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Association of β1-Adrenergic Receptor Genetic Polymorphism With Mental Stress–Induced Myocardial Ischemia in Patients With Coronary Artery Disease
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.
ABSTRACT
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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.
INTRODUCTION
Mental stress is associated with sympathetic nervous system activation and concomitant increases in blood pressure and heart rate (HR).1-2 In patients with coronary artery disease (CAD), these changes may increase vulnerability to adverse cardiovascular events such as myocardial infarction (MI), recurrent ischemia, ventricular arrhythmias, and sudden cardiac death.3-15 Furthermore, mental stress–induced myocardial ischemia (MSIMI) has been identified as a risk factor for poor outcomes in patients with CAD.3-6 The underlying mechanisms for this phenomenon have been related to increased hemodynamic reactivity to mental stress, with consequent myocardial blood supply-demand mismatch or direct vasospasm of the epicardial coronary arteries.2, 16-17 An intriguing patient characteristic that may influence the cardiovascular effects of mental stress is genetic variability. Heritable individual differences in cardiovascular functional responses to mental stress may arise from polymorphic genetic variations in the adrenergic receptors. Genetic polymorphisms of the β-adrenergic receptors have been associated with altered response to sympathetic stimulation18 and could account for individual variability in hemodynamic and myocardial ischemic responses to mental stress.
Nonsynonymous β1-adrenergic receptor (ADRB1) polymorphisms occur at codons 49 and 389.18 Similarly, β2-adren ergic receptor (ADRB2) polymorphisms occur at codons 16 and 27 (nonsynonymous) and at nucleotide 523 (synonymous).18 There is substantial evidence for the functional basis of these polymorphisms.19-38
Despite the important potential relationship between these functional polymorphisms and the observed individual variation in mental stress–induced adrenergic response, no study to date has reported a relationship between the interpatient variability in hemodynamic or myocardial ischemic responses to psychological stress and adrenergic receptor genotype. Identifying such a relationship could have important diagnostic, prognostic, and therapeutic implications for MSIMI and other related adverse cardiovascular effects. In this study, we examined the relationship between hemodynamic and myocardial ischemic responses to mental stress and 5 common functional polymorphisms of ADRB1 (codons 49 and 389) and ADRB2 (codons 16 and 27 and nucleotide 523). The candidate polymorphisms, their functional in vitro effects, and expected clinical effects are shown in Figure 1.
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Figure 1. Basic in vitro and in vivo clinical effects of candidate polymorphic adrenergic receptor variants expected to cause exaggerated hemodynamic response to mental stress. NE indicates norepinephrine. Modified from Small et al.38
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METHODS
SUBJECTS
Patients were recruited from outpatient clinics affiliated with a regional Veterans Affairs and university-based medical center. Eligibility criteria included age older than 18 years and a documented clinical diagnosis of CAD supported by the following: (1) angiographic evidence of greater than 50% stenosis in 1 or more coronary arteries, previous percutaneous coronary intervention, or coronary artery bypass graft surgery; (2) previous MI documented with elevated troponin level in the range typical of MI, Q-wave abnormalities on an electrocardiogram, or fixed perfusion abnormalities on nuclear imaging; or (3) a positive radionuclide pharmacologic or exercise stress test result. Patients were excluded if they were pregnant or had a body weight exceeding 181 kg or unstable angina or acute MI within the past 2 months before enrollment.
STUDY DESIGN
The University of Florida Institutional Review Board, Gainesville, approved the study protocol. Informed consent was obtained from all participants. Demographic and psychosocial characteristics were obtained before study procedures. Blood samples were collected from the participants for genotyping during the first visit. Mental stress tests were conducted after an overnight fast. β-Blockers, calcium channel blockers, and long-acting nitrates were withheld for about 24 hours before testing.
MENTAL STRESS PROCEDURE
Patients were initially rested in a dark and quiet room for 30 minutes while their HR and blood pressure were obtained every 5 minutes using an electrocardiogram monitor and an automatic oscillometric device (Dinamap; Critikon Inc, Tampa, Florida), respectively. Mental stress was then induced via a public speaking task performed in front of a small white-coated audience (M.H., K.M.Y., and others). Participants were given a scenario describing a real-life stressful event and were asked to make up a realistic story around it. They were given 2 minutes to prepare their speech and 3 minutes to speak. They were told that their speech would be videotaped and that the laboratory staff (M.H., K.M.Y., and others) would replay the tape to rate it for content, quality, and duration of the speech. Hemodynamic measurements were obtained every minute during the preparation and speech periods and at 1, 3, 5, and 10 minutes into the recovery period. Systolic blood pressure (SBP) and HR were used to calculate the double product (DP) value (DP = SBP x HR).
