BS59 Mechanisms underlying atrial dysfunction in heart failure: role of the mitochondrial permeability transition pore

Abstract

IntroductionHeart Failure (HF) carries significant mortality and morbidity, especially due to comorbidities such as Atrial Fibrillation (AF). Previous work illustrates that mitochondrial dysfunction underpins the pathophysiology of both HF and AF, including decreased Adenosine TriPhosphate (ATP) production, Ca2+ mishandling, oxidative stress and elevated apoptosis. In addition to these problems, recent work suggests the Mitochondrial Permeability Transition Pore (MPTP) in ventricular cardiomyocytes may become sensitised to Ca2+ during HF, leading to increased apoptosis. Nevertheless, the role of mitochondrial dysfunction has not been investigated in the atria. In this study, we investigated the role of Ca2+ sensitivity of the MPTP and mitochondrial aerobic capacity in atrial muscle of the failing heart.MethodsRight atrial appendage and right ventricular free wall were dissected from 15 sheep representing an ovine model of tachycardia-induced HF. The tissue was subsequently homogenized and differentially centrifuged, yielding isolated mitochondria. Respiratory function was measured using a respirometer, with the electron transport system (ETS) selectively probed through addition of various substrates stimulating differing ETS complexes. A Calcium Retention Capacity (CRC) assay determined MPTP Ca2+ sensitivity, which involved Ca2+ titrations onto isolated mitochondria containing a Ca2+-sensitive fluorescent dye. An increase in fluorescence marked MPTP opening.ResultsAerobic capacity was not affected by HF, but an increase in ventricular leak respiration was statistically significant (p=0.0140). HF reduced atrial mitochondrial efficiency by 68% (p=0.0063) but did not affect maximal mitochondrial respiration. There was no significant effect of HF or tissue-type on MPTP Ca2+ sensitivity and mitochondrial Ca2+ buffering capacity.ConclusionOur data suggests HF affects atrial and ventricular mitochondrial respiratory function asymmetrically, with HF affecting atrial mitochondrial efficiency and ventricular leak respiration. The COVID-19 pandemic hindered this research project;however, it provides rationale on the unequal effect of HF on mitochondrial function across the atria and ventricle. Future research should therefore consider incorporating atrial samples when assessing potential HF therapies.Conflict of InterestNil