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Calcium ions (Ca2+) play a major role in the cardiac excitation-contraction coupling. Intracellular Ca2+ concentration increases during systole and falls in diastole thereby determining cardiac contraction and relaxation. Normal cardiac function also requires perfect organization of the ion currents at the cellular level to drive action potentials and to maintain action potential propagation and electrical homogeneity at the tissue level. Any imbalance in Ca2+ homeostasis of a cardiac myocyte can lead to electrical disturbances. This review aims to discuss cardiac physiology and pathophysiology from the elementary membrane processes that can cause the electrical instability of the ventricular myocytes through intracellular Ca2+ handling maladies to inherited and acquired arrhythmias. Finally, the paper will discuss the current therapeutic approaches targeting cardiac arrhythmias.

BackgroundHeart failure (HF) is characterized by electrophysiological remodeling resulting in increased risk of cardiac arrhythmias. Previous reports suggest that elevated inward ionic currents in HF promote action potential (AP) prolongation, increased short-term variability of AP repolarization, and delayed afterdepolarizations. However, the underlying changes in late Na+ current (INaL), L-type Ca2+ current, and NCX (Na+/Ca2+ exchanger) current are often measured in nonphysiological conditions (square-pulse voltage clamp, slow pacing rates, exogenous Ca2+ buffers).MethodsWe measured the major inward currents and their Ca2+- and β-adrenergic dependence under physiological AP clamp in rabbit ventricular myocytes in chronic pressure/volume overload-induced HF (versus age-matched control).ResultsAP duration and short-term variability of AP repolarization were increased in HF, and importantly, inhibition of INaL decreased both parameters to the control level. INaL was slightly increased in HF versus control even when intracellular Ca2+ was strongly buffered. But under physiological AP clamp with normal Ca2+ cycling, INaL was markedly upregulated in HF versus control (dependent largely on CaMKII [Ca2+/calmodulin-dependent protein kinase II] activity). β-Adrenergic stimulation (often elevated in HF) further enhanced INaL. L-type Ca2+ current was decreased in HF when Ca2+ was buffered, but CaMKII-mediated Ca2+-dependent facilitation upregulated physiological L-type Ca2+ current to the control level. Furthermore, L-type Ca2+ current response to β-adrenergic stimulation was significantly attenuated in HF. Inward NCX current was upregulated at phase 3 of AP in HF when assessed by combining experimental data and computational modeling.ConclusionsOur results suggest that CaMKII-dependent upregulation of INaL in HF significantly contributes to AP prolongation and increased short-term variability of AP repolarization, which may lead to increased arrhythmia propensity, and is further exacerbated by adrenergic stress.

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The sodium-calcium exchanger (NCX) was considered to play an important role in arrhythmogenesis under certain conditions such as heart failure or calcium overload. In the present study, the effect of SEA-0400, a selective inhibitor of the NCX, was investigated on early and delayed afterdepolarizations in canine ventricular papillary muscles and Purkinje fibres by applying conventional microelectrode techniques at 37 degrees C. The amplitude of both early and delayed afterdepolarizations was markedly decreased by 1 microM SEA-0400 from 26.6+/-2.5 to 14.8+/-1.8 mV (n=9, P0.05) and from 12.5+/-1.7 to 5.9+/-1.4 mV (n=3, P0.05), respectively. In enzymatically isolated canine ventricular myocytes, SEA-0400 did not change significantly the L-type calcium current and the intracellular calcium transient, studied using the whole-cell configuration of the patch-clamp technique and Fura-2 ratiometric fluorometry. It is concluded that, through the reduction of calcium overload, specific inhibition of the NCX current by SEA-0400 may abolish triggered arrhythmias.

