To the best of our knowledge this is the first report that the S1103Y variant in SCN5A
is associated with a higher incidence of ventricular arrhythmias in African Americans with heart failure and reduced ejection fraction. Consistent with prior studies that have implicated this common genetic variant with drug-induced Long QT Syndrome (LQTS),9
SCD with cardiomegaly,12
and SIDS,10, 11
this finding strengthens the evidence that this variant is pro-arrhythmic. The specific association between the S1103Y genotype and an increased risk of arrhythmia in heart failure may have particular significance as a novel risk factor for African Americans.
While the exact mechanism by which the S1103Y variant contributes to SCD in heart failure is unclear, we propose that heart failure is an environmental stressor for Y1103 carriers. Previously, Splawski et al. demonstrated that the S1103Y variant causes a small, negative shift in sodium channel activation and increases peak transient current.9
An in silico
modeled ventricular action potential was not affected by these changes at baseline, but the addition of hERG blockade (e.g., by a QT-prolonging medication) or acidosis significantly prolonged the action potential and promoted arrhythmia susceptibility.9, 10
In our study population we propose that the metabolic abnormalities and cellular derangements accompanying heart failure may serve as pro-arrhythmic stressors for Y1103 carriers. Splawski et al. also found that decreased extracellular potassium prolonged action potentials generated with the Y1103 allele (compared to S1103 allele) and promoted arrhythmias.9
Although the serum potassium at the time of event was not universally available in our data set, we did not observe a significant difference in serum potassium level at the time of implant between patients receiving appropriate ICD therapy and those patients that did not.
We found that non-ischemic cardiomyopathy was more prevalent in patients that received appropriate ICD therapy. The association of the Y1103 allele was independent of this finding. As previous studies have not shown significant differences in the rates of ICD therapy or ventricular arrhythmias between ischemic or non-ischemic origins of cardiomyopathy14
the difference may be secondary to sample size and should be investigated further during validation. This association of S1103Y with arrhythmias in heart failure highlights increasing evidence for the general concept that certain acquired arrhythmias, such as drug-induced LQTS, manifest more commonly in individuals with a genetic predisposition; recent data suggests that up to 40% of drug-induced LQTS patients harbor otherwise clinically silent ion channel mutations.8
Arrhythmogenesis because of ion channel mutations can therefore be considered a “two-hit” model, in which specific triggers exacerbate the abnormal function of a mutant channel. For patients with an inherited arrhythmia syndrome, such as LQTS, the effects of the mutation on channel functional are more severe and require only mild arrhythmogenic triggers, such as bradycardia during sleep in LQT3 patients with SCN5A
In contrast, acquired arrhythmias due to mutations in the same ion channel loci occur with more severe environmental stressors (e.g., QT-prolonging drugs or heart failure) upon channels that are less functionally compromised.
The association of a genetic variant with life-threatening arrhythmias in heart failure may offer the possibility of genotype-specific risk-stratification strategies and targeted therapies. In the specific case of the S1103Y variant of SCN5A, which has been shown to increase the “late” or sustained Na+
, consideration of the use of agents such as ranolazine that diminish the sustained current to reduce arrhythmic events is worthy of speculation.
There are several limitations to our study. Often used as a surrogate for SCD in heart failure, ICD therapy had previously been shown to occur more frequently than SCD in a heart failure population.17
Secondly, some patients were classified as having appropriate ICD therapy if the only ICD event recorded was appropriate ATP therapy. Although a well validated method for termination of ventricular arrhythmias, individualized programming parameters could bias detection; a number of sustained ventricular tachycardia events could have been missed with conservative device programming.18, 19
Most importantly, given the limited sample size, these findings must be validated in an independent cohort. Our attempts to identify one were unsuccessful, due to the lack of well-phenotyped cohorts with sufficient African American enrollment. This fact furthers strengthens the importance of minority recruitment and enrollment in clinical and genetic cardiovascular trials. Our finding is consistent with previous reports implicating the S1103Y variant with Sudden Cardiac Death, Sudden Infant Death Syndrome, and Drug induced Long QT Syndrome and thus enhances the growing body of literature demonstrating the inherent susceptibility to potentially lethal arrhythmias in Y1103 allele carriers
In combination with traditional risk stratification tools such as EF, ECG analysis, and medical history,20
the addition of a genetic component could further strengthen the ability to identify heart failure patients at highest risk for sudden cardiac death and to identify mechanisms to prevent it. Given the relatively high prevalence of the S1103Y variant, this finding has a potentially large impact for the African American community. The possible identification of a genetic contribution to sudden cardiac death in heart failure could establish a new paradigm and is an area fertile for further investigation.