitigate genetic risk for renal dysfunction remains unclear. METHODS: This prospective cohort study included 12 680 adults aged ≥20 years, free from chronic kidney disease at baseline, enrolled in the Tohoku Medical Megabank Community-based Cohort study. A healthy lifestyle score-based on normal weight, never smoking, never drinking, regular physical activity, and a low urinary sodium-to-potassium ratio-classified participants into ideal, intermediate, or poor lifestyle groups. A polygenic risk score (PRS) was constructed using estimated glomerular filtration rate (eGFR) data from a previous multi-ancestry genome-wide association meta-analysis. The primary outcome was renal dysfunction, defined as eGFR <60.0 ml/min/1.73 m2. RESULTS: Among the 12 680 adults, 123 participants (0.9%) developed renal dysfunction during a mean follow-up of 4.4 ± 0.8 years. Poor lifestyle was consistently associated with higher risk of renal dysfunction across most PRS categories. Participants with intermediate genetic risk had elevated risk only when also exhibiting an intermediate lifestyle. Formal testing for effect modification by PRS provided modest evidence that the association between high genetic risk and increased risk of renal dysfunction was stronger among individuals with an intermediate lifestyle. Although the addition of the PRS to the model included the C-statistic, this improvement was not statistically significant. CONCLUSIONS: Maintaining a healthy lifestyle is associated with lower risk of renal dysfunction, regardless of genetic risk. Combining PRSs with lifestyle information may enhance risk stratification, although further studies are needed to improve predictive accuracy.

BACKGROUND: Although sudden cardiac death (SCD) generally occurs more frequently in men than in women, there are limited data on sex differences in SCD in patients with chronic heart failure (HF) across a range of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: We examined sex differences in SCD incidence, timing, and risk factors in 4,683 patients with chronic HF (3,186 men, 1,497 women) from a multicenter prospective observational cohort study (CHART-2). Over a median follow-up of 8.8 years after study enrollment, there were 215 SCDs (160 in men, 55 in women). The SCD incidence rates in men and women were 6.1 and 4.6 per 1,000 person-years, respectively (P=0.088). Among women, more than half the SCDs occurred in the first 5 years of follow-up. Beyond 5 years, the SCD incidence rate was significantly lower in women than in men (3.6 vs. 5.9 per 1,000 person-years, respectively; P=0.044). After adjusting for confounders, age, increased B-type natriuretic peptide, and LVEF <50% were common prognostic factors. After 5 years of follow-up, left ventricular (LV) enlargement was a risk factor for SCD in both sexes. CONCLUSIONS: These results indicate that there are sex differences in SCD, especially beyond 5 years of follow-up, with a lower prevalence in women. LV enlargement is a common long-term prognostic factor in both sexes, suggesting the importance of preventing LV remodeling in HF management.

AIMS: A decline in left ventricular ejection fraction (LVEF) is often observed in patients with heart failure with preserved ejection fraction (HFpEF) and is associated with adverse outcomes. Although baseline LVEF is crucial for assessing the risk of sudden cardiac death in patients with HF, little is known about the relationship between the decline in LVEF and lethal arrhythmic events among patients with HFpEF. METHODS AND RESULTS: We retrospectively analysed data from the CHART-2 Study. A total of 1453 patients with HF and LVEF ≥ 50% at registration (73 years, 39% female) were included and categorized into three groups based on their LVEF at the prespecified 1-year follow-up; 1316 with LVEF ≥ 50%, 120 with LVEF 36-50%, and 17 with LVEF ≤ 35%. The primary endpoint was a composite of ventricular tachycardia, ventricular fibrillation, and sudden cardiac death. All-cause death was also evaluated. During a median follow-up of 7.9 years, 79 (5.4%) patients experienced a composite event. Patients with LVEF < 50% at 1 year had a significantly higher incidence of the composite event (11.7 vs. 4.8%, P < 0.001), and all-cause death (62.8% vs. 51.8%, P = 0.006), compared to those with LVEF ≥ 50%. Importantly, a decline in LVEF to <50% was independently associated with an increased risk of the composite event (adjusted hazard ratio 1.99, 95% CI 1.04-3.79, P = 0.04). CONCLUSION: In patients with HFpEF, even a mild decline in LVEF was associated with a higher risk of ventricular tachyarrhythmia, sudden cardiac death, and all-cause death. Continuous clinical assessment and re-evaluation of LVEF is crucial for the management of patients with HFpEF. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov; unique identifier: NCT00418041.

BACKGROUND: Early detection and management of atrial fibrillation (AF) are crucial. Combined models incorporating genetic risks and clinical risks have been developed to improve predictive ability. Although sex differences have been reported in many aspects of AF, sex differences in genetic risk have not been studied. OBJECTIVE: The purpose of this study was to assess the sex difference in the effect of polygenic risk score for AF (AF-PRS) on AF prevalence using cross-sectional data from the Tohoku Medical Megabank Project Community-Based Cohort Study in Japan. METHODS: AF-PRS and Cohorts for Heart and Aging Research in Genomic Epidemiology Atrial Fibrillation (CHARGE-AF) score were used for genetic AF risks and clinical AF risks, respectively. Sex differences in the association of AF-PRS with the prevalence of AF were evaluated. RESULTS: Among 16,853 participants (mean age 63.4 years; 5182, 30.7% men), the prevalence of AF was 255 (4.9%) in men and 130 (1.1%) in women. In the group with high AF-PRS and high CHARGE-AF score, the odds ratio for AF was highest in men and women (8.2 in men and 9.4 in women), compared with that in the group with low AF-PRS and low CHARGE-AF score. Integrating AF-PRS into the CHARGE-AF score significantly enhanced the area under the receiver operating characteristic curve for AF in men (from 0.639 to 0.749) but not in women (from 0.710 to 0.733). CONCLUSION: Our study is the first to show a sex difference in the association of AF-PRS and AF prevalence. AF-PRS is more closely associated with the prevalence of AF in men than in women.

BACKGROUND: No previous studies have explored metabolites associated with both genetic predispositions to type 2 diabetes (T2DM) and T2DM onset. Therefore, we aimed to explore metabolic profiles using genetic risk to identify pathways for tailored T2DM prevention strategies. METHODS: This prospective community-based cohort study in Japan included a total of 12,461 participants aged ≥ 20 years. Genetic predictors were genome-wide and pathway-based polygenic risk scores (PRSs). We quantified 43 metabolites using nuclear magnetic resonance spectroscopy. T2DM was defined as a non-fasting glucose level of ≥ 200 mg/dL, glycated hemoglobin level ≥ 6.5%, or self-reported T2DM treatment. A modified Poisson regression model was used to examine the associations of PRSs and metabolites with T2DM incidence. Linear associations were tested using the restricted cubic spline, and mediation analysis was conducted to assess the mediating effect of metabolites on the association between PRSs and T2DM incidence. RESULTS: During the 4.3-year median follow-up period, 354 T2DM cases were identified. A higher PRS was associated with incident T2DM (relative risk [RR] 2.09, 95% confidence interval [CI], 1.68-2.60, P < 0.001, 1-standard deviation [SD] increment). The nitrogen compound transport pathway PRS was associated with incident T2DM (RR 1.32, 95% CI 1.03-1.70, P < 0.001, 1-SD increment). Fourteen metabolites like glucose, 2-ketoisocaproic acid, glutamic acid, leucine, 2-aminobutyric acid, 2-hydroxybutyric acid, valine, 3-methyl-2-oxobutyric acid, alanine, 3-hydroxybutyric acid, 3-methyl-2-oxiovaleric acid, formic acid, arginine, and tyrosine were positively associated with the risk of T2DM. Only glycine was inversely associated with the risk of T2DM. Among 43 metabolites, 14 metabolites were positively associated with PRS (P for linear trend < 0.05). 3-hydroxyisobutyric-acid, 2-Aminobutyric acid, 2-ketoisocaproic acid, 2-hydroxybutyric acid, leucine, glycine, and glucose mediated the association between PRS and incident T2DM. CONCLUSIONS: Several metabolites were found to mediate the association between PRS and incident T2DM. These findings may contribute to a better understanding of the metabolic pathways involved in genetic susceptibility to T2DM.

AIMS: The clinical guidelines categorize heart failure (HF) based on left ventricular ejection fraction (LVEF). However, the current LVEF cutoffs, 40% and 50%, may not fully address the underlying characteristics and cardiovascular risk of HF, particularly for HF with higher LVEF. This study aimed to characterize HF with supranormal ejection fraction (HFsnEF) using different LVEF cutoffs (35%, 55%, and 70% for men, and 40%, 60%, and 75% for women). METHODS AND RESULTS: This study divided 442 patients from the CHART-Omics study into four groups: HF with reduced ejection fraction (HFrEF) (n = 55, 65.5 years), HF with mildly reduced ejection fraction (HFmrEF) (n = 125, 69.3 years), HF with normal ejection fraction (HFnEF) (n = 215, 69.0 years) and HFsnEF (n = 47, 67.1 years). When clinical backgrounds were adjusted and HFnEF served as the reference, HFsnEF carried an increased hazard ratio (HR) for the composite of cardiovascular death and HF hospitalization of 2.71 (95% confidence interval [CI] 1.10-6.66, p = 0.030), while HFrEF had a HR of 3.14 (95% CI 1.36-7.23, p = 0.007). HFsnEF was characterized by an increase in relative left ventricular wall thickness and a decrease in left ventricular dimensions, whereas increased left ventricular mass and dimensions characterized HFrEF. Quantitative analysis of 4670 plasma proteins showed essential differences between HFsnEF and HFrEF, for example, 'protein synthesis' versus 'cell morphology', 'cellular assembly and organization' and 'nucleic acid metabolism' for underlying pathophysiology, and 'energy production' versus 'connective tissue disorders' and 'cell-to-cell signalling and interaction' for prognostication. CONCLUSIONS: Heart failure with supranormal ejection fraction, an unnoticed but emerging entity in HF, carries a similarly increased cardiovascular risk as HFrEF but has unique structural and plasma proteomic characteristics.

BACKGROUND: Dual antiplatelet drug administration is recommended after percutaneous coronary intervention (PCI) stent placement. Although prasugrel, a newer P2Y12 inhibitor, reportedly suppresses cardiovascular events more effectively than the traditional agent clopidogrel, its preventive effects on cerebrovascular disorders remain a topic of ongoing debate. This study aimed to examine the cerebrovascular efficacy and safety of post-PCI prasugrel and clopidogrel using extensive real-world data in Japan. METHODS: Using the CLIDAS (Clinical Deep Data Accumulation System) database, 7412 post-PCI patients who received dual antiplatelet therapy between April 2013 and March 2019 were identified. The primary end point was defined as the incidence of any stroke, while secondary end points included individual ischemic and hemorrhagic cerebrovascular events. The incidence of cerebrovascular events was compared between the prasugrel (2.5-3.75 mg daily; n=2219) and clopidogrel (75 mg daily; n=5193) groups using propensity-score inverse probability of treatment weighting and Fine and Gray models to account for competing risks. RESULTS: Within 1 year after PCI, the prasugrel group had a significantly lower incidence of cerebrovascular events (subdistribution hazard ratio, 0.46 [95% CI, 0.24-0.91]; P=0.027) than the clopidogrel group. The subgroup analyses did not show significant differences in the incidence of ischemic (subdistribution hazard ratio, 0.54 [95% CI, 0.25-1.14]; P=0.11) and hemorrhagic cerebrovascular events (subdistribution hazard ratio, 0.30 [95% CI, 0.084-1.10]; P=0.070) between the use of prasugrel and clopidogrel. One-year health care costs between patients treated with prasugrel and those treated with clopidogrel showed no significant differences. CONCLUSIONS: Our data suggest that post-PCI prasugrel use was associated with lower cerebrovascular events compared with the use of clopidogrel in combination with aspirin. Further research is necessary to substantiate the potential of prasugrel in lowering cerebrovascular risks after post-PCI while upholding a satisfactory safety profile.

BACKGROUND: Lipid-lowering therapy with high-intensity statins has not been widely implemented in Japan for patients with coronary artery disease who undergo percutaneous coronary intervention (PCI). We examined the efficacy and safety of high-intensity statin therapy in a real-world setting. METHODS AND RESULTS: We used the Clinical Deep Data Accumulation System (CLIDAS) to accumulate multimodal data from the electronic medical records of 7 cardiovascular centers. We analyzed 9,690 patients who underwent PCI between 2013 and 2019 and completed a median 2.5-year follow-up (CLIDAS-PCI database). The risk of developing major adverse cardiac and cerebrovascular events (MACCE) was significantly greater in patients with acute (ACS) than chronic (CCS) coronary syndrome. High-intensity statins were prescribed to 49% of ACS patients and 33% of CCS patients within the first 30 days after the index PCI. After propensity score matching, MACCE event rates were similar between the high- and moderate-intensity statin groups. Importantly, among ACS patients, Cox proportional hazard analysis revealed that the rate of myocardial infarction was lower (adjusted hazard ratio [aHR] 0.65; 95% confidence interval [CI] 0.44-0.97) and the rate of stroke was greater (aHR 1.71; 95% CI 1.12-2.62) in the high-intensity statin group, driven mostly by intracranial hemorrhage. CONCLUSIONS: The CLIDAS-PCI database provides real-world evidence for the efficacy and safety of high-intensity statins in Japanese ACS patients who have undergone PCI.

BACKGROUND/AIMS: Radial incision and cutting (RIC) is an alternative dilation method for stenosis of the lower gastrointestinal tract. However, its safety and efficacy for the small intestine requiring balloon-assisted enteroscopy (BAE) remain limited. Therefore, this pilot study aimed to evaluate the safety and efficacy of RIC using BAE. METHODS: We included 10 patients with Crohn's disease and performed 12 sessions of RIC for 10 lesions. The rate of adverse events 1 month after RIC was the primary outcome, whereas short- and long-term prognoses and improvements in subjective symptoms that were evaluated using a visual analog scale were the secondary outcomes. RESULTS: The technical success rate for RIC, defined as scope passage immediately following the procedure, was 100% (12/12). The rates of delayed bleeding and perforation were 0% (0/12). One patient developed restenosis because of the worsening of Crohn's disease and underwent surgery 2 months after RIC. The cumulative restenosis-, reintervention-, and surgery-free rates at 1 year after RIC were 67.5%, 78.7%, and 90.0%, respectively. Abdominal pain, abdominal bloating, nausea, and difficulties in defecation significantly improved 4 weeks after RIC. CONCLUSIONS: RIC for small intestine using BAE has the potential to be safe and effective for relieving symptoms (jRCT identifier jRCTs022200040).

BACKGROUND: Pulmonary artery compliance (PAC), which could be estimated with gas exchange pulmonary arterial capacitance (GXcap), reflects the elasticity of the pulmonary vessels, and it is known that PAC is changed by pulmonary perfusion. GXcap could be measured using ventilatory gas analysis and is calculated using O2 pulse × peak end-tidal CO2 pressure. Moreover, it is known that pulmonary perfusion by postural changes is different between chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). However, it was unclear whether GXcap could estimate PAC in CTEPH and PAH. Furthermore, it was unclear that change in GXcap with postural change (ΔGXcap) [Δ (Sitting - Supine)] was different between CTEPH and PAH. METHODS: Patients with suspected pulmonary hypertension who underwent right heart catheterization (RHC) from May 2022 to February 2023 in our institution were prospectively enrolled. Ventilatory gas analysis was performed before RHC in both the supine and sitting positions and calculated. Moreover, PAC was calculated with RHC. The diagnosis of PAH and CTEPH was based on the European Society of Cardiology/European Respiratory Society 2022 guidelines. RESULTS: Forty patients (CTEPH, n = 18; PAH, n = 22) were enrolled in this study. GXcap was positively related to PAC in these patients (R = 0.62, p < 0.001). Furthermore, PAC was significantly lower in CTEPH patients compared to PAH patients (median 1.63 mL/mmHg vs 2.05 mL/mmHg, p = 0.013). Moreover, GXcap was increased in CTEPH patients with postural change, while GXcap was decreased in PAH patients with postural change. Thus, ΔGXcap was significantly higher in CTEPH patients compared to PAH patients (median 5.8 mL × mmHg vs -2.6 mL × mmHg, p = 0.005). CONCLUSIONS: It was suggested that PAC could be moderately estimated using GXcap in PAH and CTEPH patients. Moreover, it was suggested that ΔGXcap was higher in CTEPH patients compared with PAH patients.

AIMS: Pulmonary arterial hypertension (PAH) is a life-threatening condition. Although pulmonary vasodilators have shown promise in managing PAH, the improvement in prognosis is modest, partly because of a lack of biomarkers to guide their selection. Herein, we aimed to identify molecular-based predictors of responsiveness to pulmonary vasodilators using clinical and preclinical investigations. METHODS AND RESULTS: RNA sequencing was conducted on cultured pulmonary artery smooth muscle cells (PASMCs) from patients with and without pulmonary hypertension (PH), identifying variations in 3017 genes. Next, we performed a case-control study (PAH, n = 114; non-PH, n = 70) and examined plasma samples to identify potential clinical biomarkers. PASMCs exhibited elevated expression of C1q/TNF-related protein 7 (CTRP7; log2 fold change 5.37, P < 0.01). Patients with PAH had higher plasma CTRP7 levels [19.7 (9.8-90.5)] than those without PH [11.8 (0.6-61.6) ng/mL; P < 0.01]. Plasma and single-cell assessments revealed a significant correlation between CTRP7 and interleukin (IL)-6 levels (P < 0.001). Chromatin immunoprecipitation demonstrated that IL-6 up-regulated CTRP7 in PASMCs. CTRP7 reduced the expression of prostacyclin analogue receptor (PTGIR) through Rab5a-mediated internalization, resulting in diminished responsiveness to selexipag (prostacyclin analogue). Consistent with human study results, PTGIR expression was reduced in the pulmonary arteries of hypoxic PH mice, correlating with limited responses to selexipag treatment (low cardiac output and persistent pulmonary artery resistance); this effect was mitigated by the IL-6-R neutralizing antibody or adeno-associated virus-mediated silencing of CTRP7 expression in the pulmonary arteries. CONCLUSION: In patients with PAH, RNA sequencing of PASMCs revealed elevated expression of CTRP7 among candidate biomarkers. Patients with PAH had higher plasma CTRP7 levels than those without PH. Mechanistically, CTRP7 regulated PTGIR internalization via the IL-6-Rab5a axis, influencing responsiveness to selexipag. Herein, CTRP7 emerged as a crucial biomarker associating with responsiveness to prostacyclin analogues, advancing the development of PAH treatment strategies.

BACKGROUND: The Glasgow Prognostic Score (GPS), based on C-reactive protein and serum albumin concentrations provides useful prognostic information for patients with cancer or acute decompensated heart failure (HF). Herein, we aimed to evaluate the relationship between the GPS and long-term prognosis in patients with chronic HF. METHODS: In this large multicentre prospective observational study, part of the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study, we analysed the relationship between mortality and the GPS in 6,480 patients with chronic HF (mean age, 68 ± 13 years; 69 % male). Patients with elevated C-reactive protein levels (>1.0 mg/dL) and hypoalbuminaemia (<3.5 g/dL) received a GPS of 2; those with either received a GPS of 1, and those with neither received a GPS of 0. RESULTS: During median follow-up of 9.62 years, 2,564 patients (39.6 %) died. Increased GPS was associated with a significantly higher mortality risk in Kaplan-Meier analysis (log-rank P < 0.0001). This trend was consistent across sex, age, New York Heart Association class, HF stage and type, and cancer history. Adjusted Cox proportional hazards analysis showed the following hazard ratios for all-cause death, relative to a GPS of 0, 1.27 (95 % confidence interval, 1.13-1.44; P < 0.0001) for a GPS of 1 and 1.83 (95 % confidence interval, 1.45-2.32; P < 0.0001) for a GPS of 2. This increased risk was independent of B-type natriuretic peptide levels. CONCLUSIONS: The GPS, which reflects systemic inflammation status, is a useful predictor of long-term prognosis in patients with chronic HF.

BACKGROUND: The primary prevention of atrial fibrillation (AF), which increases mortality through complications including stroke and heart failure, is important. Excessive salt intake and low potassium intake are risk factors for cardiovascular disease; however, their association with AF remains inconclusive. This study investigated the association between sodium- and potassium-related urinary markers and AF prevalence. METHODS AND RESULTS: Data from the Tohoku Medical Megabank Project Community-based Cohort Study were used in this cross-sectional study. The urinary sodium-to-potassium (Na/K) ratio and estimated 24-h sodium and potassium excretion were calculated using spot urine samples and categorized into quartiles (Q1-Q4). The prevalence of AF was the primary outcome. Of the 26,506 participants (mean age 64.8 years; 33.2% males) included in this study, 630 (2.4%) had AF. Using Q1 as the reference group, the odds ratios for AF prevalence in Q4 were 1.35 (95% confidence interval [CI] 1.07-1.73) and 1.59 (95% CI 1.20-2.12) for 24-h estimated urinary Na/K ratio and estimated 24-h sodium excretion, respectively. Estimated 24-h potassium excretion was not associated with AF prevalence. CONCLUSIONS: AF prevalence was positively associated with the urinary Na/K ratio and estimated 24-h urinary sodium excretion, but not with estimated 24-h urinary potassium excretion. Although further prospective studies are warranted, the findings of this study suggest that salt intake may be a modifiable risk factor for AF.

OBJECTIVE: The objective of this study was to investigate the inter-relationships among genetic risk, adherence to a healthy lifestyle, and susceptibility to hyperuricaemia. METHODS: This prospective cohort study was conducted with 7241 hyperuricaemia-free individuals aged ≥20 years from the Tohoku Medical Megabank Community-based cohort study. A comprehensive lifestyle score included assessment of BMI, smoking, drinking, and physical activity, and a polygenic risk score (PRS) was constructed based on uric acid loci from a previous genome-wide association study meta-analysis. A multiple logistic regression model was used to estimate the association between genetic risk, adherence to a healthy lifestyle, and hyperuricaemia incidence and to calculate the area under the receiver operating characteristic curve (AUROC). Hyperuricaemia was defined as a uric acid level of ≥7.0 mg/dL or a self-reported history of hyperuricaemia. RESULTS: Of the 7241 adults [80.7% females; mean (±s.d.) age: 57.7 (12.6) years], 217 (3.0%) developed hyperuricaemia during 3.5 years of follow-up period. Genetic risk was correlated with hyperuricaemia development (P for interaction = 0.287), and lifestyle risks were independently associated. Participants with a high genetic risk and poor lifestyle had the highest risk (odds ratio: 5.34; 95% CI: 2.61-12.10). Although not statistically significant, adding the PRS in the model with lifestyle information improved predictive ability (AUROC = 0.771, 95% CI: 0.736-0.806 for lifestyle; AUROC = 0.785, 95% CI: 0.751-0.819 for lifestyle and PRS; P= 0.07). CONCLUSION: A healthy lifestyle to prevent hyperuricaemia, irrespective of genetic risk, may mitigate the genetic risk. Genetic risk may complement lifestyle factors in identifying individuals at a heightened hyperuricaemia risk.

BACKGROUND: There are limited data on the efficacy of smartphone-based personal health records (PHRs) in patients with cardiovascular disease. This study aimed to examine the processes, outcomes and challenges associated with the implementation of integrated PHRs in patients with heart failure (HF) or coronary artery disease (CAD). METHODS: This prospective single-group study evaluated the effects of a PHR system with the capability to capture electronic health records and vital signs in patients with HF or CAD. The outcomes measured were the 6 -month changes in blood pressure (BP), body weight (BW), brain natriuretic peptide (BNP) levels, lipid profiles and haemoglobin (Hb) A1c levels. RESULTS: Between June 2021 and March 2022, we enrolled 111 patients (median age: 61 years and 47% women) with CAD and/or HF. Over 6 months, the PHR review count distribution was skewed: median 749 times (lowest 2, highest 5724)/180 days, suggesting both low and excessive PHR users. After 3 days, 23% of the patients discontinued inputting their vital signs and medication status. At 6 months, compared with patients who discontinued, those who continued to input their vital signs (N = 86) showed a significant decrease in their systolic BP and LDL-C levels but not in the diastolic BP, BW, BNP, HDL-C, triglyceride or HbA1c levels. CONCLUSIONS: The implementation of smartphone-based PHRs in daily practice is challenging for patients with HF or CAD. However, we observed positive indications of the benefits of PHR in these patients. TRIAL REGISTRATION NUMBER: UMIN000044369.

OBJECTIVES: Radial incision and cutting (RIC) is being investigated as an alternative endoscopic dilation method for lower intestinal tract stenosis, providing a high technical success rate and improving subjective symptoms. However, several patients develop re-stenosis following RIC. In this pilot study, we aimed to evaluate the safety and efficacy of triamcinolone acetonide (TA) addition after RIC. METHODS: RIC with TA was performed in 20 patients with lower gastrointestinal tract stenosis. We evaluated the rate of adverse events 2 months after RIC with TA. We investigated the short- and long-term prognoses, as well as the improvement in subjective symptoms, using a visual analog scale. RESULTS: The delayed bleeding rate after RIC was 23.8%. Endoscopic hemostasis was achieved in all patients with delayed bleeding. No perforations were observed. The cumulative re-stenosis-free, re-intervention-free, and surgery-free rates 1 year after RIC were 52.9%, 63.7%, and 85.2%, respectively. Subjective symptoms, including abdominal pain, abdominal bloating, nausea, and dyschezia, significantly improved after RIC with TA. CONCLUSION: Although additional TA administration after RIC could be safe, additional TA may not be effective on luminal patency after dilation. Further investigation is warranted.

A 69-year-old woman presented with heart failure and progressive muscle weakness and was diagnosed as anti-mitochondrial antibody (AMA) myositis with cardiac involvement. Immunosuppressive therapy with prednisolone and intravenous cyclophosphamide significantly improved the symptoms, hemodynamics, and cardiac function. Cardiac magnetic resonance (CMR) T1 and T2 mapping showed elevated native T1, T2, and extracellular volume fractions during heart failure exacerbation (day 37) compared to pre-hospitalization values (10 months before admission) and follow-up conducted 6 and 12 months after admission. This case underscores the importance of comprehensive evaluation, such as serial CMR imaging and immunosuppressive therapy, in managing myocardial involvement in AMA-positive myositis.

Heart disease is a major global threat. Triglyceride deposit cardiomyovasculopathy (TGCV) is an emerging, noncommunicable, adult-onset heart disease, first identified in Japanese patients with heart failure (HF) requiring cardiac transplantation1-3. In TGCV, defective intracellular lipolysis of long-chain triglycerides (TGs) results in cellular steatosis and energy failure mainly in cardiomyocytes4 and smooth muscle cells5, leading to HF, diffuse coronary artery disease with TG deposition and ventricular arrhythmias with high mortality6. Tricaprin, a class of medium-chain TGs, recently corrected myocardial TG lipolysis7. Here we report remarkable long-term survival and durable recovery of HF in patients with TGCV treated with supplemental tricaprin in registry studies. Our study offers a classification of heart disease caused by defective lipolysis and its possible practical treatment. Because myocardial lipid droplets are a common feature in HF and their potential as therapeutic targets has been discussed worldwide, our findings warrant investigation into other ethnicities.

The Japanese Society of Hypertension have established a blood pressure (BP) target of 130/80 mmHg for patients with coronary artery disease (CAD). We evaluated the data of 8793 CAD patients in the Clinical Deep Data Accumulation System database who underwent cardiac catheterization at six university hospitals and the National Cerebral and Cardiovascular Center (average age 70 ± 11 years, 78% male, 43% with acute coronary syndrome [ACS]). Patients were divided into two groups based on whether or not they achieved the guideline-recommended BP of <130/80 mmHg. We analyzed the relationship between BP classification and major adverse cardiac and cerebral event (MACCE) separately in two groups: those with ACS and those with chronic coronary syndrome (CCS). During an average follow-up period of 33 months, 710 MACCEs occurred. A BP below 130/80 mmHg was associated with fewer MACCEs in both the overall (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.70-1.00, p = 0.048) and the ACS group (HR 0.67, 95%CI 0.51-0.88, p = 0.003). In particular, stroke events were also lower among those with a BP below 130/80 mmHg in both the overall (HR 0.69, 95%CI 0.53-0.90, p = 0.006) and ACS groups (HR 0.44, 95%CI 0.30-0.67, p < 0.001). In conclusion, the achievement of BP guidelines was associated with improved outcomes in CAD patients, particularly in reducing stroke risk among those with ACS.

BACKGROUND: Patients with cardiac sarcoidosis (CS) are at an increased risk of fatal ventricular arrhythmic events (FVAE). However, the predictive value of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in assessing the risk of FVAE in patients with CS remains uncertain. METHODS: We included data from 121 patients with CS (39 men and 82 women; mean age: 59.5 years) who underwent FDG-PET imaging between March 2008 and November 2020, with follow-ups completed in July 2023. Of these, 82 patients had available cardiac magnetic resonance imaging data, including late gadolinium enhancement (LGE). FDG-PET images were analysed using a polar-map model to determine the regional mean percentage uptake relative to the maximal cardiac 18F-FDG uptake in each of the 17 segments defined by the American Heart Association. RESULTS: Patients experiencing FVAE after FDG-PET (n = 43) showed lower percent uptake in the basal inferoseptal segment compared to those who did not (n = 78) (41.8 ± 15.2 % vs. 54.4 ± 13.8 %, P < 0.001). Patients with a basal inferoseptal percent uptake below the median had a lower FVAE-free survival rate than those with a higher percent uptake (58.1 % vs. 78 % at 5 years, P = 0.007), which was consistent in patients with LGE in the same regions with reduced 18F-FDG uptake. A Cox hazard model indicated that the FVAE risk decreased with a hazard ratio of 0.862 (95 % CI 0.770-0.964) for every 5 % increase in basal inferoseptal percent uptake (P = 0.009). CONCLUSION: Reduced 18F-FDG uptake in the basal interventricular septum, including the inferoseptal segment, may be a valuable predictor of future FVAE in patients with CS.

OBJECTIVES: Previous studies have assessed the impact of active smoking on mortality using the population-attributable fraction (PAF). However, these studies have not included second-hand smoking (SHS), potentially underestimating smoking's impact. We compared the PAF from active smoking alone with the PAF, including SHS exposure. DESIGN: Prospective cohort study. SETTING: A community-based cohort study in Japan. PARTICIPANTS: 40 796 participants aged ≥20 years. MAIN OUTCOME MEASURES: SHS was defined as inhaling someone else's cigarette smoke at the workplace or home in the past year. We classified smoking status and SHS into ten categories: never-smoker without SHS, never-smoker with SHS, past smoker without SHS, past smoker with SHS, current smoker 1-9 cigarettes/day without SHS, current smoker 1-9 cigarettes/day with SHS, 10-19 cigarettes/day without SHS, 10-19 cigarettes/day with SHS, ≥20 cigarettes/day without SHS and ≥20 cigarettes/day with SHS. The main outcome was all-cause mortality. RESULTS: During the median follow-up period of 6.5 (5.7-7.5) years, 788 men and 328 women died. For men, compared with never-smokers without SHS, past smokers without SHS (HR, 1.39 [95% CI, 1.11 to 1.73]) and past smokers with SHS (HR, 1.48 (95% CI, 1.10 to 2.00)) were associated with all-cause mortality. For women, never-smokers with SHS had a significantly higher risk of all-cause mortality (HR, 1.36 (95% CI, 1.00 to 1.84)). Without considering SHS, 28.0% and 2.3% of all-cause mortality in men and women, respectively, were attributable to past and current smoking. Including SHS, PAF increased to 31.3% in men and 8.4% in women. CONCLUSIONS: We clarified that smoking's impact was underestimated by not accounting for SHS, especially in women. Information on SHS is crucial for understanding smoking's health impact. This study supports the importance of avoiding smoking and preventing SHS.

BACKGROUND: Hypertension is a risk factor for bleeding events and is included in the HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/Alcohol concomitantly)score. However, the effects of blood pressure (BP) and changes in BP on bleeding events in patients undergoing percutaneous coronary intervention (PCI) remain poorly understood. This study is aimed to investigate the relationship between systolic BP (SBP) changes during hospitalisation and bleeding events in patients undergoing PCI. METHODS: From the Clinical Deep Data Accumulation System database, a multicentre database encompassing seven tertiary medical hospitals in Japan that includes data for patient characteristics, medications, laboratory tests, physiological tests, cardiac catheterisation and PCI treatment, data for 6351 patients undergoing PCI between April 2013 and March 2019 were obtained. The study population was categorised into three groups based on the changes in SBP during hospitalisation: (1) elevated BP (≥20 mm Hg), (2) no change (≥-20 to <20 mm Hg) and (3) decreased BP (<-20 mm Hg) groups. The primary outcome was a 3-year major bleeding event defined as moderate or severe bleeding according to the Global Use of Streptokinase and t-PA for Occluded Coronary Arteries bleeding criteria. RESULTS: The elevated BP group exhibited significantly lower SBP at admission and higher SBP at discharge (p<0.001). Multivariable Cox hazard regression models showed that elevated BP was associated with a high risk of bleeding events (HR: 1.885; 95% CI, 1.294 to 2.748). The multivariable logistic regression model identified female sex, chronic coronary syndrome, peripheral artery disease and chronic kidney disease as independent factors associated with elevated BP. CONCLUSIONS: These findings suggest that BP management is essential to prevent bleeding events after PCI.

AIM: This study examined the relationship between genetic risk, healthy lifestyle, and risk of developing diabetes. METHODS: This prospective cohort study included 11,014 diabetes-free individuals ≥ 20 years old from the Tohoku Medical Megabank Community-based cohort study. Lifestyle scores, including the body mass index, smoking, physical activity, and gamma-glutamyl transferase (marker of alcohol consumption), were assigned, and participants were categorized into ideal, intermediate, and poor lifestyles. A polygenic risk score (PRS) was constructed based on the type 2 diabetes loci from the BioBank Japan study. A multiple logistic regression model was used to estimate the association between genetic risk, healthy lifestyle, and diabetes incidence and to calculate the area under the receiver operating characteristic curve (AUROC). RESULT: Of the 11,014 adults included (67.8% women; mean age [standard deviation], 59.1 [11.3] years old), 297 (2.7%) developed diabetes during a mean 4.3 (0.8) years of follow-up. Genetic and lifestyle score is independently associated with the development of diabetes. Compared with the low genetic risk and ideal lifestyle groups, the odds ratio was 3.31 for the low genetic risk and poor lifestyle group. When the PRS was integrated into a model including the lifestyle and family history, the AUROC significantly improved to 0.719 (95% confidence interval [95% CI]: 0.692-0.747) compared to a model including only the lifestyle and family history (0.703 [95% CI, 0.674-0.732]). CONCLUSION: Our findings indicate that adherence to a healthy lifestyle is important for preventing diabetes, regardless of genetic risk. In addition, genetic risk might provide information beyond lifestyle and family history to stratify individuals at high risk of developing diabetes.

