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: 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.

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.

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.

OBJECTIVES: Delirium is an important prognostic factor in postoperative patients undergoing cardiovascular surgery and intervention, including transcatheter aortic valve implantation (TAVI). However, delirium after transcatheter aortic valve implantation (DAT) is difficult to predict and its pathophysiology is still unclear. We aimed to investigate whether preoperative cerebral blood flow (CBF) is associated with DAT and, if so, whether CBF measurement is useful for predicting DAT. METHODS: We evaluated CBF in 50 consecutive patients before TAVI (84.7±4.5 yrs., 36 females) using 99mTc ethyl cysteinate dimer single-photon emission computed tomography. Preoperative CBF of the DAT group (N = 12) was compared with that of the non-DAT group (N = 38) using whole brain voxel-wise analysis with SPM12 and region of interest-based analysis with the easy-Z score imaging system. Multivariable logistic regression analysis with the presence of DAT was used to create its prediction model. RESULTS: The whole brain analysis showed that preoperative CBF in the insula was lower in the DAT than in the non-DAT group (P<0.05, family-wise error correction). Decrease extent ratio in the insula of the DAT group (17.6±11.5%) was also greater relative to that of the non-DAT group (7.0±11.3%) in the region of interest-based analysis (P = 0.007). A model that included preoperative CBF in the insula and conventional indicators (frailty index, short physical performance battery and mini-mental state examination) showed the best predictive power for DAT (AUC 0.882). CONCLUSIONS: These results suggest that preoperative CBF in the insula is associated with DAT and may be useful for its prediction.

INTRODUCTION: Takotsubo syndrome (TTS) is triggered mostly by physical and/or emotional stress that is processed in stress-associated brain regions, including the amygdala. However, it remains unclear whether such stress-induced brain activity is associated with TTS onset. METHODS AND RESULTS: We acquired brain [18F]-2-fluoro-deoxy-d-glucose (18F-FDG) positron emission tomography in 4 TTS patients (44-82 yrs., 3 women) on days 2-4 (acute phase) and days 29-40 (recovery phase) after diagnosis of TTS was made by coronary angiography and left ventriculogram. The 18F-FDG uptake was measured globally and also in the pre-defined regions of interest of the bilateral amygdala on the common Montreal Neurological Institute space; all 18F-FDG images were normalized using automated image pre-processing. Amygdalar activity was calculated by dividing the 18F-FDG uptake of the amygdala by the global brain uptake. Left ventriculograms showed that apical ballooning was typical at diagnosis and was then relieved in the recovery phase. Amygdalar activity in the acute phase (0.872 ± 0.032) was higher than in the recovery phase (0.805 ± 0.037) (P = 0.013). CONCLUSIONS: We report here 4 cases of TTS showing higher amygdalar activity in the acute phase as compared with the recovery phase, suggesting that increased stress-induced neurobiological activity is associated with TTS onset.

Background: Excessive alcohol consumption is associated with damage to various organs, but its multi-organ effects have not been characterised across the usual range of alcohol drinking in a large general population sample. Methods: We assessed global effect sizes of alcohol consumption on quantitative magnetic resonance imaging phenotypic measures of the brain, heart, aorta, and liver of UK Biobank participants who reported drinking alcohol. Results: We found a monotonic association of higher alcohol consumption with lower normalised brain volume across the range of alcohol intakes (-1.7 × 10-3 ± 0.76 × 10-3 per doubling of alcohol consumption, p=3.0 × 10-14). Alcohol consumption was also associated directly with measures of left ventricular mass index and left ventricular and atrial volume indices. Liver fat increased by a mean of 0.15% per doubling of alcohol consumption. Conclusions: Our results imply that there is not a 'safe threshold' below which there are no toxic effects of alcohol. Current public health guidelines concerning alcohol consumption may need to be revisited. Funding: See acknowledgements.

BACKGROUND: Danon disease is an X-linked dominant disorder with defects in the lysosome-associated membrane protein 2 (LAMP2) gene and is characterized histologically by intracellular autophagic vacuoles in skeletal and cardiac muscles. Cardiac magnetic resonance (CMR) T1 mapping potentially allows to differentiate intracellular and extracellular cardiac abnormalities with a combination of native T1 value and extracellular volume (ECV) fraction. CASE SUMMARY: We assessed CMR T1 mapping in two Danon disease patients (a 22-year-old man and his 48-year-old mother), who had a LAMP2 c.864G>A p. Val288Val mutation, and two blood relatives without Danon disease (his 47-year-old maternal aunt and 49-year-old father). The male patient underwent a left ventricular (LV) assist device implantation at 15 months after the image acquisition because he was inotrope dependent (INTERMACS profile 3) and had no noticeable psychological or musculoskeletal symptoms. His mother was in New York Heart Association Class II with mildly reduced LV ejection fraction (46%). The Danon group showed late gadolinium enhancement (LGE) in the anterior and posterolateral LV walls. In the interventricular wall, where evident LGE was not noted, the Danon group had high native T1 value, compared with the T1 value in the non-Danon group, and normal ECV fraction. Cardiac biopsy from the interventricular wall showed intracytoplasmic autophagic vacuoles, which are characteristics of Danon disease. DISCUSSION: This characteristic pattern of high native T1 and normal ECV fraction in the areas without LGE, which may reflect the existence of intracytoplasmic autophagic vacuoles, may support the differential diagnosis of Danon disease from other cardiomyopathies.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

Differences in cardiac and aortic structure and function are associated with cardiovascular diseases and a wide range of other types of disease. Here we analyzed cardiovascular magnetic resonance images from a population-based study, the UK Biobank, using an automated machine-learning-based analysis pipeline. We report a comprehensive range of structural and functional phenotypes for the heart and aorta across 26,893 participants, and explore how these phenotypes vary according to sex, age and major cardiovascular risk factors. We extended this analysis with a phenome-wide association study, in which we tested for correlations of a wide range of non-imaging phenotypes of the participants with imaging phenotypes. We further explored the associations of imaging phenotypes with early-life factors, mental health and cognitive function using both observational analysis and Mendelian randomization. Our study illustrates how population-based cardiac and aortic imaging phenotypes can be used to better define cardiovascular disease risks as well as heart-brain health interactions, highlighting new opportunities for studying disease mechanisms and developing image-based biomarkers.

