Mitochondrial Genetics in Cardiovascular Health and Disease: A Scientific Statement From the American Heart Association

Metabolic and genetic abnormalities have long been noted in cardiovascular diseases, but the contribution of mitochondrial genetic (mitochondrial DNA [mtDNA]) variation is understudied. Mitochondrial genetics is complex in that each mitochondrion contains multiple mtDNA copies that may carry different variants, which is called heteroplasmy. Heteroplasmic variation is dynamic, increases with advancing age, and may contribute to aging-related cardiovascular diseases. Pathogenic variants in mitochondrial genes of the mtDNA or nuclear genome cause mitochondrial diseases, often with cardiac involvement, particularly in patients with adult-onset disease. Population-level studies have identified mtDNA variants associated with cardiovascular risk factors and disease, but evaluation of mtDNA genetic variation is often limited to only a handful of variants and small sample sizes. Studies in animal models have linked several mtDNA variants to cardiac remodeling and dysfunction and suggest a role for mitochondrial–nuclear genetic interactions in disease penetrance. The objective of this scientific statement is to outline the current state of understanding of the role of mitochondrial genetics in cardiovascular pathobiology and highlight important gaps in knowledge. The intended audience of this scientific statement is meant to be broad, spanning clinical, translational, and basic researchers and health care professionals. Despite remaining limitations and barriers, recent advances in genomic sequencing, mtDNA gene editing modalities, and the directed differentiation of stem cells to cardiovascular cell types are creating new opportunities to advance understanding of mitochondrial genetics in cardiovascular pathophysiology.