Depression is comorbid with somatic diseases; however, the relationship between depressive symptoms and hypertension (HT), a risk factor for cardiovascular events, remains unclear. Home blood pressure (BP) is more reproducible and accurately predictive of cardiovascular diseases than office BP. Therefore, we focused on home BP and investigated whether depressive symptoms contributed to the future onset of home HT. This prospective cohort study used data from the Tohoku Medical Megabank Community-Cohort Study (conducted in the Miyagi Prefecture, Japan) and included participants with home normotension (systolic blood pressure (SBP) < 135 mmHg and diastolic blood pressure (DBP) < 85 mmHg). Depressive symptoms were evaluated using the Center for Epidemiologic Studies Depression Scale-Japanese version at the baseline survey. In the secondary survey, approximately 4 years later, the onset of home HT was evaluated (SBP ≥ 135 mmHg or DBP ≥ 85 mmHg) and was compared in participants with and without depressive symptoms. Of the 3 082 (mean age: 54.2 years; females: 80.9%) participants, 729 (23.7%) had depressive symptoms at the baseline survey. During the 3.5-year follow-up, 124 (17.0%) and 388 (16.5%) participants with and without depressive symptoms, respectively, developed home HT. Multivariable adjusted odds ratios were 1.37 (95% confidence interval (CI): 1.02-1.84), 1.18 (95% CI: 0.86-1.61), and 1.66 (95% CI: 1.17-2.36) for home, morning, and evening HT, respectively. This relationship was consistent in the subgroup analyses according to age, sex, BP pattern, and drinking habit. Depressive symptoms increased the risk of new-onset home HT, particularly evening HT, among individuals with home normotension. This prospective cohort study revealed that depressive symptoms are risk factors for new-onset home hypertension, particularly evening hypertension among individuals with home normotension. Assessing home blood pressure in individuals with depressive symptoms is important for the prevention of hypertension and concomitant cardiovascular diseases.

BACKGROUND: Balloon pulmonary angioplasty (BPA) has exhibited substantial progress in the management of chronic thromboembolic pulmonary hypertension (CTEPH). However, nearly one-half of the patients with CTEPH experience persistent pulmonary hypertension after undergoing BPA, emphasizing the need for enhanced therapies. OBJECTIVES: The authors sought to investigate the clinical significance of functional assessment-guided dilation of the pulmonary artery (PA) in patients with CTEPH undergoing BPA treatment. METHODS: The prospective single-center cohort study enrolled 95 patients who underwent 278 consecutive BPA sessions. Lung parenchymal perfusion was assessed via 2-dimensional perfusion angiography, and pressure catheter measurements were taken to determine the PA pressure ratios. The correlation between lung perfusion and the pressure ratio was analyzed to establish an optimal target pressure ratio. Patients were stratified into 2 groups, a pressure-guided group (n = 28) and an angiographic group (n = 63), to evaluate whether optimizing the pressure ratio led to improvements in residual PH and complications. RESULTS: The pressure ratio and lung perfusion measurements of 141 PA lesions were analyzed. A piecewise linear regression model identified a target pressure ratio of 0.7, associated with significant enhancement in lung perfusion. The pressure-guided strategy achieved a higher rate of mean pulmonary artery pressure <25 mm Hg (92.8% [26/28 patients] vs 60.3% [38/63 patients]; P = 0.001) and a concurrent reduction in BPA relevant complications (3.9% [4/101 sessions] vs 12.9% [23/177 sessions]; P = 0.019). CONCLUSIONS: Functional assessment-guided PA dilation with a target pressure ratio of 0.7 proved beneficial in BPA treatment for patients with CTEPH. This approach improved the residual PH and reduced complications, highlighting its potential to enhance CTEPH management outcomes.

Patients with borderline pulmonary hypertension (PH) often experience shortness of breath or exacerbation of PH during exercise, known as exercise-induced PH. However, the pathogenesis of exercise-induced post-capillary PH (post-EIPH) and its treatment strategies remain unclear. Recent guidelines and consensus documents have highlighted the benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors in heart failure and chronic kidney disease (CKD). This study aimed to investigate the effects of SGLT2 inhibitors in patients with post-EIPH and CKD. This single-center prospective cohort study enroled 10 patients with CKD (age, 68 years; female, 60%) who exhibited post-EIPH between 1 July 2022 and 31 December 2023. Post-EIPH was defined as a pulmonary capillary wedge pressure (PCWP)/cardiac output (CO) slope > 2 and peak PCWP during exercise ≥ 25 mmHg measured by catheterization. The patients received SGLT2 inhibitor treatment for 6 months. At rest, patients with post-EIPH had borderline-PH (21.5 ± 1.8 mmHg), with preserved left and right ventricular function. SGLT2 inhibitors treatment significantly reduced the PCWP/CO slope during exercise (3.9 ± 1.2 vs. 2.4 ± 1.2 mmHg/L/min, p = 0.013) and improved the 6-min walking distance (489.9 ± 80.2 vs. 568.3 ± 91.9 m, p = 0.014). Magnetic resonance imaging revealed a lower left ventricular global longitudinal strain in patients with post-EIPH, which was increased by SGLT2 inhibitor treatment (-13.8 ± 2.0 vs. -17.3 ± 2.0%, p = 0.003). SGLT2 treatment inhibitors mitigated post-EIPH hemodynamic abnormalities and exercise intolerance, suggesting their potential as its therapeutic option.

[This corrects the article DOI: 10.1016/j.ijcrp.2023.200193.].

AIMS: Atrial fibrillation (AF) frequently coexists with heart failure with preserved ejection fraction (HFpEF), and clinical outcomes of patients with AF vary depending on its subtype. While AF progression characterized by the transition from paroxysmal AF to persistent AF is sometimes observed, the incidence and clinical impact of AF progression in patients with HFpEF remain to be explored. METHODS AND RESULTS: We enrolled patients with HFpEF and paroxysmal AF from the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study. AF progression was defined as the transition from paroxysmal AF to persistent AF. A total of 718 patients (median age: 72 years, 36% were female) were enrolled. For a median follow-up of 6.0 years (interquartile range: 3.0-10.2 years), AF progression occurred in 105 patients (14.6%), with a cumulative incidence of 16.7% at 10 years. In the multivariable Cox proportional hazards model, previous hospitalization for heart failure [hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.16-2.60; P = 0.007] and left atrial diameter (per 5-mm increase) (HR 1.37, 95% CI 1.20-1.55; P < 0.001) were significantly associated with AF progression. Furthermore, AF progression was significantly linked to worsening heart failure (adjusted HR 1.68, 95% CI 1.18-2.40; P = 0.004). Notably, 27 cases (26%) of worsening heart failure occurred within 1 year following AF progression. CONCLUSION: In patients with HFpEF, AF progression is significantly associated with adverse outcomes, particularly worsening heart failure. An increased risk is observed in the early phases following progression to persistent AF. REGISTRATION: Clinical Trials.gov Identifier: NCT00418041.

AIMS: This study aimed to elucidate age-stratified clinical profiles and outcomes in patients with heart failure (HF) with preserved left ventricular ejection fraction (LVEF) (HFpEF). METHODS AND RESULTS: The Chronic Heart Failure Registry and Analysis in the Tohoku District-2 (CHART-2) Study included 2824 consecutive HFpEF patients with LVEF ≥ 50% (mean age 69.0 ± 12.3 years; 67.7% male) with a median follow-up of 9.8 years. We stratified them into five age groups: ≤54 (N = 349, 12.4%), 55-64 (N = 529, 18.7%), 65-74 (N = 891, 31.6%), 75-84 (N = 853, 30.2%), and ≥85 years (N = 202, 7.2%), and we categorized these age groups into younger (≤64 years) and older (≥65 years) groups. We compared the clinical profiles and outcomes of HFpEF patients across age groups. Younger HFpEF groups exhibited a male predominance, elevated body mass index (BMI), and poorly controlled diabetes (haemoglobin A1c > 7.0%). Older HFpEF groups were more likely to be female with multiple comorbidities, including coronary artery disease, hypertension, renal impairment, and atrial fibrillation. The positive association between elevated BMI and HFpEF was more pronounced with lower classes of age from ≥85 to ≤54 years, especially in males. With higher classes of age from ≤54 to ≥85 years, mortality rates increased, and HF death became proportionally more prevalent (Ptrend < 0.001), whereas sudden cardiac death (SCD) exhibited the opposite trend (Ptrend = 0.002). Poorly controlled diabetes emerged as the only predictor of SCD in the younger groups (adjusted hazard ratio 4.26; 95% confidence interval 1.45-12.5; P = 0.008). Multiple comorbidities were significantly associated with an increased risk of HF-related mortality in the older groups. CONCLUSIONS: Younger HFpEF patients (≤64 years) exhibit a male predominance, elevated BMI, and poorly controlled diabetes, highlighting the importance of glycaemic control in reducing SCD risk. Older HFpEF patients (≥65 years) are more likely to be female, with multiple comorbidities linked to an increased risk of HF-related mortality. These findings underscore the need for physicians to recognize age-related, distinct HFpEF phenotypes for personalized patient management.

BACKGROUND: Limited data exist on the prognostic value of changes in pulse pressure (PP, the difference between systolic and diastolic blood pressure) during hospitalization for patients with coronary artery disease who have undergone percutaneous coronary intervention (PCI). METHODS: In the Clinical Deep Data Accumulation System (CLIDAS), we studied 8,708 patients who underwent PCI. We aimed to examine the association between discharge PP and cardiovascular outcomes. PP was measured before PCI and at discharge. Patients were divided into five groups (quintiles) based on the change in PPQ1 (-18.0 ± 9.9 mmHg), Q2 (-3.8 ± 2.6), Q3 (reference; 3.7 ± 2.0), Q4 (11.3 ± 2.6), and Q5 (27.5 ± 11.2). We then analyzed the relationship between PP change and outcomes. RESULTS: The mean patient age was 70 ± 11 years, with 6,851 (78 %) men and 3,786 (43 %) having acute coronary syndrome. U-shaped relationships were observed for the incidence rates of major adverse cardiac or cerebrovascular events (MACCE, a composite endpoint of cardiovascular death, myocardial infarction, and stroke), revascularization, and hospitalization for heart failure (HF). After adjusting for confounding factors, higher PP at discharge was associated with an increased risk of MACCE (adjusted hazard ratio 1.41; 95 %CI, 1.06-1.87 in Q5 [73.9 ± 9.3 mmHg]). Evaluating PP change revealed a U-shaped association with MACCE (1.50; 1.11-2.02 in Q1 and 1.47; 0.98-2.20 in Q5). Additionally, Q5 had a higher risk for hospitalization for HF (1.37; 1.00-1.88). CONCLUSIONS: Our findings demonstrate a U-shaped association between changes in PP and cardiovascular outcomes. This data suggests the significance of blood pressure control during hospitalization for patients who have undergone PCI.

AIMS: Vericiguat has been used to treat patients with heart failure with reduced ejection fraction (HFrEF) who demonstrated worsening heart failure despite treatment with other guideline-directed medical therapies. The haemodynamic effects of vericiguat remain unclear. METHODS AND RESULTS: This study enrolled 12 patients (median age, 63 [quartiles 53.5, 70] years; 16.7%(N=2) women) with symptomatic HFrEF (New York Heart Association functional class II-IV) who demonstrated worsening heart failure despite treatment with the four foundational guideline-recommended therapies between March and December 2022, with follow-ups completed in June 2023. A balloon-tipped pulmonary artery thermodilution catheter was placed in the right internal jugular vein to perform right heart catheterisation (RHC) on day 1. Haemodynamic data were acquired before and after vericiguat intake (2.5 mg) on days 2 and 3. The data on days 2 and 3 were averaged. RHC was repeated on day 105 (37, 168). Oral intake of vericiguat 2.5 mg decreased mean pulmonary artery pressure (19.3 [14.3, 26.8] mmHg) and pulmonary artery wedge pressure (PAWP) (11 [7.5, 15] mmHg) before the intake to mean pulmonary artery pressure (17.5 [12.5, 24] mmHg) and PAWP (9.3 [6.8, 14] mmHg) at 30 min after (both P < 0.05). Reduction in PAWP was also found from 14.5 [9.5, 19.5] mmHg on day 1 to 9.5 [6.5, 12.5] mmHg on day 105 (37, 168) (P < 0.05), when vericiguat was titrated to 2.5 mg 25% (N = 3), 5 mg 50% (N = 6), and 10 mg 25% (N = 3). CONCLUSIONS: The consistent reduction in PAWP underscores the well-tolerated nature of vericiguat and its potential to enhance cardiac performance in patients with HFrEF.

No study, to our knowledge, has constructed a polygenic risk score based on clinical blood pressure and investigated the association of genetic and lifestyle risks with home hypertension. We examined the associations of combined genetic and lifestyle risks with hypertension and home hypertension. In a cross-sectional study of 7027 Japanese individuals aged ≥20 years, we developed a lifestyle score based on body mass index, alcohol consumption, physical activity, and sodium-to-potassium ratio, categorized into ideal, intermediate, and poor lifestyles. A polygenic risk score was constructed with the target data (n = 1405) using publicly available genome-wide association study summary statistics from BioBank Japan. Using the test data (n = 5622), we evaluated polygenic risk score performance and examined the associations of combined genetic and lifestyle risks with hypertension and home hypertension. Hypertension and home hypertension were defined as blood pressure measured at a community-support center ≥140/90 mmHg or at home ≥135/85 mmHg, respectively, or self-reported treatment for hypertension. In the test data, 2294 and 2322 participants had hypertension and home hypertension, respectively. Both polygenic risk and lifestyle scores were independently associated with hypertension and home hypertension. Compared with those of participants with low genetic risk and an ideal lifestyle, the odds ratios for hypertension and home hypertension in the low genetic risk and poor lifestyle group were 1.94 (95% confidence interval, 1.34-2.80) and 2.15 (1.60-2.90), respectively. In summary, lifestyle is important to prevent hypertension; nevertheless, participants with high genetic risk should carefully monitor their blood pressure despite a healthy lifestyle.

IMPORTANCE: The characteristics and treatment strategies of atrial functional mitral regurgitation (AFMR) are poorly understood. OBJECTIVE: To investigate the prevalence, clinical characteristics, and outcomes of mitral valve (MV) surgery in AFMR. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study, called the Real-World Observational Study for Investigating the Prevalence and Therapeutic Options for Atrial Functional Mitral Regurgitation (REVEAL-AFMR), was conducted across 26 Japanese centers (17 university hospitals, 1 national center, 3 public hospitals, and 5 private hospitals). All transthoracic echocardiography procedures performed from January 1 to December 31, 2019, were reviewed to enroll adult patients (aged ≥20 years) with moderate or severe AFMR, defined by preserved left ventricular function, a dilated left atrium, and an absence of degenerative valvular changes. Data were analyzed from May 8, 2023, to May 16, 2024. EXPOSURES: Mitral valve surgery, with or without tricuspid valve intervention. MAIN OUTCOMES AND MEASURES: The primary composite outcome included heart failure hospitalization and all-cause mortality. RESULTS: In 177 235 patients who underwent echocardiography, 8867 had moderate or severe MR. Within this group, 1007 (11.4%) were diagnosed with AFMR (mean [SD] age, 77.8 [9.5] years; 55.7% female), of whom 807 (80.1%) had atrial fibrillation. Of these patients, 113 underwent MV surgery, with 92 (81.4%) receiving concurrent tricuspid valve surgery. Patients who underwent surgery were younger but had more severe MR (57.5% [n = 65] vs 9.4% [n = 84]; P < .001), a larger mean (SD) left atrial volume index (152.5 [97.8] mL/m2 vs 87.7 [53.1] mL/m2; P < .001), and a higher prevalence of heart failure (according to the New York Heart Association class III [marked limitation of physical activity] or class IV [symptoms of heart failure at rest], 26.5% [n = 30] vs 9.3% [n = 83]; P < .001) than those who remained under medical therapy. During a median follow-up of 1050 days (IQR, 741-1188 days), 286 patients (28.4%) experienced the primary outcome. Despite a more severe disease status, only the surgical group showed a decrease in natriuretic peptide levels at follow-up and had a significantly lower rate of the primary outcome (3-year event rates were 18.3% vs 33.3%; log-rank, P = .03). Statistical adjustments did not alter these findings. CONCLUSIONS AND RELEVANCE: The findings of this cohort study suggest that in patients with AFMR, who were typically older and predominantly had atrial fibrillation, MV surgery was associated with lower rates of adverse clinical outcomes. Future studies are warranted to investigate a possible causal relationship to better regulate cardiovascular medicine.

BACKGROUND: Outcome measures during acute cardiovascular disease (CVD) phases, such as quality of death, have not been thoroughly evaluated. This is the first study that compared the family members' perceptions of quality of death in deceased CVD patients and in deceased cancer patients using a bereaved family survey. METHODS: Retrospectively sent questionnaire to consecutive family members of deceased patients with CVD from ten tertiary hospitals from October 2017 to August 2018. We used the short version of the Good Death Inventory (GDI) and assessed overall care satisfaction. Referencing the GDI, the quality of death was compared between CVD patients admitted to a non-palliative care unit (non-PCU) and cancer patients in palliative care units (PCU) and non-PCUs in the Japan Hospice and Palliative Care Evaluation Study (J-HOPE Study). Additionally, in the adjusted analysis, multivariable linear regression was performed for total GDI score adjusted by the patient and participant characteristics to estimate the difference between CVD and other patients. RESULTS: Of the 243 bereaved family responses in agreement (response rate: 58.7%) for CVD patients, deceased patients comprised 133 (54.7%) men who were 80.2 ± 12.2 years old on admission. The GDI score among CVD patients (75.0 ± 15.7) was lower (worse) than that of cancer patients in the PCUs (80.2 ± 14.3), but higher than in non-PCUs (74.4 ± 15.2). After adjustment, the total GDI score for CVD patients was 7.10 points lower [95% CI: 5.22-8.97] than for cancer patients in PCUs and showed no significant differences compared with those in non-PCUs (estimates, 1.62; 95% CI [-0.46 to 5.22]). CONCLUSIONS: The quality of death perceived by bereaved family members among deceased acute CVD patients did not differ significantly from that of deceased cancer patients in general wards, however, was significantly lower than that of deceased cancer patients admitted in PCUs.

BACKGROUND: GDF15 plays pivotal metabolic roles in nutritional stress and serves as a physiological regulator of energy balance. However, the patterns of GDF15 levels in underweight or obese patients with chronic heart failure (CHF) are not well-understood. METHODS: We assessed serum GDF15 levels at baseline and 3 years and the temporal changes in 940 Japanese patients (642 paired samples), as a sub-analysis of the SUPPORT trial (age 65.9 ± 10.1 years). The GDF15 levels were analyzed across BMI groups (underweight [<18.5 kg/m2; n = 50], healthy weight [18.5-22.9; n = 27 5], overweight [23-24.9; n = 234], and obese [≥25; n = 381]), following WHO recommendations for the Asian-Pacific population. Landmark analysis at 3 years assessed the association between GDF15 levels and HF hospitalization or all-cause death. RESULTS: Compared to the healthy weight group, the underweight group included more females (54.0%) with advanced HF (NYHA class III; 20.0%) and exhibited increased GDF15 level (1764 pg/mL [IQR 1067-2633]). Obese patients, younger (64.2 years) and diabetic (53%), had a similar GDF15 level to the healthy weight group. A higher baseline GDF15 level was associated with worse outcomes across the BMI spectrum. GDF15 increased by 208 [21-596] pg/mL over 3 years, with the most substantial increase observed in the underweight group (by +28.9% [6.2-81.0]). Persistently high GDF15 levels (≥1800 pg/mL) was independently associated with worse outcomes after 3 years (adjusted HR 1.8 [95%CI 1.1-2.9]). CONCLUSIONS: In underweight patients with CHF, GDF15 level was elevated at baseline and experienced the most significant increase over 3 years. Its consistent elevation suggested a worse outcome.

Depression is comorbid with somatic diseases; however, the relationship between depressive symptoms and hypertension (HT), a risk factor for cardiovascular events, remains unclear. Home blood pressure (BP) is more reproducible and accurately predictive of cardiovascular diseases than office BP. Therefore, we focused on home BP and investigated whether depressive symptoms contributed to the future onset of home HT. This prospective cohort study used data from the Tohoku Medical Megabank Community-Cohort Study (conducted in the Miyagi Prefecture, Japan) and included participants with home normotension (systolic blood pressure (SBP) < 135 mmHg and diastolic blood pressure (DBP) < 85 mmHg). Depressive symptoms were evaluated using the Center for Epidemiologic Studies Depression Scale-Japanese version at the baseline survey. In the secondary survey, approximately 4 years later, the onset of home HT was evaluated (SBP ≥ 135 mmHg or DBP ≥ 85 mmHg) and was compared in participants with and without depressive symptoms. Of the 3 082 (mean age: 54.2 years; females: 80.9%) participants, 729 (23.7%) had depressive symptoms at the baseline survey. During the 3.5-year follow-up, 124 (17.0%) and 388 (16.5%) participants with and without depressive symptoms, respectively, developed home HT. Multivariable adjusted odds ratios were 1.37 (95% confidence interval (CI): 1.02-1.84), 1.18 (95% CI: 0.86-1.61), and 1.66 (95% CI: 1.17-2.36) for home, morning, and evening HT, respectively. This relationship was consistent in the subgroup analyses according to age, sex, BP pattern, and drinking habit. Depressive symptoms increased the risk of new-onset home HT, particularly evening HT, among individuals with home normotension. This prospective cohort study revealed that depressive symptoms are risk factors for new-onset home hypertension, particularly evening hypertension among individuals with home normotension. Assessing home blood pressure in individuals with depressive symptoms is important for the prevention of hypertension and concomitant cardiovascular diseases.

BACKGROUND: Lower gastrointestinal tract stenosis is commonly diagnosed and is typically treated with surgery or endoscopic balloon dilation (EBD). Radial incision and cutting (RIC) is a novel treatment approach that has several benefits compared with EBD and surgery. Although RIC has demonstrated a high technical success rate and has been shown to improve subjective symptoms, previous studies revealed that restenosis after RIC remain unsolved. Herein, we report the design of a prospective, multicenter, single-arm, interventional, phase II trial to evaluate the safety of local triamcinolone acetonide (TA) administration and its feasibility in preventing restenosis after RIC for lower gastrointestinal tract stenosis. METHODS: The major inclusion criteria are age 20-80 years and the presence of benign stenosis in the lower gastrointestinal tract accessible by colonoscope. We will perform RIC followed by local administration of TA to 20 participants. The primary outcome is the safety of local TA administration, which will be assessed by determining the frequency of adverse events of special interest. The secondary outcomes are the technical success rate of RIC, duration of procedure, improvement in subjective symptoms, and duration of hospitalization. The outcomes, improvement in subjective symptoms, and long-term results will be evaluated using descriptive statistics, Student's t-test, and Kaplan-Meier curve, respectively. DISCUSSION: This explorative study will provide useful information regarding the safety of TA administration after RIC, which may contribute to further investigations.

AIMS: Laser speckle flowgraphy (LSFG) is a well-established tool renowned for its non-invasive and reproducible assessment of ocular blood flow. While rhythm control therapies, such as catheter ablation (CA), have shown promise in enhancing cognitive function in atrial fibrillation (AF) patients, the acute impact of CA on microcirculatory changes, particularly in ocular blood flow, remains a topic of limited understanding. The present study aims to delve into the potential of LSFG in detecting microcirculatory alterations following the restoration of sinus rhythm (SR) through CA in patients with AF. METHODS AND RESULTS: We studied 8 paroxysmal AF (Paf) and 20 persistent AF (PeAF) patients (mean age 67 ± 6 years, 26% female) undergoing CA. Ocular blood flow was assessed using LSFG by measuring the mean blur rate (MBR) pre- and post-CA. Post-CA, all PeAF patients achieved SR restoration, resulting in a significant increase in tissue MBR (10.0 ± 2.2 to 10.8 ± 2.9, P = 0.021). In contrast, Paf patients showed no significant difference between pre- and post-MBR (12.0 ± 2.7 vs. 11.8 ± 2.6, P = 0.76). CONCLUSION: LSFG analysis effectively identified microcirculatory changes in patients undergoing CA for PeAF, suggesting that therapeutic interventions targeting the heart may have broader implications for ocular and cerebral health, establishing a novel 'cardio-oculo-cerebral relationship'.

AIM: This study examined the relationship between genetic risk, healthy lifestyle, and risk of developing diabetes. METHODS: This prospective cohort study included 11,014 diabetes-free individuals ≥ 20 years old from the Tohoku Medical Megabank Community-based cohort study. Lifestyle scores, including the body mass index, smoking, physical activity, and gamma-glutamyl transferase (marker of alcohol consumption), were assigned, and participants were categorized into ideal, intermediate, and poor lifestyles. A polygenic risk score (PRS) was constructed based on the type 2 diabetes loci from the BioBank Japan study. A multiple logistic regression model was used to estimate the association between genetic risk, healthy lifestyle, and diabetes incidence and to calculate the area under the receiver operating characteristic curve (AUROC). RESULT: Of the 11,014 adults included (67.8% women; mean age [standard deviation], 59.1 [11.3] years old), 297 (2.7%) developed diabetes during a mean 4.3 (0.8) years of follow-up. Genetic and lifestyle score is independently associated with the development of diabetes. Compared with the low genetic risk and ideal lifestyle groups, the odds ratio was 3.31 for the low genetic risk and poor lifestyle group. When the PRS was integrated into a model including the lifestyle and family history, the AUROC significantly improved to 0.719 (95% confidence interval [95% CI]: 0.692-0.747) compared to a model including only the lifestyle and family history (0.703 [95% CI, 0.674-0.732]). CONCLUSION: Our findings indicate that adherence to a healthy lifestyle is important for preventing diabetes, regardless of genetic risk. In addition, genetic risk might provide information beyond lifestyle and family history to stratify individuals at high risk of developing diabetes.

We herein report a 37-year-old man who experienced recurrence of metastatic cardiac rhabdomyosarcoma along with intractable ventricular tachycardia (VT) 7 years after resection of rhabdomyosarcoma in his right elbow. At 36 years old, he developed VT unresponsive to radiofrequency catheter ablation (RFCA). Initially, the cardiac tumor was not detected, but it gradually grew in size at the RFCA site. A surgical biopsy confirmed the diagnosis of metastatic cardiac rhabdomyosarcoma. Despite radiation therapy, cardiac tumor progression and VT instability could not be prevented. Ultimately, the patient died 27 months after the initial documentation of VT.

AIMS: Growth differentiation factor-15 (GDF15), a cytokine in the transforming growth factor family, is up-regulated in stress and inflammatory conditions and is elevated in patients with heart failure (HF). However, the age-specific attributes and prognostic significance of GDF15 across age remain unknown in chronic HF (CHF). METHODS AND RESULTS: Serum levels of GDF15 were examined in 942 hypertensive patients (median 68 years) with CHF from the SUPPORT trial across the four age groups [under 50 (n = 73), 51-59 (n = 158), 60-69 (n = 296), and 70-79 years (n = 415)] and in the continuous spectrum. Clinical correlates of GDF15 were explored using the classic stepwise and LASSO (least absolute shrinkage and selection operator) regression approaches. Interaction terms with age were tested in the LASSO regression approach. The associations with the composite outcome of HF hospitalization or all-cause death were investigated across ages. Median GDF15 levels (pg/mL) increased along with aging, from 691 in under 50 years to 855 in 51-59 years, 1114 in 60-69 years, and 1516 in 70-79 years (trend P < 0.001). Age, sex, systolic blood pressure, history of diabetes, ischaemic heart disease, left ventricular (LV) end-systolic dimension, LV ejection fraction, estimated glomerular filtration rate, haemoglobin, N-terminal pro-brain natriuretic peptide (NT-proBNP), troponin, C-reactive protein, and the use of angiotensin-converting enzyme inhibitors, diuretics, and statins were mutually selected as clinical covariates of GDF15. The LASSO regression analysis identified significant interactions between age and the history of diabetes and NT-proBNP, with particularly robust associations in patients aged between 60 and 70 years. During the mean follow-up of 8.6 years, 474 composite endpoints of HF hospitalization or death occurred. GDF15 was associated with a higher risk of HF hospitalization or all-cause death [adjusted hazard ratio 1.84 (95% confidence interval 1.45-2.33)], with a particularly heightened risk in patients aged around 70 years (Pinteraction = 0.0008). The model with GDF15 on top of other established risk factors yielded marginally higher C-statistics compared with the model without GDF15 (0.803 and 0.796, P = 0.045). The additive value of GDF15 on top of other established risk factors appeared similar across ages. A universal cut-off value of 1400 pg/mL performed well in discriminating between those with and without HF hospitalization or death. CONCLUSIONS: Some clinical correlates of GDF15 have an interaction with age. GDF15 is an important determinant of cardiovascular endpoints, particularly in patients aged around 70 years. The additive value of GDF15 appeared consistent across ages, suggesting the use of a universal cut-off value.

AIMS: Although fat mass (FM) and fat-free mass (FFM) have an impact on lipid metabolism, the relationship between different body composition phenotypes and lipid profiles is still unclear. By dividing the FM and FFM by the square of the height, respectively, the fat mass index (FMI) and fat-free mass index (FFMI) can be used to determine the variations in body composition. This study aimed to investigate the relationship of combined FMI and FFMI with low-density lipoprotein cholesterol (LDL-C) levels. METHODS: This cross-sectional study comprised 5,116 men and 13,630 women without cardiovascular disease and without treatment for hypertension, and diabetes. Following sex-specific quartile classification, FMI and FFMI were combined into 16 groups. Elevated LDL-C levels were defined as LDL-C ≥ 140 mg/dL and/or dyslipidemia treatment. Multivariable logistic regression models were used to examine the relationships between combined FMI and FFMI and elevated LDL-C levels. RESULTS: Overall, elevated LDL-C levels were found in 1,538 (30.1%) men and 5,434 (39.9%) women. In all FFMI subgroups, a higher FMI was associated with elevated LDL-C levels. Conversely, FFMI was inversely associated with elevated LDL-C levels in most FMI subgroups. Furthermore, the groups with the highest FMI and lowest FFMI had higher odds ratios for elevated LDL-C levels than those with the lowest FMI and highest FFMI. CONCLUSIONS: Regardless of FFMI, FMI was positively associated with elevated LDL-C levels. Conversely, in the majority of FMI subgroups, FFMI was inversely associated with elevated LDL-C levels.

Risk factors for hypertension have been emphasized in the Japanese Society of Hypertension Guidelines for the Management of Hypertension. However, large-scale studies on the association of smoking, potassium excretion, and gamma-glutamyl transferase level with BP in the Japanese population are limited. We conducted a cross-sectional study to examine the association between hypertension risk factors and systolic blood pressure in the Tohoku Medical Megabank Community-based Cohort Study (23,446 men and 38,921 women aged ≥20 years). A model adjusted for age, body mass index, smoking status, drinking status, estimated daily salt intake, potassium excretion, (or urinary sodium-to-potassium ratio), gamma-glutamyl transferase, physical activity, education level, status of damage to homes during the Great East Japan Earthquake, and residential areas was used. The average age and systolic blood pressure were 62.5 (10.3) years for men and 59.6 (11.3) years for women, 128.9 (16.7) mmHg for men and 124.7 (17.5) mmHg for women, respectively. Body mass index estimated daily salt intake, urinary sodium-to-potassium ratio and gamma-glutamyl transferase levels were positively associated with systolic blood pressure. Compared with never-drinkers, current drinkers who consumed 23-45 g/day and ≥46.0 g/day had significantly increased systolic blood pressure. Conversely, current smokers (1-10 cigarettes/day and 11-20 cigarettes/day) were inversely associated with systolic blood pressure compared to never-smokers. Overall, systolic blood pressure was associated with gamma-glutamyl transferase and hypertension risk factors, including body mass index, alcohol consumption, estimated daily salt intake, urinary sodium-to-potassium ratio, and potassium excretion. Our findings support the notion that lifestyle modifications should be attempted to prevent hypertension.

BACKGROUND: The Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial demonstrated non-inferior efficacy endpoints for rivaroxaban monotherapy versus combination therapy (rivaroxaban plus a single antiplatelet) and superior safety endpoints in patients with atrial fibrillation and stable coronary artery disease. AIMS: This post hoc analysis investigated whether the AFIRE trial results reflected the presence or absence of prior revascularisation. METHODS: Among 2,215 patients, 1,697 (76.6%) had previously undergone revascularisation, and the remaining 518 (23.4%) had not undergone prior revascularisation. The primary efficacy endpoint was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularisation, or death from any cause, while the primary safety endpoint was major bleeding. RESULTS: In 1,697 patients with prior revascularisation, the efficacy and safety endpoints were superior for monotherapy versus combination therapy (efficacy: hazard ratio [HR] 0.62, 95% confidence interval [CI]: 0.45-0.85; p=0.003; safety: HR 0.62, 95% CI: 0.39-0.98; p=0.042). Among 518 without prior revascularisation, there were no significant differences in endpoints (efficacy: HR 1.19, 95% CI: 0.67-2.12; p=0.554; safety: HR 0.47, 95% CI: 0.18-1.26; p=0.134). There was borderline interaction of the efficacy endpoints (p=0.055) between two treatments. The safety benefit of monotherapy on any bleeding was significant in patients without prior revascularisation (HR 0.59, 95% CI: 0.38-0.93; p=0.022). CONCLUSIONS: In high-risk thrombosis patients with a history of prior revascularisation, rivaroxaban monotherapy versus combination therapy demonstrated favourable safety and efficacy outcomes.

BACKGROUND: Although fat mass index (FMI) and fat-free mass index (FFMI) affect lung function, FMI and FFMI are not independent of each other, since FMI and FFMI were calculated as fat mass and fat-free mass divided by height squared, respectively. We aimed to examine the association of combined FMI and FFMI with lung function. METHODS: In this cross-sectional study, lung function was evaluated using forced expiratory volume at 1 s (FEV1) and forced vital capacity (FVC) measured using spirometry. Both FMI and FFMI were classified into sex-specific quartiles (16 groups). Analysis of covariance was used to assess the associations of combined FMI and FFMI with lung function. The trend test was conducted by stratifying the FMI and FFMI, scoring the categories from 1-4 (lowest-highest), and entering the number as a continuous term in the regression model. RESULTS: This study included 3,736 men and 8,821 women aged ≥20 years living in Miyagi Prefecture, Japan. The mean FEV1 was 3.0 (standard deviation [SD], 0.7) L for men and 2.3 (SD, 0.5) L for women. The mean FVC was 3.8 (SD, 0.7) L for men and 2.8 (SD, 0.5) L for women. FMI was inversely associated with lung function among all FFMI subgroups in both sexes. Conversely, FFMI was positively associated with lung function in all FMI subgroups in both sexes. CONCLUSION: Higher FMI was associated with lower lung function independent of FFMI; higher FFMI was associated with higher lung function independent of FMI. Reducing FMI and maintaining FFMI might be important for respiratory health.

Masked hypertension is a risk factor for cardiovascular diseases. However, masked hypertension is sometimes overlooked owing to the requirement for home blood pressure measurements for diagnosing. Mental status influences blood pressure. To reduce undiagnosed masked hypertension, this study assessed the association between depressive symptoms and masked hypertension. This cross-sectional study used data from the Tohoku Medical Megabank Project Community-Based Cohort Study (conducted in Miyagi Prefecture, Japan, from 2013) and included participants with normotension measured at the research center (systolic blood pressure<140 mmHg and diastolic blood pressure <90 mmHg). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (Japanese version). Masked hypertension was defined as normotension measured at the research center and home hypertension (home systolic blood pressure ≥135 mmHg or home diastolic blood pressure ≥85 mmHg). The study comprised 6705 participants (mean age: 55.7 ± 13.7 years). Of these participants, 1106 (22.1%) without depressive symptoms and 393 (23.2%) with depressive symptoms were categorized to have masked hypertension. Sex-specific and age-adjusted least mean squares for home blood pressure, not for research blood pressure were significantly higher in the group with depressive symptoms in both sex categories. The multivariate odds ratio for masked hypertension in the patients with depressive symptoms was 1.72 (95% confidence interval: 1.26-2.34) in male participants and 1.30 (95% confidence interval: 1.06-1.59) in female ones. Depressive symptoms were associated with masked hypertension in individuals with normotension measured at the research center. Depressive symptoms may be one of the risk factors for masked hypertension. Depressive symptoms were associated with masked hypertension in individuals with normotension measured at research center.

