CIRCULATING MITOCHONDRIAL DNA SIGNATURE IN CARDIOMETABOLIC PATIENTS

Objective: Mitochondrial dysfunction is a hallmark of cardiometabolic diseases. Circulating mitochondrial DNA (mtDNA) profiles could refine risk stratification, but current methods do not account for different fractions of circulating mtDNA. We aimed to explore whether patients with cardiometabolic disease have a specific signature of the circulating mtDNA profile, including intracellular and cell-free fractions. Design and method: We performed a complete clinical assessment, including blood tests, 12-lead ECG and ultrasound at rest and during cardiopulmonary exercise. Ultrasound congestion was defined at rest as inferior vena cava of >=1 mm, lung B-lines >=4, or discontinuous renal venous flow. In fasting whole blood and plasma samples collected at rest, we simultaneously measured the copy number of the cellular and cell-free components of mtDNA by real-time quantitative polymerase chain reaction (qPCR) using custom standards. We calculated the ratio of cell mtDNA to cell-free mtDNA as an index of mitochondrial efficiency. Results: We enrolled 120 consecutive patients: 50 (42%) with HF and preserved ejection fraction (HFpEF), 40 (33%) with HF and reduced ejection fraction (HFrEF) and 30 (25%) at risk of developing HF; 68/120 (57%) were hypertensive; 42/120 (35%) had diabetes. Cell-free mtDNA was increased in patients with HF (with higher levels in HFrEF than HFpEF) and those with diabetes. Cell-free mtDNA was higher in patients with systemic inflammation (expressed by high-sensitivity C-reactive protein [hs-CRP] >=0.2 mg/dL with neutrophil-lymphocyte ratio [NLR] >3) and more ultrasound signs of congestion. The mtDNA ratio showed opposite trends (all p<0.05), with no significant differences in cell mtDNA. Cell-free mtDNA and mtDNA ratio independently predicted the presence of >=2 ultrasound signs of congestion and effort intolerance (peak oxygen consumption <16 mL/kg/min) at ROC analysis and using multivariable regressions after adjustment for age, sex, hs-CRP, NLR, high-sensitivity Troponin T and NT-proBNP.Conclusions: Cardiometabolic patients have an altered circulating mtDNA signature characterised by higher cell-free mtDNA and lower mtDNA ratio. Cell-free mtDNA and mtDNA ratio are associated with impaired response to exercise, higher systemic inflammation and increased congestion. Circulating mitochondrial profile could be a new biomarker of mitochondrial status in cardiometabolic diseases.