MYOCARDIAL PERFUSION IMAGING
Radionuclide imaging with technetium Tc 99m sestamibi was used. At 1 minute into the speech, a total dose of 740-1110 MBq (20 to 30 mCi) (based on the patient's body weight) was injected. The time of the injection was decided on the basis of published evidence that adrenergic sympathetic nervous system response to mental stress usually occurs quickly within the first minute of starting the stressful task.1-2 Stress perfusion images were acquired 30 to 60 minutes later using single-photon emission computed tomography (SPECT) conventional methods39 (64 projections over a circular 180° orbit, with the gamma camera set at a 140-keV energy peak with a 20% window). A high-resolution collimator and 2-dimensional Butterworth filter were used, and transaxial tomograms were reconstructed using filtered back-projection with a ramp filter. Resting images were obtained within 1 week of the stress test. The studies were interpreted by an experienced nuclear cardiologist (D.S.S.) blinded to the condition (rest vs stress) and genotype status. Another nuclear cardiologist from the data safety and monitoring board of the study performed a second reading of some randomly selected myocardial perfusion studies. The agreement rate between the 2 readers was 93%. Rest and stress images were visually compared for number and severity of perfusion defects using a 20-segment model according to published guidelines.40 A scoring method from 0 to 4 was used, with 0 representing normal uptake and 4 representing no uptake.39 A summed difference score was calculated as the difference between summed stress and rest scores. Ischemia was defined as new or worsening perfusion defects during mental stress compared with the resting baseline images with a summed difference score of at least 3.
GENOTYPING
Genotyping was performed in the laboratories of the University of Florida Center for Pharmacogenomics. Genomic DNA was isolated from whole blood using a commercially available kit (DNA Blood Isolation Kit; Qiagen, Valencia, California). Genotypes were determined by pyrosequencing (Biotage, Uppsala, Sweden) or by use of a fluorescence-based platform (TaqMan; Applied Biosystems, Foster City, California). Genotyping for ADRB2 codon 27 (rs1042714) was performed by pyrosequencing according to the published protocol.22
For the TaqMan assays, a commercially available genotyping platform was used (7900 HT SNP, Applied Biosystems). The single nucleotide polymorphism genotyping probes for ADRB1 codon 49 (rs1801252), ADRB1 codon 389 (rs1801253), ADRB2 codon 16 (rs1042713), and ADRB2 nucleotide 523 (rs1042718) assays (IDs C__8898508_10, C__8898494_10, C__2084764_20, and C__8950497_10, respectively) were used. Five-microliter reactions in 384-well plates were prepared, and the assays were performed and analyzed according to the manufacturer's recommendations.
STATISTICAL ANALYSIS
Results are expressed as mean (SD) for continuous variables and as frequencies and percentages for categorical variables. All continuous variables were checked for normality of distribution using the Kolmogorov-Smirnov test. Statistical differences between groups were determined using the t test for normally distributed data and using the Mann-Whitney test for nonnormally distributed data. Differences between categorical variables were determined using  2 analyses. P < .05 was considered statistically significant. All statistical analyses were performed using commercially available software (SAS, version 9.1; SAS Institute Inc, Cary, NC).
Departure of genotype frequencies from Hardy-Weinberg equilibrium within each race/ethnicity group was tested using 2 test with 1 df. Because of the relative rarity of a homozygous status among minor alleles for the different polymorphisms in ADRB1 and ADRB2, minor allele homozygotes and heterozygotes were combined together (the dominant mode of inheritance was assumed) for the purpose of analysis in this study. Linkage disequilibrium was evaluated within each gene using the Haploview 3.0 program (http://www.broad.mit.edu/mpg/haploview/).41 Haplotype was constructed using the PHASE version 2 method (http://www.stat.washington.edu/stephens/software.html).42
Stress hemodynamic responses were calculated as the increase in HR, DP, SBP, and diastolic blood pressure (DBP) from rest to stress. Multivariate analysis was used to examine the influence of genotypes on mental stress–induced hemodynamic changes. In addition to genotype status, this analysis included (as covariates), age, sex, race/ethnicity, and the resting hemodynamic value.