BACKGROUND: In patients with chronic heart failure (CHF), comorbidities are often managed with multiple medications, characterized by polypharmacy, leading to increased risk of potentially inappropriate medication and adverse effects. METHODS: We studied 4,876 consecutive patients with CHF (Stage C/D, age 69.0 ± 12.3 years) in the CHART-2 study to evaluate the association among polypharmacy, underuse of HF medications, and all-cause death. Polypharmacy was defined as the daily use of ≥ 8 medications for the survival classification and regression tree analysis. RESULTS: The average number of medications was 10 in the polypharmacy group and 5 in the non-polypharmacy group, respectively. Over a median of 8.3 (4.1-11.7) years, the incidence rate of all-cause death was significantly higher in the polypharmacy group (n = 2,108) than in the non-polypharmacy group (57.3 % vs. 40.6 %; adjusted hazard ratio [aHR] 1.34 (95 %CI, 1.22-1.48), P < 0.001), even in age < 55 years (26.6 % vs. 14.3 %; adjusted hazard ratio [aHR] 1.61 (95 %CI, 1.04-2.50), P = 0.033). In patients with polypharmacy, those without renin-angiotensin system inhibitors (RAS-I) and/or beta-blockers (N = 1,023) were associated with increased incidence of all-cause death as compared with those with both medications (aHR 1.18; 95 %CI 1.04-1.35, P = 0.012). CONCLUSIONS: Polypharmacy was associated with poor long-term prognosis, even in younger patients with CHF. Among 4,876 patients with CHF, 1023 (20.9%) with polypharmacy and underuse of RAS-I and/or beta-blocker were associated with increased risk of all-cause death.

OBJECTIVES: Despite the recommendation that patients with cardiovascular disease (CVD) receive bereavement care, few studies have examined the psychological disturbances in bereaved caregivers. We examined the prevalence and determinants of depression and complicated grief among bereaved caregivers of patients with CVD. METHODS: We conducted a cross-sectional survey using a self-administered questionnaire for bereaved caregivers of patients with CVD who had died in the cardiology departments of nine Japanese tertiary care centres. We assessed caregiver depression and grief using the Patient Health Questionnaire-9 (PHQ-9) and Brief Grief Questionnaire (BGQ), respectively. The questionnaire also covered caregivers' perspectives toward end-of-life care and the quality of the deceased patient's death. RESULTS: A total of 269 bereaved caregivers (mean age: 66 (57-73) years; 37.5% male) of patients with CVD were enrolled. Overall, 13.4% of the bereaved caregivers had depression (PHQ-9 ≥10) and 14.1% had complicated grief (BGQ ≥8). Depression and complicated grief's determinants were similar (ie, spousal relationship, unpreparedness for the death, financial and decision-making burden and poor communication among medical staff). Patients and caregivers' positive attitudes toward life-prolonging treatment were associated with complicated grief. Notably, in caregivers with complicated grief, there was less discussion with physicians about end-of-life care. Caregivers who felt that the patients did not receive sufficient treatment suffered more frequently from depression and complicated grief. CONCLUSIONS: Approximately 15% of bereaved caregivers of patients with CVD suffered from depression and complicated grief. Cardiologists should pay particular attention to caregivers with high-risk factors to identify those likely to develop depression or complicated grief.

INTRODUCTION: Limited data exist on the efficacy of combination therapy with ustekinumab and budesonide in patients with Crohn's disease. Our objective was to compare the clinical outcomes of ustekinumab and budesonide combination therapy with those of ustekinumab monotherapy. METHODS: In this phase 2 single-center, double-blind, randomized controlled trial, we assigned 19 patients with Crohn's disease with a Crohn's disease activity index (CDAI) equal to or greater than 220 and less than 450 in a 1:1 ratio to receive ustekinumab and budesonide or ustekinumab for 32 weeks. The primary endpoint was the clinical remission rate at 8 weeks. The secondary endpoints were the clinical remission rate at 32 weeks and mucosal healing rates at 8 and 32 weeks. RESULTS: Of 19 patients, the mean age was 37.8 years, and 42.1% were women (CDAI ≥220 and <450). There was no difference between combination therapy and ustekinumab monotherapy in terms of clinical remission rates (50.0% vs. 30.0%, p = 0.39 at 8 weeks and 37.5% vs. 20.0%, p = 0.41) and mucosal healing rates (75.0% vs. 90.0%, p = 0.40 and 37.5% vs. 60.0%, p = 0.34 at 8 and 32 weeks, respectively). The most common adverse event was an exacerbation of Crohn's. There were no differences in safety profiles between the two groups. CONCLUSIONS: Our study showed no difference between ustekinumab monotherapy and ustekinumab and budesonide combination therapy in terms of the induction and maintenance of remission (trial registration number: jRCTs021200013).

BACKGROUND: Enhanced discussions regarding end-of-life (EOL) are crucial to provide appropriate care for seriously ill patients. However, the current status of EOL discussions, especially their timing and influencing factors, among patients with cardiovascular diseases (CVD) remains unknown. METHODS AND RESULTS: We conducted a cross-sectional questionnaire survey of bereaved family members of CVD patients who died at 10 tertiary care institutes in Japan. In all, 286 bereaved family members (38.2% male; median age 66.0 [interquartile range 58.0-73.0] years) of CVD patients were enrolled; of these, 200 (69.9%) reported that their families had had EOL discussions with physicians. The major topic discussed was resuscitation (79.0%), and 21.5% discussed the place of EOL care. Most discussions were held during hospitalization of the patient (88.2%). More than half (57.1%) the discussions were initiated less than 1 month before the patient died, and 22.6% of family members felt that this timing of EOL discussions was late. Bereaved family members' perception of late EOL discussions was associated with the family members aggressive attitude towards life-prolonging treatment, less preparedness for bereavement, and less satisfaction with EOL care. CONCLUSIONS: Approximately 70% of bereaved family members of CVD patients had EOL discussions, which were often held shortly before the patient died. Further research is required to establish an ideal approach to EOL discussions at an appropriate time, which may improve the quality of EOL care.

OBJECTIVE: This study aimed to investigate the association between heart failure (HF) severity measured based on brain natriuretic peptide (BNP) levels and future bleeding events after percutaneous coronary intervention (PCI). BACKGROUND: The Academic Research Consortium for High Bleeding Risk presents a bleeding risk assessment for antithrombotic therapy in patients after PCI. HF is a risk factor for bleeding in Japanese patients. METHODS: Using an electronic medical record-based database with seven tertiary hospitals in Japan, this retrospective study included 7160 patients who underwent PCI between April 2014 and March 2020 and who completed a 3-year follow-up and were divided into three groups: no HF, HF with high BNP level and HF with low BNP level. The primary outcome was bleeding events according to the Global Use of Streptokinase and t-PA for Occluded Coronary Arteries classification of moderate and severe bleeding. The secondary outcome was major adverse cardiovascular events (MACE). Furthermore, thrombogenicity was measured using the Total Thrombus-Formation Analysis System (T-TAS) in 536 consecutive patients undergoing PCI between August 2013 and March 2017 at Kumamoto University Hospital. RESULTS: Multivariate Cox regression showed that HF with high BNP level was significantly associated with bleeding events, MACE and all-cause death. In the T-TAS measurement, the thrombogenicity was lower in patients with HF with high BNP levels than in those without HF and with HF with low BNP levels. CONCLUSIONS: HF with high BNP level is associated with future bleeding events, suggesting that bleeding risk might differ depending on HF severity.

AIM: People with high normal blood pressure (BP) have a higher risk of cardiovascular events than those with normal BP; therefore, progression to hypertension (HT) should be prevented. We aimed to assess the HT risk using central BP and carotid intima media thickness (CIMT) in people with high normal BP. METHODS: This prospective cohort study used the Tohoku Medical Megabank Community-Based Project Cohort Study (conducted from 2013 in Miyagi Prefecture in Japan). The participants had a high normal BP, defined as a systolic BP of 120-139 mmHg and diastolic BP ＜90 mmHg using brachial BP measurement during the baseline survey. The outcome was new-onset HT during the secondary survey, conducted four years after the baseline survey. RESULTS: Overall, 4,021 participants with high normal BP during the baseline survey, with an average age of 58.7 years, were included; 1,030 (26%) were diagnosed with new-onset HT during the secondary survey, 3.5±0.7 years after the baseline survey. The multivariable odds ratio (95% confidence interval) for HT in the highest versus lowest quartile of central BP was 1.7 (1.2-2.4, p=0.0030), and that of CIMT was 1.8 (1.4-2.4, p＜0.001). Subgroup analysis according to age (＜60 and ≥ 60 years) and sex revealed that the central BP was influential in groups with younger age and female individuals; CIMT was influential in all groups. CONCLUSIONS: Higher central BP and thicker CIMT at the baseline were correlated with new-onset HT in individuals with high normal BP, independent of brachial systolic BP and other cardiovascular risk factors.

AIM: The influence of family history of diabetes, probably reflecting genetic and lifestyle factors, on the association of combined genetic and lifestyle risks with diabetes is unknown. We examined these associations. METHODS: This cross-sectional study included 9,681 participants in the Tohoku Medical Megabank Community-based Cohort Study. A lifestyle score, which was categorized into ideal, intermediate, and poor lifestyles, was given. Family history was obtained through a self-reported questionnaire. A polygenic risk score (PRS) was constructed in the target data (n=1,936) using publicly available genome-wide association study summary statistics from BioBank Japan. For test data (n=7,745), we evaluated PRS performance and examined the associations of combined family history and genetic and lifestyle risks with diabetes. Diabetes was defined as non-fasting blood glucose ≥ 200 mmHg, HbA1c ≥ 6.5%, and/or self-reported diabetes treatment. RESULTS: In test data, 467 (6.0%) participants had diabetes. Compared with a low genetic risk and an ideal lifestyle without a family history, the odds ratio (OR) was 3.73 (95% confidence interval [CI], 1.92-7.00) for a lower genetic risk and a poor lifestyle without a family history. Family history was significantly associated with diabetes (OR, 3.58 [95% CI, 1.73-6.98]), even in those with a low genetic risk and an ideal lifestyle. Even among participants who had an ideal lifestyle without a family history, a high genetic risk was associated with diabetes (OR, 2.49 [95% CI, 1.65-3.85]). Adding PRS to family history and conventional lifestyle risk factors improved the prediction ability for diabetes. CONCLUSIONS: Our findings support the notion that a healthy lifestyle is important to prevent diabetes regardless of genetic risk.

AIMS: The pathophysiology of pulmonary hypertension (PH) due to left-sided heart disease (Group 2 PH) is distinct from that of other groups of PH, yet there are still no approved therapies that selectively target pulmonary circulation. The increase in pulmonary capillary pressure due to left-sided heart disease is a trigger event for physical and biological alterations of the pulmonary circulation, including the nitric oxide (NO)-soluble guanylate cyclase-cyclic guanosine monophosphate axis. This study investigated inhaled NO vasoreactivity tests for patients with Group 2 PH and hypothesized that these changes may have a prognostic impact. METHODS AND RESULTS: This was a single-centre, retrospective study with a median follow-up of 365 days. From January 2011 to December 2015, we studied 69 patients with Group 2 PH [age, 61.5 ± 13.0 (standard deviation) years; male:female, 49:20; left ventricular ejection fraction, 50.1 ± 20.4%; mean pulmonary arterial pressure, ≥25 mmHg; and pulmonary arterial wedge pressure (PAWP), >15 mmHg]. No adverse events were observed after NO inhalation. Thirty-four patients with Group 2 PH showed increased PAWP (ΔPAWP: 3.26 ± 2.22 mmHg), while the remaining 35 patients did not (ΔPAWP: -2.11 ± 2.29 mmHg). Multivariate analysis revealed that increased PAWP was the only significant predictor of all-cause death or hospitalization for heart failure (HF) after 1 year (hazard ratio 4.35; 95% confidence interval, 1.27-14.83; P = 0.019). The acute response of PAWP to NO differed between HF with preserved and reduced ejection fractions. CONCLUSIONS: Patients with Group 2 PH were tolerant of the inhaled NO test. NO-induced PAWP is a novel prognostic indicator.

This study aimed to examine whether risk of withdrawal from HTTx was higher in coastal areas that were severely damaged by tsunami than in inland areas. We conducted a cross-sectional study of 9218 participants aged ≥20 years in Miyagi, Japan. The odds ratios (ORs) and confidence interval (CI) for withdrawal from HTTx in coastal and inland groups were compared using multivariate logistic regression analysis, adjusting for potential confounders. In total, 194 of 5860 and 146 of 3358 participants in the inland and coastal groups, respectively, withdrew from HTTx treatment. OR (95%CI) of withdrawal from HTTx in the coastal group was 1.46 (1.14-1.86) compared to the inland group. According to housing damage, ORs (95% CI) in the no damage, partially destroyed, and more than half destroyed coastal groups compared with the no damage inland group were 1.62 (1.04-2.50), 1.69 (1.17-2.45), and 1.08 (0.71-1.65), respectively. In conclusion, the risk of HTTx withdrawal for participants whose homes in coastal areas were relatively less damaged was significantly higher compared with those in inland areas, while the risk of HTTx withdrawal for participants whose homes were more than half destroyed was not. Post-disaster administrative support for disaster victims is considered vital for continuation of their treatment.

BACKGROUND: Limited data exist on the prognostic significance of a history of cancer and atrial fibrillation (AF) in patients with coronary artery disease (CAD). This study aimed to evaluate the associations among a history of cancer, AF, and long-term prognosis in patients with CAD. METHODS: We studied 3,233 patients with CAD (69 ± 11 years; women, 23%) in a multicenter hospital-based cohort study, the CHART-2 and related a history of cancer and AF to cardiovascular outcomes with a median follow-up of 10.8 years. RESULTS: Of the 3,233 patients enrolled, 10.7% and 11.2% had a history of cancer and AF, respectively, while 2.8% had both. Patients with AF and a history of cancer were characterized by older age, male sex, and higher BNP levels. Anticoagulant use with warfarin or direct oral anticoagulants increased from 43% at baseline to 56% at 10 years in patients with CAD with AF and no history of cancer and increased from 49% to 83% in those with both. Patients with CAD with both comorbidities had a higher risk of a composite outcome including stroke, thrombosis, and major bleeding (Hazard Ratio [HRadjusted], 2.26; 1.50-3.40, P < 0.001). Furthermore, patients with both comorbidities had a higher risk of all-cause death (1.55; 95% confidence interval [CI] 1.12-2.12, P = 0.007) including cancer death (2.62; 1.51-4.54, P = 0.001), and new-onset heart failure (HF) requiring hospitalization (2.47; 1.54-3.96, P < 0.001). CONCLUSIONS: These results demonstrate that CAD patients with a history of cancer and AF have an increased risk of composite outcomes, including stroke, systemic thrombosis, major bleeding, all-cause death, cancer-related death, and new-onset HF.

Masked hypertension is a risk factor for cardiovascular diseases. However, masked hypertension is sometimes overlooked owing to the requirement for home blood pressure measurements for diagnosing. Mental status influences blood pressure. To reduce undiagnosed masked hypertension, this study assessed the association between depressive symptoms and masked hypertension. This cross-sectional study used data from the Tohoku Medical Megabank Project Community-Based Cohort Study (conducted in Miyagi Prefecture, Japan, from 2013) and included participants with normotension measured at the research center (systolic blood pressure<140 mmHg and diastolic blood pressure <90 mmHg). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (Japanese version). Masked hypertension was defined as normotension measured at the research center and home hypertension (home systolic blood pressure ≥135 mmHg or home diastolic blood pressure ≥85 mmHg). The study comprised 6705 participants (mean age: 55.7 ± 13.7 years). Of these participants, 1106 (22.1%) without depressive symptoms and 393 (23.2%) with depressive symptoms were categorized to have masked hypertension. Sex-specific and age-adjusted least mean squares for home blood pressure, not for research blood pressure were significantly higher in the group with depressive symptoms in both sex categories. The multivariate odds ratio for masked hypertension in the patients with depressive symptoms was 1.72 (95% confidence interval: 1.26-2.34) in male participants and 1.30 (95% confidence interval: 1.06-1.59) in female ones. Depressive symptoms were associated with masked hypertension in individuals with normotension measured at the research center. Depressive symptoms may be one of the risk factors for masked hypertension. Depressive symptoms were associated with masked hypertension in individuals with normotension measured at research center.

AIM: The influence of family history of diabetes, probably reflecting genetic and lifestyle factors, on the association of combined genetic and lifestyle risks with diabetes is unknown. We examined these associations. METHODS: This cross-sectional study included 9,681 participants in the Tohoku Medical Megabank Community-based Cohort Study. A lifestyle score, which was categorized into ideal, intermediate, and poor lifestyles, was given. Family history was obtained through a self-reported questionnaire. A polygenic risk score (PRS) was constructed in the target data (n=1,936) using publicly available genome-wide association study summary statistics from BioBank Japan. For test data (n=7,745), we evaluated PRS performance and examined the associations of combined family history and genetic and lifestyle risks with diabetes. Diabetes was defined as non-fasting blood glucose ≥ 200 mmHg, HbA1c ≥ 6.5%, and/or self-reported diabetes treatment. RESULTS: In test data, 467 (6.0%) participants had diabetes. Compared with a low genetic risk and an ideal lifestyle without a family history, the odds ratio (OR) was 3.73 (95% confidence interval [CI], 1.92-7.00) for a lower genetic risk and a poor lifestyle without a family history. Family history was significantly associated with diabetes (OR, 3.58 [95% CI, 1.73-6.98]), even in those with a low genetic risk and an ideal lifestyle. Even among participants who had an ideal lifestyle without a family history, a high genetic risk was associated with diabetes (OR, 2.49 [95% CI, 1.65-3.85]). Adding PRS to family history and conventional lifestyle risk factors improved the prediction ability for diabetes. CONCLUSIONS: Our findings support the notion that a healthy lifestyle is important to prevent diabetes regardless of genetic risk.

AIM: We examined the association between the carotid intima medica thickness (cIMT) and risk factors for atherosclerosis based on the Japan Atherosclerosis Society 2022 Atherosclerosis Prevention Guideline. METHODS: Using data from the Tohoku Medical Megabank Community-based Cohort Study, we performed a cross-sectional study that enrolled 13,366 participants (age ≥ 20 years) with an analysis of covariance to assess associations between cIMT and risk factors for atherosclerosis. The maximum common carotid artery was measured using high-resolution B-mode ultrasound. Analysis was conducted in the model adjusted for age, sex, smoking status, drinking status, body mass index (BMI), systolic blood pressure (SBP), glycated hemoglobin (HbA1c), high-density lipoprotein-cholesterol (HDL-C), non-high-density lipoprotein-cholesterol (non-HDL-C), and height. RESULTS: In this study cohort, the average age and cIMT were 57.3 (13.8) years and 0.61 (0.13) mm, respectively, which included 3,988 males (29.8%). Males had a higher cIMT than did the females. Age, height, BMI, SBP, HbA1c, and non-HDL-C were positively associated with cIMT. HDL-C was inversely associated with cIMT. Compared with never drinkers, current drinkers (≥ 46.0 g/day) had a significantly decreased cIMT. CONCLUSIONS: The cIMT was associated with atherosclerosis risk factors including age, sex, BMI, SBP, HbA1c, non-HDL-C, and HDL-C, and adequate control of risks in high-risk individuals might be required to prevent atherosclerotic cardiovascular diseases.

BACKGROUND: Heart failure (HF) is associated with a high bleeding risk after percutaneous coronary intervention (PCI). Additionally, major bleeding events increase the risk of subsequent major adverse cardiac events (MACE). However, whether brain natriuretic peptide (BNP) levels and major bleeding events following PCI are associated with MACE and all-cause death remains unknown. This study aimed to investigate the impact of HF severity or bleeding on subsequent MACE and all-cause death. METHODS: The Clinical Deep Data Accumulation System (CLIDAS), a multicenter database involving seven hospitals in Japan, was developed to collect data from electronic medical records. This retrospective analysis included 7160 patients who underwent PCI between April 2014 and March 2020 and completed a three-year follow-up. Patients were divided according to the presence of HF with high BNP (HFhBNP) (>100 pg/ml) and major bleeding events within 30 days post-PCI (30-day bleeding): HFhBNP with bleeding (n = 14), HFhBNP without bleeding (n = 370), non-HFhBNP with bleeding (n = 74), and non-HFhBNP without bleeding (n = 6702). RESULTS: In patients without 30-day bleeding, HFhBNP was a risk factor for MACE (hazard ratio, 2.19; 95% confidence interval, 1.56-3.07) and all-cause death (hazard ratio, 1.60; 95% confidence interval, 1.60-2.23). Among HFhBNP patients, MACE incidence was higher in patients with 30-day bleeding than in those without bleeding, but the difference was not significant (p = 0.075). The incidence of all-cause death was higher in patients with bleeding (p = 0.001). CONCLUSIONS: HF with high BNP and bleeding events in the early stage after PCI might be associated with subsequent MACE and all-cause death.

AIM: Impaired lung function is associated with atherosclerotic vascular events. Carotid intima-media thickness (cIMT) is a marker for subclinical atherosclerosis. However, few studies have examined the association between lung function and cIMT among never smokers or individuals stratified by age. We investigated the association between lung function and cIMT in the Japanese population. METHODS: We conducted a cross-sectional study of 3,716 men and 8,765 women aged 20 years or older living in Miyagi Prefecture, Japan. Lung function was evaluated using forced expiratory volume at 1 s (FEV1) and forced vital capacity (FVC) was measured using spirometry. The maximum common carotid artery was measured using high-resolution B-mode ultrasound. An analysis of covariance was used to assess associations between lung function and cIMT and adjusted for potential confounders. A linear trend test was conducted by scoring the categories from 1 (lowest) to 4 (highest) and entering the score as a continuous term in the regression model. RESULTS: After adjusting for potential confounders including passive smoking, lower FEV1 and FVC were associated with higher cIMT in both men and women (P＜0.001 for linear trend). This association was confirmed even when we restricted our study to never smokers. Furthermore, even when we stratified by age, an inverse association between lung function and cIMT was confirmed in middle-aged (40-64 years) and elderly participants (65-74 years). CONCLUSIONS: Lower lung function was associated with higher cIMT in the Japanese population independent of age and smoking. Assessment of atherosclerosis or lung function may be required for individuals with lower lung function or atherosclerosis.

AIM: People with high normal blood pressure (BP) have a higher risk of cardiovascular events than those with normal BP; therefore, progression to hypertension (HT) should be prevented. We aimed to assess the HT risk using central BP and carotid intima media thickness (CIMT) in people with high normal BP. METHODS: This prospective cohort study used the Tohoku Medical Megabank Community-Based Project Cohort Study (conducted from 2013 in Miyagi Prefecture in Japan). The participants had a high normal BP, defined as a systolic BP of 120-139 mmHg and diastolic BP ＜90 mmHg using brachial BP measurement during the baseline survey. The outcome was new-onset HT during the secondary survey, conducted four years after the baseline survey. RESULTS: Overall, 4,021 participants with high normal BP during the baseline survey, with an average age of 58.7 years, were included; 1,030 (26%) were diagnosed with new-onset HT during the secondary survey, 3.5± 0.7 years after the baseline survey. The multivariable odds ratio (95% confidence interval) for HT in the highest versus lowest quartile of central BP was 1.7 (1.2-2.4, p=0.0030), and that of CIMT was 1.8 (1.4-2.4, p＜0.001). Subgroup analysis according to age (＜60 and ≥ 60 years) and sex revealed that the central BP was influential in groups with younger age and female individuals; CIMT was influential in all groups. CONCLUSIONS: Higher central BP and thicker CIMT at the baseline were correlated with new-onset HT in individuals with high normal BP, independent of brachial systolic BP and other cardiovascular risk factors.

AIMS: Current approaches to classify chronic heart failure (HF) subpopulations may be limited due to the diversity of pathophysiology and co-morbidities in chronic HF. We aimed to elucidate the clusters of chronic patients with HF by data-driven approaches with machine learning in a hospital-based registry. METHODS AND RESULTS: A total of 4649 patients with a broad spectrum of left ventricular ejection fraction (LVEF) in the CHART-2 (Chronic Heart Failure Analysis and Registry in the Tohoku District-2) study were enrolled to this study. Chronic HF patients were classified using random forest clustering with 56 multiscale clinical parameters. We assessed the influence of the clusters on cardiovascular death, non-cardiovascular death, all-cause death, and free from hospitalization by HF. Latent class analysis using random forest clustering identified 10 clusters with four primary components: cardiac function (LVEF, left atrial and ventricular diameters, diastolic blood pressure, and brain natriuretic peptide), renal function (glomerular filtration rate and blood urea nitrogen), anaemia (red blood cell, haematocrit, haemoglobin, and platelet count), and nutrition (albumin and body mass index). All 11 significant clinical parameters in the four primary components and two disease aetiologies (ischaemic heart disease and valvular heart disease) showed statistically significant differences among the 10 clusters (P < 0.01). Cluster 1 (26.7% of patients), which is characterized by preserved LVEF (<59%, 37% of the total) with lowest brain natriuretic peptide (>111.3 pg/mL, 0.9%) and lowest left atrial diameter (>42 mm, 37.4%), showed the best 5 year survival rate of 98.1% for cardiovascular death, 95.9% for non-cardiovascular death, 92.9% for all-cause death, and 91.7% for free from hospitalization by HF. Cluster 10 (6.0% of the total), which is co-morbid disorders of all four primary components, showed the worst survival rate of 39.1% for cardiovascular death, 68.9% for non-cardiovascular death, 23.9% for all-cause death, and 28.1% for free from hospitalization by HF. CONCLUSIONS: These results suggest the potential applicability of the machine leaning approach, providing useful clinical prognostic information to stratify complex heterogeneity in patients with HF.

BACKGROUND: Several studies have reported some sex differences in patients with coronary artery diseases. However, the results regarding long-term outcomes in patients with chronic coronary syndrome (CCS) are inconsistent. Therefore, the present study investigated sex differences in long-term outcomes in patients with CCS after percutaneous coronary intervention (PCI). METHODS AND RESULTS: This was a retrospective, multicenter cohort study. We enrolled patients with CCS who underwent PCI between April 2013 and March 2019 using the Clinical Deep Data Accumulation System (CLIDAS) database. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, or hospitalization for heart failure. In all, 5,555 patients with CCS after PCI were included in the analysis (4,354 (78.4%) men, 1,201 (21.6%) women). The median follow-up duration was 917 days (interquartile range 312-1,508 days). The incidence of MACE was not significantly different between the 2 groups (hazard ratio [HR] 1.20; 95% confidential interval [CI] 0.97-1.47; log-rank P=0.087). After performing multivariable Cox regression analyses on 4 different models, there were still no differences in the incidence of MACE between women and men. CONCLUSIONS: There were no significant sex differences in MACE in patients with CCS who underwent PCI and underwent multidisciplinary treatments.

BACKGROUND: Although fat mass index (FMI) and fat-free mass index (FFMI) affect lung function, FMI and FFMI are not independent of each other since FMI and FFMI were calculated as fat mass and fat-free mass divided by height squared, respectively. We aimed to examine the association of combined FMI and FFMI with lung function. METHODS: In this cross-sectional study, lung function was evaluated using forced expiratory volume at 1 s and forced vital capacity was measured using spirometry. Both FMI and FFMI were classified into sex-specific quartiles (16 groups). Analysis of covariance was used to assess the associations of combined FMI and FFMI with lung function. The trend test was conducted by stratifying the FMI and FFMI, scoring the categories from 1-4 (lowest-highest), and entering the number as a continuous term in the regression model. RESULTS: This study included 3,736 men and 8,821 women aged ≥20 years living in Miyagi Prefecture, Japan. The mean FEV1 (standard deviation) was 3.0 (0.7) L for men and 2.3 (0.5) L for women. The mean FVC was 3.8 (0.7) L for men and 2.8 (0.5) L for women. The FMI was inversely associated with lung function among all FFMI subgroups in both sexes. Conversely, FFMI was positively associated with lung function in all FMI subgroups in both sexes. CONCLUSIONS: Higher FMI was associated with lower lung function independent of FFMI; higher FFMI was associated with higher lung function independent of FMI. Reducing FMI and maintaining FFMI might be important for respiratory health.

AIM: Although many epidemiological studies have shown that obesity assessed by body mass index is associated with carotid intima-media thickness (cIMT), few studies have evaluated fat-free mass, which is a component of body composition. We investigated the associations between the combined fat mass index (FMI) and fat-free mass index (FFMI) with cIMT. METHODS: We conducted a cross-sectional study of 3,873 men and 9,112 women aged 20 years or older who lived in Miyagi prefecture, Japan. The FMI and FFMI were calculated as fat mass and fat-free mass divided by height squared, respectively. The indices were classified into sex-specific quartiles and were combined into 16 groups. The maximum common carotid artery was measured using high-resolution B-mode ultrasound. An analysis of covariance was used to assess associations between the combined FMI and FFMI with cIMT adjusted for age and smoking status. The linear trend test was conducted by stratifying the FMI and FFMI, scoring the categories from 1 (lowest) to 4 (highest), and entering the number as a continuous term in the regression model. RESULTS: In multivariable models, a higher FMI was not related to higher cIMT in men and women in most FFMI subgroups. Conversely, a higher FFMI was related to higher cIMT in all FMI subgroups (p＜0.001 for linear trend). CONCLUSIONS: FMI was not associated with cIMT in most FFMI subgroups. Conversely, FFMI was positively associated with cIMT independently of FMI.

BACKGROUND: Although several studies have shown an inverse association between lung function and hypertension, few studies have examined the association between lung function and hypertension among never-smokers, and no study has investigated the association between lung function and home hypertension. We investigated the associations between lung function and hypertension in a Japanese population. INDIVIDUALS AND METHODS: We conducted a cross-sectional study of 3728 men and 8795 women aged 20 years or older living in Miyagi Prefecture, Japan. Lung function was assessed using forced expiratory volume at 1 s (FEV1) and forced vital capacity (FVC), measured by spirometry. Hypertension was defined as a casual blood pressure at least 140/90 mmHg and/or self-reported treatment for hypertension. Home hypertension was defined as morning home blood pressure at least 135/85 mmHg and/or self-reported treatment for hypertension. Multivariate logistic regression models adjusted for potential confounders were used to assess the association between lung function and hypertension. RESULTS: The mean ages (±SD) of men and women were 60.1 (±14.0) years and 56.2 (±13.4) years, respectively, and 1994 (53.5%) men and 2992 (34.0%) women had hypertension. In the multivariable models, FEV1 and FVC were inversely associated with hypertension. Inverse associations between lung function and hypertension were observed even among never-smokers. Furthermore, reduced lung function was associated with higher prevalence of home hypertension in men and women. CONCLUSION: Reduced lung function was associated with higher prevalence of hypertension, independent of smoking status. Assessment of the lung function or blood pressure may be required in individuals with reduced lung function or hypertension.

BACKGROUND: The optimal heart rate (HR) and optimal dose of β-blockers (BBs) in patients with coronary artery disease (CAD) have been unclear. We sought to clarify the relationships among HR, BB dose, and prognosis in patients with CAD using a multimodal data acquisition system. METHODS AND RESULTS: We evaluated the data for 8,744 CAD patients who underwent cardiac catheterization from 6 university hospitals and the National Cerebral and Cardiovascular Center and who were registered using the Clinical Deep Data Accumulation System. Patients were divided into quartile groups based on their HR at discharge: Q1 (HR <60 beats/min), Q2 (HR 60-66 beats/min), Q3 (HR 67-74 beats/min), and Q4 (HR ≥75 beats/min). Among patients with acute coronary syndrome (ACS) and patients with chronic coronary syndrome (CCS), those in Q4 (HR ≥75 beats/min) had a significantly greater incidence of major adverse cardiac and cerebral events (MACCE) compared with those in Q1 (ACS patients: hazard ratio 1.65, P=0.001; CCS patients: hazard ratio 1.45, P=0.019). Regarding the use of BBs (n=4,964), low-dose administration was significantly associated with MACCE in the ACS group (hazard ratio 1.41, P=0.012), but not in patients with CCS after adjustment for covariates. CONCLUSIONS: HR ≥75 beats/min was associated with worse outcomes in patients with CCS or ACS.

BACKGROUND: Prognosis of breast cancer patients has been improved along with the progress in cancer therapies. However, cancer therapeutics-related cardiac dysfunction (CTRCD) has been an emerging issue. For early detection of CTRCD, we examined whether native T1 mapping and global longitudinal strain (GLS) using cardiac magnetic resonance (CMR) and biomarkers analysis are useful. METHODS: We prospectively enrolled 83 consecutive chemotherapy-naïve female patients with breast cancer (mean age, 56 ± 13 yrs.) between 2017 and 2020. CTRCD was defined based on echocardiography as left ventricular ejection fraction (LVEF) below 53% at any follow-up period with LVEF>10% points decrease from baseline after chemotherapy. To evaluate cardiac function, CMR (at baseline and 6 months), 12‑lead ECG, echocardiography, and biomarkers (at baseline and every 3 months) were evaluated. RESULTS: A total of 164 CMRs were performed in 83 patients. LVEF and GLS were significantly decreased after chemotherapy (LVEF, from 71.2 ± 4.4 to 67.6 ± 5.8%; GLS, from -27.9 ± 3.9 to -24.7 ± 3.5%, respectively, both P < 0.01). Native T1 value also significantly elevated after chemotherapy (from 1283 ± 36 to 1308 ± 39 msec, P < 0.01). Among the 83 patients, 7 (8.4%) developed CTRCD. Of note, native T1 value before chemotherapy was significantly higher in patients with CTRCD than in those without it (1352 ± 29 vs. 1278 ± 30 msec, P < 0.01). The multivariable logistic regression analysis revealed that native T1 value was an independent predictive factor for the development of CTRCD [OR 2.33; 95%CI 1.15-4.75, P = 0.02]. CONCLUSIONS: These results indicate that CMR is useful to detect chemotherapy-related myocardial damage and predict for the development of CTRCD in breast cancer patients.

Objective Patients in whom coronavirus disease 2019 (COVID-19) was suspected or confirmed between January 1, 2020, and October 31, 2021, were enrolled from Japanese hospitals in this multicenter, retrospective, observational study. Methods Data on the treatment administered (including conventional and Kampo medicine) and changes in common cold-like symptoms (such as fever, cough, sputum, dyspnea, fatigue, and diarrhea) were collected from their medical records. The primary outcome was the number of days without a fever (with a body temperature <37°C). The secondary outcomes were symptomatic relief and the worsening of illness, defined as the presence of a condition requiring oxygen inhalation. The outcomes of patients treated with and without Kampo medicine were compared. Patients We enrolled 962 patients, among whom 528 received conventional and Kampo treatment (Kampo group) and 434 received conventional treatment (non-Kampo group). Results Overall, after adjusting for the staging of COVID-19 and risk factors, there were no significant between-group differences in the symptoms or number of days being afebrile. After performing propensity score matching and restricting the included cases to those with confirmed COVID-19 who did not receive steroid administration and initiated treatment within 4 days from the onset, the risk of illness worsening was significantly lower in the Kampo group than in the non-Kampo group (odds ratio=0.113, 95% confidence interval: 0.014-0.928, p=0.0424). Conclusion Early Kampo treatment may suppress illness worsening risk in COVID-19 cases without steroid use. Further randomized controlled studies are needed to confirm the clinical benefit of Kampo medicine for COVID-19.