1. Blockers of the rapid component of the delayed rectifier potassium current (I(Kr)) prolong cardiac action potential duration (APD) and effective refractory period (ERP) in a reverse rate-dependent manner. Since activation of beta-adrenoceptors attenuates prolongation of APD evoked by I(Kr) blockers, rate-dependent neuronal noradrenaline liberation in the myocardium may contribute to the reverse rate-dependent nature of the effects of I(Kr) blockers. In order to test this hypothesis, we studied the effects of dofetilide, a pure I(Kr) blocker, on ERP after activation or blockade of beta-adrenoceptors and after catecholamine depletion in guinea-pig left atrial myocardium paced at 3, 2 and 1 Hz, in vitro. 2. Dofetilide (100 nM) lengthened ERP in a reverse rate-dependent manner in the left atrial myocardium of guinea-pigs. Strong activation of beta-adrenoceptors using 10 nM isoproterenol abolished the dofetilide-induced lengthening of ERP at all pacing rates. 3. Blockade of the beta-adrenoceptors with metoprolol (1 micro M), atenolol (3 micro M) or propranolol (300 nM) increased the dofetilide-evoked prolongation of ERP at 3 and 2 Hz, but not at 1 Hz. As a consequence, metoprolol attenuated while propranolol and atenolol fully eliminated the reverse rate-dependent nature of the dofetilide-induced ERP lengthening. In catecholamine-depleted atrial preparations of the guinea-pig (24 h pretreatment with 5 mg kg(-1) reserpine i.p.), the effect of dofetilide on ERP was not frequency dependent, and propranolol did not alter the effects of dofetilide. 4. In contrast to results obtained in guinea-pig atrial preparations, propranolol failed to change the reverse rate-dependent effect of dofetilide on ERP in the right ventricular papillary muscles of rabbits and guinea-pigs. 5. As an indication of the functional consequences of rate-dependent noradrenaline liberation, propranolol decreased twitch tension at 3 and 2 Hz but not at 1 Hz in the atrial myocardium of control guinea-pigs, whereas no such effect was detected in catecholamine-depleted atrial preparations. Propranolol failed to change contractility of ventricular myocardium in guinea-pigs and rabbits. 6. It is concluded that rate-dependent noradrenaline release and the ensuing beta-adrenoceptor activation contributed to the reverse rate-dependent nature of ERP prolongation caused by I(Kr) blockers in isolated guinea-pig atrial myocardium.

1. Concentration-dependent effects of thymol (1 - 1000 microM) was studied on action potential configuration and ionic currents in isolated canine ventricular cardiomyocytes using conventional microelectrode and patch clamp techniques. 2. Low concentration of thymol (10 microM) removed the notch of the action potential, whereas high concentrations (100 microM or higher) caused an additional shortening of action potential duration accompanied by progressive depression of plateau and reduction of V(max). 3. In the canine cells L-type Ca current (I(Ca)) was decreased by thymol in a concentration-dependent manner (EC(50): 158+/-7 microM, Hill coeff.: 2.96+/-0.43). In addition, thymol (50 - 250 microM) accelerated the inactivation of I(Ca), increased the time constant of recovery from inactivation, shifted the steady-state inactivation curve of I(Ca) leftwards, but voltage dependence of activation remained unaltered. Qualitatively similar results were obtained with thymol in ventricular myocytes isolated from healthy human hearts. 4. Thymol displayed concentration-dependent suppressive effects on potassium currents: the transient outward current, I(to) (EC(50): 60.6+/-11.4 microM, Hill coeff.: 1.03+/-0.11), the rapid component of the delayed rectifier, I(Kr) (EC(50): 63.4+/-6.1 microM, Hill coeff.: 1.29+/-0.15), and the slow component of the delayed rectifier, I(Ks) (EC(50): 202+/-11 microM, Hill coeff.: 0.72+/-0.14), however, K channel kinetics were not much altered by thymol. These effects on Ca and K currents developed rapidly (within 0.5 min) and were readily reversible. 5. In conclusion, thymol suppressed cardiac ionic channels in a concentration-dependent manner, however, both drug-sensitivities as well as the mechanism of action seems to be different when blocking calcium and potassium channels.