Confirmation of a role for the 389R&gt;G  -1 adrenoceptor polymorphism on exercise capacity in heart failure

Sandilands, A.J.

doi:10.1136/hrt.2004.047282

Cited by 25 publications

(19 citation statements)

References 6 publications

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“…Compared with untreated patients, subjects who were treated with ␤-blockers exhibited prolonged survival that was not different between Arg389 homozygotes and Gly389 carriers in either ethnic group. These results support a benefit for the Arg/Arg389 ␤ 1 -adrenergic receptor genotype in heart failure, which are consistent with findings of smaller studies that evaluated contractile function and/or VO 2 (31,271,323). However, the data also suggest that conventional ␤-blocker therapy is sufficient to overcome any signaling differences between the Arg389 and Gly389 receptors, at least for the end point of mortality in heart failure.…”

Section: Human Studies Of Heart Failuresupporting

confidence: 89%

Adrenergic Signaling Polymorphisms and Their Impact on Cardiovascular Disease

Dorn

2010

Physiological Reviews

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This review examines the impact of recent discoveries defining personal genetics of adrenergic signaling polymorphisms on scientific discovery and medical practice related to cardiovascular diseases. The adrenergic system is the major regulator of minute-by-minute cardiovascular function. Inhibition of adrenergic signaling with pharmacological beta-adrenergic receptor antagonists (beta-blockers) is first-line therapy for heart failure and hypertension. Advances in pharmacology, molecular biology, and genetics of adrenergic signaling pathways have brought us to the point where personal genetic differences in adrenergic signaling factors are being assessed as determinants of risk or progression of cardiovascular disease. For a few polymorphisms, functional data generated in cell-based systems, genetic mouse models, and pharmacological provocation of human subjects are concordant with population studies that suggest altered risk of cardiovascular disease or therapeutic response to beta-blockers. For the majority of adrenergic pathway polymorphisms however, published data conflict, and the clinical relevance of individual genotyping remains uncertain. Here, the current state of laboratory and clinical evidence that adrenergic pathway polymorphisms can affect cardiovascular pathophysiology is comprehensively reviewed and compared, with a goal of placing these data in the broad context of potential clinical applicability.

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Section: Human Studies Of Heart Failuresupporting

confidence: 89%

Adrenergic Signaling Polymorphisms and Their Impact on Cardiovascular Disease

Dorn

2010

Physiological Reviews

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“…In a large (n = 2,460) longitudinal study of heart failure patients from Cincinnati and Philadelphia, 25 we found that Caucasian patients homozygous for Arg389 and not treated with β-blockers had significantly longer survival times than Gly389 carriers also not treated with β-blockers, consistent with the beneficial effects of Arg/Arg389 genotype described by studies evaluating contractile function and/or VO2 in heart failure 18, 20, 21 . In this study, β-blocker treatment extended survival equally in both Arg389 homozygotes and Gly389 carriers.…”

Section: Variants That Influence Catecholaminergic Signaling In the Hsupporting

confidence: 81%

“…In contrast, the Gly389 β1-adrenergic receptor signals as if it were partially β-blocked 16-19 . In early studies, homozygous Arg389 NYHA class III/IV heart failure subjects show significantly better peak oxygen consumption during graded exercise testing (a positive prognostic indicator) compared to homozygous Gly389 subjects 20,21 , reflecting the comparatively better cardiac catecholamine signaling by Arg389 β1 adrenergic receptors. For the same reason, Arg389 subjects are more sensitive to the β-blockade with metoprolol or carvedilol 22-24 , exhibiting beneficial left ventricular remodeling.…”

Section: Variants That Influence Catecholaminergic Signaling In the Hmentioning

confidence: 99%

Clinical Considerations of Heritable Factors in Common Heart Failure

Cappola

Dorn

2011

Circ Cardiovasc Genet

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“…This study, then, confirmed the hyperdynamic nature of the ␤ 1 Arg389 heart in humans. These results of exercise responsiveness have been replicated recently by another group using patients with heart failure (Sandilands et al, 2005), but the association does not appear to hold in healthy subjects (Leineweber et al, 2006). It is noteworthy, however, that direct assessment of cardiac ␤ 1 AR function by dobutamine infusion in normal subjects has shown differential responses by the ␤ 1 Arg389 genotype (Bruck et al, 2005).…”

Section: Pharmacogenetics Of Cardiac Adrenergic Signalingsupporting

confidence: 64%

Mechanisms of Pharmacogenomic Effects of Genetic Variation within the Cardiac Adrenergic Network in Heart Failure

Dorn

Liggett

2009

Mol Pharmacol

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One of the goals of pharmacogenomics is the use of genetic variants to predict an individual's response to treatment. Although numerous candidate and genome-wide associations have been made for cardiovascular response-outcomes, little is known about how a given polymorphism imposes the phenotype. Such mechanisms are important, because they tie the observed human response to specific signaling alterations and thus provide cause-and-effect relationships, aid in the design of hypothesis-based clinical studies, can help to devise workaround drugs, and can reveal new aspects of the pathophysiology of the disease. Here we discuss polymorphisms within the adrenergic receptor network in the context of heart failure and ␤-adrenergic receptor blocker therapy, where multiple approaches to understand the mechanism have been undertaken. We propose a comprehensive series of studies, ranging from transfected cells, transgenic mice, and ex vivo and in vitro human studies as a model approach to explore mechanisms of action of pharmacogenomic effects and extend the field beyond observational associations.Chronic heart failure represents a significant treatment challenge, and although various pharmacologic therapies have been introduced over the past 2 decades, mortality remains high, ϳ40 to 50% of individuals dying within 5 years of diagnosis and ϳ25% dying within the first year. Well recognized within the field is the high degree of interindividual variability in the response to drugs in the treatment of heart failure that is not readily attributed to clinical, demographic, or environmental factors (van Campen et al., 1998). This variability has led to investigation of potential genetic factors that influence drug responsiveness in heart failure, a field termed pharmacogenomics (or pharmacogenetics). In this article, we review the population genomics, molecular properties, and the results of clinical studies of common polymorphisms within the adrenergic receptor signaling network in heart failure, with an emphasis on linking potential molecular mechanisms to the human phenotypes. Here we refer to a polymorphism as a variation in a sequence, compared with a common reference sequence, that is found to occur with an allele frequency of 1% or greater in any population.In acute loss of organ perfusion from virtually any cause, or when an increase in perfusion is required, such as during exercise or stress, the body responds by activation of the sympathetic nervous system. Increases in cardiac output are due to activation of cardiomyocyte ␤-adrenergic receptors (␤AR). This system is well adapted for acute (short-term) needs for enhanced cardiac performance, consistent with the "fight-or-flight" nature of the sympathetic nervous system. However, chronic stimulation represents a less-than-optimal response to this physiologic need, and can ultimately contribute to pathogenic effects. In chronic heart failure, a persistently activated sympathetic nervous system is primarily manifested by increased plasma norepinephrine, a result o...

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Confirmation of a role for the 389R>G -1 adrenoceptor polymorphism on exercise capacity in heart failure

Cited by 25 publications

References 6 publications

Adrenergic Signaling Polymorphisms and Their Impact on Cardiovascular Disease

Adrenergic Signaling Polymorphisms and Their Impact on Cardiovascular Disease

Clinical Considerations of Heritable Factors in Common Heart Failure

Mechanisms of Pharmacogenomic Effects of Genetic Variation within the Cardiac Adrenergic Network in Heart Failure

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