Enhanced Risk Profiling of Implanted Defibrillator Shocks With Circulating SCN5A mRNA Splicing Variants: A Pilot Trial

The aim of this study was to determine the association of SCN5A cardiac sodium (Na(+)) channel mRNA splice variants in white blood cells (WBCs) with risk of arrhythmias in heart failure (HF). HF is associated with upregulation of two cardiac SCN5A mRNA splice variants that encode prematurely truncated, nonfunctional Na(+) channels. Because circulating WBCs demonstrate similar SCN5A splicing patterns, we hypothesized that these WBC-derived splice variants might further stratify patients with HF who are at risk for arrhythmias. Simultaneously obtained myocardial core samples and WBCs were compared for SCN5A variants C (VC) and D (VD). Circulating variant levels were compared among patients with HF, divided into three groups: HF without an implantable cardioverter-defibrillator (ICD), HF with an ICD without appropriate intervention, and HF with an ICD with appropriate intervention. Myocardial tissue-derived SCN5A variant expression levels strongly correlated with circulating WBC samples for both VC and VD variants (r = 0.78 and 0.75, respectively). After controlling for covariates, patients with HF who had received an appropriate ICD intervention had higher expression levels of both WBC-derived SCN5A variants compared with patients with HF with ICDs who had not received appropriate ICD intervention (odds ratio, 3.25; 95% CI, 1.64-6.45; p = 0.001). Receiver operating characteristic analysis revealed that circulating SCN5A variant levels were highly associated with the risk for appropriate ICD intervention (area under the curve ≥0.97). Circulating expression levels of SCN5A variants were strongly associated with myocardial tissue levels. Furthermore, circulating variant levels were correlative with arrhythmic risk as measured by ICD events in an HF population within 1 year. (Sodium Channel Splicing in Heart Failure Trial [SOCS-HEFT]; NCT01185587).