Introduction: Cardiac resynchronization therapy (CRT) improves systolic function and decreases arrhythmic events in heart failure (HF). HF is known to be associated with a reduction in Sarco/Endoplasmic Reticulum Ca ATPase (SERCA2a) levels. Recently, we have shown that HF downregulates full-length cardiac sodium channel (SCN5A) mRNA and upregulates the splicing variant D (VD) encoding a nonfunctional channel. The ratio of circulating VD to full-length mRNA can predict the risk of sudden death.
Hypothesis: We tested whether CRT altered circulating SERCA, full-length SCN5A mRNA and VD and further investigated its correlation with clinical parameters.
Methods: HF patients with new implantable cardioverter-defibrillators (ICDs) for primary prevention were enrolled. Clinical parameters including native QRS width and left ventricular ejection fraction (LVEF) were measured. Circulating SERCA, SCN5A and VD levels at baseline and at a follow-up visit were measured and compared using the ratio of SERCA2a to β-actin or VD to total SCN5A transcripts.
Results: A total of 107 HF patients were enrolled. At enrollment, patients with lower ejection fraction (EF) (≤30%) had higher circulating VD ratio (the ratio of VD to total SCN5A transcripts, %, 0.80±0.11 vs. 0.73±0.07, P<0.05). In patients receiving CRT, the VD ratio significantly improved (0.84±0.08 vs. 0.53±0.10, P<0.01) after a median follow-up of 256 days and the SERCA2a mRNA expression (0.93±0.47 vs. 1.73±1.35, P<0.05) significantly improved over the same period. The native QRS width (ms) shortened (172±27 vs. 127±39, P<0.05), and LVEF (%) improved (25±6 vs. 35±14, P<0.01) in the same group. In patients without CRT, we did not observe similar improvement in clinical parameters or biomarkers.
Conclusions: CRT shortened native, unpaced QRS width and improved LVEF, which might explain lower arrhythmic risk and improved contractility associated with CRT therapy. At the same time, CRT decreased the proportion of nonfunctional sodium channels and improved SERCA2a mRNA expression, which may provide mechanistic explanation for the observation.