Peripheral blood mitochondrial DNA copy number is associated with cardiac diastolic dysfunction in frail older adults

Frailty is a common geriatric syndrome associated with impaired mitochondrial biology and increased cardiovascular vulnerability in older adults. Mitochondrial DNA copy number (mtDNA-CN) is an indirect proxy of mitochondrial genome abundance, and has been linked to cardiovascular disease risk; its relationship with cardiac diastolic function in frail older patients remains unclear. This study examined the association between peripheral blood mtDNA-CN and echocardiographic diastolic function indices, and whether frailty status modifies this relationship.

We recruited 576 hospitalized older adults (aged ≥60 years) at Jiangsu Province Hospital between October 2020 and August 2022; 187 participants met all criteria. Frailty was assessed with the Physical Frailty Phenotype (PFP) scale (non-frail n = 52, pre-frail n = 77, frail n = 58). Diastolic function was evaluated by the E/A ratio, E/e', septal e' and lateral e' velocities, with left ventricular mass index (LVMI) additionally reported. mtDNA-CN was quantified by quantitative real-time PCR (qPCR). Multivariable models were adjusted for age, sex, BMI, systolic blood pressure, heart rate, HbA1c, eGFR, coronary artery disease, neutrophil percentage and platelet count; a progressive-adjustment sensitivity analysis of 11 nested models further added C-reactive protein (CRP), the complete leukocyte differential, hemoglobin, the Geriatric Nutritional Risk Index (GNRI) and physical activity level. Diagnostic models were internally validated by bootstrap optimism correction (1000 resamples) and repeated stratified 10-fold cross-validation.

mtDNA-CN decreased significantly with increasing frailty severity (P < 0.001) and was positively correlated with the E/A ratio (r = 0.494, P < 0.001), lateral e' (r = 0.479, P < 0.001) and septal e' (r = 0.291, P < 0.01), but not with E/e' (r = -0.100, P = 0.172), LVMI (r = 0.037, P = 0.611), or any structural or systolic index. In the fully adjusted models, log(mtDNA-CN) remained independently associated with the E/A ratio (β = 0.50, 95% CI 0.37-0.63), lateral e' (β = 0.44, 95% CI 0.32-0.57) and septal e' (β = 0.21, 95% CI 0.05-0.37), and the estimate was stable across all 11 progressively adjusted models. Associations were consistent across sex, diabetes, hypertension, coronary artery disease and age >80 years. Frailty status significantly amplified the association between mtDNA-CN and diastolic function (all interaction P < 0.05). Optimism-corrected AUCs for mtDNA-CN alone were 0.79, 0.81 and 0.72 for E/A, lateral e' and septal e', exceeding an age-plus-grip-strength model (0.61, 0.68, 0.63); an integrated model reached 0.79, 0.83 and 0.73.

Peripheral blood mtDNA-CN is independently associated with cardiac diastolic function in hospitalized older adults, with a more pronounced association in frail individuals. mtDNA-CN mtDNA-CN may represent a potential non-invasive marker for the early detection of diastolic impairment and may facilitate cardiovascular risk stratification in frail older adults.