Proarrhythmic Electrical Remodeling by Noncardiomyocytes at Interfaces With Cardiomyocytes Under Oxidative Stress

Abstract

Life-threatening ventricular arrhythmias, typically arising from interfaces between fibrosis and surviving cardiomyocytes, are feared sequelae of structurally remodeled hearts under oxidative stress. Incomplete understanding of the proarrhythmic electrical remodeling by fibrosis limits the development of novel antiarrhythmic strategies. To define the mechanistic determinants of the proarrhythmia in electrical crosstalk between cardiomyocytes and noncardiomyocytes, we developed a novel in vitro model of interface between neonatal rat ventricular cardiomyocytes (NRVMs) and controls [NRVMs or connexin43 (Cx43)-deficient HeLa cells] vs. Cx43+ noncardiomyocytes [aged rat ventricular myofibroblasts (ARVFs) or HeLaCx43 cells]. We performed high-speed voltage-sensitive optical imaging at baseline and following acute H2O2 exposure. In NRVM-NRVM and NRVM-HeLa controls, no arrhythmias occurred under either experimental condition. In the NRVM-ARVF and NRVM-HeLaCx43 groups, Cx43+ noncardiomyocytes enabled passive decremental propagation of electrical impulses and impaired NRVM activation and repolarization, thereby slowing conduction and prolonging action potential duration. Following H2O2 exposure, arrhythmia triggers, automaticity, and non-reentrant and reentrant arrhythmias emerged. This study reveals that myofibroblasts (which generate cardiac fibrosis) and other noncardiomyocytes can induce not only structural remodeling but also electrical remodeling and that electrical remodeling by noncardiomyocytes can be particularly arrhythmogenic in the presence of an oxidative burst. Synergistic electrical remodeling between H2O2 and noncardiomyocytes may account for the clinical arrhythmogenicity of myofibroblasts at fibrotic interfaces with cardiomyocytes in ischemic/non-ischemic cardiomyopathies. Understanding the enhanced arrhythmogenicity of synergistic electrical remodeling by H2O2 and noncardiomyocytes may guide novel safe-by-design antiarrhythmic strategies for next-generation iatrogenic interfaces between surviving native cardiomyocytes and exogenous stem cells or engineered tissues in cardiac regenerative therapies.

Effects of salt and stress on blood pressure parameters and antioxidant enzyme function in the heart and aorta of borderline hypertensive rats

“…In initiates proarrhythmic activity (Zhao et al, 2020). In our experiment, we found differences in HR that might reflect H 2 O 2 -mediated heart functionality.…”

“…It is known that H 2 O 2 is an important factor contributing to the generation of rhythm disturbances and cellular damage during reperfusion of previously ischaemic myocardium. Also, direct application of H 2 O 2 initiates proarrhythmic activity (Zhao et al., 2020 ). In our experiment, we found differences in HR that might reflect H 2 O 2 ‐mediated heart functionality.…”

“…In our experiment, we found differences in HR that might reflect H 2 O 2 ‐mediated heart functionality. H 2 O 2 can increase ATP‐sensitive K + current (Zhao et al., 2020 ) and inward‐rectifying K + current (Bychkov et al., 1999 ), which can decrease the delayed rectifier K + current (Bae et al., 2016 ). H 2 O 2 appears to have a number of different effects on L‐type Ca 2+ currents in rat ventricular myocytes, from slowing the rate of fast inactivation to a biphasic effect on the spontaneous cycle length (Bao et al., 2000 ).…”

Glycolysis Inhibition Alleviates Cardiac Fibrosis After Myocardial Infarction by Suppressing Cardiac Fibroblast Activation

“…Adult mouse CFs (AMCFs) were separated from the ventricle of the MI or sham mice with or without 2-DG treatment on the 28th day after the sham or MI surgery as described previously ( 20 , 21 ). As inadequate cells could be harvested from only one heart, two hearts were isolated together and mixed to produce one group of cardiac cells with an enzymolysis approach.…”

Myofibroblasts impair myocardial impulse propagation by heterocellular connexin43 gap-junctional coupling through micropores

“…We demonstrated that the point-to-point, single-sided CM-MF connection impaired the impulse propagation of the CM monolayers. The single-sided CM-MF connection model was also studied using a linear connection model between monolayers of CMs and MFs with Cx43 without the insertion or mixture of these two types of cells (Zhao et al, 2020). Under such a linear interface, the authors observed the spontaneous occurrence of re-entrant arrhythmias in the CM monolayer after the application of hydrogen peroxide by prolonging the action potential duration (Zhao et al, 2020).…”