A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure

Heterogeneity of heart failure (HF) phenotypes indicates contributions from underlying common polymorphisms. We considered polymorphisms in the beta(1)-adrenergic receptor (beta(1)AR), a beta-blocker target, as candidate pharmacogenomic loci. Transfected cells, genotyped human nonfailing and failing ventricles, and a clinical trial were used to ascertain phenotype and mechanism. In nonfailing and failing isolated ventricles, beta(1)-Arg-389 had respective 2.8 +/- 0.3- and 4.3 +/- 2.1-fold greater agonist-promoted contractility vs. beta(1)-Gly-389, defining enhanced physiologic coupling under relevant conditions of endogenous expression and HF. The beta-blocker bucindolol was an inverse agonist in failing Arg, but not Gly, ventricles, without partial agonist activity at either receptor; carvedilol was a genotype-independent neutral antagonist. In transfected cells, bucindolol antagonized agonist-stimulated cAMP, with a greater absolute decrease observed for Arg-389 (435 +/- 80 vs. 115 +/- 23 fmol per well). Potential pathophysiologic correlates were assessed in a placebo-controlled trial of bucindolol in 1,040 HF patients. No outcome was associated with genotype in the placebo group, indicating little impact on the natural course of HF. However, the Arg-389 homozygotes treated with bucindolol had an age-, sex-, and race-adjusted 38% reduction in mortality (P = 0.03) and 34% reduction in mortality or hospitalization (P = 0.004) vs. placebo. In contrast, Gly-389 carriers had no clinical response to bucindolol compared with placebo. Those with Arg-389 and high baseline norepinephrine levels trended toward improved survival, but no advantage with this allele and exaggerated sympatholysis was identified. We conclude that beta(1)AR-389 variation alters signaling in multiple models and affects the beta-blocker therapeutic response in HF and, thus, might be used to individualize treatment of the syndrome.     

The role of a common adenosine monophosphate deaminase (AMPD)-1 polymorphism in outcomes of ischemic and nonischemic heart failure

BACKGROUND: A common variant of the adenosine monophosphate deaminase (AMPD)-1 gene (C34T) results in enzymatic inactivity and may increase adenosine in cardiac muscle and confer cardioprotection through ischemic preconditioning. METHODS AND RESULTS: We hypothesized that AMPD1 carriers with ischemic heart failure (HF) in the Beta-Blocker Evaluation of Survival Trial (BEST) might have a relative survival advantage. Patients (n = 1038, 20% black) with ischemic (58%) and nonischemic (42%) HF were followed for an average of 2.0 years for cardiovascular mortality. DNA was purified from blood using phenol/chloroform. Genotyping was performed by polymerase chain reaction with 5' exonuclease chemistry. Differences in survival were assessed by comparing Kaplan-Meier curves with the log-rank test. Genotype frequencies differed by ethnicity (P < .001) but not by disease etiology. AMPD1 genotype did not significantly modify survival in the entire study population (hazard ratio [HR] = 0.91, 95% CI = 0.61-1.37), among ischemics (HR = 0.73, CI = 0.44-1.22, P = .23), or ischemic non-blacks (HR = 0.74, CI = 0.44-1.24, P = .25). Genotype did not modify the effect of bucindolol on mortality. CONCLUSIONS: Results of this study failed to confirm a reported survival benefit among HF patients carrying the AMPD1 T-allele. However, further studies in larger, more homogeneous populations should explore the possibility of a modest survival advantage for patients with ischemic HF.     

Designer egg evaluation in a controlled trial

OBJECTIVE: To evaluate the ability of designer eggs enriched in vitamin E, lutein, selenium (Se) and docosahexaenoic acid (DHA) to deliver micronutrients to the human in a palatable and visually acceptable form. DESIGN: Double-blind, placebo-controlled trial, two treatment groups balanced for sex and age. SETTING: Department of Biochemistry and Nutrition, SAC, Scotland. SUBJECTS: Forty healthy adult volunteers completed the study. Volunteers were recruited among staff of the Scottish Agricultural College Interventions: Volunteers consumed, for 8 weeks, either a designer egg or a normal table egg per day. Fasting blood samples were taken before and at the end of the study. RESULTS: Consumption of designer eggs enriched in vitamin E, lutein, Se and DHA significantly increased the levels of alpha-tocopherol, lutein and DHA in plasma as compared to the changes found after consumption of normal table eggs, with the largest increases found in plasma lutein (1.88-fold increase). The proportion of DHA was increased in all the main lipid classes of the plasma including triacylglycerol (2.3-fold), free fatty acids (1. 6-fold), cholesteryl ester (1.4-fold) and phospholipid (1.3-fold). Egg consumption did not change Se concentration in plasma, blood pressure, total plasma lipid concentrations or the concentrations of total cholesterol and HDL-cholesterol in plasma. CONCLUSION: Consumption of designer eggs enriched in vitamin E, lutein, DHA and Se as part of normal diet for 8 weeks effectively increased the blood levels of alpha-tocopherol, lutein and DHA. SPONSORSHIP: Scottish Office Agriculture, Environment, and Fisheries Department.