BACKGROUND: The prevalence of Fabry disease (FD) in male patients with left ventricular hypertrophy (LVH) is about 1%. From the perspective of performing more efficient screening with measurement of α-galactosidase (α-Gal) activity, it is important to raise the pretest probability. METHODS: We retrospectively investigated the prevalence of FD in 701 male patients with LVH who already had been screened by measurement of α-Gal activity in eight hospitals. From the viewpoint of enzymatic screening, we validated previously reported clinical features of FD including the electrocardiographic and echocardiographic characteristics with comparing each clinical determinant between patients with FD and non-FD patients. We finally aimed to establish a new screening approach for the detection of patients at high risk of FD. RESULTS: There were five FD patients (0.7%) in the 701 male patients with LVH. Those five patients with FD all had the cardiac variant type and age at detection of LVH was ≥35 years in all patients. In LVH patients with LV ejection fraction (EF) ≥ 50%, Pend-Q interval < 40 msec, SV1 + RV5 > 4.0 mV, and diffuse LVH were important determinants of FD. In LVH patients with LVEF < 50%, asymmetric septal hypertrophy and posterior wall motion abnormality seemed to be associated with FD. CONCLUSIONS: In our retrospective study, the prevalence of FD in male patients with LVH was found to be 0.7%. We established the efficient combinations of clinical determinants using age at detection of LVH, Pend-Q interval, high voltage, and LVH pattern in an echocardiogram.

This prospective, observational study was conducted in a university hospital to verify that intraoperative worsening of right ventricular function causes cardiac surgery-associated acute kidney injury. Adult patients undergoing cardiac surgery under mid-sternal incision with cardiopulmonary bypass were included. Echocardiographic right and left ventricular function parameters were measured before and after bypass and compared using the Wilcoxon signed-rank test. Perioperative serum creatinine values at baseline and within the first 48 hours postoperatively were measured for the diagnosis of acute kidney injury. Spearman rank-order correlation (ρ) and receiver operating characteristic analysis were used to reveal relationships. Thirty-four patients were evaluated. Right ventricular ejection fraction (56.2 ± 7.0 vs. 51.6 ± 7.2%; P = 0.0002), right ventricular fractional area change (49.1 ± 6.4 vs. 46.6 ± 5.3%; P = 0.0201; mean ± standard deviation), and left ventricular ejection fraction (57.4 ± 6.1 vs. 51.7 ± 6.2%; P < 0.0001) were significantly decreased. Central venous pressure was significantly increased (7.2 ± 3.5 vs. 9.7 ± 3.7; P = 0.0001). Serum creatinine values increased from 0.82 [0.70-1.08] to 0.99 [0.82-1.54] mg/dL (P < 0.0001; median [interquartile range]). Changes in right ventricular ejection fraction, fractional area change, and right ventricular strain during cardiovascular surgery were significantly correlated with changes in serum creatinine values. Fractional area change exhibited the strongest correlation (ρ = -0.61, P < 0.0001). Change in fractional area change showed an area under the curve of 0.902 and a cutoff value of -2.1, which predicted acute kidney injury with 92% sensitivity, 73% specificity, and 79% accuracy. The functions of both ventricles were decreased after cardiopulmonary bypass. Worsening right ventricular function was independently correlated with postoperative renal dysfunction, and fractional area change was the strongest predictor of cardiac surgery-associated acute kidney injury.

BACKGROUND: The predictive value of echocardiographic parameters for early worsening heart failure (WHF), worsening of symptoms of heart failure requiring intensification of therapy during an admission for acute decompensated heart failure (ADHF), has not been elucidated. METHODS: Sixteen centers in Japan prospectively enrolled 303 ADHF hospitalized patients who did not receive positive inotropic agents as an initial therapy. Physical and Doppler echocardiographic examinations were performed before the initial therapy and the association of low output findings and occurrence of early WHF were tested. RESULTS: Early WHF occurred in 63 patients with a median duration of 6 (IQR: 2-23) hours from the administration of the initial therapy. In patients with left ventricular (LV) ejection fraction <40% (N = 153), echocardiographic stroke volume index, and cardiac index showed greater c-index [95% confidence interval, 0.71 (0.61-0.79) and 0.72 (0.63-0.80), respectively] compared to single low perfusion finding (symptomatic hypotension, reduced pulse pressure, and impaired mentation) other than cool extremities. When physical findings were combined (low perfusion score), the predictive ability improved to the similar levels of echocardiographic LV output parameters [c-index: 0.69 (0.60-0.76)]. However, addition of cardiac index significantly improved the prognostic ability when added to low perfusion score [0.82 (0.74-0.87), p < 0.001]. In contrast, in patients with LV ejection fraction ≥40% (N = 150), low perfusion score, rather than LV output parameters, was predictive of early WHF [c-index: 0.73 (0.56-0.85)]. CONCLUSIONS: We demonstrated the predictive value of echocardiographic LV output indices for early WHF in ADHF patients with LV systolic dysfunction. These data support the motivation for routine use of echocardiography for initial assessment of ADHF.

INTRODUCTION: Bone-anchored maxillary protraction (BAMP) was devised recently as a method of direct maxillary protraction using anchor plates implanted in the maxilla and mandible without involving the teeth. Although several reports have described orthognathic effects of BAMP on patients with cleft lip and palate (CLP) with skeletal crossbite, none has described a study of Japanese patients with CLP or of BAMP treatment effects on speech in patients with CLP. This study, by performing BAMP treatment, and by evaluating speech function and skeletal and soft tissues, is intended to clarify BAMP efficacy and safety for patients with unilateral CLP (UCLP) who have skeletal crossbite. METHODS AND ANALYSIS: This single-arm, open-label, non-randomised prospective study examines 20 patients with UCLP with skeletal crossbite (Wits appraisal ≤-5.0 mm). These 10-15 year-old participants had already undergone cheiloplasty, palatoplasty and bone grafting. The anchor plates are implanted in the zygomatic process in the maxilla and in the anterior part of the mandible. Two weeks after anchor plate implantation, maxillary protraction is started using elastics. Protraction is performed at 150 g per side at the start of protraction, 200 g per side from 1 month after the start of protraction and 250 g per side from 3 months after the start of protraction. The treatment period will be approximately 1½ years. Pretreatment and post-treatment, cephalometric analysis, speech evaluation, nasopharyngeal closure function evaluation and facial soft tissue evaluation will be performed to ascertain the effects of BAMP on patients with UCLP. ETHICS AND DISSEMINATION: Ethical approval for this study has been received from Tohoku Certificated Review Board of Tohoku University, Japan, CRB2200003. The approval number is 2021-34-2. The results of this research shall be presented at domestic and international academic conferences, and be published to peer-reviewed journals. TRIAL REGISTRATION NUMBER: jRCTs022210007.

AIMS: This study aimed to examine the prognostic significance of a history of cancer and atrial fibrillation (AF) in antithrombotic therapy for patients with chronic heart failure (CHF). METHODS AND RESULTS: We enrolled consecutive 4876 CHF patients (69 ± 12 years; women, 31.9%) in our multicentre, hospital-based cohort study, the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2), with a median follow-up of 8.7 years. Among them, 14% and 41% had a history of cancer and AF, respectively. AF patients with a history of cancer were older, more frequently men. History of cancer was not statistically associated with higher rate of composite of stroke, systemic thrombosis, and major bleeding defined by International Society on Thrombosis and Haemostasis [Fine-Gray sub-distribution hazard ratio (sHR) accounting for the competing risk of all-cause death, 0.91; 95% confidence interval (CI), 0.56-1.48; P = 0.715]. The patients with history of cancer and AF had a heightened risk for the composite of stroke, systemic thrombosis, and major bleeding (sHR, 1.64; 95% CI, 1.04-2.60; P = 0.033), especially in those aged >75 years (sHR, 2.14; 95% CI, 1.01-4.53; P = 0.046) and those with ischaemic heart disease (IHD; 2.48; 1.30-4.72; P = 0.006). Furthermore, 36% of AF patients with a history of cancer did not receive anticoagulant therapy. CONCLUSIONS: The CHF patients with history of cancer and AF had higher risk for stroke, systemic thrombosis, and major bleeding, especially in the elderly and those with IHD, but considerable number of the patients did not receive anticoagulant therapy, indicating the need for better optimal anticoagulation strategy.

BACKGROUND AND AIM: The standard therapies for benign gastrointestinal stenosis are endoscopic balloon dilation or surgery; each have their advantages and disadvantages. In contrast, radial incision and cutting (RIC) is a novel approach for such stenosis. This study aimed to investigate the feasibility, safety, and effectiveness of RIC. METHODS: We enrolled 20 patients with benign stenosis of the lower gastrointestinal tract developed by various causes and conducted RIC. We evaluated the re-intervention free rate 52 weeks after RIC, technical success rate, adverse events, procedure time, and improvement of symptoms using a visual analog scale. RESULTS: We performed 20 sessions of first RIC for 20 lesions and seven sessions of additional RIC due to re-stenosis. The cumulative re-intervention-free survival rate 52 weeks after the first RIC was 55.8%. The technical success rate of the first RIC was 100% (20/20) while that of the additional RIC was 85.7% (6/7). One case developed perforation during the additional RIC and urgent surgery was performed. The additional RIC tended to show worse results in adverse events and procedure time compared with the first RIC. The patients' symptoms including abdominal bloating and dyschezia were significantly improved. CONCLUSIONS: Although RIC demonstrated a higher technical success rate for lower gastrointestinal stricture and subsequent improvement of patient symptoms, several issues including preventing delayed bleeding, perforation, and the long-term prognosis should be solved and clarified in further investigations.

Background: Although cardiac resynchronization therapy (CRT) is effective for patients with chronic heart failure (CHF) with reduced left ventricular ejection fraction and wide QRS (≥120 ms), data on the use of or long-term outcomes after CRT implantation in Japan are limited. Methods and Results: We examined proper CRT utilization and outcomes in 3,447 consecutive symptomatic CHF patients registered in the CHART-2 Study. We identified 167 potentially eligible patients and divided them into 4 groups according to the presence (+) or absence (-) of an indication for and implantation of CRT: Group A (reference group), (+)indication/(+)CRT; Group B, (+)indication/(-)CRT; Group C, (-)indication/(+)CRT; and Group D, (-)indication/(-)CRT. Based on the Japanese Circulation Society guidelines, 91 patients met the eligibility for CRT implantation, with 43 (47%) of them undergoing CRT implantation. After adjusting for confounders, age was significantly associated with no CRT use (odds ratio per 5-year increase 1.46; 95% confidence interval 1.11-2.05; P=0.012). Among the 4 groups, the cumulative incidence of cardiovascular death and CHF admission were highest in Group B and lowest in Group D (P=0.029). Conclusions: In this study, only half the eligible CHF patients properly received CRT. Aging was a significant risk factor for no CRT use. Patients without CRT despite having an indication could be at higher risk of mortality and CHF admission.

AIM: Although many epidemiological studies have shown that obesity assessed by body mass index is associated with carotid intima-media thickness (cIMT), few studies have evaluated fat-free mass, which is a component of body composition. We investigated the associations between the combined fat mass index (FMI) and fat-free mass index (FFMI) with cIMT. METHODS: We conducted a cross-sectional study of 3,873 men and 9,112 women aged 20 years or older who lived in Miyagi prefecture, Japan. The FMI and FFMI were calculated as fat mass and fat-free mass divided by height squared, respectively. The indices were classified into sex-specific quartiles and were combined into 16 groups. The maximum common carotid artery was measured using high-resolution B-mode ultrasound. An analysis of covariance was used to assess associations between the combined FMI and FFMI with cIMT adjusted for age and smoking status. The linear trend test was conducted by stratifying the FMI and FFMI, scoring the categories from 1 (lowest) to 4 (highest), and entering the number as a continuous term in the regression model. RESULTS: In multivariable models, a higher FMI was not related to higher cIMT in men and women in most FFMI subgroups. Conversely, a higher FFMI was related to higher cIMT in all FMI subgroups (p＜0.001 for linear trend). CONCLUSIONS: FMI was not associated with cIMT in most FFMI subgroups. Conversely, FFMI was positively associated with cIMT independently of FMI.

Right ventricular (RV) dysfunction caused by chronic pulmonary regurgitation (PR) is a major determinant of clinical outcome in adults with repaired tetralogy of Fallot (rTOF). However, the accurate assessment of RV function by conventional echocardiography remains challenging. This study tested the feasibility and usefulness of RV free-wall (RVFW) strain obtained by two-dimensional (2D) speckle-tracking echocardiography (STE) in evaluation of RV function in adults with rTOF by comparing cardiac magnetic resonance (CMR) imaging. We enrolled 22 consecutive patients (male/female, 8/14; mean age, 25.0 years) with rTOF who underwent transthoracic echocardiography at Tohoku University Hospital from July 2016 to June 2019. We measured RVFW strain by STE and compared them with 22 hemodynamically normal subjects (NOR) (male/female, 9/13; mean age, 32.0 years). The correlation between RV strain and CMR-derived RV ejection fraction (RVEF) or PR fraction (PRF) were also evaluated. All rTOF patients had more than moderate PR but were near asymptomatic. RVFW longitudinal strain (RVFW-LS) was significantly decreased in the rTOF group compared with that in the NOR group (-19.6 vs. -24.7, P < 0.01). In the rTOF group, RVFW-LS correlated with PRF (r = 0.44, P < 0.05), whereas RVFW circumferential strain at the mid-ventricular level correlated with RVEF (r = 0.57, P < 0.01). Intra-observer variability of RVFW strain was acceptable. These results indicate that RV systolic function and PR severity in rTOF could be assessed by RVFW strain measured by 2D STE. This method is feasible and can be used as a complement to CMR imaging.

The sodium-to-potassium (Na/K) ratio is known to be associated with blood pressure (BP). However, no reference value has been established since the urinary Na/K (uNa/K) ratio is known to have diurnal and day-to-day variations. Therefore, we investigated the number of days required to yield a better association between the morning uNa/K ratio and home BP (HBP) and determined a morning uNa/K ratio value that can be used as a reference value in participants who are not taking antihypertensive medication. This was a cross-sectional study using data from the Tohoku Medical Megabank Project Cohort Study. A total of 3122 participants borrowed HBP and uNa/K ratio monitors for 10 consecutive days. We assessed the relationship between the morning uNa/K ratio from 1 day to 10 days and home hypertension (HBP ≥ 135/85 mmHg) using multiple logistic regression models. Although a 1-day measurement of the morning uNa/K ratio was positively associated with home hypertension, multiple measurements of the morning uNa/K ratio were strongly related to home hypertension. The average morning uNa/K ratio was relatively stable after 3 days (adjusted odds ratio of home hypertension per unit increase in the uNa/K ratio for more than 3 days: 1.19-1.23). In conclusion, there was no threshold for the uNa/K ratio, and the morning uNa/K ratio was linearly associated with home hypertension. The Na/K ratio 2.0 calculated from the Dietary Reference Intakes for Japanese might be a good indication. Regarding the stability of the association between the morning uNa/K ratio and BP, more than 3 days of measurements is desirable.

BACKGROUND: Small benign intestinal stenosis is usually treated by endoscopic balloon dilation (EBD) or surgery. Although EBD and surgery are able to resolve the stenosis in most cases, they are associated with several problems such as insufficient dilation and surgical stress, respectively. On the contrary, a novel approach called radial incision and cutting (RIC) is reported to have several benefits when compared to EBD and surgery. We can currently adopt RIC only for the strictures in the colon or terminal ileum and not for those stenotic lesions present further in the small intestine where balloon-assisted endoscopy is utilized, because the long-type electric knife is currently not approved for use in Japan. We will herein conduct a pilot study to investigate the safety and feasibility of RIC for treating the benign stenoses of the small intestine using the long-type electric knife. METHODS: This will be a single-center, single-arm, interventional trial. The major criteria for inclusion will be age ranging from 20 to 80 years and the presence of benign stenosis in the small intestine. We will perform RIC on 10 participants. The primary outcome is the safety of this procedure, which will be assessed by measuring the frequency of adverse events of special interest. The secondary outcomes will be technical success rate, improvement in subjective symptoms, procedure time, and duration of hospitalization. DISCUSSION: This pilot study will provide useful information that will aid in adopting RIC for treating the benign strictures present in the small intestine. TRIAL REGISTRATION: jRCT Identifier, jRCTs022200040 . Registered on 1 March 2021.

A reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for key biologic mechanisms, could shorten the path for drug development, enhance drug cost-effectiveness and improve patient outcomes. We used highly multiplexed proteomics to address these objectives, measuring about 5000 proteins in each of 32,130 archived plasma samples from 22,849 participants in nine clinical studies. We used machine learning to derive a 27-protein model predicting 4-year likelihood of myocardial infarction, stroke, heart failure, or death. The 27 proteins encompassed 10 biologic systems, and 12 were associated with relevant causal genetic traits. We independently validated results in 11,609 participants. Compared to a clinical model, the ratio of observed events in quintile 5 to quintile 1 was 6.7 for proteins versus 2.9 for the clinical model, AUCs (95% CI) were 0.73 (0.72 to 0.74) versus 0.64 (0.62 to 0.65), c-statistics were 0.71 (0.69 to 0.72) versus 0.62 (0.60 to 0.63), and the net reclassification index was +0.43. Adding the clinical model to the proteins only improved discrimination metrics by 0.01 to 0.02. Event rates in four predefined protein risk categories were 5.6, 11.2, 20.0, and 43.4% within 4 years; median time to event was 1.71 years. Protein predictions were directionally concordant with changed outcomes. Adverse risks were predicted for aging, approaching an event, anthracycline chemotherapy, diabetes, smoking, rheumatoid arthritis, cancer history, cardiovascular disease, high systolic blood pressure, and lipids. Reduced risks were predicted for weight loss and exenatide. The 27-protein model has potential as a "universal" surrogate end point for cardiovascular risk.

BACKGROUND: The decisional burden on caregivers in the end-of-life (EOL) care for patients with cardiovascular diseases (CVD) is unknown. We aimed to evaluate the frequency and circumstances of caregiver difficulties in decision-making during EOL care for CVD patients, its determinants, and associations with psychological distress in the bereaved caregivers. METHODS: We conducted a cross-sectional survey using a questionnaire for bereaved caregivers of CVD patients who had died in 10 tertiary care centers. We assessed their overall and situation-specific decision-making difficulties during EOL care. The questionnaire also covered the attitudes of patients, caregivers, and attending physicians during EOL care and the respondents' depression (Patient Health Questionnaire-9) and grief status (Brief Grief Questionnaire). RESULTS: We enrolled 266 bereaved caregivers [median age, 65 (57-72) years; 38.4% male] of CVD patients. Overall, 28.9% of them experienced difficulties in decision-making. The most difficult decision-making situations involved informing the patient of the prognosis (18.2%), life-prolonging treatment (17.9%), and discontinuation of hydration and artificial nutrition (15.6%). Difficulties were associated with patient and/or caregiver factors (poor understanding of disease status and the patient's wishes, caregiver's emotional inability), physician factors (poor understanding of the patient's and/or caregiver's values, inadequate support for decision-making), and both (insufficient communication, conflict of opinions and wishes). Decision-making difficulties were associated with subsequent depression (20.5% vs. 10.3%, p=0.029) and complicated grief (27.0% vs. 9.0%, p<0.001) among bereaved caregivers. CONCLUSIONS: Approximately 30% of bereaved caregivers experienced decisional burdens during EOL care of CVD patients. The caregiver's decisional burdens were associated with subsequent psychological distress.

The sodium-to-potassium (Na/K) ratio is known to be associated with blood pressure (BP). However, no reference value has been established since the urinary Na/K (uNa/K) ratio is known to have diurnal and day-to-day variations. Therefore, we investigated the number of days required to yield a better association between the morning uNa/K ratio and home BP (HBP) and determined a morning uNa/K ratio value that can be used as a reference value in participants who are not taking antihypertensive medication. This was a cross-sectional study using data from the Tohoku Medical Megabank Project Cohort Study. A total of 3122 participants borrowed HBP and uNa/K ratio monitors for 10 consecutive days. We assessed the relationship between the morning uNa/K ratio from 1 day to 10 days and home hypertension (HBP ≥ 135/85 mmHg) using multiple logistic regression models. Although a 1-day measurement of the morning uNa/K ratio was positively associated with home hypertension, multiple measurements of the morning uNa/K ratio were strongly related to home hypertension. The average morning uNa/K ratio was relatively stable after 3 days (adjusted odds ratio of home hypertension per unit increase in the uNa/K ratio for more than 3 days: 1.19-1.23). In conclusion, there was no threshold for the uNa/K ratio, and the morning uNa/K ratio was linearly associated with home hypertension. The Na/K ratio 2.0 calculated from the Dietary Reference Intakes for Japanese might be a good indication. Regarding the stability of the association between the morning uNa/K ratio and BP, more than 3 days of measurements is desirable.

The traditional Japanese (Kampo) medicine, kakkonto with shosaikotokakikyosekko, has antiviral and anti-inflammatory effects. In this randomized trial, patients with mild and moderate coronavirus disease (COVID-19) were randomly allocated to the control group receiving conventional treatment for symptom relief such as antipyretics and antitussives or the Kampo group receiving mixed extract granules of kakkonto (2.5 g) and shosaikotokakikyosekko (2.5 g) three times a day for 14 days in addition to conventional treatment. The main outcome was the number of days until total symptom relief. The secondary outcome was the number of days until each symptom's relief and whether the disease progressed to respiratory failure. We enrolled a total of 161 patients (Kampo group, n = 81; control group, n = 80). The results from Kaplan-Meier estimates of symptom relief showed that there are no significant differences between the groups. However, covariate-adjusted cumulative incidence of fever relief considering competitive risk showed that the recovery was significantly faster in the Kampo group than in the control group (HR 1.76, 95% CI 1.03-3.01). Additionally, the risk of disease progression to moderate COVID-19 requiring oxygen inhalation was lower in the Kampo group than in the control group (Risk Difference -0.13, 95% CI -0.27-0.01). No significant drug-related side effects were observed. Kakkonto with shosaikotokakikyosekko is effective for fever relief with suppression of disease progression in COVID-19 patients. Clinical Trial Registration: https://jrct.niph.go.jp/en-latest-detail/jRCTs021200020, identifier [jRCTs021200020].

BACKGROUND: The causal relationship between hyperuricemia and cardiovascular diseases is still unknown. We hypothesized that hyperuricemic patients after percutaneous coronary intervention (PCI) had a higher risk of major adverse cardiovascular events (MACE). METHODS: This was a large-scale multicenter cohort study. We enrolled patients with chronic coronary syndrome (CCS) after PCI between April 2013 and March 2019 using the database from the Clinical Deep Data Accumulation System (CLIDAS), and compared the incidence of MACE, defined as a composite of cardiovascular death, myocardial infarction, and hospitalization for heart failure, between hyperuricemia and non-hyperuricemia groups. RESULTS: In total, 9,936 patients underwent PCI during the study period. Of these, 5,138 patients with CCS after PCI were divided into two group (1,724 and 3,414 in the hyperuricemia and non-hyperuricemia groups, respectively). The hyperuricemia group had a higher prevalence of hypertension, atrial fibrillation, history of previous hospitalization for heart failure, and baseline creatinine, and a lower prevalence of diabetes than the non-hyperuricemia group, but the proportion of men and age were similar between the two groups. The incidence of MACE in the hyperuricemia group was significantly higher than that in the non-hyperuricemia group (13.1 vs. 6.4%, log-rank P < 0.001). Multivariable Cox regression analyses revealed that hyperuricemia was significantly associated with increased MACE [hazard ratio (HR), 1.52; 95% confidential interval (CI), 1.23-1.86] after multiple adjustments for age, sex, body mass index, estimated glomerular filtration rate, left main disease or three-vessel disease, hypertension, diabetes mellitus, dyslipidemia, history of myocardial infarction, and history of hospitalization for heart failure. Moreover, hyperuricemia was independently associated with increased hospitalization for heart failure (HR, 2.19; 95% CI, 1.69-2.83), but not cardiovascular death or myocardial infarction after multiple adjustments. Sensitive analyses by sex and diuretic use, B-type natriuretic peptide level, and left ventricular ejection fraction showed similar results. CONCLUSION: CLIDAS revealed that hyperuricemia was associated with increased MACE in patients with CCS after PCI. Further clinical trials are needed whether treating hyperuricemia could reduce cardiovascular events or not.

OBJECTIVES: One of the most significant features of poor prognosis in COVID-19 is pulmonary fibrosis. Nintedanib is a new antifibrotic agent that interferes with processes of pulmonary fibrosis. This study aimed to investigate the efficacy and safety of nintedanib in COVID-19. METHODS: This was an interventional study in which adult patients with COVID-19 requiring mechanical ventilation were consecutively enrolled. The primary endpoint was 28-day mortality after the initiation of mechanical ventilation. The secondary endpoints were length of mechanical ventilation, volume of lung injury, and the incidence of gastrointestinal adverse events and acute liver failure. RESULTS: Thirty patients with COVID-19 underwent nintedanib therapy. We included 30 patients not receiving nintedanib as the historical control group. There were no significant differences in 28-day mortality between the groups (23.3% vs 20%, P = 0.834). Lengths of mechanical ventilation were significantly shorter in the nintedanib group (P = 0.046). Computed tomography volumetry showed that the percentages of high-attenuation areas were significantly lower in the nintedanib group at liberation from mechanical ventilation (38.7% vs 25.7%, P = 0.027). There were no significant differences in the adverse events. CONCLUSIONS: The administration of nintedanib may offer potential benefits for minimizing lung injury in COVID-19.

Recently, a high urinary sodium-to-potassium (Na/K) ratio and reduced sleep efficiency, in addition to conventional risk factors (obesity and excess alcohol intake), have been identified as risk factors for hypertension. We estimated the population attributable fraction (PAF) for home hypertension due to these risk factors in a general Japanese population. We conducted a cross-sectional study including 1384 participants (393 men and 991 women) to estimate the odds ratio (OR) and 95% confidence interval (CI) for the presence of any of the conventional risk factors using multivariable logistic regression analyses. The models were adjusted for sex, age, smoking status, and log-transformed average daily steps. We also estimated the OR and 95% CI for the presence of any of the overall risk factors. Furthermore, we calculated the PAF due to these risk factors. The results showed that the prevalence of home hypertension was 39.0% (540/1384). The presence of any of the conventional risk factors, as well as any of the overall risk factors, was significantly associated with an increased prevalence of hypertension (OR 2.80, 95% CI 2.15-3.65; OR 2.50, 95% CI 1.93-3.22, respectively). The PAF for hypertension due to the presence of any of the conventional risk factors and the PAF due to the presence of any of the overall risk factors were 30.2% and 39.0%, respectively. In conclusion, the impact of the overall risk factors, including the urinary Na/K ratio and sleep efficiency, on home hypertension was higher than that of conventional risk factors alone. The management of the urinary Na/K ratio and sleep efficiency as well as conventional risk factors might be important in the management of blood pressure.

BACKGROUND: Few risk models are available to predict future onset of atrial fibrillation (AF) in workers. We aimed to develop risk prediction models for new-onset AF, using annual health checkup (HC) data with electrocardiogram findings. METHODS AND RESULTS: We retrospectively included 56,288 factory or office workers (mean age = 51.5 years, 33.0% women) who underwent a HC at a medical center and fulfilled the following criteria; age ≥ 40 years, no history of AF, and greater than 1 annual follow-up HC in 2013-2016. Using Cox models with the Akaike information criterion, we developed and compared prediction models for new-onset AF with and without the Minnesota code information. We externally validated the discrimination accuracy of the models in a general Japanese population cohort, the Hisayama cohort. During the median 3.0-year follow-up, 209 (0.37%) workers developed AF. Age, sex, waist circumference, blood pressure, LDL cholesterol, and γ-GTP were associated with new-onset of AF. Using the Minnesota code information, the AUC significantly improved from 0.82 to 0.84 in the derivation cohort and numerically improved from 0.78 to 0.79 in the validation cohort, and from 0.77 to 0.79 in the Hisayama cohort. The NRI and IDI significantly improved in all and male subjects in both the derivation and validation cohorts, and in female subjects in both the validation and the Hisayama cohorts. CONCLUSIONS: We developed useful risk model with Minnesota code information for predicting new-onset AF from large worker population validated in the original and external cohorts, although study interpretation is limited by small improvement of AUC.

The purpose of this study was to assess whether high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-brain natriuretic peptide (NT-proBNP), and soluble urokinase plasminogen activator receptor (suPAR) differed in their ability to predict cardiovascular outcomes beyond traditional risk factors in younger and older men and women without known cardiovascular disease. Design. Prospective population-based cohort study of 1951 individuals from the MONItoring of trends and determinants in Cardiovascular disease (MONICA) study, examined 1993-1994. Participants were stratified into four groups based on sex and age. Subjects aged 41 or 51 years were classified as younger; those aged 61 or 71 years were classified as older. The principal endpoint was death from cardiovascular causes. Predictive capabilities of biomarkers were tested using Cox proportional-hazards regression, Harrell's concordance-index, net reclassification improvement, and classification and regression tree (CART) analysis. Results. Median follow-up was 18.5 years, during which 19/597 younger men, 100/380 older men, 12/607 younger women, and 46/367 older women had died from a cardiovascular cause. NT-proBNP was independently associated with death from cardiovascular causes among all participants (p ≤ .02) except younger women (p = .70), whereas hs-CRP was associated with this endpoint in men (p ≤ .007), and suPAR in older men only (p < .001). None of the biomarkers improved discrimination ability beyond traditional risk factors (p ≥ .07). However, NT-proBNP enhanced reclassification in men and older women. CART-analysis showed that NT-proBNP was generally of greater value among men, and suPAR among women. Conclusions. Hs-CRP, NT-proBNP, and suPAR displayed different associations with cardiovascular death among apparently healthy younger and older men and women.

AIMS: Prognostic impacts of serum uric acid (UA) levels in patients with chronic heart failure (CHF) remain inconclusive, especially for the whole range of serum UA levels. METHODS AND RESULTS: In the Chronic Heart Failure Registry and Analysis in the Tohoku District-2 (CHART-2) study, we enrolled 4652 consecutive patients with CHF and classified them into four groups based on baseline serum UA levels by the Classification and Regression Tree: G1 (<3.8 mg/dL, N = 313), G2 (3.8-7.1 mg/dL, N = 3070), G3 (7.2-9.2 mg/dL, N = 1018), and G4 (>9.2 mg/dL, N = 251). Mean age was 71 ± 12, 69 ± 12, 68 ± 13, and 69 ± 15 years in G1, G2, G3, and G4, respectively (P < 0.001). During the median follow-up of 6.3 years, in G1, G2, G3, and G4, 111 (35%), 905 (29%), 370 (36%), and 139 (55%) patients died and 79 (25%), 729 (24%), 300 (29%), and 115 (46%) experienced heart failure hospitalization, respectively (both P < 0.001). G1 was characterized by a significantly high prevalence of women as compared with G2, G3, and G4 (59%, 32%, 24%, and 23%, respectively). Serum creatinine levels (0.8 ± 0.4, 0.9 ± 0.4, 1.2 ± 0.6, and 1.4 ± 0.8 mg/dL, respectively), prevalence of atrial fibrillation (34%, 39%, 45%, and 50%, respectively), and diuretics use (36%, 45%, 67%, and 89%, respectively) increased from G1, G2, G3 to G4 (all P < 0.001), while left ventricular ejection fraction decreased from G1, G2, G3 to G4 (59 ± 15, 58 ± 15, 54 ± 15, and 52 ± 17%, respectively, P < 0.001). Multivariable Cox proportional hazards models showed that, as compared with G2, both G1 and G4 had increased incidence of all-cause death [adjusted hazard ratio (aHR) 1.34, 95% confidence interval (CI) 1.08-1.67, P = 0.009; aHR 1.28, 95% CI 1.02-1.61, P = 0.037, respectively] and heart failure admission (aHR 1.39, 95% CI 1.09-1.78, P = 0.008 and aHR 1.35, 95% CI, 1.06-1.71, P = 0.014, respectively). This U-shaped relationship was evident in the elderly patients. Furthermore, abnormal transitions to either higher or lower levels of serum UA from G2 were associated with increased mortality (aHR 1.29, 95% CI 1.06-1.57, P = 0.012; aHR 1.57, 95% CI 1.12-2.20, P = 0.009). CONCLUSIONS: These results demonstrate that serum UA levels have the U-shaped prognostic effects and abnormal transitions to either higher or lower levels are associated with poor prognosis in the elderly patients with CHF.

Arterial stiffness is increased with increasing age, and pulse pressure (PP), a marker of arterial stiffness, is a predictor of incident cardiovascular disease and mortality. However, the prognostic relevance of PP in heart failure (HF) with preserved ejection fraction has not been fully understood. We studied 4796 patients with HF with preserved ejection fraction from the PARAGON-HF trial. All patients underwent sequential run-in phases of valsartan and sacubitril/valsartan before randomization. We categorized patients by PP quartile and evaluated the influence of baseline PP on the PARAGON-HF primary end point (total HF hospitalizations and cardiovascular death). At screening, the median PP was 58 mm Hg (interquartile range, 50-69 mm Hg). There was a nonlinear, J-shaped association between PP and outcomes. Multivariable Cox proportional hazards models showed that patients in the highest PP quartile had a higher risk of the primary end point (adjusted hazard ratio, 1.39 [95% CI, 1.14-1.69]; P=0.001), total HF hospitalizations (adjusted hazard ratio, 1.43 [95% CI, 1.15-1.79]; P=0.001), and myocardial infarction (adjusted hazard ratio, 1.54 [95% CI, 1.06-2.23]; P=0.022) compared with those in the second (lowest risk) PP quartile. Reductions in PP during sacubitril/valsartan run-in were associated with a decreased risk of the primary end point and total HF hospitalizations. One year after randomization, PP was significantly lower in the sacubitril/valsartan group compared with the valsartan group (3.0 mm Hg decrease [95% CI, 2.4-3.5]; P<0.001). In conclusion, PP was an independent predictor of cardiovascular events in patients with HF with preserved ejection fraction enrolled in PARAGON-HF. Sacubitril/valsartan lowered PP compared with valsartan.

BACKGROUND: We established a community-based cohort study to assess the long-term impact of the Great East Japan Earthquake on disaster victims and gene-environment interactions on the incidence of major diseases, such as cancer and cardiovascular diseases. METHODS: We asked participants to join our cohort in the health check-up settings and assessment center based settings. Inclusion criteria were aged 20 years or over and living in Miyagi or Iwate Prefecture. We obtained information on lifestyle, effect of disaster, blood, and urine information (Type 1 survey), and some detailed measurements (Type 2 survey), such as carotid echography and calcaneal ultrasound bone mineral density. All participants agreed to measure genome information and to distribute their information widely. RESULTS: As a result, 87,865 gave their informed consent to join our study. Participation rate at health check-up site was about 70%. The participants in the Type 1 survey were more likely to have psychological distress than those in the Type 2 survey, and women were more likely to have psychological distress than men. Additionally, coastal residents were more likely to have higher degrees of psychological distress than inland residents, regardless of sex. CONCLUSION: This cohort comprised a large sample size and it contains information on the natural disaster, genome information, and metabolome information. This cohort also had several detailed measurements. Using this cohort enabled us to clarify the long-term effect of the disaster and also to establish personalized prevention based on genome, metabolome, and other omics information.

