Mitochondrial DNA copy number and incident heart failure: The Atherosclerosis Risk in Communities (ARIC) study

Abstract

Background: The association between mitochondrial DNA-copy number (mtDNA-CN) and incident heart failure (HF) in the general population is unclear. Methods: We examined the association between mtDNA-CN and the risk of incident HF among 10,802 participants free of HF at baseline from the Atherosclerosis Risk in Communities (ARIC) study, a large bi-racial population-based cohort. mtDNA-CN was estimated using probe intensities on the Affymetrix Genome-Wide Human single nucleotide polymorphisms Array 6.0. Incident HF events were identified through hospital discharge codes from 1987 until 2005 and through adjudication by the ARIC HF Classification Committee since 2005. Results: During a median follow-up of 23.1 years, there were 2,227 incident HF events (incidence rate 10.3 per 1000 person-years). In fully adjusted models, the hazard ratios (95% confidence intervals) for HF comparing the 2nd through 5th quintiles of mtDNA-CN to the 1st quintile were 0.91 (0.80–1.04), 0.82 (0.72–0.93), 0.81 (0.71–0.92), and 0.74 (0.65–0.85), respectively (P for trend < 0.001). In stratified analyses, the associations between mtDNA-CN and HF were similar across examined subgroups. The inverse association between mtDNA-CN and incident HF was stronger in HF with reduced ejection fraction (HFrEF) than in HF with preserved ejection fraction (HFpEF). Conclusions: In this prospective cohort, mtDNA-CN was inversely associated with the risk of incident HF suggesting that reduced levels of mtDNA-CN, a biomarker of mitochondrial dysfunction, could reflect early susceptibility to HF.

Genetic analysis of mitochondrial DNA copy number and associated traits identifies loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation, and reveals a causal association of mitochondrial function with mortality

“…This finding is consistent with a large body of work showing that mtDNA-CN measured in blood is associated with numerous aging-related phenotypes for which the primary tissue of interest is not blood (e.g. chronic kidney disease 13 , heart failure 11 , and diabetes 66 ). Also consistent with this finding is recent work demonstrating that mtDNA-CN measured in blood is associated with mtRNA expression across numerous non-blood tissues, suggesting a link between mitochondrial function measured in blood and other tissues 67 .…”

“…The relative copy number of mtDNA (mtDNA-CN) has been shown to be positively correlated with oxidative stress 6 , energy reserves, and mitochondrial membrane potential 7 . As a minimally invasive proxy measure of mitochondrial dysfunction 8 , decreased mtDNA-CN measured in blood has been previously associated with aging-related disease states including frailty 9 , cardiovascular disease [10][11][12] , chronic kidney disease 13 , neurodegeneration 14,15 , and cancer 16 .…”

Low mitochondrial copy number drives atherogenic cardiovascular disease: evidence from prospective cohort analyses in the UK Biobank combined with Mendelian Randomization

“…Consistent with the results found in our study, previous studies all showed that lower mtDNA-CN measured from peripheral blood was related to an increased risk of CVD (4)(5)(6)(7)(8)(9)(10)(11). The only prospective study that assessed the relationship between mtDNA content and either CAD or HF used the Atherosclerosis Risk in Communities (ARIC) Study (9,10).…”

“…Consistent with the results found in our study, previous studies all showed that lower mtDNA-CN measured from peripheral blood was related to an increased risk of CVD (4-11). The only prospective study that assessed the relationship between mtDNA content and either CAD or HF used the Atherosclerosis Risk in Communities (ARIC) Study (9,10). In the ARIC study, composed of 20,163 participants (2460 incident CHD) with a mean follow-up of 13.5 years, a lower mtDNA-CN was associated with an increased risk of incident CHD.…”

“…Recent epidemiological studies have assessed the associations between peripheral blood mtDNA-CN and multiple cardiovascular endpoints. These studies so far unequivocally indicated lower mtDNA-CN as an independent risk factor of prevalent CVD in case-control and retrospective cohort studies (4-7), and of incident cardiovascular disease and risk of sudden cardiac death in the prospective Atherosclerosis Risk in Communities (ARIC) study (8)(9)(10)(11). Nevertheless, apart from the ARIC study, other studies comprised a small sample size and/or limited number of cases, which might have resulted in insufficient statistical power, undermining the reliability.…”