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.

BACKGROUND: Although depressive symptoms increased mortality and hospitalization in chronic heart failure (CHF) patients, the underlying mechanism remains unclear. The aim of this study was to investigate whether an alteration in hippocampal perfusion, which is the neural substrate of depressive symptoms, is associated with changes in cardiac structures and/or functions in CHF patients. METHODS: We used baseline data of 70 CHF patients (66.8 ± 8.9 yrs, 32.5% women), including cerebral blood flow (CBF) in the hippocampus, geriatric depression scale (GDS) scores and echocardiographic parameters, in the Brain Assessment and Investigation in Heart Failure Trial (B-HeFT) (UMIN000008584). Echocardiography was repeated at 3.1 ± 0.5 years after the baseline evaluation. We first tested voxel-wise regression model with hippocampal CBF as dependent variable and each of echocardiographic parameter change as independent variable, adjusted for age and sex. Structural equation modeling was used to test a mediation effect of cognitive test scores on associations between hippocampal perfusion and changes in cardiac structures and/or functions. RESULTS: Baseline anterior hippocampal CBF was negatively correlated with changes in left ventricular posterior wall thickness (PWT) (P < 0.05 with family-wise error corrections). An existence of depressive symptoms was positively correlated with the baseline anterior CBF and negatively with the PWT changes (P < 0.05, both). There were both direct effects of the baseline anterior hippocampal CBF on PWT thinning and effects mediated through the depressive symptoms (P < 0.05, both). CONCLUSIONS: This study provides the first evidence that the alteration in hippocampal perfusion may lead to changes in cardiac structures via increase in depressive symptoms in CHF patients.

AIMS: The aim of this study was to examine the mechanisms of cognitive impairment and reversibility in elderly patients with severe aortic stenosis (AS) after transcatheter aortic valve implantation (TAVI) with special reference to cerebral blood flow (CBF). METHODS AND RESULTS: We examined 15 elderly patients with severe AS (mean age 83.2±4.5 years, 12 female) who underwent TAVI. Before and three months after TAVI, we evaluated cognitive function with the Logical Memory II test (LM II), cardiac output (CO) with echocardiography, and CBF with 99mTc single-photon emission computed tomography (SPECT). LM II score and CO were significantly increased after TAVI compared with baseline (p<0.01 for LM II, p<0.005 for CO). Notably, CBF in the local regions, including that in the right hippocampus, was significantly increased after TAVI (p<0.005 at each voxel). The patients with increased CO after TAVI also showed significantly increased CBF in the right hippocampus compared with those without it (p<0.01). Importantly, CBF in the right hippocampus was positively correlated with LM II scores (p<0.05). CONCLUSIONS: These results provide the first evidence that TAVI may improve cognitive functions associated with increased cerebral perfusion especially in the hippocampus in elderly patients with severe AS.

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.

In large population studies such as the UK Biobank (UKBB), quality control of the acquired images by visual assessment is unfeasible. In this paper, we apply a recently developed fully-automated quality control pipeline for cardiac MR (CMR) images to the first 19,265 short-axis (SA) cine stacks from the UKBB. We present the results for the three estimated quality metrics (heart coverage, inter-slice motion and image contrast in the cardiac region) as well as their potential associations with factors including acquisition details and subject-related phenotypes. Up to 14.2% of the analysed SA stacks had sub-optimal coverage (i.e. missing basal and/or apical slices), however most of them were limited to the first year of acquisition. Up to 16% of the stacks were affected by noticeable inter-slice motion (i.e. average inter-slice misalignment greater than 3.4 mm). Inter-slice motion was positively correlated with weight and body surface area. Only 2.1% of the stacks had an average end-diastolic cardiac image contrast below 30% of the dynamic range. These findings will be highly valuable for both the scientists involved in UKBB CMR acquisition and for the ones who use the dataset for research purposes.

AIMS: Recent clinical studies demonstrated the association between myocardial infarction (MI) and osteoporotic fractures. We examined whether MI causes bone loss and the effects of exercise training on bone in mice after MI. METHODS: We created a MI model in 16-week-old male apolipoprotein E-deficient mice (n = 42), which were randomly assigned to exercise group (MI-Ex) and sedentary group (MI-Sed). We also performed sham operations in other mice (n = 10). Treadmill exercise training was performed from one week after operation to eight weeks. At eight weeks, the bone parameters of the femur were measured by quantitative computed tomography, followed by histological analysis (n = 10-17). RESULTS: Bone mineral density (BMD) of the femur was significantly decreased in the MI-Sed group as compared with the sham group (P < 0.001), whereas the BMD was significantly increased in the MI-Ex group as compared with the MI-Sed group (P < 0.05). In histological analysis, Rho-associated coiled-coil kinase 2 and tartrate-resistant acid phosphate positive (bone resorptive) area in distal femur were significantly increased in the MI-Sed group as compared with the sham group (P < 0.05), whereas those parameters were significantly decreased in the MI-Ex group as compared with the MI-Sed group (P < 0.05). In contrast, alkaline phosphatase (ALP)-positive (bone-forming) area was significantly decreased in the MI-Sed group as compared with the sham group (P < 0.05), whereas ALP-positive area was significantly increased in the MI-Ex group as compared with the MI-Sed group (P < 0.05). CONCLUSIONS: The present study demonstrates that MI reduces BMD and treadmill exercise training prevents the reduction of BMD in apolipoprotein E-deficient mice.