AIMS: We aimed to examine temporal changes in left ventricular (LV) structures and their prognostic impacts in patients with heart failure (HF) and preserved ejection fraction (HFpEF). METHODS AND RESULTS: In the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) study (n = 10 219), we divided 2698 consecutive HFpEF patients (68.9 ± 12.2 years, 32.1% female) into three groups by LV hypertrophy (LVH) and enlargement (LVE) at baseline: (-)LVH/(-)LVE (n = 989), (+)LVH/(-)LVE (n = 1448), and (+)LVH/(+)LVE (n = 261). We examined temporal changes in LV structures and their prognostic impacts during a median 8.7-year follow-up. From (-)LVH/(-)LVE, (+)LVH/(-)LVE to (+)LVH/(+)LVE at baseline, the incidence of the primary outcome, a composite of cardiovascular death or HF admission, significantly increased. Among 1808 patients who underwent echocardiography at both baseline and 1 year, we noted substantial group transitions from baseline to 1 year; the transition rates from (-)LVH/(-)LVE to (+)LVH/(-)LVE, from (+)LVH/(-)LVE to (-)LVH/(-)LVE, from (+)LVH/(-)LVE to (+)LVH/(+)LVE, and from (+)LVH/(+)LVE to (+)LVH/(-)LVE were 27% (182/671), 22% (213/967), 6% (59/967), and 26% (44/170), respectively. In the univariable Cox proportional hazard model, patients who transitioned from (+)LVH/(-)LVE to (+)LVH/(+)LVE or remained in (+)LVH/(+)LVE had the worst subsequent prognosis [hazard ratio (HR) 4.65, 95% confidence interval (CI) 3.09-6.99, P < 0.001; HR 4.01, 95% CI 2.85-5.65, P < 0.001, respectively], as compared with those who remained in (-)LVH/(-)LVE. These results were unchanged after adjustment for the covariates including baseline LV ejection fraction (LVEF) and 1-year LVEF change. CONCLUSION: In HFpEF patients, LV structures dynamically change over time with significant prognostic impacts, where patients who develop LVE with LVH have the worst prognosis.

OBJECTIVES: We aimed to test our hypothesis that additional administration of traditional Japanese (Kampo) medicine, kakkonto (kakkon-to: KT) and shosaikotokakikyosekko (sho-saiko-to-ka-kikyo-sekko: SSKKS), is more effective in relieving symptoms and preventing the onset of severe infection in mild-to-moderate COVID-19 patients compared to those treated only with conventional treatment. TRIAL DESIGN: The study is designed as a multi-center, interventional, parallel-group, randomized (1:1 ratio), investigator-sponsored, two-arm study. PARTICIPANTS: Patients and inpatients will be recruited from 8 Japanese academic and non-academic hospitals. The inclusion and exclusion criteria are as follows: Inclusion criteria: 1. Diagnosed as positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 2. Clinical stages of mild-to-moderate COVID-19 3. Symptomatic 4. ≥ 20 years of age 5. Male or female 6. Ability to communicate in Japanese 7. Outpatients and inpatients 8. Provided informed consent Exclusion criteria: 1. Difficulty in providing informed consent due to dementia, psychosis, or psychiatric symptoms 2. Allergic to Kampo or Western medicines used in this study 3. Pregnant and lactating 4. Unable to follow up 5. Participating in another clinical trial or interventional study 6. Hypokalemic or taking oral furosemide or steroids 7. Determined unsuitable for this study by the physician INTERVENTION AND COMPARATOR: Patients in the control group will receive conventional treatment with antipyretics, painkillers, or antitussives for symptoms that occurred after they contracted the SARS-CoV-2 infection. Patients in the Kampo group will receive 2.5 g of KT (TJ-1@TSUMURA and Co.) and 2.5 g of SSKKS (TJ-109@TSUMURA and Co.) 3 times a day, orally, for 14 days in addition to the conventional treatment as mentioned above. MAIN OUTCOMES: The number of days till at least one of the symptoms (fever, cough, sputum, malaise, shortness of breath) improves in the first 14 days of treatment. To assess the cough, sputum, malaise, and shortness of breath, a numeric rating scale will be used to define improvement in terms of a 2-point decrease in the number of days from the start of treatment for at least 2 days. Fever will be defined as an improvement when the temperature is less than 37 °C. RANDOMIZATION: Patients are randomized (1:1 ratio) to each group using the minimization method, with balancing of the arms with severity of disease stage and patient age (< 65, 65 to < 75, or ≥ 75 years). Computer-generated random numbers will be used for the minimization method. BLINDING (MASKING): Open-label with no blinding NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): The main research hypothesis of this study is that the combination of Kampo medicine and conventional treatment will significantly improve the patients' symptoms (fever, fatigue, cough, sputum, and shortness of breath) during the first 14 days of treatment as compared with conventional treatment alone. Concerning the analysis of the primary endpoint, the duration of time before improvement of at least one of the common cold-like symptoms (fever, malaise, cough, sputum, and shortness of breath) will be estimated using the Kaplan-Meier method, and the survival curves will be compared between groups using the log-rank test. Assuming this method of analysis and based on previous studies reporting the efficacy of Kampo medicine for COVID-19 and H1N1 influenza patients, the median survival time in the Kampo medicine group is estimated as 3 days; this time will be 1.5 times longer in the control group. Assuming a one-sided significance level of 5%, a power of 70%, and an allocation ratio of 1:1, the required sample size is calculated as 126 cases. To compensate for a loss in follow-up, we plan to include 150 cases in both groups (Kampo group = 75, control group = 75). TRIAL STATUS: Protocol version 1.2 as of August 20, 2020 Recruitment start (expected): October 1, 2020 Recruitment finish (expected): October 31, 2023 TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) jRCTs021200020 . Registered on August 25, 2020 FULL PROTOCOL: The full protocol is attached as an additional file and is accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

BACKGROUND: Although balloon pulmonary angioplasty (BPA) improves symptoms and pulmonary hemodynamics in patients with chronic thromboembolic pulmonary hypertension (CTEPH), the effects of riociguat on hemodynamics and exercise capacity in patients after BPA remain to be elucidated. METHODS AND RESULTS: This study was a single-center, prospective, randomized, open-label trial. From November 2015 to November 2018, we prospectively examined 21 patients with CTEPH (65 ± 9 years old, M/F 2/19) who showed hemodynamic improvement with mean pulmonary arterial pressure (mPAP) < 30 mmHg after BPA without any vasodilators. We performed hemodynamic evaluation and expired gas analysis both at rest and during exercise in supine position using cycle ergometer. After right heart catheterization during exercise, they were randomly assigned to 2 groups with minimized method, using age, sex, and resting mPAP; riociguat (N = 10) and control (N = 11) groups. After 6 months, exercise capacity evaluated by 6-min walk distance and cardiopulmonary exercise testing, and resting hemodynamic parameters were comparable in both groups. However, cardiac output (CO) (6.0 ± 1.7-7.4 ± 1.6, P < 0.01) and pulmonary vascular resistance (4.8 ± 1.8-3.2 ± 0.7 Wood units, P = 0.02) at peak workload were significantly improved in the riociguat group as compared with the control group. The slope of linearized mPAP-CO relationship was significantly decreased in the riociguat group [14.5 (7.8, 14.7) to 6.41 (5.1, 11.4), P < 0.01] but not in the control group. CONCLUSIONS: These results indicate that riociguat exerts beneficial effects on hemodynamic response to exercise in CTEPH patients even after hemodynamic improvement by BPA.

AIMS: Asymptomatic patients with structural heart diseases are classified as a population at high risk for heart failure (HF) in Stage B. However, limited data are available regarding incidence and related factors of de-novo HF (DNHF) considering competing risk in this population. METHODS AND RESULTS: In 3362 Stage B patients (mean age 68 yrs, male 76%) from the CHART-2 Study (N = 10,219), we examined incidence of death and DNHF, defined as the first episode of either HF hospitalization or HF death, and factors related to DNHF. RESULTS: During the median 6.0-year follow-up, 627 deaths (31/1000 person-years) and 293 DNHF (15/1000 person-years) occurred. Among the 627 deaths, 212 (34%) and 325 (52%) were specified as cardiovascular and non-cardiovascular deaths, respectively. During the follow-up of 271 DNHF hospitalizations, we observed 124 deaths, including 65 (52%) cardiovascular and 47 (40%) non-cardiovascular deaths. The competing risk model showed that age, diabetes mellitus, stroke, atrial fibrillation, diastolic blood pressure, hemoglobin levels, estimated glomerular filtration ratio and left ventricular ejection fraction was significantly associated with DNHF. Bayesian structural equation modeling showed that many of these cardiac and non-cardiac variables contribute to DNHF by affecting each other, while diabetes mellitus was independently associated with DNHF. CONCLUSIONS: Stage B patients had a high incidence of DNHF as well as that of death due to both cardiovascular and non-cardiovascular causes. Thus, management of Stage B patients should include multidisciplinary approaches considering both cardiac and non-cardiac factors, in order to prevent DNHF as well as non-HF death as a competing risk. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00418041.

Many echocardiographic measures have been proposed as potential predictors of outcome following ST-elevation myocardial infarction (STEMI). We hypothesized that combining multiple echocardiographic measures in a risk model provides more prognostic information than individual echocardiographic measures. We prospectively included 373 STEMI patients which constituted our derivation cohort. We also identified 298 STEMI patients from a clinical registry that constituted our validation cohort. Echocardiogram was performed at a median of 2 days after infarction. The echocardiogram consisted of conventional and advanced measures. The end point was a composite of heart failure and/or cardiovascular death. During a median follow-up of 5.4 years, we observed 80 events in our derivation cohort. A stepwise backward Cox regression including all echocardiographic parameters identified global longitudinal strain, wall motion score index (WMSI), E/e', and E/global strain rate e (E/GLSRe) as significant predictors of outcome. A Classification and Regression Tree analysis outlined a risk model with WMSI, GLSRe, and E/e' as key echocardiographic parameters. Patients with WMSI ≥ 2.22 were at high risk, patients with WMSI < 2.22, GLSRe < 0.82s-1 and E/e'≥7.6 at intermediate risk, and patients with WMSI < 2.22 and GLSRe ≥ 0.82s-1 or GLSRe < 0.82s-1 and E/e' < 7.6 at low risk of heart failure and/or cardiovascular death. When compared with the low-risk group, an incremental risk was observed (intermediate group: HR = 2.52 [1.24;5.11], p = 0.011; high-risk group: HR = 4.37 [1.40;13.66], p = 0.011). The risk model was validated in the validation cohort (C-statistic: 0.71). In conclusion, we devised an echocardiographic risk model for STEMI patients suggesting advanced and conventional measures of systolic function and filling pressures to be important for the prognosis.

Physical activity (PA) in the daily life is strongly related to prognosis in patients with or at high risk of heart failure (HF). However, factors limiting habitual exercise and their prognostic impacts remain unknown in HF patients. We sent questionnaires asking factors limiting habitual exercise in the daily life to 8370 patients with Stage A/B/C/D HF in our nationwide registry and received valid responses from 4935 patients (mean age 71.8 years, 71.0% male). Among the 5 components consisting of "busyness", "weak will", "dislike, "socioeconomic reasons" and "diseases" in the questionnaires, "busyness" (34.5%) and "diseases" (34.7%) were the most frequently reported factors limiting habitual exercise, while "socioeconomic reasons" were the least (15.3%). Multiple Cox proportional hazard models indicated that "busyness"and "diseases" were associated with better (hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.39-0.72, P < 0.001) and worse prognosis (HR 1.57, 95% CI 1.21-1.98, P < 0.001), respectively, while other components were not. Furthermore, it was noted that, while prognostic relevance of "busyness" limiting exercise did not differ by age or sex, negative impact of "diseases" was particularly evident in patients with age < 75 years (P for interaction < 0.01). Factors limiting habitual exercise were associated with "busyness" and "diseases", but not with "weak will", "dislike, or "socioeconomic reasons". While "busyness" was associated with better prognosis regardless of age and sex, "diseases" was associated with worse prognosis in younger populations. Thus, physicians may pay more attentions to the reasons that limit exercise in the daily lives of HF patients rather than the low amount of exercise itself.

BACKGROUND: We have recently demonstrated that left ventricular ejection fraction (LVEF) dynamically changes over time with prognostic impacts in Stage C/D patients, namely, those who have a current or past history of heart failure (HF). However, it is unknown whether this is also the case in asymptomatic Stage B patients, namely, those who have a risk of HF, but do not have a history of HF. METHODS: In our CHART-2 Study (N = 10,219), we enrolled 4005 Stage B patients and divided them into 3 groups by LVEF; preserved EF (pEF, LVEF ≥50%, N = 3526), mid-range EF (mrEF, LVEF 41-49%, N = 302), and reduced EF (rEF, LVEF ≤40%, N = 177). We examined the prognostic impacts of LVEF transitions among the 3 groups in comparison with 4477 patients with Stage C/D HF. RESULTS: Stage B were characterized by less severe clinical status and better prognosis compared with Stage C/D. Stage B in mrEF and rEF at baseline dynamically transitioned to other groups at 1-year, whereas those in pEF unchanged; at 1-year, mrEF transitioned to pEF/rEF by 50/16%, and rEF transitioned to pEF/mrEF by 25/31%, respectively, whereas pEF transitioned to mrEF/rEF by only 3.6/0.7%, respectively, which were consistent with findings in findings with Stage C/D. Although LVEF decrease was directly associated with all-cause mortality in both the Stage B and Stage C/D with pEF, factors related to LVEF changes were different between the 2 groups. CONCLUSIONS: In Stage B, LVEF dynamically changes with prognostic impacts as in Stage C/D, whereas different determination factors may be involved in the 2 stages. CLINICAL TRIAL REGISTRATION: Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-2 (NCT00418041).

OBJECTIVE: It remains to be elucidated whether and how endothelial functions are impaired in peripheral circulation of patients with coronary functional disorders, such as vasospastic angina (VSA) and microvascular angina (MVA). We simultaneously examined endothelial functions of peripheral conduit and resistance arteries in patients with coronary functional disorders, with a special reference to NO and endothelium-dependent hyperpolarization factors. Approach and Results: Based on the results of invasive coronary acetylcholine testing and coronary physiological measurements, we divided 43 patients into 3 groups; VSA, MVA, and VSA+MVA. Endothelium-dependent vasodilatations of the brachial artery and fingertip arterioles to intra-arterial infusion of bradykinin were simultaneously evaluated by ultrasonography and peripheral arterial tonometry, respectively. To assess NO and endothelium-dependent hyperpolarization factors, measurements were repeated after oral aspirin and intra-arterial infusion of NG-monomethyl-L-arginine. Additionally, endothelium-independent vasodilatations to sublingual nitroglycerin and plasma levels of biomarkers for endothelial functions were measured. Surprisingly, digital vasodilatations to bradykinin were almost absent in patients with MVA alone and those with VSA+MVA compared with those with VSA alone. Mechanistically, both NO- and endothelium-dependent hyperpolarization-mediated digital vasodilatations were markedly impaired in patients with MVA alone. In contrast, endothelium-independent vasodilatations to nitroglycerin were comparable among the 3 groups. Plasma levels of soluble VCAM (vascular cell adhesion molecule)-1 were significantly higher in patients with MVA alone compared with those with VSA alone. CONCLUSIONS: These results provide the first evidence that both NO- and endothelium-dependent hyperpolarization-mediated digital vasodilatations are markedly impaired in MVA patients, suggesting that MVA is a cardiac manifestation of the systemic small artery disease.

BACKGROUND: Since most of the randomized clinical trials for heart failure (HF) were designed to exclude elderly patients, limited data are available on their clinical characteristics, prognosis, and prognostic factors. METHODS: We compared clinical characteristics, prognosis, and prognostic factors among Stage C/D HF patients in our CHART-2 Study (N = 4876, mean 69 years, women 32%, 6.3-year follow-up) by age (G1, ≤64 years, N = 1521; G2, 65-74 years, N = 1510; and G3, ≥75 years, N = 1845). RESULTS: From G1 to G3, the prevalence of women, left ventricular ejection fraction (LVEF) and plasma levels of B-type natriuretic peptide (BNP) increased (all P < 0.001). Similarly, 5-year mortality increased (9.9, 17.3 to 39.9%, P < 0.001) along with a decrease in proportion of cardiovascular death and an increase in non-cardiovascular death in both sexes. While all-cause and cardiovascular mortality was comparable between the sexes, women had significantly lower incidence of non-cardiovascular death than men in G2 and G3, which was attributable to the higher incidence of cancer death and pneumonia death in men than in women. Although NYHA functional class III-IV, chronic kidney disease, cancer, LVEF, and BNP had significant impacts on all-cause death in all groups, their impacts were less evident in G3 as compared with G1. CONCLUSIONS: The elderly HF patients, as compared with younger HF patients, were characterized by more severe clinical background, increased proportion of non-cardiovascular death and worse prognosis with different impacts of prognostic factors across the age groups.

BACKGROUND: Although cardiac troponin and natriuretic peptide have been shown to decrease after balloon pulmonary angioplasty (BPA) with improved right ventricular afterload in chronic thromboembolic pulmonary hypertension (CTEPH), biomarkers to evaluate the effects of BPA independently of heart failure status remain to be developed. METHODS: In 39 consecutive CTEPH patients including 31 who underwent BPA, we measured plasma levels of cyclophilin A (CyPA), which we demonstrated is secreted from pulmonary vascular smooth muscle cells in response to mechanical stretch and hypoxia. RESULTS: CyPA levels were elevated in CTEPH patients (12.7, IQR: 7.6-16.0) compared with 8 thromboembolic controls with a history of venous thromboembolism (4.9, IQR: 2.4-11.2) or 18 healthy controls (4.1, IQR: 2.4-6.8) (both p< 0.05) and were linearly correlated with mean pulmonary arterial pressure (r=0.50, p = 0.0003) and pulmonary vascular resistance (r=0.32, p= 0.026). BPA reduced CyPA levels and tended to lower brain-type natriuretic peptide (BNP) levels (p< 0.01 and p = 0.07). When comparing the changes in CyPA before and after BPA in the two subgroups with higher (≥35pg/mL) and normal (<35pg/mL) BNP at baseline, CyPA decreased both in patients with higher BNP and those with normal BNP (both p< 0.05). In contrast, BNP decreased only in patients with higher BNP (p< 0.05). Also, CyPA decreased both in patients with lower (<25 kg/m2) and higher (≥25kg/m2) body mass index (BMI) at baseline (both p<0.05), whereas BPA tended to reduce BNP in patients with lower BMI (p = 0.12) but not in those with higher BMI (p = 0.55). CONCLUSIONS: CyPA could be a useful biomarker to evaluate the effects of BPA even in patients with normal BNP or high BMI.

BACKGROUND: The benefits of antithrombotic therapy (ATT) for atrial fibrillation (AF) are occasionally offset by major bleeding complications. However, the clinical benefits and risks of ATT in AF patients, with special references to comorbidities, such as heart failure (HF), coronary artery disease (CAD), and the patterns of AF, remain to be fully elucidated. METHODS: A total of 3221 consecutive AF patients from our Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (N = 10,219) were divided into 4 groups based on ATT at enrollment; no-ATT, anticoagulant alone, antiplatelet alone, and both of them (AC&AP). Then, efficacy and safety outcomes including thromboembolic events, major bleeding, and mortality were evaluated among the 4 groups. RESULTS: Anticoagulant monotherapy was associated with reduced risk of ischemic stroke in patients with but not in those without HF, CAD, or non-paroxysmal AF. Although there was no significant difference in major bleeding among the 4 groups, a composite of thromboembolism and major bleeding occurred more frequently in the AC&AP group, even in combination with anticoagulants and single antiplatelet therapy, indicating that the combination therapy is more harmful than anticoagulant monotherapy for AF patients, especially for those with HF or CAD. Lastly, no-ATT group was associated with worse prognosis compared with other 3 groups. CONCLUSIONS: These results indicate that ATT is beneficial for AF patients particularly for those with HF, CAD, or non-paroxysmal AF and that among ATT, anticoagulant monotherapy may be most profitable for both clinical benefits and risks for AF patients.

Few studies have reported the relationship between reduced sleep efficiency and the prevalence of hypertension independent of sleep duration in Japan. This study aimed to evaluate whether reduced sleep efficiency, measured using an objective device for >1 week, was related to an increased prevalence of hypertension independent of sleep duration in the general Japanese population. We conducted a cross-sectional study of 904 participants aged ≥20 years who lived in Miyagi Prefecture, Japan. Sleep efficiency was measured using a contactless biomotion sleep sensor for 10 continuous days. The participants were classified into two groups according to their sleep efficiency: reduced (<90%) or not reduced (≥90%). Hypertension was defined as morning home blood pressure ≥135/85 mmHg or self-reported treatment for hypertension. Multivariable logistic regression models were used to obtain odds ratios (ORs) and 95% confidence intervals (CIs) to assess the relationship between sleep efficiency and hypertension adjusted for potential confounders. The results showed that two hundred and ninety-four individuals (32.5%) had reduced sleep efficiency, and 331 (36.6%) had hypertension. Individuals with reduced sleep efficiency had a higher body mass index and shorter sleep duration. In the multivariable analysis, reduced sleep efficiency was significantly related to an increased prevalence of hypertension (OR, 1.62; 95% CI, 1.15-2.28). In conclusion, reduced sleep efficiency was significantly related to an increased prevalence of hypertension in Japanese adults. Improvements in sleep efficiency may be important to reduce blood pressure in Japanese adults.

Background and study aims  Intestinal stricture associated with Crohn's disease (CD) is usually treated by endoscopic balloon dilation (EBD) or stricture plasty. Although EBD is effective and safe for such strictures, refractory stricture after EBD poses a problem. Hence, other novel approaches for these refractory strictures are required. On the other hand, the efficacy of radial incision and cutting (RIC) method for esophageal stricture after esophagogastric surgery is reported. In this pilot study, we adopted the RIC technique for five CD patients with refractory intestinal stricture to dilate their strictures. We conducted the RIC procedure using an electric needle knife with a ceramic tip on the top of the needle. Four cases were of anastomotic stricture after ileocecal resection and the remaining one case was of stricture due to mucosal healing. The RIC procedure was successful for all five patients. Average procedure time was 18.6 minutes. One patient developed delayed bleeding after RIC. There were no cases of perforation. RIC could be an alternative therapy for intestinal stricture associated with CD. Further studies should be conducted to clarify its efficacy and safety.

AIMS: The study aims to evaluate the prognostic significance of impaired glucose tolerance (IGT) with reference to albuminuria in patients with chronic heart failure (CHF). METHODS AND RESULTS: We examined 535 CHF patients (mean 66 years, women 25%) in the control arm of our SUPPORT trial, in which we examined additive impact of olmesartan in hypertensive patients with symptomatic CHF treated with β-blockers and/or angiotensin-converting enzyme inhibitors. We examined the association between glycaemic abnormality (assessed by 75 g of oral glucose tolerance test) and albuminuria for a composite outcome of all-cause death, myocardial infarction, stroke, and HF hospitalization. IGT patients (N = 113, mean 67.2 years) were older and more frequently treated with β-blockers compared with those with normal glucose regulation (N = 142, mean 64.0 years) and those with diabetes mellitus (N = 280, mean 65.7 years). Multivariable Cox proportional hazard models revealed that, as compared with normal glucose regulation (NGR), IGT was associated with increased risk of the outcome when complicated by albuminuria [hazard ratio (HR) 2.25; 95% confidence interval (CI) 1.14-4.42; P = 0.019] but not when uncomplicated by albuminuria (HR 0.76; 95% CI 0.35-1.60, P = 0.47) (P for interaction = 0.041). This was also the case for diabetes mellitus and albuminuria (HR 2.06; 95% CI 1.17-3.61; P = 0.012). Among IGT patients without albuminuria, 21 (29%) developed albuminuria at 1-year visit, which was again associated with poor prognosis (HR 7.36; 95% CI 1.39-38.98, P = 0.019). CONCLUSIONS: These results indicate that IGT is associated with poor prognosis when complicated by albuminuria in CHF patients, demonstrating the importance of combined early stages of glucose intolerance and renal dysfunction in the management of CHF.

OBJECTIVE: Anaphylaxis is a common, serious, systemic allergic reaction. In the United States, the change of annual hospitalization rates by anaphylaxis-trigger foods and risk factors associated with severity remain unclear. METHODS: Hospital discharge records of food-induced anaphylactic reactions of individuals younger than 20 years were obtained from Kids' Inpatient Database in 2006, 2009, and 2012 and were weighted to estimate the number of hospitalizations in the United States. We identified annual hospitalization rates by patients' characteristics and anaphylaxis-trigger foods and investigated factors associated with severity and use of mechanical ventilation with multivariable logistic regression. RESULTS: A total of 3427 hospitalizations were obtained, and annual hospitalization rates showed a significantly increasing trend from 1.2 per 100,000 children in 2006 to 1.5 per 100,000 children in 2012 (P < 0.001). The leading causes of hospitalizations due to food-induced anaphylaxis were peanuts (0.35-0.48 per 100,000 children), tree nuts and seeds (0.20-0.32 per 100,000 children), and milk products (0.09-0.13 per 100,000 children), with significantly increasing trends during 2006-2012. Milk products were significantly associated with severity (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.3-2.9). Ages between 13 and 20 years (OR, 2.7; 95% CI, 1.4-5.1) and comorbidity of asthma (OR, 2.1; 95% CI, 1.3-3.4) were significantly associated with the use of mechanical ventilation. CONCLUSIONS: The annual hospitalization rates in the entire United States showed an increasing trend during 2006-2012. The rates of peanuts, tree nuts and seeds, and milk products demonstrated upward trends. Milk products, ages between 13 and 20 years, and comorbidities of asthma were related to severity and morbidity.

BACKGROUND: Several studies have reported that C-reactive protein (CRP), an inflammatory biomarker, predicts cardiovascular events independently of low-density lipoprotein cholesterol levels. However, no study examined whether temporal changes in CRP levels are associated with clinical events in patients with previous myocardial infarction (MI). METHODS AND RESULTS: We examined 2184 consecutive patients with previous MI and CRP data at baseline in the Chronic Heart Failure Registry and Analysis in the Tohoku district-2 (CHART-2) Study. During the median 6.4 years follow-up, 592 all-cause, 245 cardiovascular, and 273 non-cardiovascular deaths occurred. Patients with CRP ≥ 2.0 mg/L at baseline had significantly increased incidence of all-cause (hazard ratio (HR) 1.68, P < 0.001) and non-cardiovascular death (HR 1.86, P < 0.001), compared with those with CRP < 2.0 mg/L. Temporal changes in CRP levels were associated with prognosis; among patients with CRP ≥ 2.0 mg/L at baseline, those with CRP ≥ 2.0 mg/L at 1-year had significantly increased incidence of all-cause (HR 2.12, P < 0.001), cardiovascular (HR 2.31, P < 0.001), and non-cardiovascular death (HR 2.29, P < 0.001). Among patients with CRP < 2.0 mg/L at baseline, those with CRP ≥ 2.0 mg/L at 1-year had significantly increased incidence of all-cause (HR 1.76, P < 0.001) and cardiovascular death (HR 2.10, P = 0.001). These results remained significant after adjusted with the inverse probability of treatment weighted models using propensity sore. Furthermore, as compared with patients with CRP < 2.0 mg/L at both baseline and 1-year, those with CRP ≥ 2.0 mg/L at both baseline and 1-year had increased incidence of all-cause, cardiovascular, and non-cardiovascular death. CONCLUSIONS: These results provide the evidence that temporal increases in CRP levels are associated with increased clinical events in patients with previous MI.

BACKGROUND: Although several factors, including heart failure (HF) and inflammation, are known to increase the incidence of cancer, it remains unknown whether HF may increase cancer mortality, especially with a reference to inflammation. METHODS AND RESULTS: We examined 8843 consecutive cardiovascular patients without a prior history of cancer in our CHART-2 Study (mean 68 yrs., female 30.9%). As compared with patients without HF (Stage A/B, N = 4622), those with HF (Stage C/D, N = 4221) were characterized by higher prevalence of diabetes, previous myocardial infarction, atrial fibrillation, and stroke. During the median 6.5-year follow-up (52,675 person-years), 282 cancer deaths occurred. HF patients had significantly higher cancer mortality than those without HF in both the overall (3.7 vs, 2.8%, hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.12-1.79, P = 0.004) and the propensity score-matched cohorts (HR 1.46, 95%CI 1.10-1.93, P = 0.008), which was confirmed in the competing risk models. The multivariable Cox proportional hazard model in the matched cohort showed that HF was associated with increased cancer mortality in patients with C-reactive protein (CRP) ≥ 2.0 mg/L (HR 1.87, 95%CI 1.18-2.96, P = 0.008) at baseline, but not in those with CRP < 2.0 mg/L (HR 0.89, 95%CI 0.54-1.45, P = 0.64) (P for interaction = 0.03). Furthermore, temporal changes in CRP levels were associated with cancer death in the overall cohort; HF patients with CRP ≥ 2.0 mg/L at both baseline and 1-year had significantly increased cancer death, while those with CRP ≥ 2.0 mg/L at baseline and < 2.0 mg/L at 1-year not. CONCLUSIONS: These results provide the first evidence that HF is associated with increased cancer death, especially when associated with prolonged inflammation.

BACKGROUND: Few simple risk models, without echocardiography have been developed for patients with heart failure (HF) and preserved left ventricular ejection fraction (LVEF) (HFpEF). METHODS: To develop a risk score to predict all-cause death for HFpEF patients, we examined 1277 HF patients with LVEF ≥50% and BNP ≥100 pg/ml in the CHART-2 Study, a large-scale prospective cohort study for HF in Japan. We selected the optimal subset of covariates for the score with Cox proportional hazard models and random survival forests (RSF). RESULTS: During the median 5.7-year follow-up, 576 deaths occurred. Cox models and RSF analyses consistently indicated age ≥75 years, albumin <3.7 g/dl, anemia, BMI <22 kg/m2, BNP ≥300 pg/ml (or NT-proBNP ≥1400 pg/ml), and BUN ≥25 mg/dl, as the important 6 prognostic variables. Incorporating these 6 variables, we developed a scoring system (3A3B score, with 2 points given to age ≥75 years and 1 point to the others based on the hazard ratios. The discrimination ability of the risk score was excellent (c-index 0.708). Regarding model goodness-of-fit, the overall gradient in 5-year risk was well captured by the score. The predictive accuracy of the 3A3B score was confirmed in the external validation cohorts from the TOPCAT trial (N = 835, c-index 0.652) and the ASIAN-HF registry (N = 170, c-index 0.741). CONCLUSIONS: We developed a simple risk score to predict long-term prognosis of HFpEF patients. The 3A3B score, comprising 6 commonly available parameters in daily practice, has potential utility in the risk stratification and management of HFpEF patients.

BACKGROUND: Self-care behaviors (ScB) are associated with symptoms and outcomes in patients with heart failure (HF). However, little is known about gender differences in the prognostic relevance of ScB in HF patients. METHODS: We examined gender differences in ScB of HF patients regarding its prognostic associations with mortality and HF hospitalization with a reference to ScB dimensions. The European Heart Failure Self-Care Behavior Scale (EHFScBS) was used to evaluate ScB in 2233 patients with Stage C/D HF in the CHART-2 Study. RESULTS: Male patients (n=1583) were younger (71 vs. 73 yrs) and had lower ScB (median 33 vs. 31) (all p<0.001) than females (n=650). During the median follow-up of 2.57 years, patients with high ScB (score 12-32, n=1090), as compared with low ScB patients (score 33-60, n=1143), had significantly increased all-cause mortality in males [adjusted hazard ratio (aHR) 1.44, p=0.02] but not in females (aHR 0.80, p=0.40) (p for interaction 0.02), while ScB was not significantly associated with incidence of HF hospitalization in both genders. Among the 3 dimensions in EHFScBS, complying with regimen was associated with decreased mortality in females, but not in males (p for interaction 0.003), while asking for help was related with increased incidence of HF hospitalization in males (aHR 1.34, p=0.072) but not in females (aHR 0.98, p=0.931) (p for interaction 0.048). CONCLUSIONS: There were gender differences in the prognostic relevance of self-care with mortality and incidence of HF hospitalization, suggesting that self-care should be implemented considering gender differences to improve prognosis.

Objective- Secondary prevention for recurrent myocardial infarction (MI) is one of the most important therapeutic goals in patients with old MI (OMI). Although statins are widely used for this purpose, there remains considerable residual risk even after LDL (low-density lipoprotein cholesterol) is well controlled by statins. Approach and Results- We examined clinical impacts of nHDL (nonhigh-density lipoprotein cholesterol) and its major components triglyceride and LDL as residual risks for acute MI recurrence, using the database of our CHART (Chronic Heart Failure Analysis and Registry in the Tohoku District)-2 Study, the largest-scale cohort study of cardiovascular patients in Japan. We enrolled 1843 consecutive old MI patients treated with statins (mean age 67.3 years, male 19.2%) in the CHART-2 Study. The incidence of recurrent acute MI during the median 8.6-year follow-up was compared among the groups divided by the levels of nHDL (<100, 100-129, and ≥130 mg/dL), LDL (<70, 70-99, and ≥100 mg/dL), triglyceride (<84, 84-149, and ≥150 mg/dL), and combination of LDL and triglyceride. Kaplan-Meier curves and multiple Cox proportional hazards models showed that higher levels of nHDL, but not LDL or triglyceride alone, were associated with higher incidence of recurrent acute MI. Furthermore, higher triglyceride levels were associated with higher incidence of recurrent MI in patients with LDL <100 mg/dL but not in those with LDL ≥100 mg/dL. Conclusions- These results indicate that management of residual risks for acute MI recurrence should include nHDL management considering both LDL and triglyceride in old MI patients under statin treatment. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00418041.

BACKGROUND: Although B-type natriuretic peptide (BNP) and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) are released in equimolar proportions, their values differ depending on clinical conditions. A useful conversion formula between BNP and NT-proBNP remains to be developed for the clinical use. AIM: To develop a conversion formula from BNP to NT-proBNP. METHODS: In the derivation cohort, 923 patients with chronic heart failure, in whom both BNP and NT-proBNP values were available, were enrolled from our SUPPORT (Supplemental Benefit of ARB in Hypertensive Patients with Stable Heart Failure using Olmesartan) trial. The validation cohort included 1154 consecutive patients with or at risk of cardiovascular diseases, in whom both BNP and NT-proBNP values were measured simultaneously at Tohoku University Hospital. We regressed log10 NT-proBNP onto log10 BNP and factors influencing BNP and NT-proBNP values. RESULTS: We adopted the model with the smallest Akaike information criterion consisting of log10 BNP, age, sex, BMI, creatinine clearance (CCr), hemoglobin, and atrial fibrillation (AF). As compared with the previously reported conversion formulas, the present conversion formula utilized non-linear transformation by spline function, and exhibited the strongest correlation between actual and calculated values of NT-proBNP (r = 0.928). The root mean squared error (RMSE) of the present conversion formula was smallest compared with the previously reported conversion formulas, indicating that this formula most effectively converts BNP values to NT-proBNP values. CONCLUSIONS: We have developed a useful conversion formula from BNP to NT-proBNP values, using age, sex, BMI, CCr, hemoglobin, and AF, which could be widely used in daily clinical practice.

