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Mustafa Hassan, MD; Kaki M. York, PhD; Haihong Li, PhD; Qin Li, MS; Yan Gong, PhD; Taimour Y. Langaee, MSPH, PhD; Roger B. Fillingim, PhD; Julie A. Johnson, PharmD; David S. Sheps, MD, MSPH

Arch Intern Med. 2008;168(7):763-770.

Background  Mental stress is associated with sympathetic adrenergic stimulation and concomitant increases in blood pressure and heart rate. Heritable individual differences in cardiovascular functional response to mental stress may arise from genetic variations in adrenergic receptors, which might produce excessive hemodynamic response to mental stress or create other conditions favoring the development of myocardial ischemia.

Methods  We examined the relationship between hemodynamic response to mental stress and mental stress–induced myocardial ischemia (MSIMI) and 5 common functional polymorphisms of β₁-adrenergic receptors (ADRB1 [OMIM 109630, accession No. 153]) and β₂-adrenergic receptors (ADRB2 [OMIM 109690, accession No. 154]). Participants were 148 patients (45 female [30.4%]) with a documented history of coronary artery disease and a mean (SD) age of 64 (9) years. Patients were enrolled between December 9, 2004, and February 21, 2007. Mental stress was induced via a public-speaking task. Rest and stress myocardial perfusion imaging was performed. Blood samples were collected and genotyped for 5 common functional polymorphisms of ADRB1 (codons 49 and 389) and ADRB2 (codons 16 and 27 and nucleotide 523). The main outcome measures were hemodynamic and myocardial ischemic responses to mental stress. Mental stress–induced myocardial ischemia was defined as new or worsening perfusion defects during mental stress with a summed (stress to rest) difference score of at least 3.

Results  A statistically significant difference was noted in the prevalences of MSIMI between genotype groups for codon 49 of ADRB1. Mental stress–induced myocardial ischemia occurred 3 times more frequently among patients homozygous for the Ser49 allele (31 of 104 patients [29.8%]) compared with 4 of 39 patients (10.3%) among the Gly49 allele carriers (P =.02). The adjusted odds ratio for the effect of genotype (Ser/Ser vs Gly carriers) on MSIMI was 3.9 (95% confidence interval, 1.2-12.5) (P =.02).

Conclusions  Our findings indicate an association between a common genetic variation in ADRB1 and myocardial ischemic response to mental stress in patients with coronary artery disease. This polymorphic genetic marker may help identify patients at increased risk for mental stress–induced adverse outcomes.

Author Affiliations: Cardiovascular Research, Division of Cardiology, Department of Medicine (Drs Hassan, York, and Sheps), Department of Epidemiology and Health Policy Research (Dr Li and Ms Li), Center for Pharmacogenomics, College of Pharmacy (Drs Gong, Langaee, and Johnson), and Department of Community Dentistry and Behavioral Science, College of Dentistry (Dr Fillingim), University of Florida, and North Florida/South Georgia Veterans Affairs Healthcare System (Drs Hassan, York, and Sheps), Gainesville.

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