Importance: Identifying brain regions associated with risk factors for dementia could guide mechanistic understanding of risk factors associated with Alzheimer disease (AD). Objectives: To characterize volume changes in brain regions associated with aging and modifiable risk factors for dementia (MRFD) and to test whether volume differences in these regions are associated with cognitive performance. Design, Setting, and Participants: This cross-sectional study used data from UK Biobank participants who underwent T1-weighted structural brain imaging from August 5, 2014, to October 14, 2016. A voxelwise linear model was applied to test for regional gray matter volume differences associated with aging and MRFD (ie, hypertension, diabetes, obesity, and frequent alcohol use). The potential clinical relevance of these associations was explored by comparing their neuroanatomical distributions with the regional brain atrophy found with AD. Mediation models for risk factors, brain volume differences, and cognitive measures were tested. The primary hypothesis was that common, overlapping regions would be found. Primary analysis was conducted on April 1, 2018. Main Outcomes and Measures: Gray matter regions that showed relative atrophy associated with AD, aging, and greater numbers of MRFD. Results: Among 8312 participants (mean [SD] age, 62.4 [7.4] years; 3959 [47.1%] men), aging and 4 major MRFD (ie, hypertension, diabetes, obesity, and frequent alcohol use) had independent negative associations with specific gray matter volumes. These regions overlapped neuroanatomically with those showing lower volumes in participants with AD, including the posterior cingulate cortex, the thalamus, the hippocampus, and the orbitofrontal cortex. Associations between these MRFD and spatial memory were mediated by differences in posterior cingulate cortex volume (β = 0.0014; SE = 0.0006; P = .02). Conclusions and Relevance: This cross-sectional study identified differences in localized brain gray matter volume associated with aging and MRFD, suggesting regional vulnerabilities. These differences appeared relevant to cognitive performance even among people considered cognitively healthy.

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.

The effectiveness of a cardiovascular magnetic resonance (CMR) scan depends on the ability of the operator to correctly tune the acquisition parameters to the subject being scanned and on the potential occurrence of imaging artifacts, such as cardiac and respiratory motion. In the clinical practice, a quality control step is performed by visual assessment of the acquired images; however, this procedure is strongly operator-dependent, cumbersome, and sometimes incompatible with the time constraints in clinical settings and large-scale studies. We propose a fast, fully automated, and learning-based quality control pipeline for CMR images, specifically for short-axis image stacks. Our pipeline performs three important quality checks: 1) heart coverage estimation; 2) inter-slice motion detection; 3) image contrast estimation in the cardiac region. The pipeline uses a hybrid decision forest method-integrating both regression and structured classification models-to extract landmarks and probabilistic segmentation maps from both long- and short-axis images as a basis to perform the quality checks. The technique was tested on up to 3000 cases from the UK Biobank and on 100 cases from the UK Digital Heart Project and validated against manual annotations and visual inspections performed by expert interpreters. The results show the capability of the proposed pipeline to correctly detect incomplete or corrupted scans (e.g., on UK Biobank, sensitivity and specificity, respectively, 88% and 99% for heart coverage estimation and 85% and 95% for motion detection), allowing their exclusion from the analyzed dataset or the triggering of a new acquisition.

BACKGROUND: The trend towards large-scale studies including population imaging poses new challenges in terms of quality control (QC). This is a particular issue when automatic processing tools such as image segmentation methods are employed to derive quantitative measures or biomarkers for further analyses. Manual inspection and visual QC of each segmentation result is not feasible at large scale. However, it is important to be able to automatically detect when a segmentation method fails in order to avoid inclusion of wrong measurements into subsequent analyses which could otherwise lead to incorrect conclusions. METHODS: To overcome this challenge, we explore an approach for predicting segmentation quality based on Reverse Classification Accuracy, which enables us to discriminate between successful and failed segmentations on a per-cases basis. We validate this approach on a new, large-scale manually-annotated set of 4800 cardiovascular magnetic resonance (CMR) scans. We then apply our method to a large cohort of 7250 CMR on which we have performed manual QC. RESULTS: We report results used for predicting segmentation quality metrics including Dice Similarity Coefficient (DSC) and surface-distance measures. As initial validation, we present data for 400 scans demonstrating 99% accuracy for classifying low and high quality segmentations using the predicted DSC scores. As further validation we show high correlation between real and predicted scores and 95% classification accuracy on 4800 scans for which manual segmentations were available. We mimic real-world application of the method on 7250 CMR where we show good agreement between predicted quality metrics and manual visual QC scores. CONCLUSIONS: We show that Reverse classification accuracy has the potential for accurate and fully automatic segmentation QC on a per-case basis in the context of large-scale population imaging as in the UK Biobank Imaging Study.

Patients with adult congenital heart disease (ACHD) are at increased risk of developing late cardiovascular complication. However, little is known about the predictive factors for long-term outcome. The Model for End-Stage Liver Disease eXcluding INR (MELD-XI) score was originally developed to assess cirrhotic patients and has the prognostic value for heart failure (HF) patients. In the present study, we examined whether the score also has the prognostic value in this population. We retrospectively examined 637 ACHD patients (mean age 31.0 years) who visited our Tohoku University hospital from 1995 to 2015. MELD-XI score was calculated as follows; 11.76 x ln(serum creatinine) + 5.11 x ln(serum total bilirubin) + 9.44. We compared the long-term outcomes between the high (≥10.4) and the low (<10.4) score groups. The cutoff value of MELD-XI score was determined based on the survival classification and regression tree (CART) analysis. The major adverse cardiac event (MACE) was defined as a composite of cardiac death, HF hospitalization, and lethal ventricular arrhythmias. During a mean follow-up period of 8.6 years (interquartile range 4.4-11.4 years), MACE was noted in 51 patients, including HF hospitalization in 37, cardiac death in 8, and lethal ventricular arrhythmias in 6. In Kaplan-Meier analysis, the high score group had significantly worse MACE-free survival compared with the low score group (log-rank, P<0.001). Multivariable Cox regression analysis showed that the MELD-XI score remained a significant predictor of MACE (hazard ratio 1.36, confidence interval 1.17-1.58, P<0.001) even after adjusting for patient characteristics, such as sex, functional status, estimated glomerular filtration rate, and cardiac function. Furthermore, CART analysis revealed that the MELD-XI score was the most important variable for predicting MACE. These results demonstrate that the MELD-XI score can effectively predict MACE in ACHD patients, indicating that ACHD patients with high MELD-XI score need to be closely followed.