BACKGROUND: Complete revascularization with PCI is not always achieved in patients with ischemic HF. Therefore, this study aimed to elucidate the prognostic impact of residual coronary stenosis (RS) after percutaneous coronary intervention (PCI) in patients with ischemic heart failure (HF). METHODS: We analyzed a total of 1307 patients with symptomatic HF and a history of PCI registered in our Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study. RS that was defined as the presence of ≥70% luminal stenosis in major coronary arteries at the last coronary angiography. RESULTS: Among the study population, 851 patients (65.1%) had RS. During a median follow-up period of 3.2 years, patients with RS had higher all-cause mortality than those without it even after propensity score matching (21.9 vs. 11.6%, log-rank P = 0.027). Multivariable Cox hazard analysis also showed the negative impact of RS on all-cause death in ischemic HF patients [hazard ratio (HR):1.62, 95% confidence interval (CI): 1.07-2.46, P = 0.024]. Importantly, when divided all subjects into three subgroups by left ventricular ejection fraction (LVEF) [LVEF < 40% (HFrEF), LVEF 40-49% (HFmrEF), and LVEF ≥ 50% (HFpEF)], inverse probability of treatment weighted method provided a similar result that RS after PCI was an independent risk factor for death in the HFpEF [HR(95%CI); 1.94(1.22-3.09), P < 0.01] and HFmrEF [4.47(1.13-14.98), P < 0.01] groups, but not in the HFrEF group [1.20(0.59-2.43), P = 0.62]. CONCLUSIONS: These results indicate that RS after PCI could aggravate long-term prognosis of ischemic HF patients with moderate- to well-preserved EF, but not those with reduced EF.

Anderson-Fabry disease (AFD) is a rare X-linked disorder caused by deficient activity of the lysosomal enzyme α-galactosidase A (α-GAL A). We herein report 10 cases of AFD in 5 families (3 men and 7 women) that were found to have a specific common mutation in R301Q [G-to-A transition in exon 6 (codon 301) resulting in the replacement of a glutamine with an arginine residue]. We evaluated their clinical characteristics, residual enzymatic activity, and plasma concentrations of globotriaosylsphingosine (Lyso-Gb3). Although all 10 cases had cardiac and renal manifestations in common, their clinical manifestations were markedly divergent despite the same genetic abnormality.

IMPORTANCE: Limited data exist on the prevalence and prognostic importance of right ventricular (RV) dysfunction for heart failure (HF) in the general population. OBJECTIVE: To assess the prevalence of RV dysfunction and its association with HF and mortality in a community-based elderly cohort. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional and time-to-event analysis of participants in the Atherosclerosis Risks in the Community (ARIC), a multicenter, population-based cohort study at the fifth study visit from 2011 to 2013, with a median follow-up of 4.1 years. This study included 1004 elderly participants in the ARIC study attending the fifth study visit who underwent both 3-dimensional and 2-dimensional RV echocardiography. Three-dimensional echocardiography data were analyzed between September 15, 2015, and July 24, 2016. EXPOSURES: Right ventricular ejection fraction (RVEF), RV-pulmonary artery (PA) coupling defined by the RVEF/PA systolic pressure (PASP) ratio, and RV longitudinal strain by 3-dimensional echocardiography. MAIN OUTCOMES AND MEASURES: For cross-sectional analysis, the prevalence of RV dysfunction across ACCF/AHA HF stages (0; A, at elevated risk for HF but without structural heart disease or clinical HF; B, structural heart disease but without clinical HF; and C, prevalent HF). For time-to-event analysis, a composite of incident HF hospitalization or all-cause death among participants free of HF at visit 5. RESULTS: Of the 1004 participants, mean (SD) age was 76 (5) years, 385 were men (38%), and 121 were black (12%). Mean (SD) RVEF was 53% (8%). Right ventricular EF, RVEF/PASP, and RV longitudinal strain were each progressively lower across advancing HF stages. Using reference limits from stage 0 participants, RVEF was abnormal in 103 asymptomatic persons with stage A HF (15%) and 27 with stage B HF (24%). Among participants free of HF at baseline, lower RVEF and worse RV-PA coupling (ie, lower RVEF/PASP ratio) both were associated with incident HF or death independent of LVEF and N-terminal pro b-type natriuretic peptide (hazard ratio, 1.20; 95% CI, 1.02-1.42 per 5% decrease in RVEF; P = .03; hazard ratio, 1.65, 95% CI, 1.15-2.37 per 0.5 unit decrease in RVEF/PASP ratio; P = .007). CONCLUSIONS AND RELEVANCE: Right ventricular function and RV-PA coupling declined progressively across American College of Cardiology Foundation/American Heart Association HF stages. Among persons free of HF, lower RVEF was associated with incident HF or death independent of LVEF or N-terminal pro b-type natriuretic peptide.

We aimed to compare the usefulness of plasma levels of B-type natriuretic peptide (BNP) for long-term risk stratification among patients with heart failure (HF) with preserved left ventricular ejection fraction (LVEF) (HFpEF), borderline HFpEF, and HF with reduced LVEF (HFrEF) in the same HF cohort. In the CHART-2 Study (N = 10,219), we categorized 4301 consecutive Stage C/D HF patients (mean age 68.7 years, female 32.4%) into 3 groups: HFpEF (LVEF ≥ 50%, N = 2893), borderline HFpEF (LVEF 40-50%, N = 666), and HFrEF (LVEF ≤ 40%, N = 742). During the median 6.3-year follow-up, all-cause deaths occurred in 887 HFpEF, 330 borderline HFpEF, and 330 HFrEF patients. Although median BNP levels increased from HFpEF, borderline HFpEF to HFrEF (85.3, 126 and 208 pg/ml, respectively, P < 0.001), the relationship between log2 BNP levels and the mortality risk was comparable among the 3 groups. As compared with patients with BNP < 30 pg/ml, those with 30-99, 100-299 and ≥ 300 pg/ml had comparably increasing mortality risk among the 3 groups (hazard ratio 2.5, 4.7 and 7.8 in HFpEF, 2.1, 4.2 and 7.0 in borderline HFpEF, and 3.0, 4.7 and 9.5 in HFrEF, respectively, all P < 0.001). BNP levels have comparable prognostic impact among HFpEF, borderline HFpEF, and HFrEF patients.

It is widely known that the incidence of pulmonary arterial hypertension (PAH) is higher in female, whereas prognosis is poorer in male patients. However, sex differences in hemodynamic response to and long-term prognosis with PAH-targeted treatment in the modern era remain to be fully elucidated. We examined the long-term prognosis of 129 consecutive PAH patients (34 males and 95 females) diagnosed in our hospital from April 1999 to October 2014, and assessed hemodynamic changes in response to PAH-targeted therapy. Female patients had better 5-year survival compared with male patients (74.0 vs. 53.4%, P = 0.003); however, higher age quartiles in females were associated with poor outcome. Follow-up examination after medical treatment showed significant decreases in mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and pulmonary arterial capacitance (PAC) in both sexes (both P < 0.05), whereas only females had a significant improvement in right ventricular end-diastolic pressure (RVEDP), right atrial pressure (RAP), cardiac index, and mixed venous oxygen saturation (SvO2) (all P < 0.05). Baseline age significantly correlated with the hemodynamic changes only in female patients; particularly, there were significant sex interactions in RVEDP and RAP (both P < 0.10). The multivariable analysis showed that SvO2 at baseline and mPAP and SvO2 at follow-up were significant prognostic factors in males, whereas the changes in mPAP, PVR, and PAC and use of endothelin-receptor antagonist in females. These results indicate that female PAH patients have better long-term prognosis than males, for which better improvements of right ventricular functions and hemodynamics may be involved.

Home telemonitoring is becoming more important to home medical care for patients with heart failure. Since there are no data on home telemonitoring for Japanese patients with heart failure, we investigated its effect on cardiovascular outcomes. The HOMES-HF study was the first multicenter, open-label, randomized, controlled trial (RCT) to elucidate the effectiveness of home telemonitoring of physiological data, such as body weight, blood pressure, and pulse rate, for Japanese patients with heart failure (UMIN Clinical Trials Registry 000006839). The primary end-point was a composite of all-cause death or rehospitalization due to worsening heart failure. We analyzed 181 recently hospitalized patients with heart failure who were randomly assigned to a telemonitoring group (n = 90) or a usual care group (n = 91). The mean follow-up period was 15 (range 0-31) months. There was no statistically significant difference in the primary end-point between groups [hazard ratio (HR), 0.95; 95% confidence interval (CI), 0.548-1.648; p = 0.572]. Home telemonitoring for Japanese patients with heart failure was feasible; however, beneficial effects in addition to those of usual care were not demonstrated. Further investigation of more patients with severe heart failure, participation of home medical care providers, and use of a more integrated home telemonitoring system emphasizing communication as well as monitoring of symptoms and physiological data are required.

OBJECTIVES: To compare mid-term outcomes between patients undergoing proximal left anterior descending artery (LAD) percutaneous coronary intervention (PCI) with second generation drug-eluting stent (DES) or bare-metal stent (BMS). BACKGROUND: PCI with BMS and first-generation DES have shown to be safe options for the treatment of proximal LAD stenosis, however associated with considerable reintervention rates. Overall, second-generation DES has proven to be superior to BMS and first-generation DES, nevertheless, its effect for proximal LAD PCI has not previously been reported. METHODS: We analyzed 2-year outcomes of 1,100 patients from the BASKET-PROVE I and II trials, referred for proximal LAD PCI with second generation DES (n = 680) or BMS (n = 420). RESULTS: The cumulative 2-year incidence of major adverse cardiac events (MACE, composite of cardiac death, myocardial infarction (MI) and target vessel revascularization (TVR)) was lower in second generation DES than in BMS treated patients (7.3% vs. 12.3%; HR 0.57, 95% CI 0.39/0.85), mainly driven by a reduced rate of TVR (3.7% vs. 10.0%; HR 0.35, CI 0.21/0.58). No difference was found in cardiac death (1.9% vs. 1.9%; HR 1.01, CI 0.42/2.44) and MI (4.4% vs. 4.7%; HR 0.93, CI 0.53/1.64). The benefit of DES use seemed to be more prominent in female patients with a reduction in MACE (P for interaction = 0.025). CONCLUSIONS: In patients with proximal LAD stenosis, treatment with second-generation DES was associated with reduced 2-year rates of adverse cardiac events and TVR compared to BMS, with reintervention rates similar to those earlier reported from bypass surgery.

OBJECTIVE: Obesity is the most common public health problem and is a clinically complicating risk factor among hospitalized children. The impact of pediatric obesity on the severity and morbidity of lower respiratory tract infections remains unclear. MATERIALS AND METHODS: We conducted a retrospective cohort study of bronchitis and pneumonia among children aged 2-20 years using hospital discharge records. The data were obtained from the Kid's Inpatient Database in 2003, 2006, 2009, and 2012, and were weighted to estimate the number of hospitalizations in the United States. We used the International Classification of Diseases, Ninth Revision, Clinical Modification code (278.0×) to classify whether the patient was obese or not. We investigated the associations between pediatric obesity and use of mechanical ventilation using multivariable logistic regression model. In addition, we ascertained the relationships between pediatric obesity, comorbid blood stream infections, mean healthcare cost, and length of hospital stay. RESULTS: We estimated a total of 133 602 hospitalizations with pneumonia and bronchitis among children aged between 2 and 20 years. Obesity was significantly associated with use of mechanical ventilation (adjusted OR 2.90, 95% CI 2.15-3.90), comorbid bacteremia or septicemia (adjusted OR 1.58, 95% CI 1.03-2.44), elevated healthcare costs (adjusted difference $383, 95%CI $276-$476), and prolonged length of hospital stay (difference 0.32 days, 95%CI 0.23-0.40 days), after adjusting for patient and hospital characteristics using multivariable logistic regression models. CONCLUSIONS: Pediatric obesity is an independent risk factor for severity and morbidity among pediatric patients with lower respiratory tract infections. These findings suggest the importance of obesity prevention for pediatric populations.

BACKGROUND: The beneficial prognostic impact of statins has been established in patients with ischemic heart disease but not in those with heart failure (HF). In addition, it is still unclear whether patients benefit from statins regardless of low-density lipoprotein cholesterol levels. METHODS AND RESULTS: We examined 2444 consecutive stage C or D HF patients with ischemic heart disease registered in CHART-2 (Chronic Heart Failure Registry and Analysis in the Tohoku District 2), a multicenter, prospective, observational cohort study in Japan. Patients were divided into 3 groups according to the Japanese standard doses of statins and statin-intensity categories defined by the 2013 American College of Cardiology and American Heart Association guidelines: higher (moderate-high)-intensity (n=868), lower (low)-intensity (n=526), and no statin (n=1050). The median follow-up period was 6.4 years (13929 person-years). Analysis with the inverse probability of treatment weighted using a propensity score for multiple treatment revealed that both the higher-intesity group (hazard ratio [HR]: 0.68; P<0.001) and the lower-intensity group (HR: 0.82; P<0.001) had significantly lower incidence of the primary end point-a composite of all-cause death and HF admission-compared with the no statin group. The higher-intensity statin group had significantly lower incidence of the primary end point (HR: 0.82; P<0.001), all-cause death (HR: 0.83; P<0.001), and HF admission (HR: 0.78; P<0.001) than the lower-intensity statin group. Moreover, the use of statins, either higher- or lower-intensity, was associated with reduced incidence of the primary end point, regardless of low-density lipoprotein cholesterol levels. CONCLUSIONS: These results suggest that statin use, particularly the use of higher-intensity statins, has a beneficial prognostic impact in HF patients with ischemic heart disease, regardless of low-density lipoprotein cholesterol levels. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00418041.

BACKGROUND: The beneficial prognostic impact of statins has been established in patients with ischemic heart disease but not in those with heart failure (HF). In addition, it is still unclear whether patients benefit from statins regardless of low-density lipoprotein cholesterol levels. METHODS AND RESULTS: We examined 2444 consecutive stage C or D HF patients with ischemic heart disease registered in CHART-2 (Chronic Heart Failure Registry and Analysis in the Tohoku District 2), a multicenter, prospective, observational cohort study in Japan. Patients were divided into 3 groups according to the Japanese standard doses of statins and statin-intensity categories defined by the 2013 American College of Cardiology and American Heart Association guidelines: higher (moderate-high)-intensity (n=868), lower (low)-intensity (n=526), and no statin (n=1050). The median follow-up period was 6.4 years (13929 person-years). Analysis with the inverse probability of treatment weighted using a propensity score for multiple treatment revealed that both the higher-intesity group (hazard ratio [HR]: 0.68; P<0.001) and the lower-intensity group (HR: 0.82; P<0.001) had significantly lower incidence of the primary end point-a composite of all-cause death and HF admission-compared with the no statin group. The higher-intensity statin group had significantly lower incidence of the primary end point (HR: 0.82; P<0.001), all-cause death (HR: 0.83; P<0.001), and HF admission (HR: 0.78; P<0.001) than the lower-intensity statin group. Moreover, the use of statins, either higher- or lower-intensity, was associated with reduced incidence of the primary end point, regardless of low-density lipoprotein cholesterol levels. CONCLUSIONS: These results suggest that statin use, particularly the use of higher-intensity statins, has a beneficial prognostic impact in HF patients with ischemic heart disease, regardless of low-density lipoprotein cholesterol levels. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00418041.

Along with a worldwide epidemiological transition and dramatic increase in the elderly population, both the incidence and prevalence of heart failure (HF) are increasing worldwide. This epidemic of HF is characterized by an increase of HF with preserved left ventricular ejection fraction (LVEF) (HFpEF) and a decrease of HF with reduced LVEF (HFrEF). Of note, transition between HFpEF and HFrEF has been recently highlighted, since it significantly relates with prognosis. Our recent studies indicated that temporary changes in LVEF are common and associated with prognosis in patients with HF. In this chapter, we summarize recent findings on temporal changes in LVEF and their prognostic impact in HF patients, acknowledging that further studies are needed to fully elucidate the pathophysiology of LVEF recovery and deterioration to improve clinical outcomes of HF patients, and also to develop therapies targeting novel pathways of myocardial recovery.

Renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system play crucial roles in heart failure with reduced ejection fraction (HFrEF). Clinical trials provide strong evidence of prognostic benefits for combination therapy with angiotensin-converting enzyme inhibitor (ACEI) and β-blocker in the treatment of HFrEF. Angiotensin receptor blocker (ARB) is not superior to ACEI in improving mortality and an alternative for patients who are intolerant to ACEI. Prognostic evidence for triple therapy which combined angiotensin receptor blocker (ARB) and ACEI in addition to β-blocker therapy, is still controversial in HFrEF. Moreover, a recent clinical trial showed that triple therapy did not provide additional benefit compared with ACEI or ARB therapy alone in mildly symptomatic HFrEF. Of note, the triple therapy can even cause harm and renal dysfunction in HF with a history of hypertension. Direct renin inhibitor (DRI) has the theoretical benefit of upstream RAAS inhibition at the point of pathway activation. However, the results from clinical trials do not support upstream renin inhibition by DRI in addition to standard therapy with ACEI in patients with HFrEF. Angiotensin receptor-neprilysin inhibitor (ARNI) which combines a neprilysin inhibitor and ARB valsartan have a unique mode of action targeting both RAAS and the natriuretic peptide systems. In contrast to the evidence in HFrEF, clinical value of combination therapy with RAAS inhibitors and β-blocker is not well established in HF with preserved EF (HFpEF). The heterogeneity of diagnostic criteria and baseline characteristics of HFpEF need further evidence for the combination therapy. However, a recent clinical trial of LCZ696 showed promising results in reducing NT-proBNP in patients with HFpEF.

AIMS: Rheumatologic disorders are characterised by inflammation and an increased risk of coronary artery disease (CAD). However, the association between rheumatologic disorders and long-term prognosis in CAD patients undergoing percutaneous coronary intervention (PCI) is unknown. Thus, we aimed to examine the association between rheumatologic disorders and long-term prognosis in CAD patients undergoing PCI. METHODS AND RESULTS: A post-hoc analysis was performed in 4605 patients (age: 63.3 ± 11.0 years; male: 76.6%) with ST-segment elevation myocardial infarction (STEMI; n = 1396), non-STEMI ( n = 1541), and stable CAD ( n = 1668) from the all-comer stent trials, the BAsel Stent Kosten-Effektivitäts Trial-PROspective Validation Examination (BASKET-PROVE) I and II trials. We evaluated the association between rheumatologic disorders and 2-year major adverse cardiac events (MACEs; cardiac death, nonfatal myocardial infarction (MI), and target vessel revascularisation (TVR)) by Cox regression analysis. Patients with rheumatologic disorders ( n = 197) were older, more often female, had a higher prevalence of renal disease, multi-vessel coronary disease, and bifurcation lesions, and had longer total stent lengths. During the 2-year follow-up, the MACE rate was 8.6% in the total cohort. After adjustment for potential confounders, rheumatologic disorders were associated with MACEs in the total cohort (adjusted hazard ratio: 1.55; 95% confidence interval (CI): 1.04-2.31) driven by the STEMI subgroup (adjusted hazard ratio: 2.38; 95% CI: 1.26-4.51). In all patients, rheumatologic disorders were associated with all-cause death (adjusted hazard ratio: 2.05; 95% CI: 1.14-3.70), cardiac death (adjusted hazard ratio: 2.63; 95% CI: 1.27-5.43), and non-fatal MI (adjusted hazard ratio: 2.64; 95% CI: 1.36-5.13), but not with TVR (adjusted hazard ratio: 0.81; 95% CI: 0.41-1.58). CONCLUSIONS: The presence of rheumatologic disorders appears to be independently associated with worse outcome in CAD patients undergoing PCI. This calls for further studies and focus on this high-risk group of patients following PCI.

AIMS: Although balloon pulmonary angioplasty (BPA) improves haemodynamics and short-term prognosis in patients with inoperable chronic thrombo-embolic pulmonary hypertension (CTEPH), the long-term effects of BPA, and procedure-related complications remain to be fully elucidated. METHODS AND RESULTS: From July 2009 to October 2016, we performed a total of 424 BPA sessions in 84 consecutive patients with inoperable CTEPH. We used 3D reconstructed computed tomography to determine target lesions of pulmonary arteries and optical computed tomography to select balloon size, if needed. In 77 patients (92%) who completed the BPA treatment [65 ± 14 (SD) years-old, male/female 14/63], haemodynamics and exercise capacity were examined at 6 months after last BPA and in the chronic phase [>12 months after first BPA, 31 (20, 41) months]. The BPA treatment significantly improved mean pulmonary arterial pressure (38 ± 10 to 25 ± 6 mmHg), pulmonary vascular resistance (7.3 ± 3.2 to 3.8 ± 1.0 Wood units), and 6-minute walk distance (380 ± 138 to 486 ± 112 m) (all P < 0.01), and the improvements persisted throughout the follow-up period (43 ± 27 months) (N = 53). In the 424 sessions, haemoptysis was noted in 60 sessions (14%), and non-invasive positive pressure ventilation (NPPV) was used to treat haemoptysis and/or hypoxemia in 33 sessions (8%). Furthermore, 5-year survival was 98.4% (only one patient died of colon cancer) with no peri-procedural death. CONCLUSION: These results indicate that BPA improves haemodynamics and exercise capacity in inoperable CTEPH patients with acceptable complication rate and that the beneficial haemodynamic effects of BPA persist for years with resultant good long-term prognosis.

UNLABELLED: The epidemiology of pediatric acute osteomyelitis in the USA, such as annual hospitalization rates and disparities with respect to age, sex, race/ethnicity, and socioeconomic status, remains unknown. We obtained discharge records of hospitalized patients with acute osteomyelitis younger than 20 years of age from the Kids Inpatient Database for 2006, 2009, and 2012. We weighted the records to estimate the number of hospitalizations in the USA and calculated the annual rates of hospitalization because of acute osteomyelitis. We used a multivariable logistic regression analysis to assess the risk factors associated with the development of septic arthritis and bacteremia/septicemia. Overall annual hospitalization rates ranged from 1.34 to 1.66/100 000 children. Male-to-female ratios were 1.6-1.8. Black children, children aged 2, 7, and 12 years, and those living in very low median household income regions were more likely to have higher hospitalization rates. The lower limbs were the most frequent infection sites. Osteomyelitis at the pelvis/thigh, upper arm, hand, and forearm was significantly associated with the development of septic arthritis and bacteremia/septicemia. We determined the epidemiological patterns of pediatric acute osteomyelitis in the USA and identified the risk factors associated with the development of septic arthritis and bacteremia/septicemia. LEVEL OF EVIDENCE: Level II.

BACKGROUND: The new category of heart failure (HF), HF with mid-range left ventricular ejection fraction (LVEF) (HFmrEF), has recently been proposed. However, the clinical features of HFmrEF, with reference to HF with preserved LVEF (HFpEF) and HF with reduced LVEF (HFrEF) in the same HF cohort, remain to be fully examined. METHODS AND RESULTS: In the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 Study, we examined 3480 consecutive HF patients with echocardiography data consisting of 2154 HFpEF (LVEF ≥50%), 596 HFmrEF (LVEF 40-49%) and 730 HFrEF (LVEF <40%). While clinical characteristics and prognostic factors of HFmrEF were intermediate between HFpEF and HFrEF, prognosis of HFmrEF resembled HFpEF and the prognostic impact of cardiovascular medications in HFmrEF resembled that of HFrEF. Analysis of LVEF transition among the three groups revealed that HFmrEF and HFrEF dynamically transitioned to other categories, especially within 1 year, whereas HFpEF did not; HFmrEF at registration transitioned to HFpEF and HFrEF by 44% and 16% at 1 year, and 45% and 21% at 3 years, respectively. Landmark analysis demonstrated that, regardless of HF stages at registration, HFmrEF patients at 1 year had mortality comparable to that of HFpEF patients, which was better than HFrEF patients, but HFmrEF patients at registration had increased mortality when transitioned to HFrEF at 1 year. CONCLUSIONS: These results indicate that clinical characteristics of HFmrEF are intermediate between HFpEF and HFrEF and that HFmrEF dynamically transitions to HFpEF or HFrEF, especially within 1 year, suggesting that HFmrEF represents a transitional status or an overlap zone between HFpEF and HFrEF, rather than an independent entity of HF.

AIMS: Although cardiac amyloidosis (CA) is characterized by significant left atrial (LA) dilatation, the characteristics of LA function remain to be fully investigated. METHODS AND RESULTS: We assessed LA function by speckle-tracking echocardiography in 124 patients with CA and sinus rhythm: 68 with light chain (AL), 29 with mutant (ATTRm), 27 with wild-type (ATTRwt) transthyretin amyloidosis. Conventional and strain-derived parameters, including LA peak longitudinal strain (LS) and strain rate (peak LSR: reservoir function; early LSR: conduit function; late LSR: active function), were assessed compared between CA patients and 20 healthy controls of similar age and gender. All LA function phases, including LA longitudinal strain, peak LSR, early and late LSR were significantly impaired in CA compared to healthy controls after adjusting for LA size, LV ejection fraction and LV filling pressures (E/E') (all P < 0.05). Peak LA LS was moderately correlated with LV global LS (R = -0.60, P < 0.001); late LSR was correlated with A wave at the level of LV inflow (R = -0.69, P < 0.001). Among the different CA subtypes, peak LS and LA active emptying fraction were worse in ATTRwt than AL and ATTRm [P < 0.05 after adjustment for age, sex, body mass index, systolic blood pressure, heart rate, LA volume index, severity of mitral regurgitation, left ejection fraction, and left ventricular end-diastolic pressure (E/E')]. CONCLUSION: In CA, LA function was severely impaired and highly correlated with LV deformation. Differences in LA function between amyloid subtypes suggest that amyloid aetiology plays a role in the pathophysiology of cardiac dysfunction in CA.

BACKGROUND: We and others have previously reported that the Great East Japan Earthquake (GEJE) caused a significant but transient increase in cardiovascular diseases and deaths in the disaster area. However, it remains to be examined whether the GEJE had a long-term prognostic influence in large-scale cohort studies. This point is important when analyzing the data before and after the GEJE in the cohort studies in the disaster area. METHODS: We examined 8676 patients registered in our Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (N=10,219) between 2006 and 2010 and were alive after March 10, 2011. RESULTS: There were 48 GEJE-related deaths, causing a sharp and transient increase in all-cause death within a month after the GEJE. However, after excluding the GEJE-related deaths, the cubic polynomial spline smoothing showed no significant increase in all-cause death, heart failure admission, non-fetal acute myocardial infarction, or non-fetal stroke during the median 3-year follow-up after the GEJE. The extrapolation curves beyond the GEJE, which were obtained by the parametric survival models based on the survival data censored on the GEJE, were not significantly different from the Kaplan-Meier curves estimating the survival functions of deaths and cardiac events during the total follow-up period without considering the impacts of the GEJE. Furthermore, the multivariate Cox proportional hazard model applied to the matched cohort of the baseline data and the data after the GEJE showed no significant differences in the impacts of prognostic factors on all-cause mortality before and after the GEJE. CONCLUSIONS: These results indicate that the GEJE had no significant long-term prognostic impact after the earthquake in cardiovascular patients in the disaster area.

BACKGROUND: The epidemiology of pediatric septic arthritis, such as annual hospitalization rates and disparities by age, gender, race/ethnicity, and socioeconomic status, remains unclear. METHODS: We obtained hospital discharge records of patients under the age of 20 years with septic arthritis from the kids inpatient database for 2006, 2009 and 2012. We weighted the records to estimate the number of hospitalizations in the US and calculated the annual rates of hospitalization due to septic arthritis. We used multivariable logistic regression to assess risk factors associated with comorbidities of osteomyelitis and bacteremia/septicemia. RESULTS: Overall annual hospitalization rates showed a decreasing trend (4.23, 3.64, and 3.28 per 100,000 children in 2006, 2009, and 2012, respectively). Children who were male, white or black, and between the ages of 0-4 years were more likely to have higher hospitalization rates than others. The proportions of hospitalizations were high among children living in lower-income areas. Large joints at the lower limbs were the most frequently affected sites of infection. Infections of large joints and age category of 10-14 years were the factors that were significantly associated with comorbidities of osteomyelitis and bacteremia/septicemia. CONCLUSIONS: We demonstrated a change in the epidemiological patterns of pediatric septic arthritis and identified risk factors associated with comorbidities of osteomyelitis and bacteremia/septicemia.

BACKGROUND: We and others have previously reported that the Great East Japan Earthquake (GEJE) caused a significant but transient increase in cardiovascular diseases and deaths in the disaster area. However, it remains to be examined whether the GEJE had a long-term prognostic influence in large-scale cohort studies. This point is important when analyzing the data before and after the GEJE in the cohort studies in the disaster area. METHODS: We examined 8676 patients registered in our Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (N=10,219) between 2006 and 2010 and were alive after March 10, 2011. RESULTS: There were 48 GEJE-related deaths, causing a sharp and transient increase in all-cause death within a month after the GEJE. However, after excluding the GEJE-related deaths, the cubic polynomial spline smoothing showed no significant increase in all-cause death, heart failure admission, non-fetal acute myocardial infarction, or non-fetal stroke during the median 3-year follow-up after the GEJE. The extrapolation curves beyond the GEJE, which were obtained by the parametric survival models based on the survival data censored on the GEJE, were not significantly different from the Kaplan-Meier curves estimating the survival functions of deaths and cardiac events during the total follow-up period without considering the impacts of the GEJE. Furthermore, the multivariate Cox proportional hazard model applied to the matched cohort of the baseline data and the data after the GEJE showed no significant differences in the impacts of prognostic factors on all-cause mortality before and after the GEJE. CONCLUSIONS: These results indicate that the GEJE had no significant long-term prognostic impact after the earthquake in cardiovascular patients in the disaster area.

AIMS: The temporal changes and sex differences in post-traumatic stress disorder (PTSD) after natural disasters remain unclear. Therefore, we examined the prevalence, prognostic impacts, and determinant factors of PTSD after the Great East Japan Earthquake (GEJE) of 11 March 2011 in cardiovascular (CV) patients registered in the Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-2 Study (n = 10 219), with a special reference to sex. METHODS AND RESULTS: By self-completion questionnaires of the Japanese-language version of the Impact of Event Scale-Revised (IES-R-J), the prevalence of PTSD, defined as IES-R-J score ≥25, was 14.8, 15.7, 7.4, and 7.5% in 2011, 2012, 2013, and 2014, respectively. The PTSD rate was higher in women than in men in all years (all P < 0.01). During a median 3.5-year follow-up period, the patients with PTSD in 2011 more frequently experienced a composite of all-cause death and hospitalization for acute myocardial infarction, stroke, and heart failure than those without PTSD [adjusted hazard ratio (aHR) 1.27, P < 0.01]. Importantly, the prognostic impacts of PTSD on all-cause death (aHR 2.10 vs. 0.87, P for interaction = 0.03) and CV death (aHR 3.43 vs. 0.90, P for interaction = 0.02) were significant in women but not in men. While insomnia medication was a prominent determinant factor of PTSD in both sexes during 2011-14, economic poverty was significantly associated with PTSD only in men. CONCLUSION: After the GEJE, marked sex differences existed in the prevalence, prognostic impacts, and determinant factors of PTSD, suggesting the importance of sex-sepcific mental stress care in disaster medicine.

Aims: The temporal changes and sex differences in post-traumatic stress disorder (PTSD) after natural disasters remain unclear. Therefore, we examined the prevalence, prognostic impacts, and determinant factors of PTSD after the Great East Japan Earthquake (GEJE) of 11 March 2011 in cardiovascular (CV) patients registered in the Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-2 Study (n = 10 219), with a special reference to sex. Methods and results: By self-completion questionnaires of the Japanese-language version of the Impact of Event Scale-Revised (IES-R-J), the prevalence of PTSD, defined as IES-R-J score ≥25, was 14.8, 15.7, 7.4, and 7.5% in 2011, 2012, 2013, and 2014, respectively. The PTSD rate was higher in women than in men in all years (all P < 0.01). During a median 3.5-year follow-up period, the patients with PTSD in 2011 more frequently experienced a composite of all-cause death and hospitalization for acute myocardial infarction, stroke, and heart failure than those without PTSD [adjusted hazard ratio (aHR) 1.27, P < 0.01]. Importantly, the prognostic impacts of PTSD on all-cause death (aHR 2.10 vs. 0.87, P for interaction = 0.03) and CV death (aHR 3.43 vs. 0.90, P for interaction = 0.02) were significant in women but not in men. While insomnia medication was a prominent determinant factor of PTSD in both sexes during 2011-14, economic poverty was significantly associated with PTSD only in men. Conclusion: After the GEJE, marked sex differences existed in the prevalence, prognostic impacts, and determinant factors of PTSD, suggesting the importance of sex-sepcific mental stress care in disaster medicine.

Although Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are serious, life-threatening reactions to drug therapies, no efforts have been made to investigate the comprehensive change in epidemiology with respect to age, sex, and race and ethnicity in children. The risk of death was 0.3% to 1.5%, and the highest hospitalization rates were in children 15 to 19 years of age, boys, and black children. The highest proportions of hospitalizations were children with very low household income, those with private insurance, and those treated at large urban teaching hospitals in the West. A significant winter-autumn predominance was observed.

Several studies revealed the epidemiology of Kawasaki disease-related hospitalizations among children in the USA and other countries. However, disparities of developing coronary artery aneurysms by race/ethnicity, patient socioeconomic status, and geographic locations remain unknown in the USA. Hospital discharge record data of patients with Kawasaki disease aged 19 years or younger were obtained from the 2003, 2006, 2009, and 2012 Kid's Inpatient Database. The data were weighted to estimate the annual hospitalization rates with respect to age, gender, and race/ethnicity in the USA. Multivariable logistic regression was conducted to ascertain the factors associated with the development of coronary artery aneurysms. Total annual hospitalization rates of Kawasaki disease showed a decreasing trend, ranging from 6.54 per 100,000 children in 2003 to 6.11 per 100,000 children in 2012 (p < 0.001). The proportions of coronary artery aneurysms among patients with Kawasaki disease ranged from 2.25 to 3.20%. Factor associated with the development of coronary artery aneurysms was hospitals in West (OR 2.15, 95% CI 1.42-3.26). Race/ethnicity, health insurance status, and household income were not associated with the development of coronary artery aneurysms. Total hospitalization rates of Kawasaki disease showed a decreasing trend. Children admitted to hospitals in West region were more likely to develop coronary artery aneurysms.

BACKGROUND: The prognostic impact of atrial fibrillation (AF) among patients at high risk for heart failure (HF) remains unclear. In addition, there is no risk estimation model for AF development in these patients. METHODS AND RESULTS: The present study included 5,382 consecutive patients at high risk of HF enrolled in the CHART-2 Study (n=10,219). At enrollment, 1,217 (22.6%) had AF, and were characterized, as compared with non-AF patients, by higher age, lower estimated glomerular filtration rate, higher B-type natriuretic peptide (BNP) level and lower left ventricular ejection fraction. A total of 116 non-AF patients (2.8%) newly developed AF (new AF) during the median 3.1-year follow-up. AF at enrollment was associated with worse prognosis for both all-cause death and HF hospitalization (adjusted hazard ratio (aHR) 1.31, P=0.027 and aHR 1.74, P=0.001, for all-cause death and HF hospitalization, respectively) and new AF was associated with HF hospitalization (aHR 4.54, P<0.001). We developed a risk score with higher age, smoking, pulse pressure, lower eGFR, higher BNP, aortic valvular regurgitation, LV hypertrophy, and left atrial and ventricular dilatation on echocardiography, which effectively stratified the risk of AF development with excellent accuracy (AUC 0.76). CONCLUSIONS: These results indicated that AF is associated with worse prognosis in patients at high risk of HF, and our new risk score may be useful to identify patients at high risk for AF onset.

