Yiyi Zhang1, Eliseo Guallar1, Foram N Ashar2, Ryan J Longchamps2, Christina A Castellani2, John Lane3, Megan L Grove4, Josef Coresh1, Nona Sotoodehnia5, Leonard Ilkhanoff6,7, Eric Boerwinkle4,8, Nathan Pankratz3, Dan E Arking2. 1. Departments of Epidemiology and Medicine, and Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, 2024 E. Monument St.. Room 2-645, Baltimore, MD 21205, USA. 2. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, Miller Research Building, Room 459, Baltimore, MD 21205, USA. 3. Department of Laboratory Medicine and Pathology, University of Minnesota, Room 1-156, Moos Tower, 515 Delaware Street SE, Minneapolis, MN 55455, USA. 4. Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA. 5. Department of Medicine, Division of Cardiology, Cardiovascular Health Research Unit, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, Washington 98101, USA. 6. Department of Medicine, Division of Cardiology, Electrophysiology Section, Northwestern University, 676 N. St. Clair, Suite 600, Chicago, Illinois, USA. 7. Inova Heart and Vascular Institute, 3300 Gallows Rd, Falls Church, VA 22042, USA. 8. Baylor College of Medicine, Human Genome Sequencing Center, One Baylor Plaza, Alkek N1419, MS: BCM226, Houston, TX 77030-3411, USA.
Abstract
AIMS: Sudden 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 RESULTS: We measured baseline mtDNA-CN in 11 093 participants from the Atherosclerosis Risk in Communities (ARIC) study. mtDNA copy number was calculated from probe intensities of mitochondrial single nucleotide polymorphisms (SNP) on the Affymetrix Genome-Wide Human SNP Array 6.0. Sudden cardiac death 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. Sudden cardiac death 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 centre, the hazard ratio for SCD comparing the 1st to the 5th quintiles of mtDNA-CN was 2.24 (95% confidence interval 1.58-3.19; P-trend <0.001). When further adjusting for traditional cardiovascular disease risk factors, prevalent coronary heart disease, heart rate, QT interval, and QRS 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. CONCLUSION: In this community-based prospective study, mtDNA-CN in peripheral blood was inversely associated with the risk of SCD. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Sudden 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 RESULTS: We measured baseline mtDNA-CN in 11 093 participants from the Atherosclerosis Risk in Communities (ARIC) study. mtDNA copy number was calculated from probe intensities of mitochondrial single nucleotide polymorphisms (SNP) on the Affymetrix Genome-Wide Human SNP Array 6.0. Sudden cardiac death 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. Sudden cardiac death 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 centre, the hazard ratio for SCD comparing the 1st to the 5th quintiles of mtDNA-CN was 2.24 (95% confidence interval 1.58-3.19; P-trend <0.001). When further adjusting for traditional cardiovascular disease risk factors, prevalent coronary heart disease, heart rate, QT interval, and QRS 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. CONCLUSION: In this community-based prospective study, mtDNA-CN in peripheral blood was inversely associated with the risk of SCD. Published on behalf of the European Society of Cardiology. All rights reserved.
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