Abstract
β-adrenergic receptor stimulation (β-ARS) is a physiological mechanism that regulates cardiovascular function under stress conditions or physical exercise. Triggered during the so-called “fight-or-flight” response, the activation of the β-adrenergic receptors located on the cardiomyocyte membrane initiates a phosphorylation cascade of multiple ion channel targets that regulate both cellular excitability and recovery and of different proteins involved in intracellular calcium handling. As a result, β-ARS impacts both the electrophysiological and the mechanical response of the cardiomyocyte. β-ARS also plays a crucial role in several cardiac pathologies, greatly modifying cardiac output and potentially causing arrhythmogenic events. Mathematical patient-specific models are nowadays envisioned as an important tool for the personalised study of cardiac disease, the design of tailored treatments, or to inform risk assessment. Despite that, only a reduced number of computational studies of heart disease have incorporated β-ARS modelling. In this review, we describe the main existing multiscale frameworks to equip cellular models of cardiac electrophysiology with a β-ARS response. We also outline various applications of these multiscale frameworks in the study of cardiac pathology. We end with a discussion of the main current limitations and the future steps that need to be taken to adapt these models to a clinical environment and to incorporate them in organ-level simulations.
Highlights
Multiscale Modelling of Abstract: β-adrenergic receptor stimulation (β-ARS) is a physiological mechanism that regulates cardiovascular function under stress conditions or physical exercise
Introduction β-adrenergic receptor stimulation (β-ARS) is a physiological response mechanism that plays a fundamental role in the regulation of cardiomyocyte activity, producing a positive inotropic, lusitropic, and chronotropic effect
Β-ARS plays a main role in a considerable number of heart diseases [5], and it is well established as an important contributor to cardiomyocyte arrhythmogenicity [6,7,8]
Summary
Several mathematical formulations, with varying degrees of complexity and physiological detail, have been proposed to date to describe different aspects of β-ARS in cardiac myocytes. The first modelling approach for the consideration of β-ARS in cardiac electrophysiology described the effects of β-ARS by upscaling the magnitude of the most significantly upregulated ion channels during the β-adrenergic response (notably ICaL and IKs ) or by shifting the activation curves of these currents [35,43] Despite its simplicity, such an approach is sufficient to replicate to a good extent the main steady-state effects of βARS at the cellular level, such as action potential shortening, increased calcium transient amplitude, or a potentiated arrhythmogenicity. The authors considered an extensive validation against published experimental data, including the temporal response of cAMP to ISO [45], PKA activation levels as a function of the concentration of cAMP [46], and PLB phosphorylation to ISO [47], together with experimental recordings of whole-cell patch-clamp ICaL current, calcium transients, and action potentials [48] This seminal model of β-ARS has been expanded in multiple subsequent studies. The modelling results highlighted the significant contribution of these pathways in regulating cardiac hypertrophy in rats
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