Genetic Determinants of Response to Beta Blockade

Not Applicable

Completed

Brief Summary: The overall goal of this project is to determine the genetic factors contributing to interindividual differences in response to beta-blockade.

Detailed Description: The Aim is to define the contribution of genetic variation to the interindividual variability in response to β-blockade. The rationale for the study is as follows: Beta-blockers prevent the activation of β-ARs and thus form the cornerstone of treatment of pathological states such as congestive heart failure and coronary artery disease. Functional polymorphisms in cardiac beta-receptors have been shown to determine response to β-blocker therapy. A physiologic stimulus such as exercise causes sympathetic stimulation and activation of the cardiac β-ARs and genotypic differences in response to β-blockers are magnified under states of heightened sympathetic activity. Thus, in addition to measuring the response to β-blockers at rest, we will also determine the response to β-blockade after sub-maximal exercise on a supine bicycle ergometer. Genetic variations that may alter sensitivity to a beta blocker will be sought.

Recruitment & Eligibility

Inclusion Criteria

Subject must be willing to give written informed consent and be able to adhere to diet and study schedules.
Subjects must be free of any clinically significant disease that requires a physician's care and/or would interfere with the study evaluations.
Subjects must have a clinically acceptable physical examination and ECG.
Laboratory tests (CBC, blood chemistries, and urinalysis) must be within clinically acceptable limits.

Exclusion Criteria

Any subject who has taken any prescription or over-the-counter drugs, other than oral contraception if female, within one week prior to study drug administration.
Subjects who are presently, or were formerly, narcotic addicts or alcoholics.
Active smokers.
Subjects who have a clinically significant allergy/intolerance to atenolol.
Females with a positive serum/urine pregnancy test at screening.
Females who are nursing.
Subjects with complete heart block/ any other significant cardiovascular disease.
Subjects with a history of asthma symptoms or medication for it within last 10 years.
Subjects who have a systolic blood pressure < 90 mm Hg or diastolic blood pressure < 50 mm Hg or heart rate < 50/min at the screening visit or on the baseline pre drug values on the study day.

Arm && Interventions

Group	Intervention	Description
Atenolol	Atenolol (β-blocker)	There is only 1 arm to this study. Intervention: All participants received atenolol. Genotyping for GRK5 was performed to identify if participants were GLN/GLN, GLN/LEU, or LEU/LEU. Heart rates were measured at rest, and as participants performed graded incremental exercise on a supine bicycle ergometer (at 25, 50, and 75 W for 2 minutes each) twice, once before and once 2.5 hours after taking 25 mg of atenolol.

Primary Outcome Measures

Name	Time	Method
Reduction in Heart Rate	2 exercise periods of 6 minutes each. 6 minutes of exercise before taking atenolol, and 6 minutes of exercise starting 2.5 hours after taking 25 mg of atenolol (2.5 hours + 6 minutes)	Reduction in heart rate based upon genotype while exercising. Participants exercised on a recumbent bike for 2 minutes at 25W, 2 minutes at 50W, and 2 minutes at 75W twice, once before taking atenolol, and once 2.5 hours after oral administration of 25 mg of atenolol. Data points represent unadjusted mean reduction in heart rate in the 3 genotype groups.

Secondary Outcome Measures