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Background: Primary electrical disorders (PEDs) are a group of cardiac rhythm abnormalities that occur in the absence of detectable structural heart disease and are a significant cause of sudden cardiac death (SCD). The initiation of cardiac muscle contraction and relaxation is orchestrated by the action potential (AP), generated through ionic changes across the membrane. Mutations in the AP-related gene CACNA2D1 have been identified as a causative factor for PED., Methods: We recruited a Chinese family with a history of arrhythmia. The proband has experienced palpitations and chest tightness for over 40 years, with symptoms worsening over the past year. Whole exome sequencing (WES) was used to determine the genetic etiologies in this family., Results: A novel heterozygous missense mutation (NM_000722.3: c.1685G > C;p.G562A) of CACNA2D1 gene was detected. Genotyping of the proband's parents indicated that the arrhythmia phenotype in the proband was caused by a de novo mutation., Conclusions: WES was utilized to explore the genetic etiology in a family with arrhythmia, leading to the identification of a novel mutation in the CACNA2D1 gene. This study not only expands the mutation spectrum of the CACNA2D1 gene but also contributes to genetic counseling and clinical diagnosis for this family., (© 2024. The Author(s).)

Background and Aims: Observational studies have associated resting heart rate with incident diabetes. Whether the associations are causal remains unclear. We aimed to examine the shape and strength of the associations and assessed the causal relevance of such associations in Chinese adults., Methods and Results: The China Kadoorie Biobank enrolled 512,891 adults in China. Cox proportional hazard regression models was conducted to estimate hazard ratios (HRs) for the associations of resting heart rate with type 2 diabetes and total diabetes. Among 92,724 participants, 36 single-nucleotide polymorphisms (SNPs) related to resting heart rate were used to construct genetic risk score. We used Mendelian randomization analyses to make the causal inferences. During a median follow-up of 9 years, 7872 incident type 2 diabetes and 13,349 incident total diabetes were documented. After regression dilution bias adjustment, each 10 bpm higher heart rate was associated with about a 26% higher risk of type 2 diabetes (HR, 1.26 [95% CI, 1.23, 1.29]) and 23% higher risk of total diabetes (HR, 1.23 [95% CI, 1.20, 1.26]). Instrumental variable analyses showed participants at top quintile compared with those at bottom quintile had 30% higher risk for type 2 diabetes (HR, 1.30 [95% CI, 1.17, 1.43]), and 10% higher risk for total diabetes (HR, 1.10 [95% CI, 1.02, 1.20])., Conclusions: This study provides evidence that resting heart rate is an important risk factor for diabetes risk. The results suggest that novel treatment approaches targeting reduction of high heart rate for incidence of diabetes may be worth further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Chymase is the major angiotensin II (Ang II)-forming enzyme in cardiovascular tissue, with an important role in atrial remodeling. This study aimed to examine the association between chymase 1 gene (CMA1) polymorphisms and atrial fibrillation (AF) in a Chinese Han population., Methods: This case-control study enrolled 126 patients with lone AF and 120 age- and sex-matched healthy controls, all from a Chinese Han population. Five CMA1 polymorphisms were genotyped., Results: The CMA1 polymorphism rs1800875 (G-1903A) was associated with AF. The frequency of the GG genotype was significantly higher in AF patients compared with controls (p = 0.009). Haplotype analysis further demonstrated an increased risk of AF associated with the rs1800875-G haplotype (Hap8 TGTTG, odds ratio (OR) = 1.668, 95% CI 1.132-2.458, p = 0.009), and a decreased risk for the rs1800875-A haplotype (Hap5 TATTG, OR = 0.178, 95% CI 0.042-0.749, p = 0.008)., Conclusions: CMA1 polymorphisms may be associated with AF, and the rs1800875 GG genotype might be a susceptibility factor for AF in the Chinese Han population.

