Enhanced risk profiling of implanted defibrillator shocks with circulating SCN5A mRNA splicing variants: A pilot trial

Ge Gao, Vikram Brahmanandam, Mihai Raicu, Lianzhi Gu, Li Zhou, Srinivasan Kasturirangan, Anish Shah, Smita I. Negi, Melissa R. Wood, Ankit Desai, Antone Tatooles, Alan Schwartz, Samuel C. Dudley

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Objectives 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).

Original languageEnglish (US)
Pages (from-to)2261-2269
Number of pages9
JournalJournal of the American College of Cardiology
Volume63
Issue number21
DOIs
StatePublished - Jun 3 2014
Externally publishedYes

Fingerprint

Defibrillators
Shock
Heart Failure
Implantable Defibrillators
Messenger RNA
Leukocytes
Sodium Channels
Cardiac Arrhythmias
ROC Curve
Area Under Curve
Up-Regulation
Odds Ratio

Keywords

  • blood test
  • sodium channel
  • sudden death

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Enhanced risk profiling of implanted defibrillator shocks with circulating SCN5A mRNA splicing variants : A pilot trial. / Gao, Ge; Brahmanandam, Vikram; Raicu, Mihai; Gu, Lianzhi; Zhou, Li; Kasturirangan, Srinivasan; Shah, Anish; Negi, Smita I.; Wood, Melissa R.; Desai, Ankit; Tatooles, Antone; Schwartz, Alan; Dudley, Samuel C.

In: Journal of the American College of Cardiology, Vol. 63, No. 21, 03.06.2014, p. 2261-2269.

Research output: Contribution to journalArticle

Gao, G, Brahmanandam, V, Raicu, M, Gu, L, Zhou, L, Kasturirangan, S, Shah, A, Negi, SI, Wood, MR, Desai, A, Tatooles, A, Schwartz, A & Dudley, SC 2014, 'Enhanced risk profiling of implanted defibrillator shocks with circulating SCN5A mRNA splicing variants: A pilot trial', Journal of the American College of Cardiology, vol. 63, no. 21, pp. 2261-2269. https://doi.org/10.1016/j.jacc.2014.02.588
Gao, Ge ; Brahmanandam, Vikram ; Raicu, Mihai ; Gu, Lianzhi ; Zhou, Li ; Kasturirangan, Srinivasan ; Shah, Anish ; Negi, Smita I. ; Wood, Melissa R. ; Desai, Ankit ; Tatooles, Antone ; Schwartz, Alan ; Dudley, Samuel C. / Enhanced risk profiling of implanted defibrillator shocks with circulating SCN5A mRNA splicing variants : A pilot trial. In: Journal of the American College of Cardiology. 2014 ; Vol. 63, No. 21. pp. 2261-2269.
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abstract = "Objectives 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).",
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T1 - Enhanced risk profiling of implanted defibrillator shocks with circulating SCN5A mRNA splicing variants

T2 - A pilot trial

AU - Gao, Ge

AU - Brahmanandam, Vikram

AU - Raicu, Mihai

AU - Gu, Lianzhi

AU - Zhou, Li

AU - Kasturirangan, Srinivasan

AU - Shah, Anish

AU - Negi, Smita I.

AU - Wood, Melissa R.

AU - Desai, Ankit

AU - Tatooles, Antone

AU - Schwartz, Alan

AU - Dudley, Samuel C.

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N2 - Objectives 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).

AB - Objectives 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).

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