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

Cardiovasc Res. 2024 May 7;120(6):596-611. doi: 10.1093/cvr/cvae012.

Abstract

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 the TriNetX database revealed that depressed patients treated with MAO inhibitors had a lower risk of arrhythmias compared with 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 tachycardia compared with wild-type 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 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.

Conclusion: Cardiac MAO-A inhibition exerts an anti-arrhythmic effect by enhancing diastolic Ca2+ handling under catecholamine stress.

Keywords: Calcium; Calcium–calmodulin (CaM)-dependent protein kinase II (CaMKII); Catecholamine; Monoamine oxidase; Oxidative damage; Protein kinase A (PKA); Ventricular arrhythmia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Calcium Signaling* / drug effects
  • Calcium* / metabolism
  • Calcium-Binding Proteins* / genetics
  • Calcium-Binding Proteins* / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Catecholamines* / metabolism
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Diastole / drug effects
  • Disease Models, Animal*
  • Female
  • Heart Rate / drug effects
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monoamine Oxidase Inhibitors* / pharmacology
  • Monoamine Oxidase* / metabolism
  • Myocytes, Cardiac* / drug effects
  • Myocytes, Cardiac* / enzymology
  • Myocytes, Cardiac* / metabolism
  • Myocytes, Cardiac* / pathology
  • Phosphorylation
  • Reactive Oxygen Species / metabolism
  • Ryanodine Receptor Calcium Release Channel* / metabolism
  • Tachycardia, Ventricular / enzymology
  • Tachycardia, Ventricular / metabolism
  • Tachycardia, Ventricular / physiopathology
  • Tachycardia, Ventricular / prevention & control

Substances

  • Monoamine Oxidase
  • Catecholamines
  • Monoamine Oxidase Inhibitors
  • Ryanodine Receptor Calcium Release Channel
  • Calcium-Binding Proteins
  • Calcium
  • monoamine oxidase A, human
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • phospholamban
  • ryanodine receptor 2. mouse
  • RyR2 protein, human
  • Reactive Oxygen Species
  • Cyclic AMP-Dependent Protein Kinases