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Role of sodium and calcium dysregulation in tachyarrhythmias in sudden cardiac death.

ABSTRACT: Despite improvements in the therapy of underlying heart disease, sudden cardiac death is a major cause of death worldwide. Disturbed Na and Ca handling is known to be a major predisposing factor for life-threatening tachyarrhythmias. In cardiomyocytes, many ion channels and transporters, including voltage-gated Na and Ca channels, cardiac ryanodine receptors, Na/Ca-exchanger, and SR Ca-ATPase are involved in this regulation. We have learned a lot about the pathophysiological relevance of disturbed ion channel function from monogenetic disorders. Changes in the gating of a single ion channel and the activity of an ion pump suffice to dramatically increase the propensity for arrhythmias even in structurally normal hearts. Nevertheless, patients with heart failure with acquired dysfunction in many ion channels and transporters exhibit profound dysregulation of Na and Ca handling and Ca/calmodulin-dependent protein kinase and are especially prone to arrhythmias. A deeper understanding of the underlying arrhythmic principles is mandatory if we are to improve their outcome. This review addresses basic tachyarrhythmic mechanisms, the underlying ionic mechanisms and the consequences for ion homeostasis, and the situation in complex diseases like heart failure.

SUBMITTER: Wagner S

PROVIDER: S-EPMC4458704 | biostudies-other | 2015 Jun

REPOSITORIES: biostudies-other

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Role of sodium and calcium dysregulation in tachyarrhythmias in sudden cardiac death.

Wagner Stefan S Maier Lars S LS Bers Donald M DM

Circulation research 20150601 12

Despite improvements in the therapy of underlying heart disease, sudden cardiac death is a major cause of death worldwide. Disturbed Na and Ca handling is known to be a major predisposing factor for life-threatening tachyarrhythmias. In cardiomyocytes, many ion channels and transporters, including voltage-gated Na and Ca channels, cardiac ryanodine receptors, Na/Ca-exchanger, and SR Ca-ATPase are involved in this regulation. We have learned a lot about the pathophysiological relevance of disturb ...[more]

PMID: 26044250

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Project description:BACKGROUND:Sudden Unexpected Death in Pediatrics (SUDP) is a tragic event, likely caused by the complex interaction of multiple factors. The presence of hippocampal abnormalities in many children with SUDP suggests that epilepsy-related mechanisms may contribute to death, similar to Sudden Unexplained Death in Epilepsy. Because of known associations between the genes SCN1A and SCN5A and sudden death, and shared mechanisms and patterns of expression in genes encoding many voltage-gated sodium channels (VGSCs), we hypothesized that individuals dying from SUDP have pathogenic variants across the entire family of cardiac arrhythmia- and epilepsy-associated VGSC genes. METHODS:To address this hypothesis, we evaluated whole-exome sequencing data from infants and children with SUDP for variants in VGSC genes, reviewed the literature for all SUDP-associated variants in VGSCs, applied a novel paralog analysis to all variants, and evaluated all variants according to American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS:In our cohort of 73 cases of SUDP, we assessed 11 variants as pathogenic in SCN1A, SCN1B, and SCN10A, genes with long-standing disease associations, and in SCN3A, SCN4A, and SCN9A, VGSC gene paralogs with more recent disease associations. From the literature, we identified 82 VGSC variants in SUDP cases. Pathogenic variants clustered at conserved amino acid sites intolerant to variation across the VGSC genes, which is unlikely to occur in the general population (p < .0001). For 54% of variants previously reported in literature, we identified conflicting evidence regarding pathogenicity when applying ACMG criteria and modern population data. CONCLUSION:We report variants in several VGSC genes in cases with SUDP, involving both arrhythmia- and epilepsy-associated genes. Accurate variant assessment as well as future studies are essential for an improved understanding of the contribution of sodium channel-related variants to SUDP.

Project description:BACKGROUND:Blacks have a higher incidence of out-of-hospital sudden cardiac death (SCD) in comparison with whites. However, the racial differences in the cumulative risk of SCD and the reasons for these differences have not been assessed in large-scale community-based cohorts. The objective of this study is to compare the lifetime cumulative risk of SCD among blacks and whites, and to evaluate the risk factors that may explain racial differences in SCD risk in the general population. METHODS:This is a cohort study of 3832 blacks and 11 237 whites participating in the Atherosclerosis Risk in Communities Study (ARIC). Race was self-reported. SCD was defined as a sudden pulseless condition from a cardiac cause in a previously stable individual, and SCD cases were adjudicated by an expert committee. Cumulative incidence was computed using competing risk models. Potential mediators included demographic and socioeconomic factors, cardiovascular risk factors, presence of coronary heart disease, and electrocardiographic parameters as time-varying factors. RESULTS:The mean (SD) age was 53.6 (5.8) years for blacks and 54.4 (5.7) years for whites. During 27.4 years of follow-up, 215 blacks and 332 whites experienced SCD. The lifetime cumulative incidence of SCD at age 85 years was 9.6, 6.6, 6.5, and 2.3% for black men, black women, white men, and white women, respectively. The sex-adjusted hazard ratio for SCD comparing blacks with whites was 2.12 (95% CI, 1.79-2.51). The association was attenuated but still statistically significant in fully adjusted models (hazard ratio, 1.38; 95% CI, 1.11-1.71). In mediation analysis, known factors explained 65.3% (95% CI 37.9-92.8%) of the excess risk of SCD in blacks in comparison with whites. The single most important factor explaining this difference was income (50.5%), followed by education (19.1%), hypertension (22.1%), and diabetes mellitus (19.6%). Racial differences were evident in both genders but stronger in women than in men. CONCLUSIONS:Blacks had a much higher risk for SCD in comparison with whites, particularly among women. Income, education, and traditional risk factors explained ?65% of the race difference in SCD. The high burden of SCD and the racial-gender disparities observed in our study represent a major public health and clinical problem.

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Role of sodium and calcium dysregulation in tachyarrhythmias in sudden cardiac death.

Publications

Role of sodium and calcium dysregulation in tachyarrhythmias in sudden cardiac death.

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