Polymorphisms of the Beta1-Adrenergic Receptor
Polymorphisms of the Beta1-Adrenergic Receptor
Background: Exercise performance in patients with congestive heart failure is partially dependent on cardiac ß1-adrenergic receptor (ß1AR) function. There are 2 common polymorphisms of the ß1AR gene that alter the encoded amino acids at positions 49 (Ser or Gly) and 389 (Gly or Arg) and alter receptor function in vitro. Their relevance to modification of cardiac function in heart failure is not known.
Methods: Exercise testing was performed in 263 patients with idiopathic or ischemic cardiomyopathy (left ventricular ejection fraction ~25%). Potential associations were sought between ß1AR genotypes and the primary outcome variables of peak oxygen consumption (VO2), heart rate response, and exercise time.
Results: The major determinants of exercise capacity were the polymorphisms at position 389, where patients homozygous for Gly389 had significantly lower peak VO2 compared with those with Arg389 (14.5 ± 0.6 vs 17.7 ± 0.4 mL/kg/min, P = .006), despite similar clinical characteristics including left ventricular ejection fraction. Consistent with a gene dose-response, heterozygosity was associated with an intermediate response (16.9 ± 0.6 mL/kg/min, P < .05). When position 49 genotypes were included, a graded relationship between the 5 2-locus haplotypes and VO2 was found. Two haplotypes displayed the most divergent peak VO2: homozygous Gly389/Ser49, and homozygous Arg389/Gly49 carriers (14.4 ± 0.5 vs 18.2 ± 0.8 mL/kg/min, P = .001). Genotype did not predict the heart rate response. The above results were independent of ß-blocker or other medication use, left ventricular ejection fraction, ß2AR genotype, or other demographic and clinical characteristics.
Conclusion: ß1AR polymorphisms are a significant determinant of exercise capacity in patients with congestive heart failure. Early identification, by genetic testing for these polymorphisms, of heart failure patients at risk for development of depressed exercise capacity may be useful for initiation of specific therapy tailored to genotype.
Activation of the sympathetic neurohormonal axis is a universal response to stress, and is the critical mechanism for increasing oxygen delivery via augmented cardiac output. A conventional view of the responsible physiology is that sympathetic catecholamines, epinephrine released from the adrenal medulla into the circulation, and norepinephrine released from sympathetic neurons directly into target organs, increase tissue blood flow by both direct cardiac and indirect vascular effects of activated adrenergic receptors. Accordingly, activation of myocardial ß1-adrenergic receptors (ß1AR) and to a lesser extent ß2AR, are primarily responsible for increased pump function via positive inotropic, chronotropic, and lusitropic effects. Activation of vascular ß2AR and, potentially, ß1AR, have primarily vasodilatory effects. Thus, oxygen demands of the stressed organism are met by a combination of adrenergic-mediated increases in ventricular performance and augmentation of tissue blood flow.
The above events address an acute imbalance between oxygen demand and supply, as with physical exertion, by acutely increasing cardiac performance. The same events are also triggered to improve cardiac performance when the supply/demand imbalance exists in heart failure, and ultimately these compensatory mechanisms appear to contribute to aspects of the disease process that include a depression of ßAR responsiveness, perhaps as a protective effect. Changes in myocardial ßAR function, the response to exercise, progression of ventricular dysfunction, and the response to agonist and antagonist therapy in heart failure display a significant degree of interindividual variation. We have considered that some of this variability could be due to genetic polymorphisms of the ß1AR or ß2AR. Indeed, we have recently shown such effects with several ß2AR polymorphic variants. The current studies were undertaken to determine whether common polymorphic variants of the ß1AR subtype can modify exercise performance in patients with heart failure.
Two common polymorphisms of the ß1AR coding region have been identified. At amino acid position 389, an Arg or Gly can be found in the general population. In cell-based studies, the Gly389 variant has been shown to have maximal levels of agonist-stimulated adenylyl cyclase activities that are 3 fold lower than the Arg389 ß1AR. Given the importance of cardiac ß1AR in catecholamine mediated inotropic and chronotropic responsiveness, we hypothesized that patients with the hyporesponsive Gly389 receptor would have a decreased exercise capacity compared with those with the Arg389 receptor. At amino acid position 49, polymorphisms result in either a Gly or Ser residue being encoded at this position. The signaling consequences of this variation are not fully understood, but it appears that agonist-promoted downregulation is enhanced with the Gly49 polymorphic ß1AR. A recent clinical study suggests that patients with heart failure with the Gly49 genotype have an improved survival compared with those with Ser49. We thus considered it prudent to assess whether this polymorphism has an effect on exercise capacity as well. So in the current work we determined exercise capacity and ß1AR genotype at positions 49 and 389 in 263 patients with heart failure to ascertain whether ß1AR polymorphisms are independent determinants of exercise capacity.
