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

BackgroundPeople with clinical depression exhibit increased risk for cardiac arrhythmias that could be related to differences in catecholamine metabolism. Emerging studies have implicated a pathophysiologic role for monoamine oxidase (MAO-A), which catalyzes catecholamine metabolism in the heart. MAO-A is the pharmacological target of some classes of anti-depressants. Here, we investigated the relationship between MAO-A activity and arrhythmogenesis. Methods & ResultsTriNetX database analysis of adult patients with depression (n=11,533) revealed that MAO inhibitor (MAOI) treatment is associated with significantly lower risk of arrhythmias compared with selective serotonin reuptake inhibitor (SSRI) treatment (16.7% vs 18.6%, p=0.0002). To determine a mechanistic link between MAO activity and arrhythmia, we utilized a genetically modified mouse model with cardiomyocyte-specific MAO-A deficiency (cMAO-Adef). Compared with wild-type (WT) mice, cMAO-Adef mice had a significant reduction in the incidence (38.9% vs. 77.8%, p=0.0409) and duration (55.33 {+/-} 26.21s vs.163.1 {+/-} 56.38s, p=0.0360) of catecholamine stress-induced ventricular tachyarrhythmias (VT). Reduced VT risk and duration were associated with altered cardiomyocyte Ca2+ handling in the cMAO-Adef hearts, including a marked increase in Ca2+ reuptake rate, decreased diastolic Ca2+ levels, decreased SR Ca2+ load and reduced Ca2+ spark activity following catecholamine stimulation relative to WT. Further analysis of molecular mechanisms revealed that altered Ca2+ handling in the cMAO-Adef hearts was related to decreased catecholamine-induced phosphorylation of Ca2+/calmodulin-dependent kinase II (CaMKII) and ryanodine receptor 2 (RyR2), and increased phosphorylation of phospholamban (PLB). ConclusionsThese findings suggest that MAO-A inhibition in cardiomyocytes mitigates arrhythmogenesis via enhanced Ca2+ reuptake that lowers diastolic Ca2+ levels thereby diminishing arrhythmic triggers following catecholamine stimulation. Thus, cardiac MAO-A represents a potential target for antiarrhythmic therapy.