To determine the relationship between genotype status and MSIMI, we used logistic regression analysis to control for possible confounding factors, including variables related to CAD disease severity (history of MI, coronary artery bypass graft surgery, and percutaneous coronary intervention), comorbid conditions (smoking status, hypertension, diabetes mellitus, and hyperlipidemia), and antianginal medication use (β-blockers and calcium channel blockers). Haplotype analysis was also performed.
RESULTS
PATIENT CHARACTERISTICS AND BASELINE DATA
A total of 148 patients were studied. There were 45 women (30.4%), and the mean age was 64 (9) years. Patients were enrolled between December 9, 2004, and February 21, 2007. Ethnicity was self-reported. Most (86.9%) were of white race/ethnicity; 7.6% were African American. All participants had CAD. Most of the patients (62.2%) met enrollment criteria based on an abnormal coronary angiogram. Ninety-three patients had recent exercise or pharmacologic stress tests; of those, 39 patients (41.9%) had inducible ischemia. Forty-five percent of patients had a history of percutaneous coronary intervention, 36.6% had prior coronary artery bypass graft surgery, and 18.9% had prior MI. Patients had other comorbid medical conditions, including hyperlipidemia (91.2%), hypertension (79.7%), past or current smoking (72.1%), and diabetes mellitus (35.8%).
One hundred sixteen patients (78.4%) reported taking β-blocker medications; of those, 64 patients were taking short-acting agents. β-Blocker use was stopped for about 24 hours before the mental stress procedure. This duration exceeds 4 to 5 half-lives for the various short-acting β-blockers. Therefore, we assumed that 96 patients (32 patients not taking any β-blockers and 64 patients taking a short-acting agent) were tested under no effect of β-blockers.
Genotypes were obtained in 94% to 99% of patients (not all variants were successfully genotyped in all patients). All allele frequencies follow the Hardy-Weinberg equilibrium for participants of white and African American race/ethnicity (2 1 < 3.40 and P > .05 for all). Demographic and clinical characteristics of the study population by genotype group are given in Table 1.
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Table 1. Baseline Characteristics of the Study Population by Genotype Groupa
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ADRB1 codons 49 and 389 were in partial linkage disequilibrium. Normalized linkage disequilibrium (D’) and r2 were 1.00 and 0.06, respectively, in patients of white race/ethnicity and 1.00 and 0.22, respectively, in African American patients. ADRB2 codons 16 and 27 and nucleotide 523 were also in partial linkage disequilibrium in both populations, with D’ ranging from 0.17 to 1.00 and r2 ranging from 0.01 to 0.29.
HEMODYNAMIC RESPONSES TO MENTAL STRESS
Mental stress induced significant changes in SBP, DBP, HR, and DP compared with the resting condition. The mean (SD) resting values were 119 (18) mm Hg for SBP, 65 (9) mm Hg for DBP, 61 (9) beats/min for HR, and 7244 (1537) for DP. The mean (SD) increase in these values from rest to stress was 41 (19) mm Hg for SBP, 27 (10) mm Hg for DBP, 19 (12) beats/min for HR, and 5564 (2882) for DP.
Using multivariate analyses to control for age, sex, race/ethnicity, and the resting hemodynamic value, the SBP, DBP, HR, and DP responses to mental stress were not statistically significantly different among any of the genotype groups for ADRB1 codon 49 or 389 and ADRB2 codon 16, codon 27, or nucleotide 523 (P > .05). The SBP response to mental stress between variants of ADRB1 codon 49 did not reach statistical significance: stress SBP was 162 mm Hg (95% confidence interval [CI], 159-166 mm Hg) among the Ser/Ser group compared with 156 mm Hg (95% CI, 150-156 mm Hg) among the Gly allele carriers (P =.08 by multivariate analysis). Hemodynamic responses to mental stress by genotype group are given in Table 2.
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Table 2. Hemodynamic and Ischemia Variables by Genotype Groupa
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MENTAL STRESS–INDUCED MYOCARDIAL ISCHEMIA
Three patients were excluded because of poor imaging quality. Thirty-six of 145 patients (24.8%) developed MSIMI. Figure 2 shows a representative example of a mental stress–induced perfusion defect on nuclear SPECT imaging. A higher HR response to mental stress in patients who developed MSIMI (22 [13] beats/min) compared with those who did not have ischemia (18 [11] beats/min) approached statistical significance (P =.06). There were no statistically significant differences in SBP (P =.8), DBP (P =.11), or DP (P =.23) responses to mental stress between the 2 groups.