Aims: Observational studies indicated that resting heart rate (RHR) was associated with diabetes mellitus (DM) risk; however, it remains unclear whether the association between RHR and DM is causal. We aimed to examine whether there was causal association of RHR with DM risk., Methods: A prospective study including 16,201 middle-aged and older Chinese (7031 males and 9170 females) derived from the Dongfeng-Tongji cohort was performed. Cox proportional hazard regression models were conducted to estimate the associations between RHR and incident DM risk. In 7481 participants, 65 single nucleotide polymorphisms related to RHR were genotyped. A genetic risk score (GRS) of RHR was calculated based on the RHR-associated variants. The causal associations of RHR with DM risk were investigated by Mendelian randomization analysis., Results: During a mean (SD) follow-up of 4.5 (0.5) years, 1110 diabetes were identified. Compared with the referential RHR group (≤ 60 beats per minute [bpm]), individuals with RHR > 80 bpm have a higher incident diabetes risk, with a hazard ratio of 1.40 (95% confidence interval [CI], 1.05-1.88). With per SD increase in the weighted genetic risk score, the resting heart rate increased by 0.71 bpm (95% CI 0.49-0.93). By using the GRS to estimate the unconfounded effect, we found that higher resting heart rate did not have a causal effect on diabetes risk (OR 1.00 [95% CI 0.95-1.05])., Conclusions: The present study supported a positive but not a causal association of RHR with incident diabetes risk. More studies are needed to verify our findings.

Western observational studies show that moderate alcohol use is associated with lower cardiovascular disease (CVD) risk, but these associations may be confounded by the healthier attributes of moderate users in these settings. Mendelian randomization analysis may help to ascertain the causal effect of moderate alcohol use on specific factors related to CVD and thereby clarify the role of alcohol. We used Mendelian randomization analysis with the aldehyde dehydrogenase 2 gene (ALDH2) as an instrumental variable to examine the association of alcohol units (10 g of ethanol) per day with heart rate-corrected QT interval and heart rate assessed from electrocardiogram among 4,588 older southern Chinese men in the Guangzhou Biobank Cohort Study (2003-2008). The F statistic was 77 for ALDH2 on alcohol use, suggesting little weak-instrument bias. Instrumental variable analysis showed that alcohol units were not associated with the corrected QT interval, with β = 1.04 (95% confidence interval: -0.61, 2.70) milliseconds, but they were associated with increased heart rate, with β = 0.98 (95% confidence interval: 0.04, 1.92) beat per minute. This study suggests that moderate alcohol use in men is not beneficial for heart function via QT interval or heart rate but could be detrimental. Future studies using specific cardiovascular outcomes may elucidate how alcohol affects different aspects of the cardiovascular system and, hence, the overall effects of alcohol on CVD can be estimated., (© The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: QT interval prolongation, a predictor of cardiac arrhythmias, and elevated heart rate are associated with higher risk of cardiovascular mortality. Observationally testosterone is associated with shorter corrected QT interval and slower heart rate; however, the evidence is open to residual confounding and reverse causality. We examined the association of testosterone with electrocardiogram (ECG) parameters using a separate-sample instrumental variable (SSIV) estimator., Methods: To minimize reverse causality, a genetic score predicting testosterone was developed in 289 young Chinese men from Hong Kong, based on a parsimonious set of single nuclear polymorphisms (rs10046, rs1008805 and rs1256031). Linear regression was used to examine the association of genetically predicted testosterone with QT interval, corrected QT interval [using the Framingham formula (QTf) and Bazett formula (QTb)] and heart rate in 4212 older (50+ years) Chinese men from the Guangzhou Biobank Cohort Study., Results: Predicted testosterone was not associated with QT interval [-0.08 ms per nmol/l testosterone, 95% confidence interval (CI) -0.81 to 0.65], QTf interval (0.40 ms per nmol/l testosterone, 95% CI -0.12 to 0.93) or heart rate (0.26 beats per minute per nmol/l testosterone, 95% CI -0.04 to 0.56), but was associated with longer QTb interval (0.66 ms per nmol/l testosterone, 95% CI 0.02 to 1.31)., Conclusions: Our findings do not corroborate observed protective associations of testosterone with QT interval or heart rate among men, but potentially suggest effects in the other direction. Replication in a larger sample is required., (© The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Estimates of the genetic influences on electrocardiographic (ECG) parameters are inconsistent in previous reports, and no such studies have been performed in China. So we estimated genetic contributions to PR and QRS intervals and the rate-adjusted QT interval (Bazett's QTc) in a Chinese rural population., Methods: A total of 2909 subjects from 847 families were enrolled in the current study. Genetic contributions to ECG parameters were estimated in two ways: correlation coefficients among family members (father-mother, parent-offspring, first sibling-other sibling) and the heritability of each of the ECG parameters., Results: Our results showed significant correlations among family members on theses parameters: the correlation coefficients for PR interval, QRS duration, QTc interval, and HR, between parent-sibling, and sibling-sibling were 0.17 and 0.13, 0.18 and 0.23, 0.22 and 0.28, 0.19 and 0.18, respectively. The heritability for PR interval, QRS duration, QTc interval, and HR were estimated as 0.34, 0.43, 0.40, and 0.34, respectively., Conclusion: Genetic factors, together with the environmental and other cofactors contribute no more than 60% to the variance of the ECG intervals, supporting the concept that multiple factors, including gene-gene and gene-environment interactions could influence ECG interval phenotypes, and genetic factors play a major role.

