In our human adult cardiomyocyte system, ranolazine (60 µM) inhibited the inward current induced by the voltage ramp protocol (Fig. ATX-II toxin from Anemonia sulcata has been shown to be a selective enhancer of late INa 49, whereas ranolazine, an anti-ischemic/antianginal drug, has been reported to be an inhibitor of late INa 50. The recordings show that the later part of the stimulus waveform, corresponding to the repolarization phase of the cardiac action potential, elicits a small inward current with peak amplitude at 0 mV (Fig. Utilizing voltage clamp electrophysiology in the whole cell configuration, we applied a voltage ramp protocol designed to mimic key features of a cardiac action potential waveform (Fig. We first investigated the properties of late INa in human adult cardiomyocytes isolated from donor hearts.
#Minimum delay coverload dependent delay series#
To address this knowledge gap, we performed a series of studies using adult human ex vivo preparations from normal and atrial fibrillation donor hearts to define the role of late INa in action potential morphology, intracellular Ca 2+ handling, contractility, arrhythmogenesis, and the potential of late INa as a target for antiarrhythmic treatment and protection against drug-induced pro-arrhythmia.ĭetection and pharmacological modulation of late INa in human adult ventricular cardiomyocytes However, the specific contribution, if any, for late INa in the genesis or suppression of arrhythmias in human cardiomyocytes is still unknown. In the context of arrhythmia genesis, role for late INa has been well studied in animal models 17. The current knowledge of the physiology and pathophysiology of late INa derives from studies conducted in rabbit, guinea pig, dog, and porcine hearts 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, non-failing/failing human hearts or patients in sinus rhythm/atrial fibrillation 17, 19, 44, 45, 46, 47, 48. Late INa contributes to the cardiac action potential morphology and is largely responsible for maintaining intracellular Na + homeostasis 17, 20, 22, 31. Consequently, a reduction of late INa could have therapeutic benefits, such as protection against drug-induced QT prolongation/pro-arrhythmia 25, 26, and may provide antiarrhythmic therapy for atrial fibrillation and ventricular tachycardia 27, 28, 29, 30, 31. An increase in late INa function has been proposed to play a pivotal role in rhythm disorders 16, 17, heart failure 18, 19, 20, 21, 22, and ischemia and hypoxia 23, 24. The utilization of recently developed human ex vivo paradigms based on organ donor hearts provides novel opportunities for translational sciences 4, 8 and may be instrumental for informing the development of a new generation of therapies by identifying critical ion channel conductances underlying pathological states 9, 10, 11, 12, 13, 14, 15.Īt present, limited information is available on the role of late sodium current (INa) in normal as well as pathological states in the human heart. Clinical attrition is in part a consequence of the inability of current preclinical models, including artificially engineered cell lines, stem cell-derived platforms and animal models, to generate data predictive of human clinical responses 6, 7. Finally, this study highlights the utility of human ex-vivo heart models for advancing cardiac translational sciences.ĭevelopment programs aiming to provide new treatments are frequently terminated prior to regulatory approval due to drug-induced cardiotoxicity or lack of adequate efficacy 1, 2, 3, 4, 5. These findings reveal a critical role for the late INa in cardiac arrhythmias and suggest that inhibition of this conductance could provide an effective therapeutic strategy. We also report that atrial tissues from donor hearts affected by atrial fibrillation exhibit arrhythmia markers in the absence of drug treatment and inhibition of late INa with GS-967 leads to a significant reduction in arrhythmic behaviour. These effects could be reversed by late INa inhibitors, ranolazine and GS-967.
Potentiation of late INa with ATX-II (anemonia sulcata toxin II) and E-4031 (selective blocker of the hERG channel) slowed the kinetics of action potential repolarization, impaired Ca 2+ homeostasis, increased contractility, and increased the manifestation of arrhythmia markers. We therefore investigated the role of this conductance in arrhythmias using adult primary cardiomyocytes and tissues from donor hearts.
However, the role of late INa in the human heart is still poorly understood. Late sodium current (late INa) inhibition has been proposed to suppress the incidence of arrhythmias generated by pathological states or induced by drugs.
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