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Biomedical subjects

Philip F Binkley

Publications and source records attributed to Philip F Binkley.

12 recordsLinked to original sources
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

Sustained restoration of autonomic balance with long- but not short-acting metoprolol in patients with heart failure.

BACKGROUND: The purpose of this study was to compare the effects of immediate-release (IR) metoprolol and extended-release (XL) metoprolol on measures of heart rate variability in chronic systolic heart failure patients. METHODS AND RESULTS: Thirteen metoprolol-treated heart failure patients were randomized to a 2-way crossover study of equal daily doses of metoprolol IR and metoprolol XL, each administered for 3 weeks. After each 3-week interval, patients underwent 24-hour Holter and ambulatory blood pressure monitoring. Over the entire 24-hour period, the ratio of high to total variability (normalized measure of parasympathetic activity) was significantly greater (P < .05), the ratio of low to total variability (normalized measure of sympathetic activity) was significantly lower (P < .05), and the ratio of high to low variability (index of parasympathetic to sympathetic balance) was greater (P < .08) for metoprolol XL compared with metoprolol IR. Over the entire 24-hour period, both systolic and diastolic blood pressure were significantly lower for metoprolol XL compared with metoprolol IR (P < .0001, and .0005, respectively). CONCLUSION: These data suggest that with twice daily dosing, metoprolol IR is inferior to metoprolol XL in its effects on heart rate variability, autonomic balance, and blood pressure in patients with heart failure.

Adrenergic beta-Antagonists↗
PubMed2006

Highly variable mRNA expression and splicing of L-type voltage-dependent calcium channel alpha subunit 1C in human heart tissues.

OBJECTIVES: The voltage-dependent L-type calcium channel alpha-subunit 1c (Cav1.2, CACNA1C) undergoes extensive mRNA splicing, leading to numerous isoforms with different functions. L-type calcium channel blockers are used in the treatment of hypertension and arrhythmias, but response varies between individuals. We have studied the interindividual variability in mRNA expression and splicing of CACNA1C, in 65 heart tissue samples, taken from heart transplant recipients. METHODS: Splice variants were measured quantitatively by polymerase chain reaction in 12 splicing loci of CACNA1C mRNA. To search for functional cis-acting polymorphisms, we determined allelic expression ratios for total CACNA1C mRNA and several splice variants using marker single nucleotide polymorphisms in exon 4 and exon 30. RESULTS: Total CACNA1C mRNA levels varied approximately 50-fold. Substantial splicing occurred in six loci generating two or more splice variants, some with known functional differences. Splice patterns varied broadly between individuals. Two heart tissues expressed predominantly the dihydropyridine-sensitive smooth muscle isoform of CACNA1C (containing exon 8), rather than the cardiac isoform (containing exon 8a). Lack of significant allelic expression imbalance, observed with total mRNA and several splice variants, argued against CACNA1C polymorphisms as a cause of variability. Taken together, highly variable splicing can cause profound phenotypic variations of CACNA1C function, potentially associated with disease susceptibility and response to L-type calcium channel blockers.

Alleles↗
PubMed2005

Psychological distress and cardiovascular disease: results from the 2002 National Health Interview Survey.

AIMS: The objective of this study was to examine the burden of psychological distress among individuals with different forms of heart disease in a large representative sample of adults. METHODS AND RESULTS: Data were obtained from the 2002 National Health Interview Survey, which is a large annual survey of the US non-institutionalized civilian population. Psychological distress was assessed with a standardized questionnaire (K6) and heart disease diagnoses were based on self-report. Among non-diseased individuals, the estimated prevalence of psychological distress was 2.8%, whereas the estimates were 10, 6.4, and 4.1% among those with congestive heart failure (CHF), myocardial infarction (MI), and coronary heart disease (CHD), respectively. Over 1 million individuals with one or more of these conditions are estimated to experience psychological distress. However, only 31-35% of the participants with heart disease and psychological distress have visited a mental health professional. The logistic regression model results indicate that MI (OR 2.0, 95% CI 1.4-3.0) and CHF (OR 3.1, 95% CI 1.8-5.1) are significantly associated with psychological distress. CONCLUSION: These findings imply that psychological distress is a significant comorbidity of cardiovascular disease. Other investigations have demonstrated a link between psychological distress and morbidity and mortality. Taken together, these findings provide the impetus for future investigations that assess the role that a medical and mental health care professional intervention may have in altering these outcomes when targeted at this distress.

Adult↗
PubMed2005

A polymorphism of the endothelial nitric oxide synthase promoter is associated with an increase in autonomic imbalance in patients with congestive heart failure.

