The Arg389Gly β1-adrenoceptor polymorphism does not affect cardiac effects of exercise after parasympathetic inhibition by atropine

Leineweber, Kirsten; Bruck, Heike; Temme, Thomas; Heusch, Gerd; Philipp, Thomas; Brodde, Otto‐Erich

doi:10.1097/01.fpc.0000184956.16077.93

Cited by 18 publications

(9 citation statements)

References 13 publications

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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: 63%

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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Section: Pharmacogenetics Of Cardiac Adrenergic Signalingsupporting

confidence: 63%

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

Dorn

Liggett

2009

Mol Pharmacol

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“…in siblings homozygous for the Arg389 allele (6,24), HR response to acute exercise has not been associated with the Arg389Gly genotype (11,29,36,38,53). In the present study, we found a modest association between the Arg389Gly variant and baseline HR50 in blacks but not in whites.…”

Section: Discussionsupporting

confidence: 53%

Genome-wide linkage scan for submaximal exercise heart rate in the HERITAGE family study

Spielmann

Leon

Rao

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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The purpose of this study was to identify regions of the human genome linked to submaximal exercise heart rates in the sedentary state and in response to a standardized 20-wk endurance training program in blacks and whites of the HERITAGE Family Study. A total of 701 polymorphic markers covering the 22 autosomes were used in the genome-wide linkage scan, with 328 sibling pairs from 99 white nuclear families and 102 pairs from 115 black family units. Steady-state heart rates were measured at the relative intensity of 60% maximal oxygen uptake (HR60) and at the absolute intensity of 50 W (HR50). Baseline phenotypes were adjusted for age, sex, and baseline body mass index (BMI) and training responses (posttraining minus baseline, ⌬) were adjusted for age, sex, baseline BMI, and baseline value of the phenotype. Two analytic strategies were used, a multipoint variance components and a regression-based multipoint linkage analysis. In whites, promising linkages (LOD Ͼ 1.75) were identified on 18q21-q22 for baseline HR50 (LOD ϭ 2.64; P ϭ 0.0002) and ⌬HR60 (LOD ϭ 2.10; P ϭ 0.0009) and on chromosome 2q33.3 for ⌬HR50 (LOD ϭ 2.13; P ϭ 0.0009). In blacks, evidence of promising linkage for baseline HR50 was detected with several markers within the chromosomal region 10q24-q25.3 (peak LOD ϭ 2.43, P ϭ 0.0004 with D10S597). The most promising regions for fine mapping in the HERITAGE Family Study were found on 2q33 for HR50 training response in whites, on 10q25-26 for baseline HR60 in blacks, and on 18q21-22 for both baseline HR50 and ⌬HR60 in whites. exercise training; linkage; quantitative trait loci; genotype IN RECENT YEARS, a large body of evidence has clearly established sedentarism as a risk factor for a number of diseases that become more prevalent with age in both sexes. In contrast, physical activity regularly performed in a variety of settings is considered beneficial because of favorable metabolic and cardiovascular outcomes (9,17,30,31,37,49). Previous studies have shown associations between elevated heart rate (HR) at rest and increased risk of both all-cause and cardiovascular mortality (7,18,21,22,25,26,33). Although HR during submaximal exercise is known to decrease in response to regular endurance training (16, 51), its recovery after maximal and submaximal exercise is considered a powerful predictor of mortality (14, 15). However, interindividual differences in training-induced changes in HR are considerable.In the Health, Risk Factors, Exercise Training and Genetics (HERITAGE) Family Study, the steady-state HR at the absolute intensity of 50 W (HR50) and relative intensity of 60% (HR60) of maximal oxygen uptake (V O 2max ) were significantly reduced after 20 wk of endurance training (51). The maximal heritability estimates for baseline HR50 and HR60 reached 59 and 46%, respectively. The maximal heritabilities were 34 and 29% for ⌬HR50 and ⌬HR60, respectively, for the changes in response to a 20-wk endurance training program (⌬, posttraining minus baseline) (5). Furthermore, complex segregation analysis support...

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“…3) (81). This holds true even when in the subjects, possible counter-regulatory parasympathetic effects were blocked by atropine: also under these conditions, exercise-induced increase in heart rate, contractility, and PRA were not different between homozygous Arg389 and Gly389 β 1 AR subjects (84). On the other hand, using a modified dobutamine stress echocardiography protocol, LaRosee et al (85) demonstrated recently that in subjects pretreated with atropine in order to exclude possible parasympathetic effects, those homozygous for the Arg389 β 1 AR variant exhibited larger inotropic and blood pressure responses than those carrying one or two Gly389 alleles.…”

Section: Functional Importance Of β 1 -Adrenoceptor Polymorphismsmentioning

confidence: 86%

“…Thus, divergent results obtained in exercise-versus dobutamine-studies could, at least partly, be due to the β 1 AR haplotype inhomogeneity of study groups. However, our recent data show that codon 49 SNP might not play a very important role: we had studied only subjects homozygous for Ser49 and had, nevertheless, found that dobutamine evoked β 1 AR-genotype-dependent effects, while exercise did not (84,86).…”

Section: Functional Importance Of β 1 -Adrenoceptor Polymorphismsmentioning

confidence: 99%

Cardiac Adrenoceptors: Physiological and Pathophysiological Relevance

Brodde¹,

Bruck²,

Leineweber³

2006

J Pharmacol Sci

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214

161

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Abstract. At present, nine adrenoceptor (AR) subtypes have been identified: α 1A -, α 1B -, α 1D -, α 2A -, α 2B -, α 2C -, β 1 -, β 2 -, and β 3 AR. In the human heart, β 1 -and β 2 AR are the most powerful physiologic mechanism to acutely increase cardiac performance. Changes in βAR play an important role in chronic heart failure (CHF). Thus, due to increased sympathetic activity in CHF, βAR are chronically (over)stimulated, and that results in β 1 AR desensitization and alterations of down-stream mechanisms. However, several questions remain open: What is the role of β 2 AR in CHF? What is the role of increases in cardiac G i -protein in CHF? Do increases in G-protein-coupled receptor kinase (GRK)s play a role in CHF? Does βAR-blocker treatment cause its beneficial effects in CHF, at least partly, by reducing GRK-activity? In this review these aspects of cardiac AR pharmacology in CHF are discussed. In addition, new insights into the functional importance of β 1 -and β 2 AR gene polymorphisms are discussed. At present it seems that for cardiovascular diseases, βAR polymorphisms do not play a role as disease-causing genes; however, they might be risk factors, might modify disease, and / or might influence progression of disease. Furthermore, βAR polymorphisms might influence drug responses. Thus, evidence has accumulated that a β 1 AR polymorphism (the Arg389Gly β 1 AR) may affect the response to βAR-blocker treatment.

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The Arg389Gly β1-adrenoceptor polymorphism does not affect cardiac effects of exercise after parasympathetic inhibition by atropine

Abstract: It appears to be unlikely that lack of Arg389Gly beta1-AR genotype-dependence of exercise-effects can be explained by influences of parasympathetic activity.

Cited by 18 publications

References 13 publications

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

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

Genome-wide linkage scan for submaximal exercise heart rate in the HERITAGE family study

Cardiac Adrenoceptors: Physiological and Pathophysiological Relevance

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