Influence of gender and race on hemodynamic response to dobutamine during dobutamine stress echocardiography.

This study sought to determine the influence of gender and/or race on the hemodynamic response to dobutamine during dobutamine stress echocardiography. Blood pressure response patterns differed by gender and race, and completion of testing was often limited because of adverse events, namely, hypertension. Gender and racial differences in blood pressure response merit consideration as potential contributors to the suboptimal response in dobutamine stress testing.

Dobutamine pharmacodynamics during dobutamine stress echocardiography and the impact of beta-blocker withdrawal: a report from the Women's Ischemic Syndrome Evaluation Study.

STUDY OBJECTIVES: To determine the pharmacodynamic parameters of dobutamine during dobutamine stress echocardiography (DSE) and to determine how beta-blocker withdrawal the evening before DSE affects responses to dobutamine during DSE. DESIGN: Retrospective analysis. SETTING: University medical center. PATIENTS: One hundred thirty-six women who had chest pain or other symptoms suggestive of myocardial ischemia and were considered to have a clinical indication for coronary angiography MEASUREMENTS AND MAIN RESULTS: Patients underwent DSE with dobutamine dosages titrated from 5 to 40 microg/kg/minute. The infusion was terminated if the patient reached target heart rate or symptoms developed. Those taking beta-blockers withheld their doses the evening before DSE. Traditional pharmacodynamic modeling revealed a wide range in responses to dobutamine. Data for 62% of patients not taking beta-blockers were described by the Emax (maximum heart rate response to dobutamine) model, whereas data for only 39% of patients taking beta-blockers were best described by this model (p = 0.01). Patients taking beta-blockers also had a smaller mean increment in left ventricular ejection fraction (10.8% +/- 4.2% vs 14.1% +/- 9.3%, p < 0.01), a trend toward a higher ED50 (dobutamine dosage rate causing half the maximum heart-rate response; median 16.8 microg/kg/min, p = 0.12) and a lower sigmoidicity factor determining the shape of the curve (median 2.1, p = 0.03). CONCLUSION: The response to dobutamine exhibits wide interpatient variability, even in the absence of beta-blockade. Nonetheless, in the absence of beta-blockers, in most patients the dobutamine response reaches a plateau by the time the maximum infusion rate (40 microg/kg/min) is reached. Withdrawal of beta-blockers the evening before DSE may be inadequate time for elimination of beta-blocker effect, requiring the addition of atropine to achieve the desired response during DSE.

Collection of genomic DNA by the noninvasive mouthwash method for use in pharmacogenetic studies.

STUDY OBJECTIVE: To determine long-term stability, quantity, and quality of genomic DNA samples collected in buccal cells by the mouthwash method, for use in pharmacogenetic studies. DESIGN: Prospective analysis. SETTING: University pharmacogenomics center in Florida and medical centers in Puerto Rico and the United States participating in a multicenter international trial. SUBJECTS: Ten volunteers at the pharmacogenomics center and 201 participants in the ongoing multicenter clinical trial. INTERVENTION: Stability of genomic DNA was determined by measuring DNA yield from mouthwash samples obtained from six volunteers and stored at room temperature over 90 days and from 201 clinical trial samples that were stored and shipped at room temperature. Whether DNA yield was higher with three 5-ml mouthwash rinses versus one 10-ml rinse was evaluated in four volunteers. Quality of genomic DNA was assessed on 32 randomly selected samples from the six volunteers in the stability study, by determining the success rate of DNA amplification with polymerase chain reaction (PCR) testing and by genotyping. MEASUREMENTS AND MAIN RESULTS: For the stability studies, the quantity of genomic DNA decreased over time with storage at room temperature (overall p < 0.01), with the largest declines occurring at 60 and 90 days. Median DNA recovery at 30 and 90 days was 59% and 28% of that at baseline, respectively. Mean +/- standard deviation, median, and range for recovery of genomic DNA from the 201 samples were 45.2 +/- 55 microg, 25.2 microg, and 1-330 microg, respectively. Median recoveries of DNA from the one-rinse and three-rinse methods were not statistically significantly different (9.1 vs 10.5 microg). All samples were amplified successfully by PCR and genotyped, indicating quality of the DNA samples. CONCLUSION: The mouthwash method for collection of genomic DNA is a simple, inexpensive, and noninvasive method that poses less risk than venipuncture and may be used in a variety of settings. Genomic DNA in mouthwash is stable for prolonged periods at room temperature, and the quantity of DNA recovered from this method is more than sufficient for pharmacogenetic studies. Such an approach should be valuable to pharmacogenetic researchers and others who are conducting genetic research.

Pharmacogenetics and cardiovascular disease: impact on drug response and applications to disease management.

The genetic polymorphisms that may affect individual responses to cardiovascular agents are reviewed, and the application of pharmacogenetics to cardiovascular disease management is discussed. Pharmacogenetics is the search for genetic polymorphisms that affect responses to drug therapy. Investigators have found many associations between genetic polymorphisms and responses to cardiovascular drugs. Some of these relationships have been demonstrated in large patient populations, such as patients with ischemic heart disease receiving statins. Study data consistently show a greater response to statins in ischemic heart disease patients with genotypes associated with worse prognoses. Studies of other polymorphisms, such as those in the genes encoding anglotensin-converting enzyme and beta 1-adrenergic receptors, have less consistently found relationships between these variations and cardiovascular drug responses. For gene-drug response associations for which the data are inconsistent, the interaction of multiple polymorphisms in multiple genes coding for proteins affected by drug therapy or influencing drug metabolism may prove to have a greater influence on drug responses than any one polymorphism. Once the polymorphisms that best determine the response to a particular drug are known and tests to rapidly identify these variations are available, individual patients may be screened for genetic polymorphisms before drug therapy is begun and the information used to choose agents with the greatest potential for efficacy and least potential for toxicity. Pharmacogenetics has many possible applications in the drug therapy of cardiovascular diseases. Much more must be learned, however, before pharmacogenetic factors can be routinely incorporated into therapeutic decisions.

Pharmacogenetics of cardiovascular drugs.

Pharmacogenetics is a field aimed at understanding the genetic contribution to inter-patient variability in drug efficacy and toxicity. Treatment of cardiovascular disease is, in most cases, guided by evidence from well-controlled clinical trials. Given the solid scientific basis for the treatment of most cardiovascular diseases, it is common for patients with a given disease to be treated in essentially the same manner. Thus, the clinical trials have been very informative about treating large groups of patients with a given disease, but are slightly less informative about the treatment of individual patients. Pharmacogenetics and pharmacogenomics have the potential of taking the information derived from large clinical trials and further refining it to select the drugs with the greatest likelihood for benefit, and least likelihood for harm, in individual patients, based on their genetic make-up. In this paper, the current literature on cardiovascular pharmacogenetics is emphasised, and how the use of pharmacogenetic/pharmacogenomic information may be particularly useful in the future in the treatment of cardiovascular diseases is also highlighted.