Genetic contributions to cardiovascular disease (CVD) are typically examined through nuclear DNA, yet mitochondrial DNA (mtDNA) is increasingly recognized as a critical, often overlooked determinant of cardiovascular risk. Given the heart's reliance on mitochondrial energy production, mitochondrial dysfunction and mtDNA alterations have emerged as important contributors to CVD pathogenesis. This review examines current evidence linking mtDNA variants, including heteroplasmy and deletions, mtDNA copy number (mtDNA-CN) dynamics, and haplogroup background to major CVD phenotypes, with particular emphasis on atherosclerosis, cardiomyopathy, myocardial infarction, stroke, hypertension, and heart failure. We conducted a comprehensive PubMed search, prioritizing human population-based and clinical studies, supplemented by key experimental data informing mechanisms. Evidence is strongest for roles of mtDNA variants and heteroplasmy in cardiomyopathies/heart failure, as well as hypertension by impairing mitochondrial energy production and generating harmful oxidants, creating a continuous cycle of mitochondrial injury with further mtDNA damage, besides additional contributions from mtDNA-CN, large deletions, and mitochondrial haplogroups. Mechanistically, mtDNA abnormalities may promote vascular inflammation, endothelial dysfunction, and altered immune signalling; the inflammatory response is a central pathogenic driver of cardiovascular disease, directly promoting atherosclerotic plaque instability, adverse myocardial remodelling, and the progression of heart failure. We subsequently evaluate the evidence for each CVD phenotype in relation to these mtDNA markers. Lastly, current knowledge gaps, methodological challenges, and future research priorities are discussed to support the integration of mtDNA into cardiovascular research and precision medicine.
Aims Elevated remnant cholesterol is a causal risk factor for atherosclerotic cardiovascular disease. Here, we tested the hypothesis that high levels of remnant cholesterol are observationally associated with increased risk of heart failure in individuals in the general population with and without statin therapy. Methods and results We included 108,500 and 428,922 individuals free of baseline heart failure from the Copenhagen General Population Study (CGPS) and the UK Biobank, two cohort studies of the adult Danish and UK general populations started in 2003-2015 and 2006-2010. During median 9.2 and 13.7 years of follow-up, 5321(4.9%) and 21,428(4.3%) developed heart failure in the two studies. Diagnoses of heart failure were retrieved from Danish and UK national health registers.For individuals with and without statin therapy and in both the CGPS and the UK Biobank, stepwise higher remnant cholesterol were associated with stepwise increasing risk of a diagnosis of heart failure. For individuals without statin therapy, those with remnant cholesterol ≥1.5 mmol/L(≥59 mg/dL) compared to those with remnant cholesterol <0.5 mmol/L(<19 mg/dL), the multivariable adjusted hazard ratios for risk of heart failure were 1.40(95% confidence interval: 1.19-1.63) in the CGPS and 1.61(1.38-1.89) in the UK Biobank. Corresponding hazard ratios for individuals with statin therapy were 1.63(1.29-2.07) and 1.60(1.24-2.07), respectively. Conclusion In 108,500 and 428,922 individuals from the general populations of Denmark and the UK, stepwise higher levels of remnant cholesterol were associated with stepwise increasing risk of heart failure in individuals with and without statin therapy.
