Arrhythmogenic Mechanisms in Heart Failure: Linking β-Adrenergic Stimulation, Stretch, and Calcium

Abstract

Heart failure (HF) is associated with elevated sympathetic tone and mechanical load. Both systems activate signaling transduction pathways that increase cardiac output, but eventually become part of the disease process itself leading to further worsening of cardiac function. These alterations can adversely contribute to electrical instability, at least in part due to the modulation of Ca2+ handling at the level of the single cardiac myocyte. The major aim of this review is to provide a definitive overview of the links and cross talk between β-adrenergic stimulation, mechanical load, and arrhythmogenesis in the setting of HF. We will initially review the role of Ca2+ in the induction of both early and delayed afterdepolarizations, the role that β-adrenergic stimulation plays in the initiation of these and how the propensity for these may be altered in HF. We will then go onto reviewing the current data with regards to the link between mechanical load and afterdepolarizations, the associated mechano-sensitivity of the ryanodine receptor and other stretch activated channels that may be associated with HF-associated arrhythmias. Furthermore, we will discuss how alterations in local Ca2+ microdomains during the remodeling process associated the HF may contribute to the increased disposition for β-adrenergic or stretch induced arrhythmogenic triggers. Finally, the potential mechanisms linking β-adrenergic stimulation and mechanical stretch will be clarified, with the aim of finding common modalities of arrhythmogenesis that could be targeted by novel therapeutic agents in the setting of HF.

Neuregulin-1β Partially Improves Cardiac Function in Volume-Overload Heart Failure Through Regulation of Abnormal Calcium Handling

“…Abnormal Ca 2+ handling in cardiomyocytes has been increasingly implicated in the development of HF and has been shown to influence excitation-contraction coupling (ECC) and cell function, which leads to systolic dysfunction and arrhythmias (Johnson and Antoons, 2018). Recent studies have revealed that intracellular Ca 2+ dynamics are impaired before myocardial contractility is weakened.…”

Regression from pathological hypertrophy is sexually dimorphic and stimulus-specific

“…Then, following the removal of the agonists, we studied the time course of regression, specific pathways that were regulated during regression, and we studied these processes in both males and females. Iso and Ang II are known to act through different pathways with Iso activating adrenergic receptors that are a class of G-protein coupled receptors on the cell surface that cause a canonical signaling cascade leading to increased concentration of Ca 2+ in the cytosol (36) . This increase ultimately results in faster contractions of the cardiomyocytes and mimics the increased work load observed in the disease state.…”

Calcium Handling Defects and Cardiac Arrhythmia Syndromes

“…The following sections will provide further insights into intracellular Ca 2+ handling maladies in the most prevalent inherited and acquired arrhythmia syndromes, caused by channelopathies and defects in Ca 2+ handling genes. Ca 2+ handling defects also have an arrhythmogenic role in diseases, such as heart failure and cardiomyopathies, however they are beyond the scope of the present review [see recent reviews (Coppini et al, 2018;Johnson and Antoons, 2018;Denham et al, 2018)].…”