Genome-Wide Association of Implantable Cardioverter-Defibrillator Activation With Life-Threatening Arrhythmias

OBJECTIVES: 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). BACKGROUND: Most individuals that receive implantable cardioverter-defibrillators never experience a life-threatening arrhythmia. Genetic factors may help identify who is most at risk. METHODS: 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. RESULTS AND CONCLUSIONS: We did not find any associations reaching genome-wide significance, with the strongest association at chromosome 13, rs11856574 at P = 5×10⁻⁶. 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. TRIAL REGISTRATION: ClinicalTrials.gov NCT00664807

Genome-wide association results of Cases with LTA vs. Controls without a LTA.

<p>Association −log(P-values) are plotted according to position in the genome. Points indicate genotyped (circle) or imputed (triangle) SNPs.</p

Top regions associated at P<10⁻⁵.

<p>*imputed; #SNPs at P<10⁻⁴ indicates the number of SNPs at P<10⁻⁴ within +/−150 kb of the top SNP that were either directly genotyped or imputed (genotyped/imputed).</p

Demographics of Cases and Controls at Time of ICD Implantation.

<p>Demographics of Cases and Controls at Time of ICD Implantation.</p

Electrophysiological characteristics of cases and controls.

<p>Electrophysiological characteristics of cases and controls.</p

Magnetic resonance imaging in patients with a pacemaker system designed for the magnetic resonance environment

Background Magnetic resonance imaging (MRI) of pacemaker patients is contraindicated due to documented potential risks to the patient from hazardous interactions between the MRI and pacemaker system. Objective The purpose of this prospective, randomized, controlled, worldwide clinical trial was to evaluate the safety and effectiveness of a pacemaker system designed for safe use in MRI for any bradycardia indicated patient. Methods Patients (n = 464) were randomized to undergo an MRI scan between 9 and 12 weeks postimplant (MRI group, n = 258) or not to undergo MRI (control group, n = 206) after successful implantation of the specially designed dual-chamber pacemaker and leads. Patients were monitored for arrhythmias, symptoms, and pacemaker system function during 14 nonclinically indicated relevant brain and lumbar MRI sequences. Sequences were performed at 1.5 T and included scans with high radiofrequency power deposition and/or high gradient dB/dt exposure. Clinical evaluation of the pacemaker system function occurred immediately before and after MRI, 1 week and 1 month post-MRI, and at corresponding times for the control group. Primary endpoints for safety analyzed the MRI procedure complication-free rate and for effectiveness compared capture and sensing performance between MRI and control groups. Results No MRI-related complications occurred during or after MRI, including sustained ventricular arrhythmias, pacemaker inhibition or output failures, electrical resets, or other pacemaker malfunctions. Pacing capture threshold and sensed electrogram amplitude changes were minimal and similar between study groups. Conclusion This trial documented the ability of this pacemaker system to be exposed in a controlled fashion to MRI in a 1.5 T scanner without adverse impact on patient outcomes or pacemaker system function

Study design for genome-wide association study of ICD activation with LTA.

<p>Study design for genome-wide association study of ICD activation with LTA.</p

Baseline use of key medications.

<p>Baseline use of key medications.</p