Abstract
IntroductionHeart failure (HF) downregulates full-length cardiac sodium channel (SCN5A) mRNA and upregulates the splicing variant D (VD), which encodes a prematurely truncated, nonfunctional channel. Recently, we have shown that the ratio of circulating VD to full-length mRNA can predict the risk of sudden death. Cardiac resynchronization therapy (CRT) improves heart function and decreases arrhythmic events. Nevertheless, the mechanisms are unclear.HypothesisWe tested whether CRT altered circulating full-length SCN5A mRNA and VD and further investigated its correlation with clinical parameters in HF.MethodsHF patients with new implantable cardioverter-defibrillators (ICDs) for primary prevention were enrolled. Circulating SCN5A and VD levels at baseline and at a follow-up visit were measured and compared using the ratio of VD to total SCN5A transcripts. The change of VD was expressed as the difference between the proportion of VD levels at baseline and at a follow-up visit.ResultsA total of 81 HF patients were enrolled. At enrollment, patients with lower ejection fraction (EF) (≤30%) had higher circulating VD levels (0.80±0.11 vs. 0.73±0.07, P<0.05). After a median follow-up of 235 days, the VD ratio significantly improved (0.84±0.08 vs. 0.74±0.10, P<0.01) in patients receiving CRT. In patients without CRT, the VD ratio had significantly increased (0.77±0.07 vs 0.84±0.05, P<0.05). In patients with CRT, the change of the VD ratio significantly correlated with left ventricular end systolic diameter (r=0.853, p<0.01), EF (r=-0.643, p<0.05) and ischemic cardiomyopathy (r=0.645, p<0.05).ConclusionsCRT decreased the proportion of nonfunctional sodium channels, which may explain the lower arrhythmic risk with CRT therapy. Furthermore, the improvement was more prominent in patients with left ventricular dilation, lower EF and ischemic cardiomyopathy.