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

ABSTRACT: 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).

SUBMITTER: Gao G

PROVIDER: S-EPMC4096784 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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

Gao Ge G Brahmanandam Vikram V Raicu Mihai M Gu Lianzhi L Zhou Li L Kasturirangan Srinivasan S Shah Anish A Negi Smita I SI Wood Melissa R MR Desai Ankit A AA Tatooles Antone A Schwartz Alan A Dudley Samuel C SC

Journal of the American College of Cardiology 20140402 21

<h4>Objectives</h4>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).<h4>Background</h4>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 migh ...[more]

PMID: 24703920

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Project description:ObjectivesThis study sought to test specialized processing of laser Doppler signals for discriminating ventricular fibrillation (VF) from common causes of inappropriate therapies.BackgroundInappropriate implantable cardioverter-defibrillator (ICD) therapies remain a clinically important problem associated with morbidity and mortality. Tissue perfusion biomarkers, implemented to assist automated diagnosis of VF, sometimes mistake artifacts and random noise for perfusion, which could lead to shocks being inappropriately withheld.MethodsThe study tested a novel processing algorithm that combines electrogram data and laser Doppler perfusion monitoring as a method for assessing circulatory status. Fifty patients undergoing VF induction during ICD implantation were recruited. Noninvasive laser Doppler and continuous electrograms were recorded during both sinus rhythm and VF. Two additional scenarios that might have led to inappropriate shocks were simulated for each patient: ventricular lead fracture and T-wave oversensing. The laser Doppler was analyzed using 3 methods for reducing noise: 1) running mean; 2) oscillatory height; and 3) a novel quantification of electromechanical coupling which gates laser Doppler relative to electrograms. In addition, the algorithm was tested during exercise-induced sinus tachycardia.ResultsOnly the electromechanical coupling algorithm found a clear perfusion cut off between sinus rhythm and VF (sensitivity and specificity of 100%). Sensitivity and specificity remained at 100% during simulated lead fracture and electrogram oversensing. (Area under the curve running mean: 0.91; oscillatory height: 0.86; electromechanical coupling: 1.00). Sinus tachycardia did not cause false positive results.ConclusionsQuantifying the coupling between electrical and perfusion signals increases reliability of discrimination between VF and artifacts that ICDs may interpret as VF. Incorporating such methods into future ICDs may safely permit reductions of inappropriate shocks.

Dataset Information

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

Publications

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

Similar Datasets

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