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Genome-wide association of implantable cardioverter-defibrillator activation with life-threatening arrhythmias.

ABSTRACT: To identify genetic factors that would be predictive of individuals who require an implantable cardioverter-defibrillator (ICD), we conducted a genome-wide association study among individuals with an ICD who experienced a life-threatening arrhythmia (LTA; cases) vs. those who did not over at least a 3-year period (controls).Most individuals that receive implantable cardioverter-defibrillators never experience a life-threatening arrhythmia. Genetic factors may help identify who is most at risk.Patients with an ICD and extended follow-up were recruited from 34 clinical sites with the goal of oversampling those who had experienced LTA, with a cumulative 607 cases and 297 controls included in the analysis. A total of 1,006 Caucasian patients were enrolled during a time period of 13 months. Arrhythmia status of 904 patients could be confirmed and their genomic data were included in the analysis. In this cohort, there were 704 males, 200 females, and the average age was 73.3 years. We genotyped DNA samples using the Illumina Human660 W Genotyping BeadChip and tested for association between genotype at common variants and the phenotype of having an LTA.We did not find any associations reaching genome-wide significance, with the strongest association at chromosome 13, rs11856574 at P?=?5×10??. Loci previously implicated in phenotypes such as QT interval (measure of the time between the start of the Q wave and the end of the T wave as measured by electrocardiogram) were not found to be significantly associated with having an LTA. Although powered to detect such associations, we did not find common genetic variants of large effect associated with having a LTA in those of European descent. This indicates that common gene variants cannot be used at this time to guide ICD risk-stratification.ClinicalTrials.gov NCT00664807.

SUBMITTER: Murray SS

PROVIDER: S-EPMC3256134 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Genome-wide association of implantable cardioverter-defibrillator activation with life-threatening arrhythmias.

Murray Sarah S SS Smith Erin N EN Villarasa Nikki N Nahey Tara T Lande Jeff J Goldberg Harold H Shaw Marian M Rosenthal Lawrence L Ramza Brian B Alaeddini Jamshid J Han Xinqiang X Damani Samir S Soykan Orhan O Kowal Robert C RC Topol Eric J EJ

PloS one 20120111 1

<h4>Objectives</h4>To identify genetic factors that would be predictive of individuals who require an implantable cardioverter-defibrillator (ICD), we conducted a genome-wide association study among individuals with an ICD who experienced a life-threatening arrhythmia (LTA; cases) vs. those who did not over at least a 3-year period (controls).<h4>Background</h4>Most individuals that receive implantable cardioverter-defibrillators never experience a life-threatening arrhythmia. Genetic factors ma ...[more]

PMID: 22247754

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Project description:BackgroundCardiac sarcoidosis (CS) predisposes to sudden cardiac death (SCD). Guidelines for implantable cardioverter defibrillators (ICDs) in CS have been issued by the Heart Rhythm Society in 2014 and the American College of Cardiology/American Heart Association/Heart Rhythm Society consortium in 2017. How well they discriminate high from low risk remains unknown.MethodsWe analyzed the data of 398 patients with CS detected in Finland from 1988 through 2017. All had clinical cardiac manifestations. Histological diagnosis was myocardial in 193 patients (definite CS) and extracardiac in 205 (probable CS). Patients with and without Class I or IIa ICD indications at presentation were identified, and subsequent occurrences of SCD (fatal or aborted) and sustained ventricular tachycardia were recorded, as were ICD indications emerging first on follow-up.ResultsOver a median of 4.8 years, 41 patients (10.3%) had fatal (n=8) or aborted (n=33) SCD, and 98 (24.6%) experienced SCD or sustained ventricular tachycardia as the first event. By the Heart Rhythm Society guideline, Class I or IIa ICD indications were present in 339 patients (85%) and absent in 59 (15%), of whom 264 (78%) and 30 (51%), respectively, received an ICD. Cumulative 5-year incidence of SCD was 10.7% (95% CI, 7.4%-15.4%) in patients with ICD indications versus 4.8% (95% CI, 1.2%-19.1%) in those without (χ2=1.834, P=0.176). The corresponding rates of SCD were 13.8% (95% CI, 9.1%-21.0%) versus 6.3% (95% CI, 0.7%-54.0%; χ2=0.814, P=0.367) in definite CS and 7.6% (95% CI, 3.8%-15.1%) versus 3.3% (95% CI, 0.5%-22.9%; χ2=0.680, P=0.410) in probable CS. In multivariable regression analysis, SCD was predicted by definite histological diagnosis (P=0.033) but not by Class I or IIa ICD indications (P=0.210). In patients without ICD indications at presentation, 5-year incidence of SCD, sustained ventricular tachycardia, and emerging Class I or IIa indications was 53% (95% CI, 40%-71%). By the American College of Cardiology/American Heart Association/Heart Rhythm Society guideline, all patients with complete data (n=245) had Class I or IIa indications for ICD implantation.ConclusionsCurrent ICD guidelines fail to distinguish a truly low-risk group of patients with clinically manifest CS, the 5-year risk of SCD approaching 5% despite absent ICD indications. Further research is needed on prognostic factors, including the role of diagnostic histology. Meanwhile, all patients with CS presenting with clinical cardiac manifestations should be considered for an ICD implantation.

Project description:Background One third of primary prevention implantable cardioverter-defibrillator patients receive appropriate therapy, but all remain at risk of defibrillator complications. Information on these complications in contemporary cohorts is limited. This study assessed complications and their risk factors after defibrillator implantation in a Dutch nationwide prospective registry cohort and forecasts the potential reduction in complications under distinct scenarios of updated indication criteria. Methods and Results Complications in a prospective multicenter registry cohort of 1442 primary implantable cardioverter-defibrillator implant patients were classified as major or minor. The potential for reducing complications was derived from a newly developed prediction model of appropriate therapy to identify patients with a low probability of benefitting from the implantable cardioverter-defibrillator. During a follow-up of 2.2 years (interquartile range, 2.0-2.6 years), 228 complications occurred in 195 patients (13.6%), with 113 patients (7.8%) experiencing at least one major complication. Most common ones were lead related (n=93) and infection (n=18). Minor complications occurred in 6.8% of patients, with lead-related (n=47) and pocket-related (n=40) complications as the most prevailing ones. A surgical reintervention or additional hospitalization was required in 53% or 61% of complications, respectively. Complications were strongly associated with device type. Application of stricter implant indication results in a comparable proportional reduction of (major) complications. Conclusions One in 13 patients experiences at least one major implantable cardioverter-defibrillator-related complication, and many patients undergo a surgical reintervention. Complications are related to defibrillator implantations, and these should be discussed with the patient. Stricter implant indication criteria and careful selection of device type implanted may have significant clinical and financial benefits.

Dataset Information

Genome-wide association of implantable cardioverter-defibrillator activation with life-threatening arrhythmias.

Publications

Genome-wide association of implantable cardioverter-defibrillator activation with life-threatening arrhythmias.

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