MOLECULAR MECHANISM OF the association between atrial fibrillation and heart failure inCLUDEs Energy METABOLIC DYSREGULATION DUE to MITOCHONDRIAL DYSFUNCTION.

Abstract

BACKGROUND\nAtrial fibrillation (AF) and heart failure (HF) commonly coexist, yet the molecular mechanisms of this association have not been determined. We hypothesized that an energy deficit due to mitochondrial dysfunction plays a significant role in pathogenic link between AF and HF.\n\n\nMETHODS AND RESULTS\nMyocardial energy metabolism and mitochondria were examined in atrial tissue samples from patients and mice (cardiac specific LKB1 knockout) with HF and/or AF. There was significant atrial energy (ATP) deficit in patients with HF (11.5±1.3 nmoles/mg, n=10; versus without HF 17±3.8 nmoles/mg, n=5, p=0.032). AF was associated with further energy depletion (ATP 5.4±1.2 nmoles/mg, n=9) in HF (p=0.001) and metabolic stress (AMP/ATP 1.6±0.1 vs 0.7±0.2 in HF alone; p=0.043). The left atrium demonstrated lower ATP than the right (p=0.004). Mitochondrial dysfunction and remodeling caused ATP depletion with impaired oxidative phosphorylation complexes (succinate dehydrogenase and cytochrome c oxidase), increased reactive oxygen species, and mtDNA damage in mice and human atria with AF and HF.\n\n\nCONCLUSIONS\nMolecular mechanisms of the association between HF and AF include an energy deficit due to mitochondrial dysfunction in atrial myocardium. Mitochondrial functional and structural remodeling in human and mouse atria is associated with energy metabolic dysregulation and oxidative stress that promote AF in HF and vice versa.