BACKGROUND: Cardiovascular resonance (CMR) imaging is a standard imaging modality for assessing cardiovascular diseases (CVDs), the leading cause of death globally. CMR enables accurate quantification of the cardiac chamber volume, ejection fraction and myocardial mass, providing information for diagnosis and monitoring of CVDs. However, for years, clinicians have been relying on manual approaches for CMR image analysis, which is time consuming and prone to subjective errors. It is a major clinical challenge to automatically derive quantitative and clinically relevant information from CMR images. METHODS: Deep neural networks have shown a great potential in image pattern recognition and segmentation for a variety of tasks. Here we demonstrate an automated analysis method for CMR images, which is based on a fully convolutional network (FCN). The network is trained and evaluated on a large-scale dataset from the UK Biobank, consisting of 4,875 subjects with 93,500 pixelwise annotated images. The performance of the method has been evaluated using a number of technical metrics, including the Dice metric, mean contour distance and Hausdorff distance, as well as clinically relevant measures, including left ventricle (LV) end-diastolic volume (LVEDV) and end-systolic volume (LVESV), LV mass (LVM); right ventricle (RV) end-diastolic volume (RVEDV) and end-systolic volume (RVESV). RESULTS: By combining FCN with a large-scale annotated dataset, the proposed automated method achieves a high performance in segmenting the LV and RV on short-axis CMR images and the left atrium (LA) and right atrium (RA) on long-axis CMR images. On a short-axis image test set of 600 subjects, it achieves an average Dice metric of 0.94 for the LV cavity, 0.88 for the LV myocardium and 0.90 for the RV cavity. The mean absolute difference between automated measurement and manual measurement is 6.1 mL for LVEDV, 5.3 mL for LVESV, 6.9 gram for LVM, 8.5 mL for RVEDV and 7.2 mL for RVESV. On long-axis image test sets, the average Dice metric is 0.93 for the LA cavity (2-chamber view), 0.95 for the LA cavity (4-chamber view) and 0.96 for the RA cavity (4-chamber view). The performance is comparable to human inter-observer variability. CONCLUSIONS: We show that an automated method achieves a performance on par with human experts in analysing CMR images and deriving clinically relevant measures.

Severe pulmonary arterial hypertension (PAH) rarely develops in children with an atrial septal defect (ASD), even those with a large defect. We herein report the case of a 27-year-old man with a moderate-sized secundum ASD and right ventricular failure due to severe PAH, which developed in his early teens. He was diagnosed as having a genetic mutation of the bone morphogenetic protein receptor-2 (BMPR2) gene and was successfully treated with bilateral lung transplantation with ASD path closure. In patients with congenital heart disease, a genetic analysis may provide information about the lifetime risk of developing PAH.

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.

OBJECTIVE: Drug-eluting stent-induced coronary hyperconstricting responses remain an important issue. The adventitia harbors a variety of components that potently modulate vascular tone, including sympathetic nerve fibers (SNF) and vasa vasorum. Catheter-based renal denervation (RDN) inhibits sympathetic nerve activity. We, thus, examined whether RDN suppresses drug-eluting stent-induced coronary hyperconstricting responses, and if so, what mechanisms are involved. APPROACH AND RESULTS: Protocol 1: pigs implanted with everolimus-eluting stents into the left coronary arteries underwent coronary angiography at 1 month after implantation for assessment of coronary vasomotion and adventitial SNF formation. Drug-eluting stent-induced coronary hyperconstricting responses were significantly enhanced associated with enhanced coronary adventitial SNF and vasa vasorum formation. Protocol 2: pigs implanted with everolimus-eluting stents were randomly assigned to the RDN or sham group. The RDN group underwent renal ablation. At 1 month, RDN significantly caused marked damage of the SNF at the renal arteries without any stenosis, thrombus, or dissections. Notably, RDN significantly upregulated the expression of α2-adrenergic receptor-binding sites in the nucleus tractus solitarius, attenuated muscle sympathetic nerve activity, and decreased systolic blood pressure and plasma renin activity. In addition, RDN attenuated coronary hyperconstricting responses to intracoronary serotonin at the proximal and distal stent edges associated with decreases in SNF and vasa vasorum formation, inflammatory cell infiltration, and Rho-kinase expression/activation. Furthermore, there were significant positive correlations between SNF and vasa vasorum and between SNF and coronary vasoconstricting responses. CONCLUSIONS: These results provide the first evidence that RDN ameliorates drug-eluting stent-induced coronary hyperconstricting responses in pigs in vivo through the kidney-brain-heart axis.

Case: A 72-year-old man presented to our hospital after ingesting insecticide containing approximately 2 mL/kg diethylene glycol, which exceeded the lethal dose of 1 mL/kg. The patient recovered from critical symptoms on acute phase until day 3, but received artificial ventilation for muscle weakness secondary to sensorimotor neuropathy on days 11-54. Outcome: Even after marked improvement from sensorimotor neuropathy, the patient continued to complain of orthostatic hypotension. Autonomic neuropathy was identified by positive result of a head-up tilt test, and reduction in coefficient of variation of R-R intervals and cardiac iodine-123-metaiodobenzylguanidine uptake for the assessment of cardiac sympathetic activity. The patient's symptoms fully recovered 2 years after the exposure to diethylene glycol. Conclusion: This case shows the first report of delayed autonomic neuropathy after recovery from severe sensorimotor neuropathy, and suggests the importance of continuous monitoring for late-onset neurological complications.

