Enhanced risk profiling of implanted defibrillator shocks with circulating SCN5A mRNA splicing variants: a pilot trial.
OBJECTIVE
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).


BACKGROUND
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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).
Section of Cardiology and the Jesse Brown VAMC, University of Illinois at Chicago, Chicago, Illinois.
Ge
G
Gao
Section of Cardiology and the Jesse Brown VAMC, University of Illinois at Chicago, Chicago, Illinois.
Vikram
V
Brahmanandam
Section of Cardiology and the Jesse Brown VAMC, University of Illinois at Chicago, Chicago, Illinois.
Mihai
M
Raicu
Section of Cardiology and the Jesse Brown VAMC, University of Illinois at Chicago, Chicago, Illinois.
Lianzhi
L
Gu
Section of Cardiology and the Jesse Brown VAMC, University of Illinois at Chicago, Chicago, Illinois.
Li
L
Zhou
Section of Cardiology and the Jesse Brown VAMC, University of Illinois at Chicago, Chicago, Illinois.
Srinivasan
S
Kasturirangan
University of Illinois at Chicago College of Medicine, Chicago, Illinois.
Anish
A
Shah
The University of Texas Health Science Center, Houston, Texas.
Smita I
SI
Negi
Section of Cardiology and the Jesse Brown VAMC, University of Illinois at Chicago, Chicago, Illinois.
Melissa R
MR
Wood
Section of Cardiology and the Jesse Brown VAMC, University of Illinois at Chicago, Chicago, Illinois; Institute for Personalized Respiratory Medicine and Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois.
Ankit A
AA
Desai
Transplant/Mechanical Assist, Advocate Christ Medical Center, Oak Lawn, Illinois.
Antone
A
Tatooles
Departments of Medical Education and Pediatrics, University of Illinois at Chicago, Chicago, Illinois.
Alan
A
Schwartz
Section of Cardiology and the Jesse Brown VAMC, University of Illinois at Chicago, Chicago, Illinois. Electronic address: samuel_dudley@brown.edu.
Samuel C
SC
Dudley
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D003430:Cross-Sectional Studies; D017147:Defibrillators, Implantable / Q000009:adverse effects; D004554:Electric Countershock / Q000009:adverse effects; D005260:Female; D006333:Heart Failure / Q000097:blood* / Q000235:genetics / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000097:blood* / Q000235:genetics; D010865:Pilot Projects; D020033:Protein Isoforms / Q000097:blood* / Q000235:genetics; D012333:RNA, Messenger / Q000097:blood* / Q000235:genetics; D012307:Risk Factors
D015415:Biomarkers; D062554:NAV1.5 Voltage-Gated Sodium Channel; D020033:Protein Isoforms; D012333:RNA, Messenger; C568320:SCN5A protein, human
blood test; sodium channel; sudden death