A computational modelling approach combined with cellular electrophysiology data provides insights into the therapeutic benefit of targeting the late Na⁺ current

Abstract

Key pointsr The ventricular action potential plateau is a phase of high resistance, which makes ventricular myocytes vulnerable to small electrical perturbations.r We developed a computationally based model of GS-458967 interaction with the cardiac Na+ channel, informed by experimental data recorded from guinea pig isolated single ventricular myocytes.r The model predicts that the therapeutic potential of GS-458967 derives largely from the designed property of significant potent selectivity for INaL.Abstract Selective inhibition of the slowly inactivating or late Na + current (I NaL ) in patients with inherited or acquired arrhythmia syndrome may confer therapeutic benefit by reducing the incidence of triggers for arrhythmia and suppressing one component of arrhythmia-promoting cardiac substrates (e.g. prolonged refractoriness and spatiotemporal dispersion of action potential duration). Recently, a novel compound that preferentially and potently reduces I NaL , GS-458967 (IC 50 for block of I NaL = 130 nM) has been studied. Experimental measurements of the effects of GS-458967 on endogenous I NaL in guinea pig ventricular myocytes demonstrate a robust concentration-dependent reduction in action potential duration (APD). Using experimental data to calibrate I NaL and the rapidly activating delayed rectifier K + current, I Kr , in the Faber-Rudy computationally based model of the guinea pig ventricular action potential, we simulated effects of GS-458967 on guinea pig ventricular APD. GS-458967 (0.1 μM) caused a 28.67% block of I NaL and 12.57% APD shortening in experiments, while the model predicted 10.06% APD shortening with 29.33% block of I NaL . An additional effect of I NaL block is to reduce the time during which the membrane potential is in a high resistance state (i.e. the action potential plateau). To test the hypothesis that targeted block of I NaL would make ventricular myocytes less susceptible to small electrical perturbations, we used the computational model to test the degree of APD prolongation induced by small electrical perturbations in normal cells and in cells with simulated long QT syndrome. The model predicted a substantial dose-dependent reduction in sensitivity to small electrical perturbations as evidenced by action potential duration at 90% repolarization variability in the presence of GS-458967-induced I NaL block. This effect was especially potent in the 'disease setting' of inherited long QT syndrome. Using a combined experimental and theoretical approach, our results suggest that I NaL block is a potent therapeutic strategy. This is because reduction of I NaL stabilizes the action potential waveform by reducing depolarizing current during the plateau phase of the action potential. This reduces the most vulnerable phase of the action potential with high membrane resistance. In summary, by reducing the sensitivity of the myocardial substrate to small electrical perturbations that promote arrhythmia triggers, agents such as GS-458967 may constitute an effective antiarrhythmic pharmacolog...

Mitochondrial‐Mediated Oxidative Ca 2+ /Calmodulin‐Dependent Kinase II Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An In Silico Study

“…Compared with I NaCa and I CaL inhibition, blocking the I Na,L reduces depolarizing current during the plateau phase of the AP and thus may be more potent and safer. In line with this, it has been reported that a selective I Na,L inhibitor, GS‐458967, prevents APD prolongation without affecting AP upstroke velocity in guinea pig ventricular myocytes 65, 66. Ranolazine, another Na + channel blocker, has been shown to reduce EAD and DAD occurrence in various settings where I NaL is enhanced 59…”

Changes in Intracellular Na+ following Enhancement of Late Na+ Current in Virtual Human Ventricular Myocytes

“…Rather, an enhancement of I Na-L per se plays a more important role in [Na + ] i changes. [23](cf Discussion).…”

“…First, I Na-L was increased 2-fold to approximate the changes in I Na-L utilized in a number of different experimental settings that have evaluated repolarization variability caused by changes in I Na-L [3,23]. These results are shown as hatched black lines, superimposed on our baseline simulations.…”

“…These findings suggest that it is not solely a progressive increase in [Na + ] i per se that is the main trigger for pro-arrhythmic changes in the ventricular myocardium. Instead, it is likely that the extraordinary efficacy of I Na-L as a current source (or initiator) for pro-arrhythmia in human ventricles is ‘indirect’ as has been pointed out previously [14,20,22,23]. …”

“…In turn, these changes in [Na + ] i could alter the dynamic balance and/or longer-term homeostatic capacity of one or more of the Na + -dependent regulatory mechanisms summarized above. It is also now well recognized that (mainly as a consequence of the very high resistance state of the cardiac myocyte during the entire duration of the action potential plateau) the I Na-L can significantly change the action potential waveform, and may also alter cell-to-cell electrotonic communication [14,22,23]. …”