Simulation Study of Cellular Electric Properties in Heart Failure

Abstract

Patients with severe heart failure are at high risk of sudden cardiac death. In the majority of these patients, sudden cardiac death is thought to be due to ventricular tachyarrhythmias. Alterations of the electric properties of single myocytes in heart failure may favor the occurrence of ventricular arrhythmias in these patients by inducing early or delayed afterdepolarizations. Mathematical models of the cellular action potential and its underlying ionic currents could help to elucidate possible arrhythmogenic mechanisms on a cellular level. In the present study, selected ionic currents based on human data are incorporated into a model of the ventricular action potential for the purpose of studying the cellular electrophysiological consequences of heart failure. Ionic currents that are not yet sufficiently characterized in human ventricular myocytes are adopted from the action potential model developed by Luo and Rudy (LR model). The main results obtained from this model are as follows: The action potential in ventricular myocytes from failing hearts is longer than in nonfailing control hearts. The major underlying mechanisms for this prolongation are the enhanced activity of the Na+-Ca2+ exchanger, the slowed diastolic decay of the [Ca2+]i transient, and the reduction of the inwardly rectifying K+ current and the Na+-K+ pump current in myocytes of failing hearts. Furthermore, the fast and slow components of the delayed rectifier K+ current (I(Kr) and I(Ks), respectively) are of utmost importance in determining repolarization of the human ventricular action potential. In contrast, the influence of the transient outward K+ current on APD is only small in both cell groups. Inhibition of I(Kr) promotes the development of early afterdepolarizations in failing, but not nonfailing, myocytes. Furthermore, spontaneous Ca2+ release from the sarcoplasmic reticulum triggers a premature action potential only in failing myocytes. This model of the ventricular action potential and its alterations in heart failure is intended to serve as a tool for investigating the effects of therapeutic interventions on the electric excitability of the human ventricular myocardium.

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts

“…In multicellular preparations and intact hearts, EADs constitute an important cellular mechanism for triggered activity (1,47). It appears that downregulation of multiple K ϩ channel currents, i.e., I to1 , I K1 , and I Ks , is responsible for the delayed repolarization and favors the genesis of EADs in the three regions, which is consistent with earlier simulation studies (25,35). Therefore, pharmacological therapy to activate or potentiate I K (48) may be efficacious in controlling life-threatening ventricular arrhythmias in patients with HF.…”

The role of arrhythmias in the progression of heart failure

“…a'i the lQ~a.J:d t:.ec:tifut:. CJl..t:.-rent, X KI , and the transient outward current, ITO' [5,6]; as well as a decrease in Na/K pump current [7]. It should be pointed out that the clinical relevance of the prolongation of action potential duration is still uncertain, since it has been shown to be present mostly at long, and often unphysiologic, cycle lengths.…”

Cardiac cell modelling: Observations from the heart of the cardiac physiome project

“…Modelling of human ventricular cells started with a study by Priebe and Beuckelmann (1998), aimed at understanding the effects of electrophysiological alterations in heart failure. In this study, models were developed to describe normal and failing human myocytes with similar approaches to those previously used for cardiac cells of other species.…”