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.
Highlights
In the normal adult mammalian left ventricle, electrically excitable cardiomyocytes comprise 80% of the volume but only 30% of the cell number (Vliegen et al, 1991)
Single neonatal rat ventricular cardiomyocytes (NRVMs) are practically indistinguishable from single noncardiomyocytes in a mixture of both cell types
Optical voltage impulses of non-excitable noncardiomyocytes if any were readily distinguished from optical action potentials of excitable NRVMs due to slower upstroke and diminished voltage amplitudes
Summary
In the normal adult mammalian left ventricle, electrically excitable (capable of firing all-or-none action potentials) cardiomyocytes comprise 80% of the volume but only 30% of the cell number (Vliegen et al, 1991). Ventricular noncardiomyocytes (predominantly fibroblasts and endothelial cells) are electrically non-excitable (incapable of firing action potentials), but they outnumber cardiomyocytes and comprise the cellular majority in the heart. The ratio of noncardiomyocytes to cardiomyocytes increases further, and the noncardiomyocyte composition changes as new active myofibroblasts over-replace old quiescent fibroblasts. Myofibroblasts are noncardiomyocytes that share features with both cardiomyocytes and fibroblasts. Myofibroblasts do not exist in healthy young myocardium. They only proliferate in the injured, diseased, aged, or therapeutically ablated myocardium, by phenotypic conversion of existing fibroblasts, epithelial–mesenchymal transition, or de novo production. Fibrosis develops as myofibroblasts deposit collagen bundles to salvage the compromised cardiac mechanical function, albeit at the cost of higher risk of life-threatening ventricular arrhythmias (Nguyen et al, 2014)
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