Background: We recently reported that an S140G mutation in human KCNQ1, an alpha subunit of potassium channels, was involved in the pathogenesis of familial atrial fibrillation (AF), but it is not clear whether the mutation is associated with other cardiac arrhythmias., Objective: The purpose of this study was to further explore the association of the KCNQ1 S140G mutation with cardiac arrhythmias., Methods: We produced a transgenic mouse model with myocardium-specific expression of the human KCNQ1 S140G mutation under the control of an alpha-cardiac myosin heavy chain promoter by standard transgenic procedure and evaluated the relationship between the KCNQ1 mutation and its phenotypes in a human family., Results: Four lines of transgenic mice were established with a high level of human KCNQ1 S140G expression in the heart. Frequent episodes of first-, second-, advanced-, or third-degree atrioventricular block (AVB) occurred in at least 65% of transgenic descendants from the four lines. However, none of the five wild-type transgenic lines presented with AVBs. HMR1556, a KCNQ1-specific blocker, can terminate the AVBs. With the exception of at most three AF individuals, at least 13 AF patients were found to show obviously slow ventricular response, which may be one manifestation of AVBs. Interestingly, AF was not detected in these transgenic mice., Conclusion: The results suggest that human KCNQ1 S140G is also likely to be a causative mutation responsible for AVBs. The transgenic mouse model is a potential tool to explore mechanisms of AVBs.

Resting heart rate is significantly associated with cardiovascular morbidity and mortality. However, the extent to which resting heart rate is genetically determined is poorly understood, and no genes have been found that contribute to variation in resting heart rate. Because signaling through the beta1 adrenergic receptor is a key determinant of cardiac function, we tested whether polymorphisms in this receptor are associated with resting heart rate. A cohort of >1,000 individuals of Chinese and Japanese descent, from nuclear families, was genotyped for two polymorphisms, resulting in a serine/glycine substitution at amino acid 49 (Ser49Gly) and an arginine/glycine substitution at residue 389 (Arg389Gly), in the beta1 adrenergic receptor. For comparison, polymorphisms in the beta2 and beta3 adrenergic receptors were also evaluated. The Ser49Gly polymorphism was significantly associated (P=.0004) with resting heart rate, independent of other variables, such as body-mass index, age, sex, ethnicity, exercise, smoking, alcohol intake, hypertension status, and treatment with beta blockers. The data support an additive model in which individuals heterozygous for the Ser49Gly polymorphism had mean heart rates intermediate to those of either type of homozygote, with Ser homozygotes having the highest mean heart rate and with Gly homozygotes having the lowest. Neither the Arg389Gly polymorphism in the beta1 adrenergic receptor nor polymorphisms in the beta2 and beta3 adrenergic receptors were associated with resting heart rate. The heritability of heart rate was 39.7% +/- 7.1% (P<10-7).