OBJECTIVES: To characterize effects of chronically elevated blood pressure on the brain, we tested for brain white matter microstructural differences associated with normotension, pre-hypertension and hypertension in recently available brain magnetic resonance imaging data from 4659 participants without known neurological or psychiatric disease (62.3±7.4 yrs, 47.0% male) in UK Biobank. METHODS: For assessment of white matter microstructure, we used measures derived from neurite orientation dispersion and density imaging (NODDI) including the intracellular volume fraction (an estimate of neurite density) and isotropic volume fraction (an index of the relative extra-cellular water diffusion). To estimate differences associated specifically with blood pressure, we applied propensity score matching based on age, sex, educational level, body mass index, and history of smoking, diabetes mellitus and cardiovascular disease to perform separate contrasts of non-hypertensive (normotensive or pre-hypertensive, N = 2332) and hypertensive (N = 2337) individuals and of normotensive (N = 741) and pre-hypertensive (N = 1581) individuals (p<0.05 after Bonferroni correction). RESULTS: The brain white matter intracellular volume fraction was significantly lower, and isotropic volume fraction was higher in hypertensive relative to non-hypertensive individuals (N = 1559, each). The white matter isotropic volume fraction also was higher in pre-hypertensive than in normotensive individuals (N = 694, each) in the right superior longitudinal fasciculus and the right superior thalamic radiation, where the lower intracellular volume fraction was observed in the hypertensives relative to the non-hypertensive group. SIGNIFICANCE: Pathological processes associated with chronically elevated blood pressure are associated with imaging differences suggesting chronic alterations of white matter axonal structure that may affect cognitive functions even with pre-hypertension.

BACKGROUND: It remains to be elucidated whether cardiac sympathetic nervous activity is impaired in patients with Anderson-Fabry disease (AFD).Methods and Results:We performed 123I-meta-iodobenzylguanidine (MIBG) scintigraphy and gadolinium-enhanced cardiovascular magnetic resonance (CMR) in 5 AFD patients. MIBG uptake in the inferolateral wall, where wall thinning and delayed enhancement were noted on CMR, was significantly lower compared with the anteroseptal wall. The localized reduction in MIBG uptake was also noted in 2 patients with no obvious abnormal findings on CMR. CONCLUSIONS: Cardiac sympathetic nervous activity is impaired in AFD before development of structural myocardial abnormalities. (Circ J 2016; 80: 2550-2551).

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).

PURPOSE: To evaluate whether the extent of perfusion defects assessed by examining lung perfused blood volume (PBV) images is a stronger estimator of the clinical severity of chronic thromboembolic pulmonary hypertension (CTEPH) compared with other computed tomography (CT) findings and noninvasive parameters. MATERIALS AND METHODS: We analyzed 46 consecutive patients (10 men, 36 women) with CTEPH who underwent both dual-energy CT and right-heart catheter (RHC) examinations. Lung PBV images were acquired using a second-generation dual-source CT scanner. Two radiologists independently scored the extent of perfusion defects in each lung segment employing the following criteria: 0, no defect, 1, defect in <50% of a segment, 2, defect in ≥50% of a segment. Each lung PBV score was defined as the sum of the scores of 18 segments. In addition, all of the following were recorded: 6-min walk distance (6MWD), brain natriuretic peptide (BNP) level, and RHC hemodynamic parameters including pulmonary artery pressure (PAP), right ventricular pressure (RVP), cardiac output (CO), the cardiac index (CI), and pulmonary vascular resistance (PVR). Bootstrapped weighted kappa values with 95% confidence intervals (CIs) were calculated to evaluate the level of interobserver agreement. Correlations between lung PBV scores and other parameters were evaluated by calculating Spearman's rho correlation coefficients. Multivariable linear regression analyses (using a stepwise method) were employed to identify useful estimators of mean PAP and PVR among CT, BNP, and 6MWD parameters. A p value<0.05 was considered to reflect statistical significance. RESULTS: Interobserver agreement in terms of the scoring of perfusion defects was excellent (κ=0.88, 95% CIs: 0.85, 0.91). The lung PBV score was significantly correlated with the PAP (mean, rho=0.48; systolic, rho=0.47; diastolic, rho=0.39), PVR (rho=0.47), and RVP (rho=0.48) (all p values<0.01). Multivariable linear regression analyses showed that only the lung PBV score was significantly associated with both the mean PAP (coefficient, 0.84, p<0.01) and the PVR (coefficient, 28.83, p<0.01). CONCLUSION: The lung PBV score is a useful and noninvasive estimator of clinical CTEPH severity, especially in comparison with the mean PAP and PVR, which currently serve as the gold standards for the management of CTEPH .

BACKGROUND: Depressive symptoms and memory impairment are prevalent in patients with chronic heart failure (CHF). Although the mechanisms remain to be elucidated, the hippocampus (an important brain area for emotion and memory) may be a possible neural substrate for these symptoms. METHODS AND RESULTS: We prospectively enrolled 40 Stage C patients, who had past or current CHF symptoms, and as controls 40 Stage B patients, who had structural heart disease but had never had CHF symptoms, in Brain Assessment and Investigation in Heart Failure Trial (B-HeFT) (UMIN000008584). As the primary index, we measured cerebral blood flow (CBF) in the 4 anterior-posterior segments of the hippocampus, using brain MRI analysis. Depressive symptoms, immediate memory (IM) and delayed memory (DM) were assessed using Geriatric Depression Scale (GDS), and Wechsler Memory Scale-revised (WMS-R), respectively. Hippocampus CBF in the most posterior segment was significantly lower in Stage C than in Stage B group (P=0.029 adjusted for Holm's method). Multiple regression analysis identified significant association between hippocampus CBF and GDS or DM score in Stage C group (all P<0.05). GDS score was significantly higher, and IM and DM scores were lower in Stage C patients with hippocampus CBF below the median than those with hippocampus CBF above the median (all P<0.05). CONCLUSIONS: Hippocampus abnormalities are associated with depressive symptoms and cognitive impairment in CHF patients. (Circ J 2016; 80: 1773-1780).

