Mitochondrial dysfunction as an arrhythmogenic substrate: a translational proof-of-concept study in patients with metabolic syndrome in whom post-operative atrial fibrillation develops

Abstract

Objectives: This study sought to provide bedside evidence of the potential link between cardiac mitochondrial dysfunction and arrhythmia as reported in bench studies.

Background: Atrial fibrillation (AF) is a frequent complication of cardiac surgery. Underlying mechanisms of post-operative atrial fibrillation (POAF) remain largely unknown. Because cardiac mitochondrial dysfunction has been reported in clinical conditions with a high risk of POAF, we investigated whether a causal link exists between POAF onset and pre-operative function of cardiac mitochondria.

Methods: Pre-operative mitochondrial respiration and calcium retention capacity, respiratory complex activity, and myocardial oxidative stress were quantified in right atrial tissue from 104 consecutive patients with metabolic syndrome, in sinus rhythm, and undergoing coronary artery bypass graft surgery.

Results: In this high-risk population, POAF occurred in 44% of patients. Decreased pre-operative mitochondrial respiration and increased sensitivity to calcium-induced mitochondrial permeability transition pore opening were significantly associated with POAF. Adenosine diphosphate-stimulated mitochondrial respiration supported by palmitoyl-l-carnitine was significantly lower in POAF patients and remained independently associated with AF onset after adjustment for age, body mass index, heart rate, beta-blocker use, and statin medication (multivariate logistic regression coefficient per unit = -0.314 ± 0.144; p = 0.028). Gene expression profile analysis identified a general downregulation of the mitochondria/oxidative phosphorylation gene cluster in pre-operative atrial tissue of patients in whom AF developed.

Conclusions: Our prospective study identifies an association between pre-operative mitochondrial dysfunction of the atrial myocardium and AF occurrence after cardiac surgery in patients with metabolic disease, providing novel insights into the link between mitochondria and arrhythmias in patients.

Keywords: ADP; AF; ATP; BMI; CABG; MnSOD; OXPHOS; POAF; ROS; SR; V(Cox); V(palm+ADP); adenosine diphosphate; adenosine diphosphate–stimulated respiration supported by palmitoyl-l-carnitine; adenosine triphosphate; atrial fibrillation; body mass index; cardiac surgery; complex IV–related uncoupled maximum respiration; coronary artery bypass graft; diabetes; gene expression; mCRC; mPTP; manganese superoxide dismutase; mitochondria; mitochondrial calcium retention capacity; mitochondrial permeability transition pore; oxidative phosphorylation; post-operative atrial fibrillation; reactive oxygen species; sinus rhythm.