Chronic obstructive pulmonary disease (COPD) is associated with long-term all-cause death after percutaneous coronary intervention with bare-metal stents. Regarding other outcomes, previous studies have shown conflicting results and the impact of drug-eluting stent (DES) in this population is not well known. We analyzed 4,605 patients who underwent percutaneous coronary intervention with bare-metal stents (33.1%) or DES (66.9%) from the Basel Stent Kosten-Effektivitats Trial-Prospective Validation Examination trials I and II. COPD patients (n = 283, 6.1%), were older and had more frequently a smoking or cardiovascular event history. At 2-year follow-up, cumulative event rates for patients with versus without COPD were the following: major adverse cardiac events (MACE: composite of cardiac death, nonfatal myocardial infarction, and target vessel revascularization): 15.2% versus 8.1% (p <0.001); all-cause death: 11.7% versus 2.4% (p <0.001); cardiac death: 5.7% versus 1.2% (p <0.001); myocardial infarction: 3.5% versus 1.9% (p = 0.045); definite/probable/possible stent thrombosis: 2.5% versus 0.9% (p = 0.01); and major bleeding: 4.2% versus 2.1% (p = 0.014). After adjusting for confounders including smoking status, COPD remained an independent predictor for MACE (hazard ratio [HR] 1.80, 95% confidence interval [CI] 1.31 to 2.49), all-cause death (HR 3.62, 95% CI 2.41 to 5.45), cardiac death (HR 3.12, 95% CI 1.74 to 5.60), and stent thrombosis (HR 2.39, 95% CI 1.03 to 5.54). We did not find evidence of an interaction between COPD and DES implantation (p for interaction = 0.29) for MACE. In conclusion, COPD is associated with increased 2-year rates of all-cause death, cardiac death, and stent thrombosis after stent implantation. DES use appears to be beneficial also in patients with COPD.

At the national level, IgA vasculitis-related hospitalizations among children in the USA are scarce. Furthermore, nationwide epidemiology and hospital course of children with IgA vasculitis have not been fully described in the USA, and disparities by race/ethnicity remain unknown. Hospital discharge records of patients aged 19 years or younger were obtained from the 2003, 2006, 2009, and 2012 Kids' Inpatient Database, and they were weighted to estimate the annual hospitalization rates with respect to age, gender, and race/ethnicity in the USA. Annual hospitalization rates were calculated using weighted case estimates and US census data. Negative binomial regression was used to ascertain the factors associated with length of hospital stay. Total annual hospitalization rates showed a significant decreasing trend, ranging from 2.45 per 100,000 children in 2003 to 1.89 per 100,000 children in 2012 (p < 0.001). The peak ages of the hospitalized children with IgA vasculitis were 2 and 7 years, and male-to-female ratios were 1.38-1.44. Factors associated with length of hospital stay were patients' ages (10-14 and 15-19 years), race/ethnicity (Hispanic, Asian, and Pacific Islander), comorbid electrolyte abnormality, GI hemorrhage, intussusception, renal symptoms, and GI symptoms. The annual hospitalization rates for IgA vasculitis are declining in the USA across multiple age groups. GI and renal manifestations are associated with increased length of hospital stay.

BACKGROUND: Although balloon pulmonary angioplasty (BPA) improves the hemodynamics and prognosis of patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), the mechanisms of improvement in oxygenation remain to be elucidated. METHODS AND RESULTS: From August 2013 to May 2015, we performed a total of 113 BPA procedures in 24 patients with inoperable CTEPH (mean 4.7 procedures per patient). Median age was 70 [60, 74] years and 18 were female (75%). We examined hemodynamics, respiratory functions, and intrapulmonary shunt before and after the BPA procedure. Mean pulmonary arterial pressure (37 [28, 45] to 23[19, 27] mmHg, P<0.01), pulmonary vascular resistance (517 [389, 696] to 268 [239, 345] dyne/s/cm(5)) and 6-min walk distance (390 [286, 484] to 490 [411, 617] m, P<0.01) were significantly improved after BPA therapy. Furthermore, arterial oxygen partial pressure (PaO2, 54.8 [50.0, 60.8] to 65.2 [60.6, 73.2] %, P<0.01) and intrapulmonary shunt (23.4±6.0% to 19.3±5.0%, P<0.01) were also significantly ameliorated. In the multivariate analysis, decrease in intrapulmonary shunt after BPA was significantly correlated with improvement of both PaO2(r(2)=0.26, P<0.01) and SaO2(r(2)=0.49, P<0.01) after BPA. CONCLUSIONS: These results indicated that BPA improved not only pulmonary hemodynamics but also oxygenation with a resultant decrease in intrapulmonary shunt. (Circ J 2016; 80: 2227-2234).

BACKGROUND: There is no robust evidence of pharmacological interventions to improve mortality in heart failure (HF) patients with preserved left ventricular ejection fraction (LVEF) (HFpEF). In this subanalysis study of the SUPPORT Trial, we addressed the influence of LVEF on the effects of olmesartan in HF. METHODS AND RESULTS: Among 1,147 patients enrolled in the SUPPORT Trial, we examined 429 patients with reduced LVEF (HFrEF, LVEF <50%) and 709 with HFpEF (LVEF ≥50%). During a median follow-up of 4.4 years, 21.9% and 12.5% patients died in the HFrEF and HFpEF groups, respectively. In HFrEF patients, the addition of olmesartan to the combination of angiotensin-converting enzyme inhibitor (ACEI) and β-blocker (BB) was associated with increased incidence of death (hazard ratio (HR) 2.26, P=0.002) and worsening renal function (HR 2.01, P=0.01), whereas its addition to ACEI or BB alone was not. In contrast, in HFpEF patients, the addition of olmesartan to BB alone was significantly associated with reduced mortality (HR 0.32, P=0.03), whereas with ACEIs alone or in combination with BB and ACEI was not. The linear mixed-effect model showed that in HFpEF, the urinary albumin/creatinine ratio was unaltered when BB were combined with olmesartan, but significantly increased when not combined with olmesartan (P=0.01). CONCLUSIONS: LVEF substantially influences the effects of additive use of olmesartan, with beneficial effects noted when combined with BB in hypertensive HFpEF patients. (Circ J 2016; 80: 2155-2164).

BACKGROUND: It remains to be elucidated whether addition of renin-angiotensin-aldosterone system (RAAS) inhibitors and/or β-blockers to loop diuretics has a beneficial prognostic impact on chronic heart failure (CHF) patients. METHODS AND RESULTS: From the Chronic Heart failure Analysis and Registry in the Tohoku district 2 (CHART-2) Study (n=10,219), we enrolled 4,134 consecutive patients with symptomatic stage C/D CHF (mean age, 69.3 years, 67.7% male). We constructed Cox models for composite of death, myocardial infarction, stroke and HF admission. On multivariate inverse probability of treatment weighted (IPTW) Cox modeling, loop diuretics use was associated with worse prognosis with hazard ratio (HR) 1.28 (P<0001). Furthermore, on IPTW multivariate Cox modeling for multiple treatments, both low-dose (<40 mg/day) and high-dose (≥40 mg/day) loop diuretics were associated with worse prognosis with HR 1.32 and 1.56, respectively (both P<0.001). Triple blockade with RAS inhibitor(s), mineral corticoid (aldosterone) receptor antagonist(s) (MRA), and β-blocker(s) was significantly associated with better prognosis in those on low-dose but not on high-dose loop diuretics. CONCLUSIONS: Chronic use of loop diuretics is significantly associated with worse prognosis in CHF patients in a dose-dependent manner, whereas the triple combination of RAAS inhibitor(s), MRA, and β-blocker(s) is associated with better prognosis when combined with low-dose loop diuretics. (Circ J 2016; 80: 1396-1403).

BACKGROUND: Although left atrial (LA) enlargement is a recognized risk factor for adverse cardiovascular outcomes, emerging evidence supports the importance of LA function. We examined LA emptying fraction (LAEF) across the spectrum of cardiovascular disease burden in a large cohort of elderly adults living in the community. METHODS AND RESULTS: We studied 1142 participants in the Atherosclerosis Risk in Communities (ARIC) study who were in sinus rhythm, free of valvular disease, and had acceptable quality 3-dimensional echocardiograms (mean age, 76±5 years; 59% women). We determined the cross-sectional correlates of LAEF and compared LAEF among elderly adults without cardiovascular disease or cardiovascular risk factors (n=201), those with hypertension (n=734), and those with overt heart failure (HF; n=207). In multivariable analysis, lower LAEF was associated with higher LA volumes and worse left ventricular systolic and diastolic functions. Elderly participants free of cardiovascular disease or risk factors had smaller LA volumes than those with hypertension (LA volume max/ body surface area 30.2±6.6 versus 33.0±9.0 mL/m(2); P=0.001), but similar LAEF (55.2±10.3% versus 53.8±11.5%, respectively; P=0.357). Participants with HF had higher LA volume (39.8±13.3 mL/m(2)) and worse LAEF (47.6±14.6%) than participants with hypertension or participants free of cardiovascular disease or risk factors (all P<0.001). CONCLUSIONS: In a community-based cohort, LA function was impaired in participants with prevalent HF, but there were no significant differences in LA function between participants with hypertension and those with free of cardiovascular disease or risk factors, despite greater LA size in the former.

BACKGROUND: The prognostic impact of new-onset atrial fibrillation (AF) is not fully elucidated. METHODS AND RESULTS: We examined 4,818 consecutive stage C/D chronic heart failure (CHF) patients in the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (n=10,219). At enrollment, 1,859 (38.6%) of them had AF. Compared with the 2,953 patients without AF, AF patients were characterized by higher age (71 vs. 68 years), lower estimated glomerular filtration rate (58.9 vs. 61.9 ml/min/1.73 m(2)), higher brain natriuretic peptide (152 vs. 74.5 pg/ml), similar left ventricular ejection fraction (56.8 vs. 56.5%), and a similar prescription rate of β-blockers (48.1 vs. 50.6%) and renin-angiotensin system (RAS) inhibitors (72.9 vs. 71.6%). Among the patients without AF at enrollment, 106 (3.6%) developed new AF during the median 3.2-year follow-up, which was associated with increased mortality (adjusted hazard ratio, 1.72; P=0.013). In contrast, neither paroxysmal nor chronic AF at enrollment was associated with increased mortality. The mortality rate was significantly high in the first year after the onset of new AF. On inverse probability of treatment weighting analysis using propensity score, RAS inhibitors and statins were associated with reduced incidence of new AF, and diuretics were associated with increase of new AF. CONCLUSIONS: Onset of new AF, but not a history of AF, is associated with increased mortality in CHF patients, especially in the first year.

BACKGROUND: Pulmonary arterial hypertension with systemic dysfunctions, including metabolic disorders and renal dysfunction, has a poor prognosis. However, it remains to be elucidated whether chronic thromboembolic pulmonary hypertension (CTEPH) is also associated with systemic dysfunctions, and if so, whether balloon pulmonary angioplasty (BPA) improves them. METHODS AND RESULTS: Fifty-five consecutive patients who underwent BPA from March 2012 to December 2014 for systemic dysfunctions, including glycemic control, lipid profiles, renal and vascular function, and nutritional status were examined. The analyses were performed before and after BPA (mean, 3.5 sessions/patient) and changes in hemodynamic parameters were compared. The average follow-up period was 474±245 days. Baseline prevalence of hypertension, diabetes mellitus, dyslipidemia and advanced chronic kidney disease was 58, 7, 33 and 36%, respectively. BPA caused marked hemodynamic improvements in the CTEPH patients. Importantly, BPA also significantly improved dysglycemia (fasting blood sugar, hemoglobin A1c and homeostatic assessment model of insulin resistance), renal (creatinine and estimated glomerular filtration rate) and vascular (cardio-ankle vascular index) functions and nutritional status (albumin, cholesterols, and body mass index). Importantly, there were positive correlations between the degrees of the hemodynamic improvements and those of other improvements. CONCLUSIONS: These results indicate that BPA may exert multiple beneficial effects in CTEPH patients, not only in terms of hemodynamics but also in other systemic functions, with positive correlations among them.

BACKGROUND: Obesity and asthma are common health problems in the United States. OBJECTIVE: The objective of this study was to evaluate the clinical and economic burdens of obesity on hospitalized children with acute asthma exacerbation in 2012. METHODS: Hospital discharge records of patients aged 2 to 18 years with a diagnosis of asthma were obtained from the 2012 Kids' Inpatient Database, wherein the data were compiled by the Agency for Healthcare Research and Quality. The discharge records were weighted to estimate the number of hospitalizations because of asthma exacerbations in the United States. To classify whether the patient was obese or not, we used the International Classification of Diseases, Ninth Revision, Clinical Modification code 278.0x. We compared the odds of using noninvasive or invasive mechanical ventilation, mean total charges for inpatient service, and length of hospital stay between obese and nonobese patients. RESULTS: A total of 74,338 patient discharges were extracted. Of these, 3,494 discharges were excluded because of chronic medical conditions. Using discharge weight variables, we estimated a total of 100,157 hospitalizations with asthma exacerbations among children aged between 2 and 18 years in 2012. Obesity was significantly associated with higher odds of using mechanical ventilation (odds ratio 1.59, 95% CI 1.28-1.99), higher mean total hospital charges (adjusted difference: $1588, 95% CI $802-$2529), and longer mean length of hospital stay (0.24 days, 95% CI 0.17-0.32 days) compared with nonobesity. CONCLUSIONS: These findings suggest that obesity is a significant risk factor of severe asthma exacerbation that requires mechanical ventilation, and obesity is an economically complicating factor.

OBJECTIVES: The purpose of this study was to investigate the prognostic value of global longitudinal strain (GLS) in heart failure with reduced ejection fraction (HFrEF) patients in relation to all-cause mortality. BACKGROUND: Measurement of myocardial deformation by 2-dimensional speckle tracking echocardiography, specifically GLS, may be superior to conventional echocardiographic parameters, including left ventricular ejection fraction, in predicting all-cause mortality in HFrEF patients. METHODS: Transthoracic echocardiographic examinations were retrieved for 1,065 HFrEF patients admitted to a heart failure clinic. The echocardiographic images were analyzed, and conventional and novel echocardiographic parameters were obtained. RESULTS: Many of the conventional echocardiographic parameters proved to be predictors of mortality. However, GLS remained an independent predictor of mortality in the multivariable model after adjusting for age, sex, body mass index, total cholesterol, mean arterial pressure, heart rate, ischemic cardiomyopathy, percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery, noninsulin dependent diabetes mellitus, and conventional echocardiographic parameters (hazard ratio [HR]: 1.15; 95% confidence interval [CI]: 1.04 to 1.27; p = 0.008, per 1% decrease). No other echocardiographic parameter remained an independent predictor after adjusting for these variables. Furthermore, GLS had the highest C-statistics of all the echocardiographic parameters and added incremental prognostic value with a significant increase in the net reclassification improvement (p = 0.009). Atrial fibrillation (AF) modified the relationship between GLS and mortality (p value for interaction = 0.036); HR: 1.08 (95% CI: 0.97 to 1.19), p = 0.150 and HR: 1.22 (95% CI: 1.15 to 1.29), p < 0.001, per 1% decrease in GLS for patients with and without AF, respectively. Sex also modified the relationship between GLS and mortality (p value for interaction = 0.047); HR: 1.23 (95% CI: 1.16 to 1.30), p < 0.001 and HR: 1.09 (95% CI: 0.99 to 1.20), p = 0.083, per 1% decrease in GLS for men and women, respectively. CONCLUSIONS: GLS is an independent predictor of all-cause mortality in HFrEF patients, especially in male patients without AF. Furthermore, GLS was a superior prognosticator compared with all other echocardiographic parameters.

Heart failure (HF) is an epidemic in healthcare worldwide, including Asia. It appears that HF will become more serious in the near future, with the epidemiological transition and ageing of the population. However, in contrast to Western countries, information on HF epidemiology is still limited in Asia, particularly in South Asia. In this review, we will briefly summarize available information regarding the current and future burden of HF in Asia, which indicates the importance of both primary prevention of underlying diseases of HF and secondary prevention, including management of ischaemic HF, HF with preserved EF, and HF in the elderly.

We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, β-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96-1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19-2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and β-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11-1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01-2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24-2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and β-blockers was associated with increased adverse cardiac events. This study is registered at clinicaltrials.gov-NCT00417222.

BACKGROUND: The effectiveness of statins remains to be examined in patients with heart failure (HF) with preserved ejection fraction (EF). METHODS AND RESULTS: Among 4,544 consecutive HF patients registered in the Chronic Heart Failure Registry and Analysis in the Tohoku district-2 (CHART-2) between 2006 and 2010, 3,124 had EF ≥50% (HFpEF; mean age 69 years; male 65%) and 1,420 had EF <50% (HF with reduced EF (HFrEF); mean age 67 years; male 75%). The median follow-up was 3.4 years. The 3-year mortality in HFpEF patients was lower in patients receiving statins [8.7% vs. 14.5%, adjusted hazard ratio (HR) 0.74; 95% confidence interval (CI), 0.58-0.94; P<0.001], which was confirmed in the propensity score-matched cohort (HR, 0.72; 95% CI, 0.49-0.99; P=0.044). The inverse probability of treatment weighted further confirmed that statin use was associated with reduced incidence of all-cause death (HR, 0.71; 95% CI, 0.62-0.82, P<0.001) and noncardiovascular death (HR, 0.53; 95% CI, 0.43-0.66, P<0.001), specifically reduction of sudden death (HR, 0.59; 95% CI, 0.36-0.98, P=0.041) and infection death (HR, 0.53; 95% CI, 0.35-0.77, P=0.001) in HFpEF. In the HFrEF cohort, statin use was not associated with mortality (HR, 0.87; 95% CI, 0.73-1.04, P=0.12), suggesting a lack of statin benefit in HFrEF patients. CONCLUSIONS: These results suggest that statin use is associated with improved mortality rates in HFpEF patients, mainly attributable to reductions in sudden death and noncardiovascular death.

BACKGROUND: Recent trends in the clinical characteristics, management and prognosis of dilated cardiomyopathy (DCM) remain to be examined in Japan. METHODS AND RESULTS: We compared 306 and 710 DCM patients in the Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-1 (2000-2005, n=1,278) and the CHART-2 (2006-present, n=10,219) Studies, respectively. Between the 2 groups of DCM patients, there were no significant differences in baseline characteristics. The prevalence of hypertension, dyslipidemia and diabetes mellitus were all significantly increased from the CHART-1 to the CHART-2 Study. The use of β-blockers and aldosterone antagonists was significantly increased, while that of loop diuretics and digitalis was significantly decreased in the CHART-2 Study. The 3-year mortality rate was significantly improved from 14% in the CHART-1 to 9% in the CHART-2 Study (adjusted HR, 0.60; 95% CI: 0.49-0.81; P=0.001). In particular, 3-year incidence of cardiovascular death was significantly decreased (adjusted HR, 0.26; 95% CI: 0.14-0.50, P<0.001), while that of HF admission was not (adjusted HR, 0.90; 95% CI: 0.59-1.37, P=0.632). The prognostic improvement was noted in patients with BNP <220 pg/ml, LVEF>40%, β-blocker use and aldosterone antagonist use. CONCLUSIONS: Long-term prognosis of DCM patients has been improved, along with the implementation of evidence-based medication in Japan.

BACKGROUND: The risk of patients with aortic stenosis (AS) should be stratified not only by AS severity but also by comorbidities. METHODS AND RESULTS: We aimed to develop a risk score for mortality in 412 patients with AS (pressure gradient ≥30 mmHg, mean age 74.9 years, male 52.4%) in the CHART-2 Study (n=10,219). During a 3-year follow-up, 73 (17.7%) patients died. Crude 3-year mortality of patients in New York Heart Association (NYHA) classes I, II, and III/IV was 9.5%, 16.5%, and 49.7%, respectively (P<0.001). Stepwise Cox regression analysis showed that the combination of 7 factors was the best model to predict the mortality of AS patients, who were scored according to their hazard ratios, including NYHA class III-IV (score 6), male sex (3), serum albumin level ≤4 g/dl (2), aortic peak flow ≥4.5 m/s (2), age ≥75 years (2), chronic kidney disease (2), and anemia (1). Receiver-operating characteristic analysis showed excellent association between the sum of the scores and 3-year mortality (area under the curve, 0.78). The multivariate Cox proportional hazard model demonstrated that the present risk score also well stratified the mortality risk. CONCLUSIONS: The present study demonstrates that, in addition to the classical prognostic factors related to symptoms and AS severity, various comorbidities are associated with mortality. Thus, the present comprehensive risk score may be useful for risk stratification of AS patients.

BACKGROUND: We aimed to elucidate the prognostic impact of anemia with special reference to the clinical background of patients with chronic heart failure (CHF). METHODS AND RESULTS: We examined 4,646 consecutive patients with Stage C/D CHF registered in the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (n=10,219). Among them, 1,627 (35%) had anemia and were characterized by higher age (74 vs. 66 years), lower estimated glomerular filtration rate (52.8 vs. 66.1 ml/min/1.73 m(2)) and higher B-type natriuretic peptide levels (154.5 vs. 81.8 pg/ml) (all P<0.001) but comparable left ventricular ejection fraction (LVEF; 57.5 vs. 56.7%). Anemic patients were more frequently treated with diuretics (55.1 vs. 42.3%) but less often treated with β-blockers (45.4 vs. 51.1%) (both P<0.001). During a median follow-up of 3.8 years, 371 and 272 patients died with and without anemia, respectively (22.8 vs. 9.0%, adjusted hazard ratio 1.40; 95% confidence interval 1.15-1.71, P=0.001). Subgroup analysis revealed that the prognostic impact of anemia was comparable in terms of age, sex, renal function and double product, but differed by LVEF level and CHF etiology (both, P for interaction <0.001). In particular, a difference in the prognostic impact of LVEF level was noted in patients with ischemic heart disease. CONCLUSIONS: These results indicate that the prognostic impact of anemia is evident in CHF patients with preserved EF and it differs by CHF etiology.

BACKGROUND: Temporal trends in clinical characteristics, management and prognosis of patients with symptomatic heart failure (HF) remain to be elucidated in Japan. METHODS AND RESULTS: From the Chronic Heart Failure Analysis and Registry in the Tohoku District-1 (CHART-1; 2000-2005, n=1,278) and CHART-2 (2006-present, n=10,219) Studies, we enrolled 1,006 and 3,676 consecutive symptomatic stage C/D HF patients, respectively. As compared with the patients in the CHART-1 Study, those in the CHART-2 Study had similar age and sex prevalence, and were characterized by lower brain natriuretic peptide, higher prevalence of preserved left ventricular ejection fraction (LVEF) and higher prevalence of hypertension, diabetes mellitus and ischemic heart disease (IHD), particularly IHD with LVEF ≥50%. From CHART-1 to CHART-2, use of renin-angiotensin system inhibitors, β-blockers and aldosterone antagonists was significantly increased, while that of loop diuretics and digitalis was decreased. Three-year incidences of all-cause death (24 vs. 15%; adjusted hazard ratio [adjHR], 0.73; P<0.001), cardiovascular death (17 vs. 7%; adjHR, 0.38; P<0.001) and hospitalization for HF (30 vs. 17%; adjHR, 0.51; P<0.001) were all significantly decreased from CHART-1 to CHART-2. In the CHART-2 Study, use of β-blockers was associated with improved prognosis in patients with LVEF <50%, while that of statins was associated with improved prognosis in those with LVEF ≥50%. CONCLUSIONS: Along with implementation of evidence-based medications, the prognosis of HF patients has been improved in Japan. ( TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00418041)

BACKGROUND: We examined the prevalence, predictors and prognostic impact of post-traumatic stress disorder (PTSD) after the Great East Japan Earthquake in patients with cardiovascular disease (CVD) in the CHART-2 study. METHODS AND RESULTS: The prevalence of PTSD was 14.7% at 6 months after the Earthquake. Female sex, experiencing the Tsunami, property loss, poverty, and insomnia medication use were associated with PTSD. The patients with PTSD more frequently experienced a composite of death, acute myocardial infarction, stroke and heart failure (18.5% vs. 15.0%, P=0.035). CONCLUSIONS: PTSD was frequent in CVD patients after the Earthquake and had an adverse prognostic impact.

BACKGROUND: It is unclear whether the prognostic impact of diabetes mellitus (DM) in chronic heart failure (CHF) is influenced by ischemic heart disease (IHD) and/or nephropathy. METHODS AND RESULTS: We enrolled 4,065 consecutive patients with stage C/D CHF (mean age, 69.0 years; 68.7% male) in the CHART-2 Study (n=10,219). We defined DM as current history of DM treatment or HbA1c ≥6.5% (National Glycohemoglobin Standardization Program [NGSP]), and nephropathy as urine albumin:creatinine ratio ≥30 mg/g or urine dipstick test ≥(±) at enrollment. Impacts of DM and nephropathy on the composite of death, myocardial infarction, stroke, and HF admission were examined. Among the 4,065 patients, 1,448 (35.6%) had DM, while IHD and nephropathy were also noted in 1,644 (40.4%) and in 1,549 (38.1%), respectively. During the median follow-up of 2.88 years, 1,025 (25.2%) reached the composite endpoint. On multivariate Cox regression, DM was significantly associated with the composite endpoint in all patients (HR, 1.17; P=0.02), and in those with IHD (HR, 1.38; P=0.004), but not in those without IHD (HR, 1.12; P=0.22; P for interaction=0.12). Furthermore, when the patients were stratified by nephropathy, DM was associated with worse prognosis only in the IHD patients with nephropathy. CONCLUSIONS: The prognostic impact of DM was more evident in patients with IHD than in those without IHD, particularly when complicated with nephropathy.

BACKGROUND: The effectiveness of statins remains to be examined in patients with heart failure (HF) with preserved ejection fraction (EF). METHODS AND RESULTS: Among 4,544 consecutive HF patients registered in the Chronic Heart Failure Registry and Analysis in the Tohoku district-2 (CHART-2) between 2006 and 2010, 3,124 had EF ≥50% (HFpEF; mean age 69 years; male 65%) and 1,420 had EF <50% (HF with reduced EF (HFrEF); mean age 67 years; male 75%). The median follow-up was 3.4 years. The 3-year mortality in HFpEF patients was lower in patients receiving statins [8.7% vs. 14.5%, adjusted hazard ratio (HR) 0.74; 95% confidence interval (CI), 0.58-0.94; P<0.001], which was confirmed in the propensity score-matched cohort (HR, 0.72; 95% CI, 0.49-0.99; P=0.044). The inverse probability of treatment weighted further confirmed that statin use was associated with reduced incidence of all-cause death (HR, 0.71; 95% CI, 0.62-0.82, P<0.001) and noncardiovascular death (HR, 0.53; 95% CI, 0.43-0.66, P<0.001), specifically reduction of sudden death (HR, 0.59; 95% CI, 0.36-0.98, P=0.041) and infection death (HR, 0.53; 95% CI, 0.35-0.77, P=0.001) in HFpEF. In the HFrEF cohort, statin use was not associated with mortality (HR, 0.87; 95% CI, 0.73-1.04, P=0.12), suggesting a lack of statin benefit in HFrEF patients. CONCLUSIONS: These results suggest that statin use is associated with improved mortality rates in HFpEF patients, mainly attributable to reductions in sudden death and noncardiovascular death.

BACKGROUND: We aimed to elucidate the prognostic impact of anemia with special reference to the clinical background of patients with chronic heart failure (CHF). METHODS AND RESULTS: We examined 4,646 consecutive patients with Stage C/D CHF registered in the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (n=10,219). Among them, 1,627 (35%) had anemia and were characterized by higher age (74 vs. 66 years), lower estimated glomerular filtration rate (52.8 vs. 66.1 ml/min/1.73 m(2)) and higher B-type natriuretic peptide levels (154.5 vs. 81.8 pg/ml) (all P<0.001) but comparable left ventricular ejection fraction (LVEF; 57.5 vs. 56.7%). Anemic patients were more frequently treated with diuretics (55.1 vs. 42.3%) but less often treated with β-blockers (45.4 vs. 51.1%) (both P<0.001). During a median follow-up of 3.8 years, 371 and 272 patients died with and without anemia, respectively (22.8 vs. 9.0%, adjusted hazard ratio 1.40; 95% confidence interval 1.15-1.71, P=0.001). Subgroup analysis revealed that the prognostic impact of anemia was comparable in terms of age, sex, renal function and double product, but differed by LVEF level and CHF etiology (both, P for interaction <0.001). In particular, a difference in the prognostic impact of LVEF level was noted in patients with ischemic heart disease. CONCLUSIONS: These results indicate that the prognostic impact of anemia is evident in CHF patients with preserved EF and it differs by CHF etiology.

BACKGROUND: The risk of patients with aortic stenosis (AS) should be stratified not only by AS severity but also by comorbidities. METHODS AND RESULTS: We aimed to develop a risk score for mortality in 412 patients with AS (pressure gradient ≥30 mmHg, mean age 74.9 years, male 52.4%) in the CHART-2 Study (n=10,219). During a 3-year follow-up, 73 (17.7%) patients died. Crude 3-year mortality of patients in New York Heart Association (NYHA) classes I, II, and III/IV was 9.5%, 16.5%, and 49.7%, respectively (P<0.001). Stepwise Cox regression analysis showed that the combination of 7 factors was the best model to predict the mortality of AS patients, who were scored according to their hazard ratios, including NYHA class III-IV (score 6), male sex (3), serum albumin level ≤4 g/dl (2), aortic peak flow ≥4.5 m/s (2), age ≥75 years (2), chronic kidney disease (2), and anemia (1). Receiver-operating characteristic analysis showed excellent association between the sum of the scores and 3-year mortality (area under the curve, 0.78). The multivariate Cox proportional hazard model demonstrated that the present risk score also well stratified the mortality risk. CONCLUSIONS: The present study demonstrates that, in addition to the classical prognostic factors related to symptoms and AS severity, various comorbidities are associated with mortality. Thus, the present comprehensive risk score may be useful for risk stratification of AS patients.

BACKGROUND: Temporal trends in clinical characteristics, management and prognosis of patients with symptomatic heart failure (HF) remain to be elucidated in Japan. METHODS AND RESULTS: From the Chronic Heart Failure Analysis and Registry in the Tohoku District-1 (CHART-1; 2000-2005, n=1,278) and CHART-2 (2006-present, n=10,219) Studies, we enrolled 1,006 and 3,676 consecutive symptomatic stage C/D HF patients, respectively. As compared with the patients in the CHART-1 Study, those in the CHART-2 Study had similar age and sex prevalence, and were characterized by lower brain natriuretic peptide, higher prevalence of preserved left ventricular ejection fraction (LVEF) and higher prevalence of hypertension, diabetes mellitus and ischemic heart disease (IHD), particularly IHD with LVEF ≥50%. From CHART-1 to CHART-2, use of renin-angiotensin system inhibitors, β-blockers and aldosterone antagonists was significantly increased, while that of loop diuretics and digitalis was decreased. Three-year incidences of all-cause death (24 vs. 15%; adjusted hazard ratio [adjHR], 0.73; P<0.001), cardiovascular death (17 vs. 7%; adjHR, 0.38; P<0.001) and hospitalization for HF (30 vs. 17%; adjHR, 0.51; P<0.001) were all significantly decreased from CHART-1 to CHART-2. In the CHART-2 Study, use of β-blockers was associated with improved prognosis in patients with LVEF <50%, while that of statins was associated with improved prognosis in those with LVEF ≥50%. CONCLUSIONS: Along with implementation of evidence-based medications, the prognosis of HF patients has been improved in Japan. ( TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00418041)

BACKGROUND: Recent trends in the clinical characteristics, management and prognosis of dilated cardiomyopathy (DCM) remain to be examined in Japan. METHODS AND RESULTS: We compared 306 and 710 DCM patients in the Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-1 (2000-2005, n=1,278) and the CHART-2 (2006-present, n=10,219) Studies, respectively. Between the 2 groups of DCM patients, there were no significant differences in baseline characteristics. The prevalence of hypertension, dyslipidemia and diabetes mellitus were all significantly increased from the CHART-1 to the CHART-2 Study. The use of β-blockers and aldosterone antagonists was significantly increased, while that of loop diuretics and digitalis was significantly decreased in the CHART-2 Study. The 3-year mortality rate was significantly improved from 14% in the CHART-1 to 9% in the CHART-2 Study (adjusted HR, 0.60; 95% CI: 0.49-0.81; P=0.001). In particular, 3-year incidence of cardiovascular death was significantly decreased (adjusted HR, 0.26; 95% CI: 0.14-0.50, P<0.001), while that of HF admission was not (adjusted HR, 0.90; 95% CI: 0.59-1.37, P=0.632). The prognostic improvement was noted in patients with BNP <220 pg/ml, LVEF>40%, β-blocker use and aldosterone antagonist use. CONCLUSIONS: Long-term prognosis of DCM patients has been improved, along with the implementation of evidence-based medication in Japan.

OBJECTIVE: Chronic thromboembolic pulmonary hypertension (CTEPH) is a fatal disease that is distinct from pulmonary arterial hypertension (PAH). Although CTEPH is characterized by obstruction of major pulmonary artery because of chronic thrombus, it remains unclear whether CTEPH is associated with prothrombotic condition. APPROACH AND RESULTS: In addition to conventional markers, GTP-bound levels of Rap1, RhoA, RalA, Rac1, and Ras in platelets, which are implicated for platelet activation, were measured in patients without pulmonary hypertension (non-PH, n=15), patients with PAH (n=19), and patients with CTEPH (n=25). Furthermore, the responsiveness to ex vivo thrombin stimulation was also evaluated. The ratios of the P-selectin positive platelets in the non-PH patients, patients with PAH, and patients with CTEPH were 1.40% (median and interquartile range, 0.83-1.82), 2.40% (1.80-3.39), and 2.63% (1.90-8.22), respectively (non-PH versus CTEPH, P<0.01). The activated GPIIb/IIIa-positive platelets were 6.01% (1.34-7.87), 11.39% (5.69-20.86), and 9.74% (7.83-24.01), respectively (non-PH versus CTEPH, P=0.01). GTP-bound RhoA was 1.79% (0.94-2.83), 4.03% (2.01-5.14), and 2.01% (1.22-2.48), respectively (non-PH versus PAH, P=0.04), and GTP-bound RalA was 1.58% (1.08-2.11), 3.02% (2.03-3.54), and 2.64% (1.42-4.28), respectively (non-PH versus PAH, P=0.023; non-PH versus CTEPH, P=0.048). In contrast, Rac1, Rap1, or Ras was not activated in any groups. The platelets of patients with CTEPH exhibited hyperresponsiveness to ex vivo thrombin stimulation compared with those of non-PH patients when evaluated for the surface markers. Either D-dimer or fibrin degradation product level was not increased in patients with CTEPH. CONCLUSIONS: These results provide the first direct evidence that platelets of patients with CTEPH are highly activated and exhibit hyperresponsiveness to thrombin stimulation.