BACKGROUND: It remains to be determined whether balloon pulmonary angioplasty (BPA) improves biventricular cardiac functions and pulmonary flow in patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS AND RESULTS: We enrolled 30 consecutive patients with inoperable CTEPH who underwent BPA, and carried out serial cardiac magnetic resonance imaging (CMR; M/F, 9/21; median age, 65.2 years). No patient died during the treatment or follow-up period. BPA significantly improved WHO functional class (III/IV, 83.0 to 4.0%), 6-min walking distance (330.2±168.7 to 467.3±114.4 m), mean pulmonary artery pressure (40.8±10.7 to 23.2±4.94 mmHg), pulmonary vascular resistance (9.26±4.19 to 3.35±1.40 WU) and cardiac index (2.19±0.64 to 2.50±0.57 L·min·m(2); all P<0.01). CMR also showed improvement of right ventricular (RV) ejection fraction (EF; 41.3±12.4 to 50.7±8.64%), left ventricular (LV) end-diastolic volume index (72.1±14.0 to 81.6±18.6 ml/m(2)) and LV stroke volume index (41.0±9.25 to 47.8±12.3 ml/m(2); all P<0.01). There was a significant correlation between change in RVEF and LVEF (Pearson's r=0.45, P=0.01). Average velocity in the main pulmonary artery was also significantly improved (7.50±2.43 to 9.79±2.92 cm/s, P<0.01). CONCLUSIONS: BPA improves biventricular functions and pulmonary flow in patients with inoperable CTEPH. (Circ J 2016; 80: 1470-1477).

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.

Bradyarrhythmia is usually a spontaneously subsiding complication of cervical spinal cord injury. However, in severe cases, it can lead to cardiac arrest. We report a case of cervical spinal cord injury, complicated by right-sided infective endocarditis after the placement of a temporary pacing catheter in the right ventricle for severe bradyarrhythmia that led to cardiac arrest. Although the patient׳s condition was successfully treated by pacing catheter removal and pharmacological therapy, right-sided infective endocarditis would be a fatal complication in cases of cervical spinal cord injury where cardiac pacing is required for long-term refractory severe bradyarrhythmia.

Heart failure (HF) is characterized by a blood supply which is insufficient to meet the body's demand. HF can potentially affect the brain and is associated with a high prevalence of depression. However, the mechanisms by which the two are related remain largely unclear. Structural abnormalities of the ventral hippocampus have been observed in depression but have never been reported in HF. In this study, we thus investigated structural brain abnormality in HF using voxel-based morphometry (VBM) and histological analysis in a rat model of HF. T2-weighted images were obtained in rats with HF (n = 20) and sham rats (n = 17) and VBM was used to produce gray matter concentration (GMC) maps. Twenty-four hour locomotor activity was used as a sign of depressive behavior. Brains of HF and sham rats (n = 8, each) were fixed and histologically analyzed for the measurement of neurogenesis, the number of astrocytes and neurite outgrowth in the ventral hippocampus. VBM demonstrated significant GMC decrease in the hippocampus, which was restricted to the ventral segment. Similarly, neurogenesis and neurite outgrowth were significantly decreased and the number of astrocytes was significantly increased in HF rats as compared with sham rats in the ventral hippocampus. GMC values in the ventral hippocampus were significantly and negatively correlated with 24 hour locomotor activity in HF rats. In conclusion, the present study has demonstrated for the first time that the structural abnormality of the ventral hippocampus is associated with depressive symptoms in HF rats.

Dilated cardiomyopathy is a delayed-onset and rarely reported cardiac complication of burn injury although the mechanism remains unclear. We thus report a case of dilated cardiomyopathy following severe burn injury, in which technetium 99m sestamibi single-photon emission computed tomography (SPECT), iodine-123 beta-methyl-iodophenylpentadecanoic acid SPECT and 18F-fluorodeoxyglucose positron emission tomography (PET) were performed to evaluate the pathophysiologic condition in combination with cardiac catheterization and myocardial biopsy. The cardiac PET and SPECT images showed reduced myocardial blood flow, decreased fatty acid metabolism, and increased glucose utilization in the left ventricular lateral wall in spite of normal coronary angiography, no significant cardiac fibrosis, and inflammatory cell infiltration, which suggests that myocardial ischemia due to microcirculatory disturbance in hypermetabolic state associated with burn injury might be a causative mechanism of dilated cardiomyopathy in this case. A beta blocker, bisoprolol, was successfully introduced in this patient in combination with oral inotropic agents, pimobendan and digitalis after the prolonged use of intravenous dobutamine infusion, which might have been beneficial for this patient with burn-associated dilated cardiomyopathy not only to reduce regional myocardial ischemia but also to attenuate hypermetabolic state after severe burn injury. <Learning objective: Dilated cardiomyopathy complicated with burn injury has been reported to cause a sudden attack of dyspnea and death. This case report suggests that burn-associated dilated cardiomyopathy may be caused by relative myocardial ischemia due to microvascular disturbance in hypermetabolic state associated with burn injuries and can be treated effectively with beta blockers with or without oral inotropic agents.>.

BACKGROUND: It remains to be elucidated whether brain activity is altered in takotsubo cardiomyopathy. METHODS AND RESULTS: We measured cerebral blood flow (CBF) in 3 consecutive patients with takotsubo cardiomyopathy using (99m)Tc ethyl cysteinate dimmer single photon-emission computed tomography (SPECT) in the acute and chronic phases. In all patients, CBF was significantly increased in the hippocampus, brainstem and basal ganglia and significantly decreased in the prefrontal cortex in the acute phase, which changes subsided in the chronic phase with full recovery of cardiac wall motion. CONCLUSIONS: These results provide the first direct evidence for brain activation in takotsubo cardiomyopathy.

