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Biomedical subjects

Glen E Cooke

Publications and source records attributed to Glen E Cooke.

7 recordsLinked to original sources
PubMed2006

Detection of coronary artery disease in orthotopic heart transplant recipients with 64-detector row computed tomography angiography.

Cardiac transplant recipients develop coronary artery disease in the form of cardiac allograft vasculopathy (CAV), and still undergo annual left heart catheterizations for detection at most centers. We prospectively enrolled 20 cardiac transplant recipients scheduled for annual left heart catheterization with X-ray coronary angiography (XRA) to also undergo electrocardiographically gated coronary computed tomography angiography (CTA), which was performed on a 64-detector computed tomography scanner. CTA detected more CAV vs XRA in 4 patients and less CAV in 0 patient, resulting in good overall agreement between the two modalities (kappa = 0.69). CTA may be superior to conventional catheter-based angiography to identify non-obstructive vessel wall disease that may go unrecognized with catheter-based angiography alone.

Adult↗
PubMed2006

Effect of platelet antigen polymorphism on platelet inhibition by aspirin, clopidogrel, or their combination.

OBJECTIVES: We studied the modifier effect of platelet antigen polymorphism (PlA2) on platelet inhibition by acetylsalicylic acid (ASA, i.e., aspirin), clopidogrel, or their combination in patients with coronary heart disease. BACKGROUND: Clopidogrel, when administered with ASA, was shown to significantly improve the outcome of patients with acute coronary syndromes compared with patients receiving only ASA. We have shown previously that the effect of ASA on platelets is modified by the glycoprotein IIIa single nucleotide polymorphism PlA2. Hence, an important pharmacogenetic question remains whether the antiplatelet effect of clopidogrel is uniform for all patients or, like acetylsalicylic acid, more selective. METHODS: Thirty PlA1/A1 and 30 PlA1/A2 patients were assigned randomly to ASA 325 mg/day, clopidogrel 75 mg/day, or both. After 10 days, platelet function was studied. RESULTS: Clopidogrel provided stronger platelet inhibition than ASA with adenosine diphosphate as the agonist, and combination therapy resulted in greater inhibition than either inhibitor used alone (p < 0.0001). The use of ASA resulted in greater inhibition compared with clopidogrel with epinephrine (p < 0.0001) and collagen as agonists (p < 0.0001). With collagen as the agonist, platelets from PlA1/A2 donors were markedly and significantly less inhibited by ASA (p = 0.005). In contrast, with clopidogrel, no significant difference could be detected between inhibition of Pl(A1/A1) and Pl(A1/A2) platelets. CONCLUSIONS: The combination of ASA and clopidogrel appears superior to either agent alone in inhibiting platelet function. Pl(A2) functions as an important modifier for platelet responsiveness to ASA but not to clopidogrel. These findings could have significant impact on the future design of pharmacogenetic antithrombotic strategies for patients with coronary heart disease.

Adenosine Diphosphate↗
PubMed2006

Estradiol increases platelet aggregation in Pl(A1/A1) individuals.

BACKGROUND: The platelet glycoprotein IIb/IIIa receptor is a key mediator of platelet aggregation and intracoronary thrombosis. Studies have suggested that hormone replacement therapy (HRT) may increase coronary events in postmenopausal women. OBJECTIVES: We sought to characterize the relationship between the estrogen concentration expected in HRT and platelet aggregation. DESIGN AND RESULTS: Platelet aggregation studies were performed using epinephrine on 30 healthy individuals (15 Pl(A1/A1) and 15 Pl(A1/A2)) before and after incubation with beta-estradiol (E2) (10(-11) mol/L). The effect of E2 10(-11) mol/L on Pl(A1/A1) platelets demonstrated a significant increase (P = .03) in aggregation compared with baseline. In contrast, with the same concentration of E2, aggregation of Pl(A1/A2) platelets decreased significantly compared with baseline (P < .0001). CONCLUSIONS: Estrogen concentration similar to that expected in HRT resulted in an increase in platelet aggregation in Pl(A1/A1) individuals, but not in Pl(A1/A2) individuals. The data may provide further insight for the increase in coronary events seen in HRT clinical trials and suggest that further evaluation is needed to better define the role of pharmacogenetics in HRT.

