Electrophysiological properties under heart failure conditions in a human ventricular cell: A modeling study

Abstract

Heart failure (HF) is one of the major diseases across the world. During HF the electrophysiology of the failing heart is remodeled, which renders the heart more susceptible to ventricular arrhythmias. In this study, we quantitatively analyze the effects of electrophysiological remodeling of the major currents of human ventricular myocytes on the dynamics of the failing heart. We develop a HF model using a modified version of a recently published model of the human ventricular action potential, the O'Hara-Virag-Varro-Rudy (OVVR) model. The proposed HF model incorporates recently available HF clinical data. It can reproduce most of the action potential (AP) properties of failing myocytes, including action potential duration (APD), amplitude (APA), notch (APN), plateau (APP), resting membrane potential (RMP), and maximum upstroke velocity (dV/dtmax). In addition, the model reproduces the behavior of the [Na+], concentration and [Ca(2)+]i dynamics. Moreover, the HF model exhibits alternans with a fast pacing frequency and can induce early afterdepolarizations (EADs). Additionally, blocking the late sodium current shortens the APD and suppresses EADs, in agreement with experimental findings. The dynamics of the proposed model are assessed through investigating the rate dependence of the AP and the dynamics of the major currents. The steady-state (S-S) and S1-S2 restitution curves along with accommodation to an abrupt change in cycle length were evaluated. Our study should help to elucidate the roles of alterations in electrophysiological properties during HF. Also, this HF cellular model could be used to study HF in a realistic geometry and could be embedded into a model of HF electromechanics to investigate electrical and mechanical properties simultaneously during HF.

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

“…I Na reduction is well established in HF,4, 5, 6 but the possibility that sodium channel density and/or function is differentially remodeled within the various subcellular compartments (microdomains) of failing cardiomyocytes has not been previously addressed. Sodium channel clusters in various cardiomyocyte microdomains exhibit distinct current amplitudes and gating properties 9.…”

“…In failing hearts, reduced sodium current (I Na ) contributes to slowed conduction 4, 5, 6. Na V 1.5 is the major pore‐forming protein of the cardiac sodium channel and is responsible for the fast entry of sodium ions into cardiomyocytes, thereby underlying the upstroke of the action potential and mediating cardiac conduction.…”

Clinical phenotypes in acute and chronic infarction explained through human ventricular electromechanical modelling and simulations

“…For chronic post-MI, ionic remodelling measured from minipigs 5 months post-MI with heart failure were used to generate Chronic BZ (affecting only the BZ) and Chronic RZ1 (also affecting the remote myocardium). Another type of remodelling, Chronic RZ2, was established based on multiple experimental data from failing human cardiomyocytes [45][46][47][48][49][50][51][52][53][54][55][56] . Furthermore, reduction of sodium current 46 and SERCA 47 , with enhanced CaMKII activity and slower calcium release 57,58 were also implemented in Chronic BZ, RZ1 and RZ2, as observed in human failing cardiomyocytes.…”

Sensitivity analysis of ventricular activation and electrocardiogram in tailored models of heart-failure patients

“…Newer electrophysiological models of ventricular myocytes have been recently developed based on particular experimental datasets, but their robustness in reproducing tissue, cellular, and sub-cellular behavior has been shown to be similar [10,17,30]. Furthermore, previous studies have shown that HF entails remodeling of cellular electrophysiology in the myocardium [52] and included it in cellular models [13,54]. In this study we used an undiseased human ventricular cell model as a reference, since we could not be sure about either to what extent ventricular cells had modified their electrophysiology for each patient or, considering they had modified it, whether their remodeling was homogeneous in both ventricles.…”