Abstract 20362: The Ser96Ala Variant of the Histidine-Rich Calcium-Binding Protein is Associated With Appropriate ICD Shocks in Cardiomyopathy Patients

Introduction: Our ability to predict the patients at highest risk for arrhythmias and sudden cardiac death (SCD) remains inadequate. Alanine allele carriers of the Ser96Ala (S96A) single-nucleotide polymorphism (SNP) in the histidine-rich Ca 2+ -binding (HRC) protein had more ventricular arrhythmias (VA) and SCD in a small Greek case-control study. Basic science supports a potential mechanism for this Ca 2+ handling variant in arrhythmia susceptibility, data confirming its clinical relevance is lacking. Methods: We screened 1718 cardiomyopathy (CM) subjects (mean age=62 yrs, EF=21%; 80% male, 81% white, 18% African American, 70% ischemic) with implantable cardioverter defibrillators (ICDs) from the prospective, multicenter, NIH-funded Genetic Risk Assessment of Defibrillator Events (GRADE) study. HRC S96A SNP allele discrimination was performed by real time PCR. Subjects were followed for up to 5 years to the primary endpoint of freedom from appropriate ICD shocks and the secondary endpoint of death/heart transplant/VAD placement. Results were compared by genotype using Kaplan-Meier analysis and Log Rank testing. Results: Genotyping revealed 597 SS homozygotes, 794 SA heterozygotes, and 327 AA homozygotes (96A allele freq. 42.1%). Significantly more whites were carriers of the 96A variant than African Americans (67.5% vs 55.9%; P Conclusion: We confirmed that carrying one or two copies of the HRC 96A allele is associated with a higher risk of VAs requiring appropriate ICD shocks in heart failure patients with severe CM. This finding provides further evidence of the importance of Ca 2+ handling genes in arrhythmia susceptibility, and may help to target those patients who will benefit most from ICD therapy. Figure: A) Freedom from ICD Shocks in HRC 96SS vs 96A Carriers (SA + AA). B) Endpoint Outcome in HRC 96SS vs 96A Carriers (SA + AA)