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Figure 2. Nuclear perfusion images on the short axis (A) and horizontal long axis (B). The mental stress images show an inferior perfusion defect. There is partial reversibility of the defect in the resting images.
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We observed a statistically significant difference in the prevalences of MSIMI between genotype groups for ADRB1 codon 49. 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). This finding is shown in Figure 3. Similar statistically significant findings were observed for this genotype when the analysis was limited to patients of white race/ethnicity (P =.02) and to patients tested under no effect of β-blockers (P =.03).
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Figure 3. Prevalence of mental stress–induced myocardial ischemia (MSIMI) by ADRB1 codon 49 genotype groups. Mental stress–induced myocardial ischemia occurred 3 times more frequently among the patients homozygous for the Ser49 allele compared with the Gly49 allele carriers (P =.02, 2 test).
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Using logistic regression analysis to control for possible confounding factors (see the "Statistical Analysis" subsection of the "Methods" section), genotype status for ADRB1 codon 49 was statistically significantly associated with the development of MSIMI (P =.02). The adjusted odds ratio for the effect of genotype (Ser/Ser vs Gly carriers) on MSIMI was 3.9 (95% CI, 1.2-12.5) (P =.02). The unadjusted odds ratio for the same effect was 3.7 (95% CI, 1.2-11.3). Mental stress–induced myocardial ischemia was not statistically significantly associated with any of the polymorphisms for ADRB1 codon 389 or ADRB2 codon 16, codon 27, or nucleotide 523. Haplotype analysis showed that ADRB1 codon 49 is driving the association of this gene with MSIMI. The adjusted odds ratio for carriers of haplotype ADRB1 Ser49/Arg389 vs noncarriers relative to MSIMI was 2.6 (95% CI, 1.1-6.0), indicating that haplotype did not provide more predictive power. The prevalence of MSIMI across genotype groups is summarized in Table 2.
COMMENT
In this study, we identified ADRB1 genetic variants that were associated with a statistically significant difference in myocardial ischemic response to mental stress in a cohort of patients with CAD. A homozygous status for ADRB1 Ser49 was associated with a 3-fold higher prevalence of MSIMI. Hemodynamic responses were not statistically significantly different among the various genotype groups examined in this study. However, a homozygous status for ADRB1 Ser49 approached statistically significant higher SBP responses to mental stress compared with the Gly allele carriers.
We explored the association between adrenergic receptor genetic polymorphisms and hemodynamic and myocardial ischemic responses to mental stress because of basic and clinical studies18, 37 suggesting that specific genetic variability related to these receptors may be linked to excessive physiologic responses to adrenergic stimulation. Our results are consistent with these studies.
ADRB1 is extensively expressed in many organ systems and exerts control over critical cardiovascular, pulmonary, metabolic, and autonomic nervous system functions. A common nonsynonymous ADRB1 polymorphism occurs at codon 49 with a variation that results in serine or glycine (A>G substitution at nucleotide 145). In vitro functional studies30-31 have associated the Ser49 variant of ADRB1 with reduced agonist-promoted down-regulation. This translates into enhanced end-organ response to adrenergic stimulation. There is evidence for the association of this genotype with adverse cardiovascular phenotypes. McCaffery et al36 found that this variant was associated with significantly higher resting SBP and DBP during mental stress in young healthy twin pairs. Another study43 related this genotype to increased resting HR in individuals of Chinese and Japanese descent. Other studies have linked this genotype to mortality,35 disease progressions,44 and exercise capacity45 in patients with heart failure. Our results in the present study are consistent with these observations.
ADRB1 is the most abundant receptor type in human coronary arteries.46 Stimulation of ADRB1 results in coronary vasodilation in healthy subjects.47 This effect seems to be endothelium independent, suggesting that it would not be different in the presence of atherosclerosis and endothelial dysfunction.48-51 Our findings in this study indicate that the increased prevalence of MSIMI observed among patients with the Ser/Ser genotype of ADRB1 codon 49 was not mediated through exaggerated hemodynamic responses to mental stress. It is intriguing to consider that coronary dilation in patients with CAD may result in reduced flow to tissues distal to a significant epicardial coronary stenosis due to increased flow to normal areas. Therefore, it is possible that excessive coronary dilation in response to ADRB1 stimulation in patients with CAD having this genotype could result in myocardial ischemia due to reduced flow to areas distal to a critical stenosis.