Antigens, Neoplasm↗
PubMed2006

The safety and efficacy of aspirin and clopidogrel as a combination treatment in patients with coronary heart disease.

The use of aspirin and clopidogrel in combination has become part of the standard clinical care of patients with coronary artery disease. The use of this combination provides significant benefits compared with the use of aspirin alone in patients with acute coronary syndromes, and in patients treated with percutaneous coronary intervention with stent placement (both bare metal and drug-eluting stents). Clinical trials have demonstrated significant efficacy of this dual therapy; however, there is the potential for significant bleeding complications from the synergistic antiplatelet effects. In total, it appears that when there is vessel injury (mechanical from perctutaneous coronary intervention or a ruptured plaque), dual antiplatelet therapy with aspirin and clopidogrel results in improved outcomes, albeit with a small but significant inherent risk of increased bleeding.

Aspirin↗
PubMed2005

Pharmacogenetics of multigenic disease: heart disease as an example.

We now have a greater understanding of the workings of the human genome as well as a wide assortment of pharmacological and mechanical therapies that clearly improve mortality and quality of life for our patients with cardiovascular disease, but these areas of therapeutics and genomics have essentially advanced independently with little interaction up until recently. Pharmacogenetics is the study of the effect of a medication as it relates to single or defined sets of genes. A major goal will be to integrate the two so that true personalized therapy can be delivered. This review explores the clinical implications of the complex interactions in multigenic disease and pharmacology with examples of atherosclerosis and heart failure. The therapies of today are the direct result of understanding the epidemiological, molecular and genetic basis of cardiovascular disease with the application to clinical practice. The complexity of multigenic disease and the promise of pharmacogenetics will require that we improve on the methods of drug evaluation and this includes the need for new statistical methods, bioinformatics, and novel clinical trial design with sufficient power to detect differences in therapy. There must be a continued effort to apply biological and mechanistic plausibility in understanding disease and pharmacology but openness to new ideas and concepts, especially in understanding the workings of the genome.

Antigens, Human Platelet↗
PubMed2003

A meta-analysis of studies on the association of the platelet PlA polymorphism of glycoprotein IIIa and risk of coronary heart disease.

The Pl(A2) polymorphism of the glycoprotein IIIa subunit of the fibrinogen receptor (GPIIb-IIIa) has been reported by some studies to be associated with an increased risk of coronary thrombosis. Following the first paper on the subject in 1996, a large number of studies have investigated the relationship between this polymorphism and coronary thrombosis, either at the epidemiological or at the cellular and molecular levels. The cellular and molecular studies have shown in a consistent manner that this polymorphism increases platelet responsiveness. In contrast, epidemiological studies have generated inconsistent results regarding the clinical impact of Pl(A2). We consider 12 epidemiological studies that investigate the link between presence/absence of this polymorphism and presence/absence of coronary heart disease. Each is a case-control study that reports an odds ratio. The studies are not directly comparable because they differ greatly in their patient pools and also in the way the data are analysed. We present several meta-analyses of these 12 studies. The simplest one is based on a standard frequentist random effects model with a normal distribution for the study effects (the per-study population log-odds ratios). We also consider a Bayesian version of this model, with a diffuse prior for the mean and variance of the normal distribution of the study effects. The conclusions from both of these analyses is about the same, and is that there is evidence that the Pl(A2) polymorphism is associated with an increased risk of coronary heart disease. A look at the reported log-odds ratios across studies suggests that the study effects do not come from a symmetric distribution. For this reason, we also consider semi-parametric priors for the distribution of the study effects. These priors are specifically designed for this kind of meta-analysis, and are based on a certain class of mixtures of Dirichlet priors. They can be designed to concentrate most of their mass around the family of normal distributions, but still allow for any other distribution. The semi-parametric Bayesian model continues to give evidence of an association between the Pl(A2) polymorphism and the risk of coronary heart disease.

Bayes Theorem↗