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

Shi, Q.; Malik, H.; Streeter, J.; Wang, J.; Huo, R.; Crawford, R. M.; Shih, J. C.; Chen, B.; Hall, D.; Abel, E. D.; Song, L.-S.; Anderson, E. J.

doi:10.1101/2022.09.29.510139

bioRxiv · 10.1101/2022.09.29.510139

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

Shi, Q.·Malik, H.·Streeter, J.·Wang, J.·Huo, R.·Crawford, R. M.·Shih, J. C.·Chen, B.·Hall, D.·Abel, E. D.·Song, L.-S.·Anderson, E. J.

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Abstract

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.

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Shi, Q., Malik, H., Streeter, J., Wang, J., Huo, R., Crawford, R. M., Shih, J. C., Chen, B., Hall, D., Abel, E. D., Song, L.-S., Anderson, E. J.. 2022-10-02. Cardiac MAO-A inhibition protects against catecholamine-induced ventricular arrhythmias via enhanced diastolic calcium control. https://doi.org/10.1101/2022.09.29.510139

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