Cardiac MAO-A inhibition protects against catecholamine-induced ventricular arrhythmias via enhanced diastolic calcium control.

AIMS:A mechanistic link between depression and risk of arrhythmias could be attributed to altered catecholamine metabolism in the heart. Monoamine oxidase-A (MAO-A), a key enzyme involved in catecholamine metabolism and longstanding antidepressant target, is highly expressed in the myocardium. The present study aimed to elucidate the functional significance and underlying mechanisms of cardiac MAO-A in arrhythmogenesis. METHODS AND RESULTS:Analysis of TriNetX database revealed that depressed patients treated with MAO inhibitors had a lower risk of arrhythmias compared to those treated with selective serotonin reuptake inhibitors. This effect was phenocopied in mice with cardiomyocyte-specific MAO-A deficiency (cMAO-Adef), which showed a significant reduction in both incidence and duration of catecholamine stress-induced ventricular tachyarrhythmias (VT) compared to wildtype mice. Additionally, cMAO-Adef cardiomyocytes exhibited altered Ca2+ handling under catecholamine stimulation, with increased diastolic Ca2+ reuptake, reduced diastolic Ca2+ leak, and diminished systolic Ca2+ release. Mechanistically, cMAO-Adef hearts had reduced catecholamine levels under sympathetic stress, along with reduced levels of reactive oxygen species (ROS) and protein carbonylation, leading to decreased oxidation of Type II PKA and CaMKII. These changes potentiated phospholamban (PLB) phosphorylation thereby enhancing diastolic Ca2+ reuptake while reducing ryanodine receptor 2 (RyR2) phosphorylation to decrease diastolic Ca2+ leak. Consequently, cMAO-Adef hearts exhibited lower diastolic Ca2+ levels and fewer arrhythmogenic Ca2+ waves during sympathetic overstimulation. CONCLUSIONS:Cardiac MAO-A inhibition exerts an anti-arrhythmic effect by enhancing diastolic Ca2+ handling under catecholamine stress. TRANSLATIONAL PERSPECTIVE:This study implicates catecholamine metabolism in arrhythmogenesis and reveals that monoamine oxidase is linked to Ca2+ regulation in the heart. It further illustrates therapeutic potential of cardiac MAO-A inhibition as a dual-purpose drug target to simultaneously manage depression and lower arrhythmia risk in affected patients.