Sodium Channel Splicing in Heart Failure Trial

Scientific Background and Significance

Introduction:

Congestive heart failure (CHF) represents a major health care concern in the United States. It has been estimated that approximately 5 million patients in the U.S. have CHF, and nearly 550,000 people are diagnosed with this disease annually.1 It is known that sudden cardiac death occurs more frequently in the setting of structural heart disease. Moreover, the risk for sudden cardiac death is 6 to 9 times greater in the heart failure population, and cardiac arrhythmias are perhaps the leading cause of death in CHF patients. 2,3 Currently, both the American College of Cardiology and the American Heart Association endorse the placement of internal cardioverter-defibrillators (ICDs) in patients with ischemic cardiomyopathy, reasonable life expectancy, and reduced ejection fraction below 40% (class I, level of evidence A).4 Additionally, placement of ICDs is recommended in non-ischemic cardiomyopathy patients who meet similar requirements with an ejection fraction of less than 35% (class I, level of evidence B).4 Despite these recommendations for primary prevention of sudden death by way of ICD implantation, more than half of the patients receiving a device are likely to not experience an arrhythmic event that necessitates ICD shock delivery.3 ICD devices, on average, cost $20-50,000 exclusive of operative and follow up costs. Currently, risk stratification of sudden cardiac death and the need for ICD placement is essentially dependent upon assessment of left ventricular ejection fraction. Other methods employed for risk stratification are signal averaged electrocardiogram (ECG) and another electrocardiographic technique known as T-wave alternans. Although these methods are FDA approved from risk prediction of cardiac death, such techniques are not widely employed in the U.S. given equipment and personnel costs to implement them. Thus, alternative testing for risk assessment for the development of sudden cardiac death in the heart failure population is desirable.

Role of Sodium Channels and the SCN5A Gene:

The cardiac voltage-gated sodium (Na+) channel, SCN5A, is the main channel generating current for electrical propagation in heart muscle and is the target of many antiarrhythmic drugs. Defective expression of the cardiac Na+ channel results in increased arrhythmic risk as evidenced by sudden death in the Brugada Syndrome.5 SCN5A mutations have also been implicated in the inherited long-QT syndrome, which can result in the development of the fatal dysrhythmias like ventricular fibrillation and torsades de pointes.6 Additionally, mutations in the SCN5A gene have also been proposed to exist and enhance risk for drug-induced dysrhythmias.7 Many studies have been done to shed light on the role of this tetrodotoxin-insensitive sodium channel in disease states. It has been demonstrated that mutated sodium channels in dilated cardiomyopathy may function differently depending upon the specific mutation type of the principal Na+ channel alpha-subunit.8 Specifically, Nguyen et al have demonstrated that these mutations may lead to changes in physiological function such as slower action potential rise time, enhanced late sodium current during steady state, or impaired inactivation.8 Additional mutations in the SCN5A gene have been linked to shifts in voltage dependence of Na+ channel inactivation in patients with idiopathic ventricular fibrillation.9 Additional research has concluded that decreased inactivation of late sodium currents may contribute to action potential prolongation.10 A different SCN5A gene abnormality, the E161K mutation, has been shown to lead to decreased sodium current density and a an 11.9 mV positive shift in the cell membrane half-maximal activation potential.11 Therefore, mutations of the Na+ channel can cause altered channel behavior and arrhythmias.