Abstract
Cardiac death remains one of the leading causes of mortality worldwide. Recent research has shed light on pathophysiological mechanisms underlying cardiac death, and several genetic variants in novel candidate genes have been identified as risk factors. However, the vast majority of studies performed so far investigated genetic associations with specific forms of cardiac death only (sudden, arrhythmogenic, ischemic etc.). The aim of the present investigation was to find a genetic marker that can be used as a general, powerful predictor of cardiac death risk. To this end, a case-control association study was performed on a heterogeneous cohort of cardiac death victims (n=360) and age-matched controls (n=300). Five single nucleotide polymorphisms (SNPs) from five candidate genes (beta2 adrenergic receptor, nitric oxide synthase 1 adaptor protein, ryanodine receptor 2, sodium channel type V alpha subunit and transforming growth factor-beta receptor 2) that had previously been shown to associate with certain forms of cardiac death were genotyped using sequence-specific real-time PCR probes. Logistic regression analysis revealed that the CC genotype of the rs11720524 polymorphism in the SCN5A gene encoding a subunit of the cardiac voltage-gated sodium channel occurred more frequently in the highly heterogeneous cardiac death cohort compared to the control population (p=0.019, odds ratio: 1.351). A detailed subgroup analysis uncovered that this effect was due to an association of this variant with cardiac death in chronic ischemic heart disease (p=0.012, odds ratio = 1.455). None of the other investigated polymorphisms showed association with cardiac death in this context. In conclusion, our results shed light on the role of this non-coding polymorphism in cardiac death in ischemic cardiomyopathy. Functional studies are needed to explore the pathophysiological background of this association.
Highlights
Though the past decades have seen a rapid development in the field of therapeutic options, sudden cardiac death (SCD) still remains a leading cause of mortality worldwide [1]
Five candidate genes of cardiac death have been selected from the current literature and one representative single nucleotide polymorphism from each gene was genotyped by quantitative PCR using allele-specific TaqMan probes
Our results revealed that the CC genotype of the rs11720524 (G/C) single nucleotide polymorphisms (SNPs) of the SCN5A gene occurred more frequently in the cardiovascular death cohort compared to the control group (47.90% vs. 36.99%, p = 0.019, odds ratios (OR) = 1.351), while none of the other studied polymorphisms showed any significant differences in this respect
Summary
Though the past decades have seen a rapid development in the field of therapeutic options, sudden cardiac death (SCD) still remains a leading cause of mortality worldwide [1]. The underlying pathological processes—acute or chronic heart failure—might be elicited by numerous factors including coronary artery disease, hypertension, valvular dysfunctions, primary cardiomyopathy, inflammatory diseases as well as arrhythmias. Myocardial hypoxia is a potent arrhythmogenic factor that impairs ionic homeostasis by blocking ion pumps and thereby interferes with cardiac ion channel conductance in the plasma membrane [3]. The emergence of arrhythmogenic foci in myocardial remodeling compromises the electrical activity of the heart, playing a causative role in the occurrence of fatal arrhythmias that underlie sudden decompensation and cardiac death [4, 5]. Genetic markers governing structural remodeling include a large body of genetic variants that impair force generation, calcium cycling and transcriptional regulation of cardiac gene expression [6] as well as perturbed expression of regulatory microRNAs [7]
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