BACKGROUND: In addition to its well-recognized role in the regulation of vascular tone, nitric oxide modulates sympathetic and parasympathetic nervous system activities. Abnormalities of both autonomic control and nitric oxide synthase activity are known to occur in patients with congestive heart failure. Recently, a polymorphism of the promoter of the endothelial nitric oxide synthase (eNOS) gene has been associated with a reduction of eNOS activity. This study tested the hypothesis that patients with congestive heart failure who are homozygous for this polymorphism will have a more advanced imbalance of autonomic activity. METHODS: Patients who have congestive heart failure were tested for the presence of an eNOS promoter polymorphism (thymidine to cytosine transition [T(-786)C]). Spectral analysis of heart rate variability was performed to quantify sympathetic and parasympathetic autonomic activity, which were compared between subjects homozygous for the polymorphism and all other subjects. RESULTS: Patients homozygous for the polymorphism of the eNOS promoter had a greater autonomic imbalance as reflected by significant differences in high- and low-frequency heart rate variability. These differences in autonomic function were noted in the absence of intergroup differences in patterns of respiratory variability, demographic features, and despite a higher mean ejection fraction in patients homozygous for the polymorphism. CONCLUSIONS: Patients with congestive heart failure who are homozygous for this polymorphism of the eNOS promoter were found to have a more advanced autonomic imbalance. This polymorphism may serve as a marker for patients at increased risk for sudden death and more rapid progression of disease.

Autonomic Nervous System↗
PubMed2005

Depressive symptoms and inflammation among heart failure patients.

BACKGROUND: Psychological depression has been linked to heart failure, both an antecedent to and as a risk factor for poor outcomes among patients with existing heart failure. Elevated levels of proinflammatory cytokines have been proposed as a possible physiological link between the 2 conditions. The objective of this study was to examine the proinflammatory cytokines interleukin (IL)-6, IL-1beta, and tumor necrosis factor-alpha (TNFalpha) in heart failure patients with and without elevated symptoms of depression. METHODS: Thirty-two heart failure patients were recruited from an outpatient heart failure clinic. Depressive symptoms were measured with the Beck Depression Inventory (BDI), and a patient was classified as having elevated symptoms of depression if he/she scored > or = 10. The cognitive-affective subscale score of the BDI, which measures depressed mood independent of physical symptoms, was also examined. RESULTS: In the multiple linear regression models controlling for age, sex, smoking, and antidepressant medication use, there was no relation between BDI score and IL-6 (P = .7612) or IL-1beta (P = .8261). However, there was a statistically significant positive relation between BDI score and TNFalpha (P = .0374). There was also a significant relation between an elevated cognitive-affective score and TNFalpha (P = .0322) but no association with IL-6 (P = .8593) or IL-1beta (P = .3737). CONCLUSIONS: The association between TNFalpha and the cognitive-affective subscale, which eliminates the physical signs and symptoms that are shared by depression and heart failure, demonstrates a depression-specific activation of proinflammatory cytokines that may promote disease progression and mortality in patients with heart failure.

Depression↗
PubMedDate not supplied

Pathophysiology of plaque instability: insights at the genomic level.

Atherosclerosis and plaque rupture represent complex "traits" of unknown cause that involve multiple genes and their variants. Novel genomic technologies provide us with the tools that will allow for the identification of groupings of genes that determine either susceptibility or resistance relative to the development of atherosclerosis and its thromboembolic complications. This information may, in turn, lead to a clearer understanding of the cause and risk for atherosclerosis. Diagnostic tools, as well as preventive and therapeutic strategies, will be derived from such heightened understanding of the disease process. With this chapter, we have presented the current state of knowledge of atherosclerosis genomics.

Arteriosclerosis↗
PubMedDate not supplied

A polymorphism of the gene encoding AMPD1: clinical impact and proposed mechanisms in congestive heart failure.

A vast array of gene polymorphisms have been described, and further discovery of these gene variants will continue as the human genome is defined. Therefore, selection of a single polymorphism to investigate in relation to disease evolution or outcome must be motivated by specific physiologic, pathophysiologic, or epidemiologic associations. A significant gene polymorphism may result in an alteration of protein function, or be associated with disease incidence or outcome. Prevalence of the polymorphism in the general population is of extreme importance, as it must be common enough to warrant interest in its clinical impact. The polymorphism of the gene encoding for the enzyme adenosine monophosphate deaminase 1 results in an abnormal protein necessary in skeletal muscle metabolism. While its physiologic effects are not completely understood, it has been associated with improved morbidity and mortality in patients with cardiovascular disease.

AMP Deaminase↗