Sensitivity analysis revealing the effect of modulating ionic mechanisms on calcium dynamics in simulated human heart failure

Abstract

Abnormal intracellular Ca2+ handling is the major contributor to the depressed cardiac contractility observed in heart failure. The electrophysiological remodeling associated with this pathology alters both the action potential and the Ca2+ dynamics, leading to a defective excitation-contraction coupling that ends in mechanical dysfunction. The importance of maintaining a correct intracellular Ca2+ concentration requires a better understanding of its regulation by ionic mechanisms. To study the electrical activity and ionic homeostasis of failing myocytes, a modified version of the O’Hara et al. human action potential model was used, including electrophysiological remodeling. The impact of the main ionic transport mechanisms was analyzed using single-parameter sensitivity analyses, the first of which explored the modulation of electrophysiological characteristics related to Ca2+ exerted by the remodeled parameters. The second sensitivity analysis compared the potential consequences of modulating individual channel conductivities, as one of the main effects of potential drugs, on Ca2+ dynamic properties under both normal conditions and in heart failure. The first analysis revealed the important contribution of the sarcoplasmic reticulum Ca2+-ATPase (SERCA) dysfunction to the altered Ca2+ homeostasis, with the Na+/Ca2+ exchanger (NCX) and other Ca2+ cycling proteins also playing a significant role. Our results highlight the importance of improving the SR uptake function to increase Ca2+ content and restore Ca2+ homeostasis and contractility. The second sensitivity analysis highlights the different response of the failing myocyte versus the healthy myocyte to potential pharmacological actions on single channels. The result of modifying the conductances of the remodeled proteins such as SERCA and NCX in heart failure has less impact on Ca2+ modulation. These differences should be taken into account when designing drug therapies.