Genetic variation in alpha2-adrenoreceptors and heart rate recovery after exercise

Author:

Kohli Utkarsh123,Diedrich André143,Kannankeril Prince J.53,Muszkat Mordechai13,Sofowora Gbenga G.123,Hahn Maureen K.1267,English Brett A.28,Blakely Randy D.297,Stein C. Michael123,Kurnik Daniel12310

Affiliation:

1. Department of Medicine, Vanderbilt University, Nashville, Tennessee;

2. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee;

3. Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee;

4. Department of Biomedical Engineering Vanderbilt University, Nashville, Tennessee;

5. Department of Pediatrics, Vanderbilt University, Nashville, Tennessee;

6. Division of Genetic Medicine, Vanderbilt University, Nashville, Tennessee; and

7. Centre for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee;

8. Parexel International Early Phase, Glendale, California; and

9. Department of Psychiatry, Vanderbilt University, Nashville, Tennessee;

10. Clinical Pharmacology Unit, Section of Clinical Pharmacology and Toxicology, Rambam Health Care Campus, Haifa, Israel

Abstract

Heart rate recovery (HRR) after exercise is an independent predictor of adverse cardiovascular outcomes. HRR is mediated by both parasympathetic reactivation and sympathetic withdrawal and is highly heritable. We examined whether common genetic variants in adrenergic and cholinergic receptors and transporters affect HRR. In our study 126 healthy subjects (66 Caucasians, 56 African Americans) performed an 8 min step-wise bicycle exercise test with continuous computerized ECG recordings. We fitted an exponential curve to the postexercise R-R intervals for each subject to calculate the recovery constant (kr) as primary outcome. Secondary outcome was the root mean square residuals averaged over 1 min (RMS1min), a marker of parasympathetic tone. We used multiple linear regressions to determine the effect of functional candidate genetic variants in autonomic pathways (6 ADRA2A, 1 ADRA2B, 4 ADRA2C, 2 ADRB1, 3 ADRB2, 2 NET, 2 CHT, and 1 GRK5 ) on the outcomes before and after adjustment for potential confounders. Recovery constant was lower (indicating slower HRR) in ADRA2B 301–303 deletion carriers ( n = 54, P = 0.01), explaining 3.6% of the interindividual variability in HRR. ADRA2A Asn251Lys, ADRA2C rs13118771, and ADRB1 Ser49Gly genotypes were associated with RMS1min. Genetic variability in adrenergic receptors may be associated with HRR after exercise. However, most of the interindividual variability in HRR remained unexplained by the variants examined. Noncandidate gene-driven approaches to study genetic contributions to HRR in larger cohorts will be of interest.

Funder

HHS | NIH | National Center for Research Resources (NCRR)

HHS | National Institutes of Health (NIH)

Publisher

American Physiological Society

Subject

Genetics,Physiology

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