Preventing arrhythmias and sudden cardiac death in long QT syndrome type 3 through pharmacological late sodium current inhibition

Long QT syndrome type 3 (LQT3) is a rare genetic disorder caused by mutations in the SCN5A gene encoding the cardiac sodium channel, and is characterized by prolonged QT intervals on the ECG, and increased risk for sudden death due to ventricular tachyarrhythmias, in particular torsades de pointes. LQT3 patients are often bradycardic and display arrhythmias predominantly during rest or sleep [Schwartz et al. 2001]. Compared to other LQT subtypes, LQT3 patients are particularly at risk for sudden death, and cardiac arrest (rather than syncope) is often the first clinical event [Zareba et al. 2001]. Pharmacological treatment options for LQT3 are limited. At the moment, high risk LQT3 patients are treated with implantation of an implantable converter defibrillator (ICD), often in combination with beta-blockers [Mönnig et al. 2005]. ICD implantation however has serious complications and tremendous impact on quality of life. The biophysical defect underlying LQT3 involves a disrupted inactivation of the sodium channel leading to an increased late sodium current (INaL) [Remme et al. 2008, Moreno and Clancy 2012]. Enhanced INaL has been increasingly recognized for its mechanistic role in various cardiovascular pathologies other than LQT3, including angina pectoris, myocardial ischemia, and heart failure [Remme and Wilde 2013]. A sustained influx of sodium ions through increased INaL leads to action potential (AP) prolongation, early afterdepolarizations (EADs), and ventricular arrhythmias [Moreno and Clancy 2012]. Longer-term consequences of increased INaL include elevated intracellular sodium and calcium levels, facilitating the occurrence of pro-arrhythmic delayed afterdepolarizations (DADs) and triggered activity [Pieske and Houser 2003, Noble and Noble 2006]. Enhanced INaL may also contribute to the bradycardia typically observed in LQT3 patients, which is associated with excessive QT-prolongation [Veldkamp et al. 2003]. The INaL inhibitor ranolazine has been shown to shorten AP duration and prevent EAD and DAD formation under experimental conditions of enhanced INaL [Song et al. 2004, Wu et al. 2004]. INaL inhibition by compounds such as ranolazine may thus provide a useful and beneficial therapeutic approach in LQT3 patients, not only through stabilizing repolarization abnormalities, but also by resolving bradycardia and preventing more long-term detrimental effects of intracellular sodium/calcium overload. These combined actions constitute a novel therapeutic approach for LQT3, employing pathways not targeted by currently available therapies. While the efficacy of INaL inhibitors in patients with angina pectoris has been extensively studied [Maier 2009], very few clinical studies have so far addressed their use in other diseases associated with enhanced INaL. In a small set of 5 patients carrying the SCN5A-deltaKPQ mutation, short-term ranolazine infusion significantly decreased QTc-intervals, suggesting a beneficial effect on repolarization [Moss et al. 2008]. Our own preliminary data suggests that ranolazine has beneficial cellular effects in cardiomyocytes of LQT3 mice [Remme et al. 2010]. Extensive studies are now required to further investigate the experimental and clinical effects of INaL inhibitors, as well as their efficacy and selectivity in the setting of different SCN5A mutations. Here, assessment of the distinct biophysical and pharmacological properties of various SCN5A mutations within the endogenous cardiomyocyte environment is essential. Apart from isolated myocytes from transgenic mice, cardiomyocytes derived from induced pluripotent stem (iPS) cells obtained from patients may be used. Together with our collaborators, we have recently generated iPS-derived cardiomyocytes obtained from a human SCN5A-1795insD mutation carrier for this purpose [Davis et al. 2012]. Thus, to optimally investigate the therapeutic potential of INaL inhibitors in the treatment of LQT3, we will employ a translational approach including in vivo, ex vivo and in vitro experiments in transgenic mouse models, in vitro measurements in human iPS-derived cardiomyocytes, and preliminary clinical studies in LQT3 patients. We will investigate the potential of INaL inhibitors to: - Shorten action potential duration and prevent the occurrence of afterdepolarizations (considered a hallmark of pro-arrhythmia) - Normalize abnormal intracellular sodium and calcium homeostasis - Shorten the QT-interval - Prevent sinusbradycardia and concomitant excessive QT-prolongation Together, these actions may work in concert to prevent ventricular arrhythmias and sudden cardiac death in LQT3 patients. Furthermore, we aim to develop iPS-derived LQT3 cardiomyocytes obtained from LQT3 patients as a preclinical tool for assessment of therapeutic efficacy of future novel INaL inhibitors. Our ultimate goal is to extend results from our translational research into a novel pharmacological treatment strategy in LQT3 patients.