Biomedical subjects

Dhananjay Vaidya

Publications and source records attributed to Dhananjay Vaidya.

10 recordsLinked to original sources

PubMed2007

Platelet functional implications of glycoprotein Ibalpha polymorphisms in African Americans.

The platelet glycoprotein Ibalpha is crucial in the binding of platelets to Von Willebrand Factor within areas of high stress. A single nucleotide polymorphism of GP Ibalpha gives rise to the Ko(a) (HPA-2b) and the -5C Kozak polymorphism. The presence of these polymorphisms has been associated with an increased risk for atherothrombotic disease. The Ko(a) polymorphism has been shown to have a higher prevalence in African Americans compared to American Caucasians. However, very little is known regarding any functional consequences of these platelet polymorphisms in African Americans. We assessed the prevalence of the Ko and -5C Kozak polymorphisms in a population of both African American and American Caucasian patients with and without CAD and determined whether there were platelet functional consequences in both groups. We studied 99 patients of which 22 were African American and 77 were American Caucasian. Aggregations were performed and shear induced platelet plug formation was tested using a platelet function analyzer. The HPA-2b allele was significantly higher in African Americans when compared to Caucasians (P = 0.001). Genotype frequencies of the -5C Kozak polymorphism were not significantly different between the two groups. We found no differences in platelet aggregation in African Americans who were either heterozygous or homozygous for the HPA-2b allele or the -5C Kozak allele when compared to American Caucasians of the same category. We found no significant differences in PFA-100 testing. We conclude from our study that these polymorphisms do not lead to altered platelet function in African Americans.

Black or African American↗

PubMed2006

Glucose levels in the normal range predict incident diabetes in families with premature coronary heart disease.

PURPOSE: Little is known about excess risk of incident diabetes conferred by fasting plasma glucose (FPG) within the normal range (<5.6 mmol/l) for high risk families. METHODS: Healthy 30-59 year old non-diabetic siblings (N = 542) of index cases with documented premature coronary disease were followed prospectively for type 2 diabetes. RESULTS: During 8.7+/-3 years of follow-up, incident diabetes was identified in 7.8%. Rates were incremental with baseline non-diabetes FPG thresholds of 5.0, 5.6, 6.1, and 6.7 mmol/l (p for trend < 0.0001). FPG was the strongest predictor of incident diabetes even across levels within the normal range. The multivariable adjusted relative risk was 14.9 (95% CI = 3.4-65.2) at FPG thresholds > or =5.0 mmol/l versus FPG <5.0 mmol/l. The maximal diagnostic efficiency for FPG was 5.50 mmol/l; with sensitivity and specificity 0.782. All FPG thresholds in the normal range between 5.0 and 5.6 mmol/l showed efficiency levels >0.74. The overall area under the ROC curve predicting incident diabetes for normal and prediabetes ranges of FPG was 0.867. CONCLUSION: Higher FPG levels within the designated "normal" range in high risk families are a potent independent risk factor for type 2 diabetes and may serve as a sentinel to trigger primary preventive interventions.

Adult↗

PubMed2006

Sex differences in platelet reactivity and response to low-dose aspirin therapy.

CONTEXT: Recent randomized trials suggest that women may not accrue the same cardioprotective benefits as men do from low-dose aspirin therapy used in primary prevention. Failure of aspirin to suppress platelet aggregation in women is one hypothesized mechanism. OBJECTIVE: To examine differential platelet reactivity to low-dose aspirin therapy by sex. DESIGN, SETTING, AND PARTICIPANTS: A clinical trial of aspirin at 81 mg/d for 14 days was conducted in 571 men and 711 women. Baseline and post-aspirin therapy measures included platelet aggregation to arachidonic acid, adenosine diphosphate, epinephrine, and platelet function analyzer closure time. MAIN OUTCOME MEASURE: Sex differences in cyclooxygenase 1 (COX-1) direct and indirect platelet activation pathways before and after administration of aspirin. RESULTS: In 10 of the 12 platelet agonist exposures, women's platelets were significantly more reactive at baseline. However, after aspirin therapy, the percent aggregation to arachidonic acid (the direct COX-1 pathway) decreased more in women than in men (P<.001) and demonstrated near total suppression of residual platelet reactivity in both men and women. In COX-1 indirect pathways, women experienced the same or more platelet inhibition than men in 8 of the 9 assays yet retained modestly greater platelet reactivity after aspirin therapy. In multivariable analysis, female sex significantly predicted aggregation to 2 muM and 10 muM of adenosine diphosphate (P = .02 and <.001, respectively) and collagen at 5 mug/mL (P<.001) independent of risk factors, age, race, menopausal status, and hormone therapy. CONCLUSIONS: Women experienced the same or greater decreases in platelet reactivity after aspirin therapy, retaining modestly more platelet reactivity compared with men. However, most women achieved total suppression of aggregation in the direct COX-1 pathway, the putative mechanism for aspirin's cardioprotection.