Background:Microalbuminuria, traditionally defined as urinary albumin/creatinine ratio (UACR) ≥30 mg/g, is a risk factor for mortality even in patients with preserved glomerular filtration rate (GFR). The prognostic impact of subclinical microalbuminuria, however, remains unknown in patients with chronic heart failure (CHF).Methods and Results:In the Chronic Heart Failure Analysis and Registry in the Tohoku District 2 Study, we enrolled 2,039 consecutive symptomatic CHF patients (median age, 67.4 years; 68.9% male) after excluding those on hemodialysis. On classification and regression tree analysis, UACR=10.2 mg/g and 27.4 mg/g were identified as the first and second discriminating points to stratify the risk for composite of death, acute myocardial infarction, HF admission and stroke, therefore subclinical microalbuminuria was defined as UACR ≥10.2 and <27.4 mg/g. There were 506 composite endpoints (24.8%) during the median follow-up of 2.69 years. On Kaplan-Meier analysis and multivariate Cox modeling, subclinical microalbuminuria was significantly associated with increased composite endpoints with hazard ratios of 1.90 (P<0.001) and 2.29 (P<0.001) in patients with preserved (>60 ml·min-1·1.73 m-2, n=1,129) or mildly reduced eGFR (30-59.9 ml·min-1·1.73 m-2, n=789), respectively. In patients with severely reduced GFR (eGFR <30 ml·min-1·1.73 m-2, n=121), >80% had microalbuminuria or macroalbuminuria, and only 9.1% were free from any composite endpoints.Conclusions:Subclinical microalbuminuria was associated with increased risk of cardiovascular events in CHF patients with mildly reduced or preserved renal function.

RATIONALE: Cyclophilin A (CyPA) is secreted from vascular smooth muscle cells (VSMCs) by oxidative stress and promotes VSMC proliferation. However, the role of extracellular CyPA and its receptor Basigin (Bsg, encoded by Bsg) in the pathogenesis of pulmonary hypertension (PH) remains to be elucidated. OBJECTIVE: To determine the role of CyPA/Bsg signaling in the development of PH. METHODS AND RESULTS: In the pulmonary arteries of patients with PH, immunostaining revealed strong expression of CyPA and Bsg. The pulmonary arteries of CyPA(±) and Bsg(±) mice exposed to normoxia did not differ in morphology compared with their littermate controls. In contrast, CyPA(±) and Bsg(±) mice exposed to hypoxia for 4 weeks revealed significantly reduced right ventricular systolic pressure, pulmonary artery remodeling, and right ventricular hypertrophy compared with their littermate controls. These features were unaltered by bone marrow reconstitution. To further evaluate the role of vascular Bsg, we harvested pulmonary VSMCs from Bsg(+/+) and Bsg(±) mice. Proliferation was significantly reduced in Bsg(±) compared with Bsg(+/+) VSMCs. Mechanistic studies demonstrated that Bsg(±) VSMCs revealed reduced extracellular signal-regulated kinase 1/2 activation and less secretion of cytokines/chemokines and growth factors (eg, platelet-derived growth factor-BB). Finally, in the clinical study, plasma CyPA levels in patients with PH were increased in accordance with the severity of pulmonary vascular resistance. Furthermore, event-free curve revealed that high plasma CyPA levels predicted poor outcome in patients with PH. CONCLUSIONS: These results indicate the crucial role of extracellular CyPA and vascular Bsg in the pathogenesis of PH.

AIMS: We have previously demonstrated that [(18)F]fluorodeoxyglucose (FDG) accumulation is increased in the right ventricular (RV) free wall of patients with pulmonary hypertension (PH), and that this accumulation is ameliorated after the treatment with epoprostenol associated with improvement of haemodynamic overload. The aim of this study was to examine whether enhanced RV FDG accumulation by gated positron emission tomography (PET) has a prognostic impact in patients with PH. METHODS AND RESULTS: We examined the prognostic impact of the RV standardized uptake value (SUV) of FDG-PET corrected for the partial volume effect (cRV-SUV) in 27 patients with PH who underwent gated FDG-PET from March 2001 to June 2004. During the follow-up period of 69 ± 49 (mean ± SD) months, among the 27 patients, 15 showed clinical worsening (CW) and 11 died. FDG-PET examination showed that cRV-SUV was significantly higher in the CW group compared with the non-CW group (10.1 vs. 7.6, P = 0.02). Univariate Cox hazard analysis showed that cRV-SUV was significantly correlated with the time to CW (hazard ratio 1.25, 95% confidence interval 1.04-1.51, P = 0.02), which remained significant even after adjustment of World Health Organization functional class. Kaplan-Meier analysis showed that the patients with cRV-SUV ≥8.3 had poor prognosis compared with those with cRV-SUV <8.3 (log-rank P = 0.005 for time to CW and P = 0.07 for mortality). CONCLUSION: These results indicate that enhanced FDG accumulation in the RV free wall may be a novel prognostic factor in patients with PH.

AIMS: It is still controversial whether elevated baseline heart rate (HR) is associated with higher mortality in patients with heart failure (HF) with preserved ejection fraction (HFpEF). We compared the impacts of baseline HR on mortality in patients with HFpEF and those with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: We enrolled consecutive 2688 patients in Stage C or D HF with sinus rhythm from our Chronic Heart Failure Analysis and Registry in the Tohoku District 2 (CHART-2) Study (n = 10 219). The prognostic impact of HR increase was compared between the two groups, defined as left ventricular ejection fraction of < 50% (HFrEF) and > 50% (HFpEF). Cox regression analysis revealed that elevated baseline HR was associated with increased all-cause mortality in both groups [hazard ratio for the highest tertile (HH) 1.77 in HFrEF, P = 0.008; HH1.82 in HFpEF, P = 0.001]. However, as for mode of death, elevated HR was associated with cardiovascular (CV) death in HFpEF (HH 2.17, P = 0.012), but the association was modest in HFrEF (HH1.49, P = 0.14): in particular, impact on HF death was different between HFpEF (HH 3.79, P = 0.020) and HFrEF (HH 1.07, P = 0.864). In contrast, the prognostic impact of baseline HR on non-CV death was noted only in patients with HFrEF. β-Blocker therapy was associated with reduced HF mortality in HFrEF (hazard ratio 0.49, P = 0.038) but not in HFpEF (hazard ratio 0.64, P = 0.321). CONCLUSIONS: Elevated HR was associated with increased CV death in HFpEF compared with HFrEF, although its impact on all-cause mortality was comparable between the two groups.

BACKGROUND: The gender differences in patients with chronic heart failure (CHF) remain to be fully elucidated in the Japanese population. METHODS AND RESULTS: We examined gender differences in clinical characteristics, treatment and long-term outcome in 4,736 consecutive CHF patients in stage C/D (mean age, 69 years) out of 10,219 patients registered in the CHF Registry, named CHART-2 Study (NCT 00418041). Compared with male patients (68%, n=3,234), female patients (32%, n=1,502) were 3.8 years older and had lower prevalence of ischemic heart disease, diabetes, smoking, myocardial infarction and cancer. At baseline, women had higher prevalence of preserved left ventricular function but had higher NYHA functional class and increased brain natriuretic peptide level. In women, aspirin, β-blockers and statins were less frequently used and diuretics were more frequently used. Crude mortality rate was similar between the genders during the median 3.1-year follow-up (52.4/1,000 and 47.3/1,000 person-years for women and men, respectively, P=0.225). On multivariate Cox regression analysis, women had a reduced risk of mortality (adjusted HR, 0.791; 95% CI: 0.640-0.979, P=0.031). CONCLUSIONS: Substantial gender differences exist in stage C/D CHF patients in real-world practice in Japan. Although female CHF patients had better survival than male patients after adjustment for baseline differences, crude mortality rate was similar between the genders, possibly reflecting relatively severer clinical manifestations in women.

BACKGROUND: Although the need for nursing care (NC) in heart failure (HF) patients is recognized, detailed information on the current status in Japan is lacking. METHODS AND RESULTS: In the CHART-2 Study, we obtained information on daily life, physical ability, nutrition and mental status for 4,174 patients (mean age, 67.1±10.8 years; 73.3% male) out of 10,219 patients. We examined the prevalence, baseline characteristics and clinical outcomes of stage B and C/D HF patients requiring NC. The prevalence of HF requiring NC was significantly higher in stage C/D (38.6%) than in stage B (30.4%; P<0.001). Among the reasons for requiring NC, physical dysfunction was most prevalent in both stage B (20.6%) and C/D (29.0%). Compared with the non-NC group, the NC group was characterized by higher age, higher prevalence of female gender and cerebrovascular disease, and increased plasma brain natriuretic peptide regardless of HF stage. During a median follow-up of 12.7 months after the survey, the NC group had a significantly higher mortality compared with the non-NC group (9.6% vs. 3.6%, P<0.001). On multivariate logistic analysis depressive mental status (hazard ratio [HR], 3.61; P<0.001) and dementia (HR, 2.70; P<0.001) were significantly associated with NC need. CONCLUSIONS: In HF patients, NC need is considerably high and is associated with increased mortality regardless of HF stage in Japan.

BACKGROUND: Microalbuminuria, traditionally defined as urinary albumin/creatinine ratio (UACR) ≥30 mg/g, is a risk factor for mortality even in patients with preserved glomerular filtration rate (GFR). The prognostic impact of subclinical microalbuminuria, however, remains unknown in patients with chronic heart failure (CHF). METHODS AND RESULTS: In the Chronic Heart Failure Analysis and Registry in the Tohoku District 2 Study, we enrolled 2,039 consecutive symptomatic CHF patients (median age, 67.4 years; 68.9% male) after excluding those on hemodialysis. On classification and regression tree analysis, UACR=10.2 mg/g and 27.4 mg/g were identified as the first and second discriminating points to stratify the risk for composite of death, acute myocardial infarction, HF admission and stroke, therefore subclinical microalbuminuria was defined as UACR ≥10.2 and <27.4 mg/g. There were 506 composite endpoints (24.8%) during the median follow-up of 2.69 years. On Kaplan-Meier analysis and multivariate Cox modeling, subclinical microalbuminuria was significantly associated with increased composite endpoints with hazard ratios of 1.90 (P<0.001) and 2.29 (P<0.001) in patients with preserved (>60 ml·min(-1)·1.73 m(-2), n=1,129) or mildly reduced eGFR (30-59.9 ml·min(-1)·1.73 m(-2), n=789), respectively. In patients with severely reduced GFR (eGFR <30 ml·min(-1)·1.73 m(-2), n=121), >80% had microalbuminuria or macroalbuminuria, and only 9.1% were free from any composite endpoints. CONCLUSIONS: Subclinical microalbuminuria was associated with increased risk of cardiovascular events in CHF patients with mildly reduced or preserved renal function.

BACKGROUND: The gender differences in patients with chronic heart failure (CHF) remain to be fully elucidated in the Japanese population. METHODS AND RESULTS: We examined gender differences in clinical characteristics, treatment and long-term outcome in 4,736 consecutive CHF patients in stage C/D (mean age, 69 years) out of 10,219 patients registered in the CHF Registry, named CHART-2 Study (NCT 00418041). Compared with male patients (68%, n=3,234), female patients (32%, n=1,502) were 3.8 years older and had lower prevalence of ischemic heart disease, diabetes, smoking, myocardial infarction and cancer. At baseline, women had higher prevalence of preserved left ventricular function but had higher NYHA functional class and increased brain natriuretic peptide level. In women, aspirin, β-blockers and statins were less frequently used and diuretics were more frequently used. Crude mortality rate was similar between the genders during the median 3.1-year follow-up (52.4/1,000 and 47.3/1,000 person-years for women and men, respectively, P=0.225). On multivariate Cox regression analysis, women had a reduced risk of mortality (adjusted HR, 0.791; 95% CI: 0.640-0.979, P=0.031). CONCLUSIONS: Substantial gender differences exist in stage C/D CHF patients in real-world practice in Japan. Although female CHF patients had better survival than male patients after adjustment for baseline differences, crude mortality rate was similar between the genders, possibly reflecting relatively severer clinical manifestations in women.

BACKGROUND: Although the need for nursing care (NC) in heart failure (HF) patients is recognized, detailed information on the current status in Japan is lacking. METHODS AND RESULTS: In the CHART-2 Study, we obtained information on daily life, physical ability, nutrition and mental status for 4,174 patients (mean age, 67.1±10.8 years; 73.3% male) out of 10,219 patients. We examined the prevalence, baseline characteristics and clinical outcomes of stage B and C/D HF patients requiring NC. The prevalence of HF requiring NC was significantly higher in stage C/D (38.6%) than in stage B (30.4%; P<0.001). Among the reasons for requiring NC, physical dysfunction was most prevalent in both stage B (20.6%) and C/D (29.0%). Compared with the non-NC group, the NC group was characterized by higher age, higher prevalence of female gender and cerebrovascular disease, and increased plasma brain natriuretic peptide regardless of HF stage. During a median follow-up of 12.7 months after the survey, the NC group had a significantly higher mortality compared with the non-NC group (9.6% vs. 3.6%, P<0.001). On multivariate logistic analysis depressive mental status (hazard ratio [HR], 3.61; P<0.001) and dementia (HR, 2.70; P<0.001) were significantly associated with NC need. CONCLUSIONS: In HF patients, NC need is considerably high and is associated with increased mortality regardless of HF stage in Japan.

A 47-year-old Japanese woman was transported to our hospital due to acute heart failure (AHF). She had been diagnosed with primary hyperparathyroidism (pHPT) and undergone parathyroidectomy 3 months previously. Chest X-ray showed marked cardiomegaly and severe pulmonary congestion, and transthoracic echocardiography indicated both left ventricular (LV) systolic and diastolic dysfunction, complicated with extensive massive myocardial calcification and no LV hypertrophy. Computed tomography also showed massive myocardial calcification in the posterior wall of the LV and the interventricular septum. After treatment with furosemide, olprinone, and carperitide under Swan-Ganz monitoring, LV ejection fraction was almost normalized. However, cardiac catheterization in the chronic phase indicated that LV diastolic dysfunction still existed, which might be affected by myocardial calcification. We followed this patient using spironolactone (25 mg/day), perindopril (8 mg/day), and bisoprolol (1.25 mg/day), with no further episode of heart failure for at least 6 months. Here, we report a rare case of AHF complicated with massive myocardial calcification possibly caused by primary hyperparathyroidism. <Learning objective: This is the first case report of acute heart failure due to left ventricular systolic and diastolic dysfunction, complicated with massive myocardial calcification, "porcelain heart", possibly caused by primary hyperparathyroidism.>.

OBJECTIVE: The pleiotropic effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) independent of cholesterol-lowering effects are thought to be mediated through inhibition of the Rho/Rho-kinase pathway. However, we have previously demonstrated that the pleiotropic effects of regular-dose statins are mediated mainly through inhibition of the Rac1 signaling pathway rather than the Rho/Rho-kinase pathway, although the molecular mechanisms of the selective inhibition of the Rac1 signaling pathway by regular-dose statins remain to be elucidated. In this study, we tested our hypothesis that small GTP-binding protein GDP dissociation stimulator (SmgGDS) plays a crucial role in the molecular mechanisms of the Rac1 signaling pathway inhibition by statins in endothelial cells. APPROACH AND RESULTS: In cultured human umbilical venous endothelial cells, statins concentration-dependently increased SmgGDS expression and decreased nuclear Rac1. Statins also enhanced SmgGDS expression in mouse aorta. In control mice, the protective effects of statins against angiotensin II-induced medial thickening of coronary arteries and fibrosis were noted, whereas in SmgGDS-deficient mice, the protective effects of statins were absent. When SmgGDS was knocked down by its small interfering RNA in human umbilical venous endothelial cells, statins were no longer able to induce Rac1 degradation or inhibit angiotensin II-induced production of reactive oxygen species. Finally, in normal healthy volunteers, statins significantly increased SmgGDS expression with a significant negative correlation between SmgGDS expression and oxidative stress markers, whereas no correlation was noted with total or low-density lipoprotein-cholesterol. CONCLUSIONS: These results indicate that statins exert their pleiotropic effects through SmgGDS upregulation with a resultant Rac1 degradation and reduced oxidative stress in animals and humans.

BACKGROUND: Although angiotensin receptor blockers (ARBs) are now one of the first-line drug classes for the management of hypertension, recommendations for the management of chronic heart failure (CHF) are limited. The supplemental benefit of angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial investigates whether an additive treatment with an ARB, olmesartan, reduces the mortality and morbidity in hypertensive patients with stable chronic heart failure. METHODS AND RESULTS: The SUPPORT trial is a prospective randomized open-label blinded endpoint study. Between October 2006 and March 2010, 1147 stable CHF patients treated with evidence-based medications were successfully randomized to either olmesartan or control group. In the olmesartan group, the ARB was initiated at the dose of 5.0-10mg, and was then increased up to 40mg/day, when possible. No ARBs were allowed in the control group. Primary outcome measure in the SUPPORT trial is the composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke and hospital admission due to worsening heart failure. The participants will be followed for at least 3 years until March 2013. CONCLUSIONS: The SUPPORT trial will elucidate the supplemental benefits of an ARB, olmesartan, in hypertensive patients with CHF.

INTRODUCTION: Despite the encouraging results from several randomised controlled trials (RCTs) and meta-analyses, the ability of home telemonitoring for heart failure (HF) to improve patient outcomes remains controversial as a consequence of the two recent large-scale RCTs. However, it has been suggested that there is a subgroup of patients with HF who may benefit from telemonitoring. The aim of the present study was to investigate whether an HF management programme using telemonitoring could improve outcomes in patients with HF under the Japanese healthcare system. METHODS AND ANALYSIS: The Home Telemonitoring Study for Japanese Patients with Heart Failure (HOMES-HF) study is a prospective, multicentre RCT to investigate the effectiveness of home telemonitoring on the primary composite endpoint of all-cause death and rehospitalisation due to worsening HF in recently admitted HF patients (aged 20 and older, New York Heart Association classes II-III). The telemonitoring system is an automated physiological monitoring system including body weight, blood pressure and pulse rate by full-time nurses 7 days a week. Additionally, the system was designed to make it a high priority to support patient's self-care instead of an early detection of HF decompensation. A total sample size of 420 patients is planned according to the Schoenfeld and Richter method. Eligible patients are randomly assigned via a website to either the telemonitoring group or the usual care group by using a minimisation method with biased-coin assignment balancing on age, left ventricular ejection fraction and a history of ischaemic heart disease. Participants will be enrolled until August 2013 and followed until August 2014. Time to events will be estimated using the Kaplan-Meier method, and HRs and 95% CIs will be calculated using the Cox proportional hazards models with stratification factors. TRIAL REGISTRATION: The study is registered at UMIN Clinical Trials Registry (UMIN000006839).

BACKGROUND: Oxidative stress induces secretion of cyclophilin A (CyPA) from vascular smooth muscle cells and it plays a crucial role in the pathogenesis of atherosclerosis in mice. Therefore, we tested our hypothesis that plasma CyPA levels are increased in patients with coronary artery diseases (CAD). METHODS AND RESULTS: In 320 consecutive patients undergoing coronary angiography, we examined the relationship between plasma CyPA levels and the severity of CAD. We measured plasma CyPA by an immunoassay based on the sandwich technique. Plasma CyPA levels were significantly higher in patients with significant coronary stenosis compared to those without it (P<0.001). A positive correlation was noted between plasma CyPA levels and significant coronary stenosis. The average number of stenotic coronary arteries and the need for coronary intervention were significantly increased in the quartiles of higher CyPA levels (both P<0.001). Indeed, the plasma CyPA level significantly correlated with the presence of CAD (adjusted odds ratio for CAD, 6.20; 95% confidence interval, 3.14-12.27; P<0.001). Interestingly, plasma levels of CyPA increased according to the number of atherosclerotic risk factors, all of which induce oxidative stress. Furthermore, plasma levels of CyPA significantly reduced after medical treatment of risk factors. Finally, CyPA was strongly expressed in coronary atherosclerotic plaque in patients with myocardial infarction. CONCLUSIONS: Plasma CyPA level is a novel biomarker for oxidative stress and CAD in humans.

BACKGROUND: Elevated blood urea nitrogen (BUN) observed in patients hospitalized for acute heart failure syndrome (AHFS) may represent increased neurohumoral activation. The purpose of this study was to examine the prognostic impact of BUN changes during hospitalization on the long-term prognosis of AHFS patients. METHODS AND RESULTS: The Tohoku Acute Heart Failure Registry (n=497) is a multicenter retrospective cohort study enrolling AHFS patients who were admitted in 2007. The 337 survivors (mean age, 76 years; 52% male) were divided into 3 groups according to tertiles of BUN change during hospitalization: Decreased (D-BUN, ΔBUN (BUN level at discharge-BUN level at hospitalization)≤-1.63 mg/dl, n=112); Unchanged (U-BUN, ΔBUN-1.64 to 5.73 mg/dl, n=113); Increased (I-BUN, ΔBUN>5.73 mg/dl, n=112). The D-BUN group had higher prevalence of lowest glomerular filtration rate during hospitalization, whereas the I-BUN group had higher systolic blood pressure. During a median follow-up period of 2.3 years after discharge, the Kaplan-Meier curve showed that D-BUN and I-BUN had worse prognosis compared with U-BUN. Multivariable logistic model showed that all-cause death was more frequent in I-BUN (hazard ratio, 2.94; 95% confidence interval, 1.51-5.73; P<0.001). Subgroup analysis revealed that BUN increase during hospitalization was associated with all-cause death, regardless of renal function. CONCLUSIONS: AHFS patients with a BUN increase during hospitalization have worse long-term prognosis, independent of renal function.

BACKGROUND: The prognostic impact of nutritional status is poorly understood in asymptomatic patients with structural and/or functional heart diseases, classified as stage B in the ESC/AHA/ACC chronic heart failure (HF) guidelines. METHODS AND RESULTS: We evaluated the impact of nutrition, using the controlling nutritional status (CONUT) score, calculated by the serum albumin and total cholesterol levels,and lymphocyte number, in 3,421 stage B patients from the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 Study (mean age: 66.9±12.7 years, male: 71.6%). During a median follow-up of 2.89 years, 224 patients died from cardiovascular (45%, n=102) and noncardiovascular (55%, n=123) causes and 139 experienced hospitalization for HF. Survival at 3 years in patients with CONUT 0-1 (reference, n=2,121), 2 (n=693) and ≥3 (n=607) was 95.5, 92.3, and 73.2%, respectively (P<0.001). The adjusted Cox hazard analyses revealed that the CONUT score was significantly associated with increased incidence of all-cause death (hazard ratio 1.27 per point increase; 95% confidence interval, 1.16-1.39, P<0.001). Subgroup analysis showed that per point increase in the CONUT score was significantly associated with a 17% increase in HF hospitalization in patients ≥70 years old (P=0.049), but not in those aged <70 years. CONCLUSIONS: In the current stage B patients, poor nutritional status was associated with increased incidence of death for the overall population and of HF hospitalization for the elderly proportion.

BACKGROUND: Heart failure (HF) is a complex clinical syndrome, resulting from structural and/or functional cardiac disease. The aim of this study was to determine whether the activity of Rho-kinase, which has been identified as an important therapeutic target of cardiovascular disease, is enhanced in HF patients. METHODS AND RESULTS: Total and phosphorylated forms of myosin binding subunit (t-MBS and p-MBS), a substrate of Rho-kinase, were measured on western blotting in circulating leukocytes, and the p-MBS/t-MBS ratio was defined as an index of systemic Rho-kinase activity. First, during the time-course of acute HF (n=12), Rho-kinase activity was significantly elevated in the acute phase compared to the chronic phase (1.19 ± 0.06 vs. 0.97 ± 0.04, P<0.05). Next, Rho-kinase activity was examined in 30 controls and 130 chronic HF patients (cardiomyopathy, n=57; valvular heart disease, n=35; ischemic heart disease [IHD], n=33; and others, n=5). As compared with the controls, Rho-kinase activity was significantly elevated in the total HF group (1.14 ± 0.02 vs. 0.77 ± 0.05, P<0.0001) and in each underlying heart disease (P<0.05 each). Importantly, in the high-risk non-IHD group, Rho-kinase activity was significantly associated with plasma brain nutriuretic peptide level. Finally, p-MBS was expressed in myocardial biopsy samples (immunohistochemistry) in chronic HF patients (n=36), independent of Rho-kinase activity in leukocytes. CONCLUSIONS: Rho-kinase is activated in HF patients, suggesting that it could be a new therapeutic target of the disorder.

BACKGROUND: The appropriate target ranges of heart rate (HR) and systolic blood pressure (SBP) for the management of chronic heart failure (CHF) patients remain to be elucidated in a large-scale cohort study. METHODS AND RESULTS: We examined 3,029 consecutive CHF patients with sinus rhythm (SR) (mean age, 67.9 years) registered in the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 Study (CHART-2; NCT00418041). There were 357 deaths (11.8%) during the median follow-up of 3.1 years. We first performed the classification and regression tree analysis for mortality, identifying SBP <89 mmHg, HR >70 beats/min and SBP <115 mmHg as the primary, secondary and tertiary discriminators, respectively. According to these, we divided the patients into low- (n=1,131), middle- (n=1,624) and high-risk (n=274) groups with mortality risk <10%, 10-20% and >20%, respectively. The low-risk group was characterized by SBP >115 mmHg and HR <70 beats/min and the high-risk group by SBP <89 mmHg regardless of HR values or SBP 89-115 mmHg and HR >76 beats/min. Multivariate Cox regression analysis revealed that the hazard ratio of all-cause death for low-, middle- and high-risk groups was 1.00 (reference), 1.48 (95% confidence interval (CI): 1.10-1.99, P=0.009) and 2.44 (95% CI 1.66-3.58, P<0.001), respectively. Subgroup analysis revealed that age ≥70 years, diabetes, or reduced left ventricular function had higher hazard ratios in the high-risk group. CONCLUSIONS: The results demonstrate the usefulness of combined risk stratification of HR and SBP in CHF patients with SR.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is characterized by multiple co-morbidities, including chronic kidney disease that is one of the prognostic risks for these patients. This study was performed to evaluate the value of determination of albuminuria using a urine dipstick test (UDT), combined with estimated glomerular filtration rate (eGFR), for predicition of mortality in HFpEF. METHODS AND RESULTS: We enrolled 2465 consecutive patients with overt HF with EF ≥50% in our Chronic Heart Failure Analysis and Registry in the Tohoku District 2 (CHART-2) study (NCT00418041). We defined trace or more UDT as positive. We divided the patients into the following four groups based on eGFR and UDT; group 1 (G1) (eGFR ≥60, negative UDT), G2 (eGFR ≥60, positive UDT), G3 (eGFR <60, negative UDT), and G4 (eGFR <60, positive UDT). In total, 29.5% of the HFpEF patients had a positive UDT. HFpEF patients with a positive UDT were characterized by higher brain natriuretic peptide levels and frequent histories of hypertension or diabetes. During a mean follow-up of 2.5 years, HFpEF patients with a positive UDT showed higher mortality in each stratum of eGFR levels. A multivariable adjusted Cox model showed that when compared with G1 (reference), the hazard ratio of all-cause death for G2, G3, and G4 was 2.44 (95% confidence interval 1.47-4.05, P=0.001), 1.43 (0.92-2.23, P=0.12), and 2.71 (1.72-4.27, P<0.001), respectively. Furthermore, the prognostic value of a positive UDT was robust for both cardiovascular and non-cardiovascular deaths. CONCLUSIONS: These results indicate that measurement of albuminuria in addition to eGFR is useful for appropriate risk stratification in HFpEF patients.

BACKGROUND: Distal-type chronic thromboembolic pulmonary hypertension (CTEPH) is a fatal disease for which a new therapeutic strategy needs to be developed. We examined the effects of percutaneous transluminal pulmonary angioplasty (PTPA). METHODS AND RESULTS: We prospectively enrolled 12 patients with distal-type CTEPH. After stabilizing their condition with pulmonary vasodilators, we then performed PTPA, which markedly improved pulmonary hemodynamics and pulmonary artery structure, as confirmed by angiography and optical coherence tomography, and also significantly improved their long-term prognosis compared with 39 historical controls. CONCLUSIONS: PTPA is a promising therapeutic option for distal-type CTEPH.

BACKGROUND: Post-capillary pulmonary hypertension (pc-PH) is a disorder with elevated pulmonary arterial pressure and pulmonary vascular resistance (PVR) because of left heart disease (LHD), and is classified as reactive (PVR >2.5 WU) or passive (PVR ≤ 2.5 WU). However, the clinical significance of these pc-PH subtypes remains to be elucidated. METHODS AND RESULTS: We examined 676 consecutive patients with chronic heart failure (CHF) (NYHA ≥ 2), and found that 158 (23%) had pc-PH: reactive pc-PH in 58 and passive pc-PH in 100. Univariate analysis showed that 4 factors were significantly associated with reactive pc-PH and multivariate analysis showed that female sex was the only independent predictor of reactive pc-PH (odds ratio 2.12, 95% confidence interval (CI) 1.05-4.30, P=0.03). During the mean follow-up period of 2.6 years, 125 CHF patients (18%) died, including 22 with reactive pc-PH and 24 with passive pc-PH (P<0.001). Multivariate Cox regression analysis showed that elevated PVR was independently associated with higher mortality (hazard ratio 1.18, 95%CI 1.03-1.35, P=0.02). Kaplan-Meier analysis demonstrated that the prognosis of patients with reactive pc-PH was significantly worse than for those with no PH or passive pc-PH. Reactive pc-PH was a significant prognostic factor regardless of CHF etiology (ischemic vs. non-ischemic) or reduced/preserved LV ejection fraction (HFrEF vs. HFpEF). CONCLUSIONS: Reactive pc-PH is characterized by predominant female sex and is a significant prognostic factor of LHD with PH.

BACKGROUND: Ezetimibe is an inhibitor of cholesterol absorption in the intestine. We examined whether ezetimibe improves endothelial function, and if so, what mechanisms are involved. METHODS AND RESULTS: Nineteen healthy subjects (male/female 14/5; mean age, 31±3 [SD] years-old) were randomized to receive ezetimibe (10mg/day) or pravastatin (10mg/day) for 4 weeks in a cross-over manner with a 4-week washout interval. Lipid profiles, flow-mediated dilatation (FMD) and Rho-kinase activity of circulating leukocytes (the extent of phosphorylation of myosin binding subunit, a Rho-kinase substrate) were examined. We also evaluated remnant-like particle cholesterol (RLP-C) known as an up-regulator of Rho-kinase and cholesterol absorption status by measuring cholestanol and campesterol/lathosterol ratio (CLR) (both absorption markers). Although ezetimibe and pravastatin equally reduced low-density lipoprotein cholesterol (E: -25% vs. P: -21%), the CLR was reduced by ezetimibe but was rather increased by pravastatin (E: -41% vs. P: +37%; P<0.01). Reduction in RLP-C by ezetimibe was greater compared with pravastatin (E: -33% vs. P: -14%; P<0.05). Importantly, ezetimibe significantly improved FMD (26%, P<0.05) and reduced Rho-kinase activity (-21%, P<0.05), whereas pravastatin had no such effects. A significant correlation was noted between the reduction in cholestanol and the improvement in FMD (P<0.05). CONCLUSIONS: These results indicate that ezetimibe improves endothelial function and inhibits Rho-kinase activity associated with the inhibition of cholesterol absorption, suggesting novel anti-atherogenic effects of the agent in humans.

BACKGROUND: Hospitalization due to acute heart failure syndrome (AHFS) is an indicator of worsened prognosis for patients with cardiovascular disease (CVD). The Chronic Heart Failure Analysis and Registry in the Tohoku District 2 (CHART-2) Study was designed to elucidate characteristics and prognosis of patients at high risk for CVD progression due to AHFS. METHODS AND RESULTS: The CHART-2 Study is a prospective observational multicenter cohort study. Patients with overt HF, structural cardiac disorder but without HF, or with coronary artery disease (CAD) have been consecutively enrolled from October 2006. As of March 2010, a total of 10,219 patients have been recruited, making the Study the largest multicenter prospective cohort of HF patients in Japan. The mean patient age was 68.2±12.3 years and male patients accounted for 69.8%. Overt HF was observed in 46.3% of patients; and 53.7% did not have HF but were at high risk for AHFS. As HF stage progressed, the prognostic risks (eg, chronic kidney disease, reduced ejection fraction, and increased B-type natriuretic peptide level) became more prominent. Compared with the previous CHART-1 study, the prevalence of ischemic etiology and risk factors (hypertension, diabetes) have increased, as in Western studies. CONCLUSIONS: This first report demonstrates the trend of westernization of ischemic etiology and clinical characteristics of HF patients in Japan, indicating the importance of appropriate management and prevention of CAD to prevent AHFS.

BACKGROUND: Pulmonary arterial hypertension (PAH) remains a serious disease characterized by elevated pulmonary artery pressure (PAP) and increased pulmonary vascular resistance (PVR). Among its subtypes, PAH associated with connective tissue disease (CPAH) has the worse prognosis, because of resistance to conventional vasodilator therapy. We hypothesized that intensive immunosuppressive therapy (IIT) could improve the pulmonary hemodynamics in CPAH. METHODS AND RESULTS: In our pulmonary hypertension (PH) cohort of 182 patients, we evaluated 13 consecutive patients with CPAH who received IIT combined with cyclophosphamide and glucocorticosteroids (IIT group, mean age 45 ± 8 years, 12 females and 1 male). We compared them with 8 historical controls (control group: mean age 52 ± 18 years, 8 females) for pulmonary hemodynamics and prognosis. Both groups were treated with conventional vasodilator therapy. Although the mean PAP (mPAP) remained unchanged in the control group, IIT significantly decreased mPAP (40 ± 9 to 29 ± 11 mmHg, P < 0.01) and tended to decrease PVR (700 ± 434 to 481 ± 418 dyne·s·cm⁻⁵, P=0.07). Importantly, in 6 of the 13 patients in the IIT group, mPAP was almost normalized (< 25 mmHg) and remained stabilized for more than 1 year. Furthermore, the IIT group showed significantly better prognosis compared with the control group (P<0.01). CONCLUSIONS: These results suggest that IIT as well as conventional vasodilator therapy improves the pulmonary hemodynamics and long-term prognosis of patients with CPAH.

BACKGROUND: Prognostic impact of body mass index (BMI) in Japanese patients with chronic heart failure (HF) remains unclear. METHODS AND RESULTS: We examined the relationship between BMI and the prognosis of Japanese HF patients in the Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART) study. The study sample was 972 Japanese chronic HF patients (mean age, 68.2 ± 13.5; male 65.2%). We categorized them into 5 groups; BMI <18.5, 18.5 to 22.9, 23.0 to 24.9 (reference), 25.0 to 29.9, and ≥ 30.0. Using a Cox hazards model, the relationships between BMI and deaths or admission for worsening HF were studied in detail. Mean follow-up period was 3.4 ± 1.7 years. Multivariate analysis showed that, as compared with reference group (BMI 23.0 to 24.9), hazard ratios (HR) for all-cause death showed a U-shaped association with 1.70 (95% confidence interval; 1.04-2.76), 1.23 (0.85-1.78), 1.26 (0.84-1.90), and 2.75 (1.51-5.00) among those with BMI<18.5, 18.5 to 22.9, 25.0 to 29.9, and ≥ 30.0, respectively. There were significant and suggestive U-shaped associations between BMI and cardiac-cause death or admission for worsening HF. CONCLUSIONS: Both high and low BMIs were associated with increased outcomes, suggesting that extreme obesity is not beneficial in improving the prognosis of Japanese chronic HF patients.