Cardiac arrest and subsequent cardiopulmonary resuscitation (CPR) induce hippocampal damage, which has been identified using histological analysis of post-mortem brains. Voxel-based morphometry (VBM), an in-vivo assessment of regional differences in the concentration or volume of a particular tissue such as gray matter, has revealed CPR-induced decreases in gray matter in the hippocampus, where histopathological findings were observed. However, the potential link between the changes in gray matter detected by VBM and hippocampal damage has not been investigated directly. In this study, we compared results obtained using VBM directly to results from histological analyses in the same CPR rat brains, which exhibited neuronal loss and microglial invasion in the CA1 region of the hippocampus (CA1). T2-weighted images were obtained and preprocessed for VBM to produce gray matter concentration (GMC) maps in rats with asphyxia-induced cardiac arrest and CPR and sham-operated controls (n=12 each). Brains were fixed, and the number of neurons and microglia in CA1 were counted. VBM revealed a significant decrease in GMC in CPR rats compared to sham-operated controls. The CPR-induced decrease in GMC was localized to CA1, which is the same brain region where neuronal loss and microglial invasion were noted in response to CPR. GMC values were positively correlated with the number of neurons and tended to be negatively correlated with the number of microglia in CA1 of CPR rats. In conclusion, these results indicate that VBM-detected alterations in gray matter can be used as a surrogate marker for hippocampal damage following CPR.

BACKGROUND: Myocardial ischemia in the anterior wall of the left ventricule (LV) and in the inferior wall and/or right ventricle (RV) shows different manifestations that can be explained by the different innervations of cardiac afferent nerves. However, it remains unclear whether information from different areas of the heart, such as the LV and RV, are differently processed in the brain. In this study, we investigated the brain regions that process information from the LV or RV using cardiac electrical stimulation and functional magnetic resonance imaging (fMRI) in anesthetized rats because the combination of these two approaches cannot be used in humans. METHODOLOGY/PRINCIPAL FINDINGS: An electrical stimulation catheter was inserted into the LV or RV (n = 12 each). Brain fMRI scans were recorded during LV or RV stimulation (9 Hz and 0.3 ms width) over 10 blocks consisting of alternating periods of 2 mA for 30 sec followed by 0.2 mA for 60 sec. The validity of fMRI signals was confirmed by first and second-level analyses and temporal profiles. Increases in fMRI signals were observed in the anterior cingulate cortex and the right somatosensory cortex under LV stimulation. In contrast, RV stimulation activated the right somatosensory cortex, which was identified more anteriorly compared with LV stimulation but did not activate the anterior cingulate cortex. CONCLUSION/SIGNIFICANCE: This study provides the first evidence for differences in brain activation under LV and RV stimulation. These different brain processes may be associated with different clinical manifestations between anterior wall and inferoposterior wall and/or RV myocardial ischemia.

The effects of oxygen availability on neurovascular coupling were investigated using simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), in addition to the monitoring of physiological parameters, in 16 α-chloralose-anesthetized rats. Mild hypoxic hypoxia (oxygen saturation=83.6±12.1%) induced significant reductions in fMRI responses (P<0.05) to electrical stimulation in the forepaw, but EEG responses remained unchanged. In addition, the changes in oxygen saturation were linearly correlated with the changes in the fMRI responses. These data further emphasize the importance of oxygen availability, which may regulate neurovascular coupling via the oxygen-dependent enzymatic synthesis of messenger molecules.

The simultaneous recordings of neuronal and hemodynamic signals have revealed a significant involvement of high frequency bands (e.g., gamma range, 25-70 Hz) in neurovascular coupling. However, the dependence on a physiological parameter is unknown. In this study, we performed simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) recordings in 12 Wistar rats using a conventional forepaw stimulation paradigm and concurrently monitored the systemic physiological parameters of the partial pressure of arterial oxygen, partial pressure of arterial carbon dioxide, pH, mean arterial blood pressure, and heart rate through the rat femoral artery. The high frequency bands in the artifact-free EEG signals, especially those in the gamma range, demonstrated a maximum correlation with fMRI signals in the rat somatosensory cortex. A multiple linear regression analysis demonstrated that the correlation coefficient between the gamma power and fMRI signal depended on the actual values of the physiological parameters (R(2)=0.20, p<0.05), whereas the gamma power and fMRI signal by itself were independent. Among the parameters, the heart rate had a statistically significant slope (95% CI: 0.00027-0.0016, p<0.01) in a multiple linear regression model. These results indicate that neurovascular coupling is mainly driven by gamma oscillations, as expected, but coupling or potential decoupling is strongly influenced by systemic physiological parameters, which dynamically reflect the baseline vital status of the subject.

Although cardiac sensation, such as palpitation or chest pain, is common and is sometimes a malignant sign of heart diseases, the mechanism by which the human brain responds to afferent signals from the heart remains unclear. In this study, we investigated whether electrical stimulation of the heart provokes brain responses in humans. We examined 15 patients (age: 65.4 ± 3.1 years old, 11 males and 4 females) implanted with either a cardiac pacemaker or cardiac resynchronization therapy (CRT) device. Electroencephalogram (EEG) was simultaneously recorded from the vertex during right ventricular pacing at 70-100 beats/min at baseline (1.5 V) and intense (6-8 V) stimulation sessions. We evaluated brain responses to cardiac electrical stimulation by measuring cerebral potentials that were obtained by subtracting the average of 100 EEG waves triggered by cardiac pacing during baseline stimulation from those during the intense stimulation. Intense stimulation of the cardiac pacemaker or CRT device reproducibly induced cardiac sensation in 6 out of the 15 patients; namely, the remaining 9 patients showed no reproducible response. Brain responses were evident by averaging cerebral potentials from all of the 15 patients and those from 6 patients with reproducible cardiac sensation. To the best our knowledge, this is the first report that demonstrates the brain responses to cardiac electrical stimulation in humans. This new method should be useful for examining pathophysiology of cardiac diseases with pathological cardiac sensation, including cardiac anxiety and silent myocardial ischemia.

