AHA Scientific Statement Highlights Emerging Role of Mitochondrial Genetics in Cardiovascular Disease: Circulation Study Reveals

According to a recent AHA Scientific Statement, despite ongoing limitations, recent advances in genomic sequencing (Next-Generation Sequencing), gene-editing technologies, and the directed differentiation of induced pluripotent stem cells (iPSCs) into cardiovascular cell types are creating new opportunities to deepen our understanding of mitochondrial genetics, its dynamic behavior, and its critical role in cardiovascular pathobiology and disease.

This scientific statement paper is published in Circulation in December 2025.

The Heart’s Energy Crisis: Complexity of Mitochondrial Function

The heart is one of the most energetically demanding organs in the body, consuming approximately 6 grams of ATP per day, mostly generated through oxidative phosphorylation (OXPHOS). The machinery required for OXPHOS relies on a complex coordinated effort between the mitochondrial genome (mtDNA) and the nuclear genome. Clinical understanding has been complicated by the unique genetics of mitochondria, particularly the phenomenon of heteroplasmy, where an individual mitochondrion contains multiple copies of mtDNA, some carrying different genetic variants. Heteroplasmy is widespread in the general population, and higher levels of these heteroplasmic variants accumulate as patients advance in age, believed to contribute directly to prevalent, aging-related CVD.

Overcoming Diagnostic Barriers Through Genomic Advances

For clinicians, diagnosing and understanding the contribution of mtDNA variation has historically been hampered by complex methodologic limitations. Recent technological breakthroughs, including Next-Generation Sequencing (NGS), have created new opportunities for understanding the role of mtDNA in cardiovascular pathobiology. NGS now permits the identification of mtDNA variants, particularly low-level heteroplasmic variants, at an unprecedented scale. However, accurate diagnosis and research still face considerable technical hurdles, such as the need for sophisticated bioinformatic filtering to exclude fragments of mitochondrial DNA inserted into the nuclear genome (NuMTs), which can contaminate results. These advances facilitate highly granular analyses, moving beyond limited studies that assessed only a handful of specific mtDNA variants.

Mitochondrial Variation Linked to Common CVD Risk

Population-level and real-world studies confirm that mtDNA variation is strongly associated with established cardiovascular risk factors and outcomes. Higher levels of heteroplasmic variants in circulating blood samples are associated with advancing age and overall CVD risk. Furthermore, common CVD risk factors, such as combustible cigarette smoking, obesity, and Type 2 diabetes, have been directly linked to alterations in mtDNA copy number and increased mtDNA damage in cardiovascular tissues. Additionally, specific mitochondrial haplogroups (groups of similar mtDNA sequences) modify the penetrance of disease and are associated with conditions like hypertension, atherosclerosis, myocardial infarction (MI), and atrial fibrillation.

Critical Cardiac Manifestations in Mitochondrial Syndromes

Mitochondrial diseases, caused by pathogenic variants in either the nuclear or mitochondrial genome, are multi-systemic conditions, with cardiac involvement occurring in approximately 30% of genetically confirmed adult cases. For adults with these disorders, CVD is the most common cause of death. The cardiac manifestations are highly variable but frequently include cardiomyopathy (affecting 29%–40% of patients) and ECG abnormalities (affecting 39%–68% of patients). Hypertrophic cardiomyopathy (HCM) is the most common form of cardiomyopathy, but dilated (DCM) and restrictive forms are also seen. Clinicians must be vigilant for severe manifestations like heart failure, ventricular tachyarrhythmias, and sudden cardiac death (SCD). Patients with specific syndromes, such as Kearns-Sayre syndrome, are highly predisposed to atrioventricular conduction defects that can lead to SCD. Regular cardiac screening, including ECG and echocardiograms, is thus essential for patients with diagnosed mitochondrial diseases.

Potential Clinical Implications for Cardiologists

Mitochondrial genetics is central to cardiovascular health. Practicing cardiologists may like to consider:

• Suspect Mitochondrial Involvement: Consider mitochondrial disorders, even if primary symptoms are non-syndromic, particularly in cases of unexplained cardiomyopathy or arrhythmias.
• Order Comprehensive Genetic Testing: For suspected mitochondrial disorders, general gene panels are often insufficient; mtDNA analysis, whole exome sequencing, or whole genome sequencing are recommended first-line tests to capture variants in both nuclear and mitochondrial genomes.
• Recognize High-Risk Markers: Elevated heteroplasmy levels and mtDNA damage are associated with common CVD risk factors (smoking, aging, T2DM), necessitating rigorous risk factor modification alongside standard treatment.

Reference: Fetterman JL, Chinnery PF, McClellan R, Wallace DC, Suomalainen A, Ojala T, Lewis SC, Ballinger SW, American Heart Association Council on Genomic and Precision Medicine Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation Council on Cardiovascular and Stroke Nursing Council on Peripheral Vascular Disease. Mitochondrial Genetics in Cardiovascular Health and Disease: A Scientific Statement From the American Heart Association. Circulation.