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BETA-1 ADRENERGIC RECEPTOR GENOTYPE SER49GLY IS ASSOCIATED WITH BETA-BLOCKER SURVIVAL BENEFIT IN PATIENTS WITH HEART FAILURE
E861 JACC March 27, 2012 Volume 59, Issue 13
Heart Failure BETA-1 ADRENERGIC RECEPTOR GENOTYPE SER49GLY IS ASSOCIATED WITH BETA-BLOCKER SURVIVAL BENEFIT IN PATIENTS WITH HEART FAILURE ACC Oral Contributions McCormick Place South, S406b Sunday, March 25, 2012, 11:00 a.m.-11:15 a.m.
Session Title: Joint Oral Session of the Heart Failure Society of America and the American College of Cardiology: Individualizing Pharmacological Therapy in Heart Failure Abstract Category: 13. Heart Failure: Therapy Presentation Number: 921-4 Authors: Jasmine Talameh, Amanda Garrand, Jalal Ghali, Ron M. Oren, Stephanie Dunlap, Adrian Van Bakel, Ileana Pina, J. Herbert Patterson, Carla Sueta, Frank McGrew, Alan Miller, Todd Schwartz, Kirkwood Adams, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA Background: Although beta-blockers (BB) reduce mortality in patients (Pts) with heart failure (HF), genetic differences in neurohormonal activation may limit effectiveness. Systematic review identified 3 adrenergic receptor SNPs as primary candidates. We report on the beta-1 receptor Gly49 variant that results in agonist-induced receptor down-regulation in vitro. We hypothesized Gly49-carriers would have reduced response to BB compared to Ser49-homozygotes. Methods: This hypothesis was tested in the UNITE-HF DNA Registry, a prospective, observational, multicenter study of the genomics of HF in US Pts seen in HF specialty clinics. Data on BB use and survival (death index) were examined in Pts mostly enrolled from 2000-2002. Adjusted Cox models (including race) assessed BB*Ser49Gly interaction and the association between BB and survival stratified by Ser49Gly genotype. Results: Data were available in 715 Pts on baseline BB use, vital status and Ser49Gly genotype (68% Ser49-homozygous and 32% Gly49carriers). The cohort was 63% male, 38% African-American (AA) and 44% ischemic etiology. Age of the cohort was 57±13 years (mean±SD), LVEF 32±16%, NYHA class 2.5±0.6 and SBP 119±22 mmHg. Baseline drug use included ACEI or ARB (89%), diuretics (89%) and spironolactone (24%). BB utilization was 68% consistent with the enrollment period. Baseline characteristics were similar by genotype except AA race (33% Ser49homozygotes vs 49% Gly49-carriers, p<0.001). There were 348 deaths (52% Gly49-carriers, 47% Ser49-homozygotes) at an average follow-up of 6.9±3.6 years. BB use was associated with reduced mortality in the overall study population (adjusted HR=0.72, 95% CI 0.56 - 0.91, p=0.004) and Ser49-homozygotes (adjusted HR=0.56, 95% CI 0.42 - 0.75, p<0.001) but not Gly49-carriers (adjusted HR=1.28, 95% CI 0.80 - 2.04, p=0.31). The adjusted interaction between Ser49Gly genotype and BB association with overall survival was p=0.004. These findings were independent of race (AA vs Non-AA). Conclusions: In this US sample, BB use was associated with prolonged survival in Ser49 homozygotes, but not in Gly49-carriers. This novel hypothesis-generating finding warrants replication in a prospective trial.
Heart Failure BETA-1 ADRENERGIC RECEPTOR GENOTYPE SER49GLY IS ASSOCIATED WITH BETA-BLOCKER SURVIVAL BENEFIT IN PATIENTS WITH HEART FAILURE ACC Oral Contributions McCormick Place South, S406b Sunday, March 25, 2012, 11:00 a.m.-11:15 a.m.
Session Title: Joint Oral Session of the Heart Failure Society of America and the American College of Cardiology: Individualizing Pharmacological Therapy in Heart Failure Abstract Category: 13. Heart Failure: Therapy Presentation Number: 921-4 Authors: Jasmine Talameh, Amanda Garrand, Jalal Ghali, Ron M. Oren, Stephanie Dunlap, Adrian Van Bakel, Ileana Pina, J. Herbert Patterson, Carla Sueta, Frank McGrew, Alan Miller, Todd Schwartz, Kirkwood Adams, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA Background: Although beta-blockers (BB) reduce mortality in patients (Pts) with heart failure (HF), genetic differences in neurohormonal activation may limit effectiveness. Systematic review identified 3 adrenergic receptor SNPs as primary candidates. We report on the beta-1 receptor Gly49 variant that results in agonist-induced receptor down-regulation in vitro. We hypothesized Gly49-carriers would have reduced response to BB compared to Ser49-homozygotes. Methods: This hypothesis was tested in the UNITE-HF DNA Registry, a prospective, observational, multicenter study of the genomics of HF in US Pts seen in HF specialty clinics. Data on BB use and survival (death index) were examined in Pts mostly enrolled from 2000-2002. Adjusted Cox models (including race) assessed BB*Ser49Gly interaction and the association between BB and survival stratified by Ser49Gly genotype. Results: Data were available in 715 Pts on baseline BB use, vital status and Ser49Gly genotype (68% Ser49-homozygous and 32% Gly49carriers). The cohort was 63% male, 38% African-American (AA) and 44% ischemic etiology. Age of the cohort was 57±13 years (mean±SD), LVEF 32±16%, NYHA class 2.5±0.6 and SBP 119±22 mmHg. Baseline drug use included ACEI or ARB (89%), diuretics (89%) and spironolactone (24%). BB utilization was 68% consistent with the enrollment period. Baseline characteristics were similar by genotype except AA race (33% Ser49homozygotes vs 49% Gly49-carriers, p<0.001). There were 348 deaths (52% Gly49-carriers, 47% Ser49-homozygotes) at an average follow-up of 6.9±3.6 years. BB use was associated with reduced mortality in the overall study population (adjusted HR=0.72, 95% CI 0.56 - 0.91, p=0.004) and Ser49-homozygotes (adjusted HR=0.56, 95% CI 0.42 - 0.75, p<0.001) but not Gly49-carriers (adjusted HR=1.28, 95% CI 0.80 - 2.04, p=0.31). The adjusted interaction between Ser49Gly genotype and BB association with overall survival was p=0.004. These findings were independent of race (AA vs Non-AA). Conclusions: In this US sample, BB use was associated with prolonged survival in Ser49 homozygotes, but not in Gly49-carriers. This novel hypothesis-generating finding warrants replication in a prospective trial.