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.

Individual L-type calcium channels are fundamentally affected in severe human heart failure. This is probably important for the impairment of cardiac excitation-contraction coupling.

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1. Transmembrane current through ATP-regulated K+ channels (IK(ATP)) was measured in ventricular heart cells of the guinea-pig in the whole-cell and cell-attached patch configurations under conditions of metabolic poisoning with the mitochondrial uncoupler 2,4-dinitrophenol (DNP). 2. Maintained exposure of the cells to DNP resulted in a transient appearance of whole-cell IK(ATP). When IK(ATP) had reached several nanoamps, blocking the forward-running Na+-K+ pump with 0.5 mm strophanthidin decreased IK(ATP) after a delay. The time course of this decrease could be described by a single exponential function, which yielded a time constant (r) of 4-51 + 1P89 s (n = 8). 3. Hyperpolarization from 0 mV to -100 or -150 mV for 2 s caused IK(ATP) (measured at 0 mV) to decrease by 34-2 + 14 1 % (n = 8) and 37X6 + 9 4% (n = 8), respectively. After the hyperpolarizing pulse, IK(ATP) returned to its higher initial level within a couple of seconds. 4. Driving the pump backwards by removing the extracellular K+ ions caused the permanent disappearance of DNP-induced IK(ATP).5. Application of 0 5 mm strophanthidin in the absence of external K+ ions induced a transient increase in IK(ATP), as did washing out the glycoside (n = 5). 6. When pump action was inhibited by using Nae, K+-free Tyrode solution (see Methods) in the bath, strophanthidin did not have a comparable direct effect on IK(ATP)* 7. In cell-attached patches, strophanthidin applied via the bath caused a reduction in IK(ATP) with a similar time course to that in whole-cell experiments. This suggests that the interaction between the pump molecules and the KATP channels is not restricted to closely neighbouring molecules. 8. The data support the hypothesis that [ATP]

In guinea-pig ventricular myocytes, cell swelling by incubation in hypotonic solution caused a pronounced shortening of the action potential duration (APD 90 : 15.5±14.6% compared to control; mean ± SD) after a latency of 12 min when the intracellular ATP concentration was 2 mM. This shortening was partially reversible within 10 min after reperfusion with isotonic solution (APD 90 : 80.5±12.1% compared to control). With 5 mM intracellular ATP in the pipette electrode, the effect of cell swelling on the action potential was significantly reduced. Incubation with 1 µM glibenclamide, a blocker of the ATP-dependent K + current (I KATP ), abolished the swelling-induced shortening of the action potential duration, whereas incubation with 0.5 mM 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS), a blocker of the swelling-induced Cl -current (I Cl,swell ), had no effect on the action potential duration in hypotonic solution. Simultaneous measurements of membrane currents substantiate that I KATP is the current that underlies this effect. These results suggest that in the ischaemic myocardium I KATP may be partially activated by cell swelling, resulting in a shortening of the action potential duration before the intracellular ATP concentration has fallen below 2 mM.