Background: Exercise performance in patients with congestive heart failure is partially dependent on cardiac ß1-adrenergic receptor (ß1AR) function. There are 2 common polymorphisms of the ß1AR gene that alter the encoded amino acids at positions 49 (Ser or Gly) and 389 (Gly or Arg) and alter receptor function in vitro. Their relevance to modification of cardiac function in heart failure is not known.
Methods: Exercise testing was performed in 263 patients with idiopathic or ischemic cardiomyopathy (left ventricular ejection fraction ~25%). Potential associations were sought between ß1AR genotypes and the primary outcome variables of peak oxygen consumption (VO2), heart rate response, and exercise time.
Results: The major determinants of exercise capacity were the polymorphisms at position 389, where patients homozygous for Gly389 had significantly lower peak VO2 compared with those with Arg389 (14.5 ± 0.6 vs 17.7 ± 0.4 mL/kg/min, P = .006), despite similar clinical characteristics including left ventricular ejection fraction. Consistent with a gene dose-response, heterozygosity was associated with an intermediate response (16.9 ± 0.6 mL/kg/min, P < .05). When position 49 genotypes were included, a graded relationship between the 5 2-locus haplotypes and VO2 was found. Two haplotypes displayed the most divergent peak VO2: homozygous Gly389/Ser49, and homozygous Arg389/Gly49 carriers (14.4 ± 0.5 vs 18.2 ± 0.8 mL/kg/min, P = .001). Genotype did not predict the heart rate response. The above results were independent of ß-blocker or other medication use, left ventricular ejection fraction, ß2AR genotype, or other demographic and clinical characteristics.
Conclusion: ß1AR polymorphisms are a significant determinant of exercise capacity in patients with congestive heart failure. Early identification, by genetic testing for these polymorphisms, of heart failure patients at risk for development of depressed exercise capacity may be useful for initiation of specific therapy tailored to genotype.
Activation of the sympathetic neurohormonal axis is a universal response to stress, and is the critical mechanism for increasing oxygen delivery via augmented cardiac output. A conventional view of the responsible physiology is that sympathetic catecholamines, epinephrine released from the adrenal medulla into the circulation, and norepinephrine released from sympathetic neurons directly into target organs, increase tissue blood flow by both direct cardiac and indirect vascular effects of activated adrenergic receptors. Accordingly, activation of myocardial ß1-adrenergic receptors (ß1AR) and to a lesser extent ß2AR, are primarily responsible for increased pump function via positive inotropic, chronotropic, and lusitropic effects. Activation of vascular ß2AR and, potentially, ß1AR, have primarily vasodilatory effects. Thus, oxygen demands of the stressed organism are met by a combination of adrenergic-mediated increases in ventricular performance and augmentation of tissue blood flow.
The above events address an acute imbalance between oxygen demand and supply, as with physical exertion, by acutely increasing cardiac performance. The same events are also triggered to improve cardiac performance when the supply/demand imbalance exists in heart failure, and ultimately these compensatory mechanisms appear to contribute to aspects of the disease process that include a depression of ßAR responsiveness, perhaps as a protective effect. Changes in myocardial ßAR function, the response to exercise, progression of ventricular dysfunction, and the response to agonist and antagonist therapy in heart failure display a significant degree of interindividual variation. We have considered that some of this variability could be due to genetic polymorphisms of the ß1AR or ß2AR. Indeed, we have recently shown such effects with several ß2AR polymorphic variants. The current studies were undertaken to determine whether common polymorphic variants of the ß1AR subtype can modify exercise performance in patients with heart failure.
Two common polymorphisms of the ß1AR coding region have been identified. At amino acid position 389, an Arg or Gly can be found in the general population. In cell-based studies, the Gly389 variant has been shown to have maximal levels of agonist-stimulated adenylyl cyclase activities that are 3 fold lower than the Arg389 ß1AR. Given the importance of cardiac ß1AR in catecholamine mediated inotropic and chronotropic responsiveness, we hypothesized that patients with the hyporesponsive Gly389 receptor would have a decreased exercise capacity compared with those with the Arg389 receptor. At amino acid position 49, polymorphisms result in either a Gly or Ser residue being encoded at this position. The signaling consequences of this variation are not fully understood, but it appears that agonist-promoted downregulation is enhanced with the Gly49 polymorphic ß1AR. A recent clinical study suggests that patients with heart failure with the Gly49 genotype have an improved survival compared with those with Ser49. We thus considered it prudent to assess whether this polymorphism has an effect on exercise capacity as well. So in the current work we determined exercise capacity and ß1AR genotype at positions 49 and 389 in 263 patients with heart failure to ascertain whether ß1AR polymorphisms are independent determinants of exercise capacity.
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