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?-blocker therapy and heart rate control during exercise testing in the general population: role of a common G-protein ?-3 subunit variant.

ABSTRACT: Impaired heart rate (HR) response to exercise is associated with increased cardiovascular morbidity and mortality. We analyzed whether common variants (rs5443/C825T and rs5442/G814A) in the G-protein ?3 subunit (GNB3) gene modulate interindividual variation in ?-blocker responses with respect to HR.Among 1614 subjects (347 current ?-blocker users) of a population-based study, HR during symptom-limited exercise testing was analyzed by multilevel linear regression models adjusted for potential confounders.In ?-blocker users, but not in nonusers, HR was attenuated in rs5443 T allele carriers (TC/TT vs CC) with lower adjusted HR over the entire exercise period from rest to peak workload (3.5 bpm; 95% CI: 1.1-5.8; p < 0.01), and during recovery (4.2 bpm; 95% CI: 0.6-7.8; p = 0.02). The genotype-related HR reducing effect at peak exercise varied by up to 7.5 bpm (CC vs TT), more than a third (35.9%) of the total ?-blocker effect (20.9 bpm). By contrast, rs5442 had no impact on any HR-related parameter.In this population-based sample, a common GNB3 polymorphism (C825T) was significantly related with response to ?-blocker therapy with respect to HR during exercise and HR recovery, respectively. Further prospective studies are needed to confirm these associations and to examine their potential clinical relevance.

SUBMITTER: Dorr M

PROVIDER: S-EPMC3074105 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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β-blocker therapy and heart rate control during exercise testing in the general population: role of a common G-protein β-3 subunit variant.

Dörr Marcus M Schmidt Carsten O CO Spielhagen Thomas T Bornhorst Alexa A Hentschel Katharina K Franz Christina C Empen Klaus K Kocher Thomas T Diehl Scott R SR Kroemer Heyo K HK Völzke Henry H Ewert Ralf R Felix Stephan B SB Rosskopf Dieter D

Pharmacogenomics 20100901 9

<h4>Aim</h4>Impaired heart rate (HR) response to exercise is associated with increased cardiovascular morbidity and mortality. We analyzed whether common variants (rs5443/C825T and rs5442/G814A) in the G-protein β3 subunit (GNB3) gene modulate interindividual variation in β-blocker responses with respect to HR.<h4>Materials & methods</h4>Among 1614 subjects (347 current β-blocker users) of a population-based study, HR during symptom-limited exercise testing was analyzed by multilevel linear regr ...[more]

PMID: 20860462

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Project description:The acute heart rate response to exercise, i.e., heart rate increase during and heart rate recovery after exercise, has often been associated with all-cause and cardiovascular mortality. The long-term response of heart rate to exercise results in favourable changes in chronotropic function, including decreased resting and submaximal heart rate as well as increased heart rate recovery. Both the acute and long-term heart rate response to exercise have been shown to be heritable. Advances in genetic analysis enable researchers to investigate this hereditary component to gain insights in possible molecular mechanisms underlying interindividual differences in the heart rate response to exercise. In this review, we comprehensively searched candidate gene, linkage, and genome-wide association studies that investigated the heart rate response to exercise. A total of ten genes were associated with the acute heart rate response to exercise in candidate gene studies. Only one gene (CHRM2), related to heart rate recovery, was replicated in recent genome-wide association studies (GWASs). Additional 17 candidate causal genes were identified for heart rate increase and 26 for heart rate recovery in these GWASs. Nine of these genes were associated with both acute increase and recovery of the heart rate during exercise. These genes can be broadly categorized into four categories: (1) development of the nervous system (CCDC141, PAX2, SOX5, and CAV2); (2) prolongation of neuronal life span (SYT10); (3) cardiac development (RNF220 and MCTP2); (4) cardiac rhythm (SCN10A and RGS6). Additional 10 genes were linked to long-term modification of the heart rate response to exercise, nine with heart rate increase and one with heart rate recovery. Follow-up will be essential to get functional insights in how candidate causal genes affect the heart rate response to exercise. Future work will be required to translate these findings to preventive and therapeutic applications.

Dataset Information

?-blocker therapy and heart rate control during exercise testing in the general population: role of a common G-protein ?-3 subunit variant.

Publications

β-blocker therapy and heart rate control during exercise testing in the general population: role of a common G-protein β-3 subunit variant.

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