Sodium Channel Splicing in Heart Failure Trial (SOCS-HEFT) Prospective Study

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. 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. Currently, both
the American College of Cardiology and the American Heart Association endorse the placement
of implantable cardioverter-defibrillators (ICDs) in patients with ischemic cardiomyopathy,
reasonable life expectancy, and reduced ejection fraction below 40% (class I, level of
evidence A). 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). 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 therapy delivery. ICD devices, on
average, cost $20,000-50,000 exclusive of operative and follow up costs. Currently, risk
stratification of sudden cardiac death and the need for ICD placement are 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 for 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. 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. Additionally,
mutations in the SCN5A gene have also been proposed to exist and enhance risk for
drug-induced dysrhythmias.

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. 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. Additional
mutations in the SCN5A gene have been linked to shifts in voltage dependence of Na+ channel
inactivation in patients with idiopathic ventricular fibrillation. Prior research has
suggested that decreased inactivation of late sodium currents may contribute to action
potential prolongation. A different SCN5A gene abnormality has been shown to lead to
decreased sodium current density and an positive shift in the cell membrane half-maximal
activation potential. Therefore, mutations of the Na+ channel can cause altered channel
behavior and arrhythmias.

Previous study showed that disruptions in sodium handling may result in change in calcium
homeostasis via action of the Na+/Ca2+ exchanger. Overall, such changes in sodium current
(INa) are likely to significantly contribute to arrhythmia in the setting of failing
myocardium.

At the genome level, research has focused on the role of SCN5A gene mutations in
arrhythmogenesis. Nevertheless, the investigators have recently described acquired defects
in Na+ channel messenger RNA (mRNA) that result in reduced Na+ current and occur only in
failing hearts. Three 3'-terminal SCN5A mRNA splicing variants were identified and
characterized in failing human heart ventricles. Additional measurements suggested that the
truncation mutants could cause electrical abnormalities severe enough to contribute to
arrhythmic risk. Also, the investigators showed that lymphocytes process sodium channels
similarly to cardiomyocytes. Thus, lymphocyte SCN5A mRNA processing may serve as a surrogate
marker to assess SCN5A function at the cardiac level and may correlated with arrhythmic risk
in high risk populations. This study will determine if SCN5A variant levels are predictive
of appropriate ICD therapies in patients with a newly implanted ICD.

Inclusion Criteria:

1. All patients must be greater than 18 years of age.

2. All patients must be able to give informed consent.

3. Patients must receive an ICD within 10 days for primary prevention.

Exclusion Criteria:

1. Patients less than 18 years of age.

2. History of congenital heart disease.

3. History of congenital electrophysiological disorders like the long-QT syndrome or
Brugada disease.

4. Patients have an ICD implanted for secondary prevention.

5. Patients taking immunosuppressive medications, have chronic infection, or have an
acute or chronic inflammatory illness that might alter white cell mRNA expression.

6. Patients with any illness expected to result in death within 18 months of enrollment.

7. Patients with white blood cell dyscrasia or cancers.

8. Patients with end-stage renal disease (ESRD) on hemodialysis or peritoneal dialysis

9. Current illicit drug use.

10. Inability to give informed consent.