Although patients with atrial fibrillation (AF) have an increased risk of embolic stroke, some clinicians hesitate to provide anticoagulation therapy for these patients during electroconvulsive therapy (ECT), which is widely applied for the treatment of intractable depression, bipolar disorder, and catatonic schizophrenia, because of potential intracerebral hemorrhage. We report on a 77-year-old female depressive patient with AF treated with aspirin but not on anticoagulation therapy because of poor compliance who developed embolic stroke 1 day after the last ECT. The CHADS2 score of this patient was 2 and included the age and hypertension. The present case suggests that anticoagulation therapy should be considered for patients with obvious risks of embolic stroke when they are subjected to ECT.

OBJECTIVE: To test the hypothesis that gut stimulation provokes autonomic arousal via activation of regional cerebral cortices. How the human brain processes interoceptive signals and forms initial autonomic arousal is one of the key questions to be answered in research on emotion. METHODS: Twelve healthy males participated in this study. A barostat bag was inserted in the rectum and intermittently inflated with 0, 20, or 40 mm Hg at random for 80 seconds. H(2)(15)O positron emission tomography (PET) of the brain, electrocardiography, and blood sampling for catecholamines were performed. Changes in regional cerebral blood flow were interpreted using statistical parametric mapping. RESULTS: Rectal distention with 40 mm Hg induced a significant increase in heart rate, low frequency (LF)/high frequency (HF) ratio of heart rate variability, and plasma adrenaline. Activated brain areas that were associated with increased heart rate during rectal distention were the right insula, right operculum, right dorsolateral prefrontal cortex, putamen, thalamus, periaqueductal gray, and cerebellum (p < .001, uncorrected), whereas those that were associated with an increased LF/HF ratio were the bilateral insula, putamen, thalamus, midbrain, pons, and cerebellum (p < .001, uncorrected). Activated brain areas that were associated with increased plasma adrenaline were the right insula, right orbitofrontal cortex, right parahippocampal gyrus, putamen, thalamus, periaqueductal gray, pons, and cerebellum (p < .001, uncorrected). CONCLUSION: Our results suggest that the right insula and the related body mapping regions may form the functional module of sympathetic arousal in response to gut stimulation.

BACKGROUND: Superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis is a safe and effective treatment for moyamoya disease. Symptomatic cerebral hyperperfusion is a potential complication of this procedure, especially in adult cases. Accurate diagnosis of postoperative hyperperfusion is important because its treatment is contradictory to that for ischemia. Intraoperative techniques to detect hyperperfusion are still lacking. METHODS: We performed intraoperative infrared (IR) brain surface monitoring in a 36-year-old man who underwent left STA-MCA anastomosis. FINDINGS: IR monitoring not only detected the patency of bypass, as also confirmed by conventional Doppler sonography and postoperative magnetic resonance angiography, but also delineated the local brain surface hemodynamics after revascularization. Analysis of gradation value disclosed an abnormal increase in brain surface cerebral blood flow (indirectly indicated as a temperature change) after removal of the temporary clip. The patient suffered from transient right upper extremity numbness and dysarthria due to focal hyperperfusion from postoperative days 2 through 6. Intensive blood pressure control completely relieved his symptoms, and he was discharged without neurologic deficit. CONCLUSIONS: Intraoperative brain surface monitoring by IR imaging may be useful to predict cerebral hyperperfusion after revascularization surgery for moyamoya disease. Further evaluation with a larger number of patients is necessary to validate this technique.

Surgical revascularization for moyamoya disease prevents cerebral ischemic attacks by improving CBF. But little is known about the changes of intraoperative cerebral hemodynamics and its effect on postoperative neurological status including symptomatic cerebral hyperperfusion. To address this issue, we applied a novel infrared camera system (IRIS-V thermographic system) for real-time, visual monitoring of surface CBF during surgery in patients with moyamoya disease. Seven patients (8 sides, male:female= 3:4, 7-62 years old) with moyamoya disease were included in the study. After STA-MCA anastomosis, STA were occluded transiently and recanalized, and whole sequence was recorded by IRIS-V system. Correlation between clinical, radiological findings and infrared imaging were investigated. Patency of bypass was confirmed by this camera during surgery in all cases. The intraoperative imaging patterns were divided into two groups. Group A: Change of brain surface color (++) (3 cases). Group B: Change of brain surface color (-) (4 cases). Transient symptomatic hyperperfusion occurred in all patients in Group A, whereas all patients in Group B showed non-symptomatic transient focal hyperperfusion on SPECT. No patient suffered permanent neurological deterioration compared to preoperative status. Characteristic pattern of the intraoperative cerebral hemodynamics as delineated by IRIS-V could be the optimal predictor for postoperative transient symptomatic hyperperfusion after direct bypass in patients with moyamoya disease.

To elucidate the central roles of histamine receptors in cardiovascular regulatory system, systolic, mean, and diastolic blood pressures (BPs) and heart rate (HR) were examined in conscious H(1) receptor gene knockout (H(1)KO) mice, H(2) receptor gene knockout (H(2)KO) mice, H(1) and H(2) receptor gene double knockout (DKO) mice, and their respective control mice by the tail-cuff system. Histamine, histamine-trifluoromethyl-toluidine derivative (HTMT, an H(1) agonist), dimaprit (an H(2) agonist), and immepip (an H(3) agonist) were intrathecally administered to these KO mice and control mice. Basal BPs and HR were not different among these three KO mice and their control or wild-type mice. Intrathecal administration of histamine significantly increased BPs and decreased HR in control mice. The increases in BPs were produced by histamine in H(1)KO and H(2)KO mice and by HTMT and dimaprit in C57BL mice. The pressor responses by HTMT and dimaprit in C57BL mice were greater than those by histamine in H(1)KO and H(2)KO mice, although the same decreases in HR were induced by histamine in C57BL and H(1)KO mice and by dimaprit in C57BL mice. The selective stimulation of H(3) receptors by immepip produced a consistent decrease in BPs in control mice. These results obtained with the exogenous selective agonists of three histamine receptors suggest that the pressor responses to histamine are mediated through the stimulation of both H(1) and H(2) receptors, whereas the atropine-sensitive decrease in heart rate is mainly due to H(2) receptors which activate the vagal output to the heart.