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

Abstract

Aim: 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.

Materials & methods: Among 1614 subjects (347 current β-blocker users) of a population-based study, HR during symptom-limited exercise testing was analyzed by multilevel linear regression models adjusted for potential confounders.

Results: In β-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 β-blocker effect (20.9 bpm). By contrast, rs5442 had no impact on any HR-related parameter.

Conclusion: In this population-based sample, a common GNB3 polymorphism (C825T) was significantly related with response to β-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.

Figure 1. β-blocker use, GNB3 C825T genotype and heart rate response during exercise

Full model adjusted for age, sex, systolic and diastolic blood pressure, hypertension, smoking status, use of angiotensin-converting enzyme inhibitors and digitalis, and β-blocker doses among β-blocker users. p-values at specific time points of exercise (multilevel linear regression model). ^†p < 0.05; ^‡p < 0.05; ^§p < 0.05; ^¶p < 0.01 (TC/TT vs CC).

Figure 2. Heart rate reduction at peak exercise in

β-blocker users compared with nonusers. Heart rate reduction at peak exercise in β-blocker users compared with nonusers for all subjects (blue column) and stratified by GNB3 genotype (green column for CC, light purple column for TC and purple column for TT). Values are means adjusted for age, sex, systolic and diastolic blood pressure, hypertension, smoking status, use of angiotensin-converting enzyme inhibitors and digitalis, and β-blocker doses among β-blocker users. ^†p < 0.05; ^‡p < 0.01 (multilevel linear regression model).

Figure 3. β-blocker use, GNB3 C825T genotype and heart rate recovery

Full model: adjusted for age, sex, systolic and diastolic blood pressure, hypertension, smoking status, use of angiotensin-converting enzyme inhibitors and digitalis, and β-blocker doses among β-blocker users. p-values at specific time points of exercise (multilevel linear regression model). ^†p < 0.05; ^‡p < 0.05; ^§p < 0.05, ^¶p < 0.01 (TC/TT vs CC).