陈实
中国医学科学院阜外医院 心脏外科
OBJECTIVE:Daytime napping has been reported to have a potential association with an increased risk of cardiovascular diseases (CVDs) in several cohort studies, but the causal effects are unclear. In this study, we aimed to investigate the relationship between daytime napping and CVDs, as well as to validate causality in this relationship by Mendelian randomization (MR).METHODS:A two-sample MR method was used to evaluate the causal effect of daytime napping on CVDs. The exposure of daytime napping was extracted from publicly available genome-wide association studies (GWASs) in the UK Biobank, and the outcomes of 14 CVDs were obtained from the FinnGen consortium. A total of 49 single-nucleotide polymorphisms (SNPs) were used as the instrumental variables. The effect estimates were calculated by using the inverse-variance weighted method.RESULTS:The MR analyses showed that genetically predicted daytime napping was associated with an increased risk of five CVDs, including heart failure (odds ratio (OR): 1.71, 95% CI: 1.19-2.44, p = 0.003), hypertension (OR: 1.51, 95% CI: 1.05-2.16, p = 0.026), atrial fibrillation (OR: 1.71, 95% CI: 1.02-2.88, p = 0.042), cardiac arrythmias (OR: 1.47, 95% CI: 1.47, 95% CI: 1.01-2.13, p = 0.042) and coronary atherosclerosis (OR: 1.77, 95% CI: 1.17-2.68, p = 0.006). No significant influence was observed for other CVDs.CONCLUSION:This two-sample MR analysis suggested that daytime napping was causally associated with an increased risk of heart failure, hypertension, atrial fibrillation, cardiac arrythmias and coronary atherosclerosis.
Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese 2024
Cardiac hypertrophy can develop to end-stage heart failure (HF), which inevitably leading to heart transplantation or death. Preserving cardiac function in cardiomyocytes (CMs) is essential for improving prognosis in hypertrophic cardiomyopathy (HCM) patients. Therefore, understanding transcriptomic heterogeneity of CMs in HCM would be indispensable to aid potential therapeutic targets investigation. We isolated primary CM from HCM patients who had extended septal myectomy, and obtained transcriptomes in 338 human primary CM with single-cell tagged reverse transcription (STRT-seq) approach. Our results revealed that CMs could be categorized into three subsets in nonfailing HCM heart: high energy synthesis cluster, high cellular metabolism cluster and intermediate cluster. The expression of electron transport chain (ETC) was up-regulated in larger-sized CMs from high energy synthesis cluster. Of note, we found the expression of Cytochrome c oxidase subunit 7B (COX7B), a subunit of Complex IV in ETC had trends of positively correlation with CMs size. Further, by assessing COX7B expression in HCM patients, we speculated that COX7B was compensatory up-regulated at early-stage but down-regulated in failing HCM heart. To test the hypothesis that COX7B might participate both in hypertrophy and HF progression, we used adeno associated virus 9 (AAV9) to mediate the expression of Cox7b in pressure overload-induced mice. Mice in vivo data supported that knockdown of Cox7b would accelerate HF and Cox7b overexpression could restore partial cardiac function in hypertrophy. Our result highlights targeting COX7B and preserving energy synthesis in hypertrophic CMs could be a promising translational direction for HF therapeutic strategy.
Journal of molecular and cellular cardiology 2024
Background Patients with arrhythmogenic right ventricular cardiomyopathy are at risk for life-threatening ventricular tachyarrhythmias, but progressive heart failure (HF) may occur in later stages of disease. This study aimed to characterize potential risk predictors and develop a model for individualized assessment of adverse HF outcomes in arrhythmogenic right ventricular cardiomyopathy. Methods and Results Longitudinal and observational cohorts with 290 patients with arrhythmogenic right ventricular cardiomyopathy from the Fuwai Hospital in Beijing, China, and 99 patients from the University Heart Center in Zurich, Switzerland, with follow-up data were studied. The primary end point of the study was heart transplantation or death attributable to HF. The model was developed by Cox regression analysis for predicting risk and was internally validated. During 4.92±3.03 years of follow-up, 48 patients reached the primary end point. The determinants of the risk prediction model were left ventricular ejection fraction, serum creatinine levels, moderate-to-severe tricuspid regurgitation, and atrial fibrillation. Implantable cardioverter-defibrillators did not reduce the occurrence of adverse HF outcomes. Conclusions A novel risk prediction model for arrhythmogenic right ventricular cardiomyopathy has been developed using 2 large and well-established cohorts, incorporating common clinical parameters such as left ventricular ejection fraction, serum creatinine levels, tricuspid regurgitation, and atrial fibrillation, which can identify patients who are at risk for terminal HF events, and may guide physicians to assess individualized HF risk and to optimize management strategies.
Journal of the American Heart Association 2022
Inflammation and fibrosis are intertwined mechanisms fundamentally involved in heart failure. Detailed deciphering gene expression perturbations and cell-cell interactions of leukocytes and non-myocytes is required to understand cell-type-specific pathology in the failing human myocardium. To this end, we performed single-cell RNA sequencing and single T cell receptor sequencing of 200,615 cells in both human dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) hearts. We sampled both lesion and mild-lesion tissues from each heart to sequentially capture cellular and molecular alterations to different extents of cardiac fibrosis. By which, left (lesion) and right ventricle (mild-lesion) for DCM hearts were harvest while infarcted (lesion) and non-infarcted area (mild-lesion) were dissected from ICM hearts. A novel transcription factor AEBP1 was identified as a crucial cardiac fibrosis regulator in ACTA2+ myofibroblasts. Within fibrotic myocardium, an infiltration of a considerable number of leukocytes was witnessed, especially cytotoxic and exhausted CD8+ T cells and pro-inflammatory CD4+ T cells. Furthermore, a subset of tissue-resident macrophage, CXCL8hiCCR2+HLA-DRhi macrophage was particularly identified in severely fibrotic area, which interacted with activated endothelial cell via DARC, that potentially facilitate leukocyte recruitment and infiltration in human heart failure.
Basic research in cardiology 2021
Arrhythmogenic cardiomyopathy (ACM) is a familial cardiomyopathy featured by fibrofatty replacement of cardiomyocytes. Responsible genetic factors are not discernible in approximately one-third of ACM probands. To investigate this further, we performed whole genome sequencing in 14 mutation-negative ACM probands who underwent cardiac transplantation, and we identified one ACM proband with a rare homozygous missense variant in PNPLA2 (c.245G > A, p.G82D), a rate-limiting enzyme that hydrolyzes triglycerides into fatty acids and diacylglycerol. Bioinformatic analysis suggested that this missense variant may lead to loss of function and therefore impair lipid catabolism. Genetic screening in this proband's family also inferred that the homozygous variant cosegregated with disease. To validate the pathogenicity of this variant and confirm its association with ACM, we established a knockin mouse model carrying the orthologous human homozygous PNPLA2 variant. Interestingly, mice with the homozygous variant presented with arrhythmias and significant cardiac dysfunction at 12 weeks, whereas heterozygous mice were not affected. Moreover, those homozygous mice suffered sudden death and/or heart failure by the age of 14 weeks. Pathological examination showed that extensive lipogenesis in cardiomyocytes and cardiac fibrosis were prominent in the myocardium. Herein, our data demonstrated that the homozygous missense variant PNPLA2 (c.245G > A, p.G82D) associated with a recessive form of ACM.
Clinical genetics 2019
