The role of β-adrenergic system remodeling in human heart failure: A mechanistic investigation

https://doi.org/10.1016/j.yjmcc.2020.12.004Get rights and content
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Highlights

  • β-adrenergic stimulation acts differently in failing compared to normal myocytes.

  • β-adrenergic receptors isoforms modulate the electrophysiology.

  • Mechanisms for arrhythmogenesis are enhanced in heart failure.

Abstract

β-adrenergic receptor antagonists (β-blockers) are extensively used to improve cardiac performance in heart failure (HF), but the electrical improvements with these clinical treatments are not fully understood. The aim of this study was to analyze the electrophysiological effects of β-adrenergic system remodeling in heart failure with reduced ejection fraction and the underlying mechanisms. We used a combined mathematical model that integrated β-adrenergic signaling with electrophysiology and calcium cycling in human ventricular myocytes. HF remodeling, both in the electrophysiological and signaling systems, was introduced to quantitatively analyze changes in electrophysiological properties due to the stimulation of β-adrenergic receptors in failing myocytes. We found that the inotropic effect of β-adrenergic stimulation was reduced in HF due to the altered Ca2+ dynamics resulting from the combination of structural, electrophysiological and signaling remodeling. Isolated cells showed proarrhythmic risk after sympathetic stimulation because early afterdepolarizations appeared, and the vulnerability was greater in failing myocytes. When analyzing coupled cells, β-adrenergic stimulation reduced transmural repolarization gradients between endocardium and epicardium in normal tissue, but was less effective at reducing these gradients after HF remodeling. The comparison of the selective activation of β-adrenergic isoforms revealed that the response to β2-adrenergic receptors stimulation was blunted in HF while β1-adrenergic receptors downstream effectors regulated most of the changes observed after sympathetic stimulation. In conclusion, this study was able to reproduce an altered β-adrenergic activity on failing myocytes and to explain the mechanisms involved. The derived predictions could help in the treatment of HF and guide in the design of future experiments.

Keywords

Electrophysiology
Simulation
Heart failure
β-Adrenergic signaling

Abbreviations

AP
action potential
β-AR
β-adrenergic receptor
CaT
Ca2+ transient
cav
caveolar signaling domain
cyt
cytosolic signaling domain
ecav
extracaveolar signaling domain
HF
Heart failure
iso
isoproterenol
SR
sarcoplasmic reticulum
TDR
transmural dispersion of repolarization

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