The prevalence of MSIMI among patients in this study was 24.8%; this is somewhat lower than the rates reported in other studies.2-7 The ischemia detection methods used in those studies differ from ours. We used perfusion SPECT imaging, while most of the previous studies1-4,6, 10-11 used radionuclide ventriculography. It has been shown that detection of MSIMI using SPECT imaging has good sensitivity, specificity, and reproducibility.52 It is also possible that the lower prevalence of ischemia among patients in our study is due to differences in the patient population. Our study did not require a positive exercise stress test result or a critical coronary stenosis for inclusion, while most of the previous studies did.1-6,8-11,17 The definition of ischemia used in our protocol is new or worsening perfusion defects with a summed difference score of at least 3, considering that MSIMI is usually of less magnitude than exercise or pharmacologic stress–induced ischemia.2
A limitation of this study is the small sample size. However, our study is one of the largest in this area of the literature focusing on MSIMI. Despite this potential limitation, we were able to observe a strong association between variants of ADRB1 codon 49 and the prevalence of MSIMI. It is possible that physiologic functional differences in the mental stress response between variants of other polymorphisms are not as marked as those for ADRB1 codon 49 and that a larger sample size is needed to demonstrate those differences. This may also be true for the absence of an association between these genotypes and hemodynamic responses to mental stress. As such, the lack of a statistically significant association between these genotypes and hemodynamic and myocardial ischemic responses to mental stress should be interpreted with caution. We do not believe that racial/ethnic admixture in the study population affected our findings. We did not have enough power to detect differences among African Americans; however, limiting the analysis solely to persons of white race/ethnicity yielded the same results as those for the whole cohort. Another limitation of our study pertains to repeated testing because we performed analyses for 5 different polymorphisms, which raises the possibility of false-positive associations. This is less likely given the observed level of statistical significance and the consistency of our findings with the published literature regarding the functional and clinical effects of the polymorphic variation at ADRB1 codon 49.18, 20-21,35-37,43-45
In this study, 52 patients were tested while under the effect of β-blocker agents. However, we do not believe that β-blocker effect is responsible for the differences observed in the study results for several reasons. First, the number of patients tested under the effect of β-blockers did not statistically significantly differ between ADRB1 codon 49 genotype groups. Second, the differences observed between variants of ADRB1 codon 49 remained statistically significant when the analysis was limited to patients tested under no effect of β-blockers. Third, we controlled for β-blocker status in the statistical analysis for MSIMI.
CONCLUSIONS
In this study, we report for the first time (to our knowledge) an association between a common genetic polymorphic variation in ADRB1 and myocardial ischemic response to mental stress in patients with CAD. Our findings suggest that a common genetic marker may help identify those patients at statistically significantly increased risk for mental stress–induced adverse outcomes. This may help in developing targeted pharmacologic or behavioral interventions to reduce the risk of mental stress–induced events and to improve prognosis in this population. Moreover, genetic predictors of mental stress ischemia may provide information regarding the mechanisms underlying this process.
AUTHOR INFORMATION
Correspondence: David S. Sheps, MD, MSPH, Cardiovascular Research, Division of Cardiology, Department of Medicine, University of Florida, 1601 SW Archer Rd, Code 111-D, Gainesville, FL 32608 (shepsds{at}medicine.ufl.edu).
Accepted for Publication: November 13, 2007.
Author Contributions: Drs Hassan, Li, and Gong and Ms Li had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Hassan, York, and Sheps. Acquisition of data: Hassan, York, Johnson, and Sheps. Analysis and interpretation of data: Hassan, York, H. Li, Q. Li, Gong, Langaee, Fillingim, Johnson, and Sheps. Drafting of the manuscript: Hassan. Critical revision of the manuscript for important intellectual content: Hassan, York, H. Li, Q. Li, Gong, Langaee, Fillingim, Johnson, and Sheps. Statistical analysis: Hassan, H. Li, Q. Li, and Gong. Obtained funding: Sheps. Administrative, technical, and material support: Langaee and Fillingim. Study supervision: Johnson and Sheps.
Financial Disclosure: None reported.
Funding/Support: This study was supported by grants HL 070265 and HL 072059 from the National Heart, Lung, and Blood Institute and by resources and the use of facilities at the Department of Veterans Affairs Medical Center, Gainesville.
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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