ABSTRACTAimsSudden cardiac death (SCD) is a major public health burden. Mitochondrial dysfunction has been implicated in a wide range of cardiovascular diseases including cardiomyopathy, heart failure, and arrhythmias, but it is unknown if it also contributes to SCD risk. We sought to examine the prospective association between mtDNA copy number (mtDNA-CN), a surrogate marker of mitochondrial function, and SCD risk.Methods and ResultsWe measured baseline mtDNA-CN in 11,093 participants from the Atherosclerosis Risk in Communities (ARIC) study. mtDNA-CN was calculated from probe intensities of mitochondrial single nucleotide polymorphisms (SNP) on the Affymetrix Genome-Wide Human SNP Array 6.0. SCD was defined as a sudden pulseless condition presumed due to a ventricular tachyarrhythmia in a previously stable individual without evidence of a non-cardiac cause of cardiac arrest. SCD cases were reviewed and adjudicated by an expert committee. During a median follow-up of 20.4 years, we observed 361 SCD cases. After adjusting for age, race, sex, and center, the hazard ratio (HR) for SCD comparing the 1st to the 5th quintiles of mtDNA-CN was 2.24 (95% CI 1.58 to 3.19; p-trend <0.001). When further adjusting for traditional CVD risk factors, prevalent CHD, heart rate, and QT interval duration, the association remained statistically significant. Spline regression models showed that the association was approximately linear over the range of mtDNA-CN values. No apparent interaction by race or by sex was detected.ConclusionIn this community-based prospective study, mtDNA-CN in peripheral blood was inversely associated with the risk of SCD.
P6400Role of copy number variants in sudden cardiac death: genetic analysis and translation into clinical practice