Adenosine Diphosphate↗

PubMed2006

Evaluation of platelet function in aspirin treated patients with CAD.

BACKGROUND: Studies of platelet function in the acute coronary syndrome (ACS) have revealed both increased and unchanged platelet activation. To obtain a better understanding of platelet function in coronary artery disease in the setting of aspirin therapy, we performed platelet functional testing in patients with ACS and compared results to patients without CAD. METHODS: We measured platelet aggregation and activation in response to ADP and epinephrine in 80 age and gender matched hospitalized patients (40 with ACS, 40 with non-cardiac chest pain (NCCP)). All subjects received ASA (81-325 mg). Platelet aggregation was performed using standard light transmission in platelet-rich plasma and activation was measured via flow cytometric analyses. We also studied platelet function under high shear rates measured by the platelet function analyzer (PFA-100). RESULTS: ASA effect was found to be present in all subjects by blunted platelet aggregation in response to arachidonic acid. Patients with ACS showed significantly higher levels of platelet aggregation to epinephrine compared to patients with NCCP (p = 0.001). Other measures of platelet function including ADP aggregation, Pselectin, activated glycoprotein IIb/IIIa expression, and PFA-100 were unchanged between the two groups. CONCLUSIONS: We have found conflicting results of platelet functional testing in ACS. Specifically aspirin therapy in patients with ACS is effective in suppressing the platelet release response and is effective in the partial suppression of platelet aggregation; however, it appears that ACS patients have increased platelet aggregation to adrenergic stimuli when compared to age and gender matched controls without CAD despite the use of aspirin. In some studies, because ACS patients have an accentuated response to adrenergic stimuli this might be interpreted as aspirin resistance. Our study suggests that depending on the assay used to determine aspirin resistance, not all patients with this label are resistant to the biological effects of aspirin but they may have higher than normal baseline platelet sensitivity to adrenergic stimuli.

Aged↗

PubMed2005

Altered right atrial excitation and propagation in connexin40 knockout mice.

BACKGROUND: Intercellular coupling via connexin40 (Cx40) gap junction channels is an important determinant of impulse propagation in the atria. METHODS AND RESULTS: We studied the role of Cx40 in intra-atrial excitation and propagation in wild-type (Cx40(+/+)) and knockout (Cx40(-/-)) mice using high-resolution, dual-wavelength optical mapping. On ECG, the P wave was significantly prolonged in Cx40(-/-) mice (13.4+/-0.5 versus 11.4+/-0.3 ms in Cx40(+/+)). In Cx40(+/+) hearts, spontaneous right atrial (RA) activation showed a focal breakthrough at the junction of the right superior vena cava, sulcus terminalis, and RA free wall, corresponding to the location of the sinoatrial node. In contrast, Cx40(-/-) hearts displayed ectopic breakthrough sites at the base of the sulcus terminalis, RA free wall, and right superior vena cava. Progressive ablation of such sites in 4 Cx40(-/-) mice resulted in ectopic focus migration and cycle length prolongation. In all Cx40(-/-) hearts the focus ultimately shifted to the sinoatrial node at a very prolonged cycle length (initial ectopic cycle length, 182+/-20 ms; postablation sinus cycle length, 387+/-44 ms). In a second group of experiments, epicardial pacing at 10 Hz revealed slower conduction in the RA free wall of 5 Cx40(-/-) hearts than in 5 Cx40(+/+) hearts (0.61+/-0.07 versus 0.94+/-0.07 m/s; P<0.05). Dominant frequency analysis in Cx40(-/-) RA demonstrated significant reduction in the area of 1:1 conduction at 16 Hz (40+/-10% versus 69+/-5% in Cx40(+/+)) and 25 Hz (36+/-11% versus 65+/-9% in Cx40(+/+)). CONCLUSIONS: This is the first demonstration of intra-atrial block, ectopic rhythms, and altered atrial propagation in the RA of Cx40(-/-) mice.

Algorithms↗

PubMed2005

Impact of a community-based multiple risk factor intervention on cardiovascular risk in black families with a history of premature coronary disease.

BACKGROUND: Black subjects with a family history of premature coronary heart disease (CHD) have a marked excess risk, yet barriers prevent effective risk reduction. We tested a community-based multiple risk factor intervention (community-based care [CBC]) and compared it with "enhanced" primary care (EPC) to reduce CHD risk in high-risk black families. METHODS AND RESULTS: Black 30- to 59-year-old siblings of a proband with CHD aged <60 years were randomized for care of BP > or =140/90 mm Hg, LDL cholesterol > or =3.37 mmol/L, or current smoking to EPC (n=168) or CBC (n=196) and monitored for 1 year. EPC and CBC were designed to eliminate barriers to care. The CBC group received care by a nurse practitioner and a community health worker in a community setting. The CBC group was 2 times more likely to achieve goal levels of LDL cholesterol and blood pressure compared with the EPC group (95% CI, 1.11 to 4.20 and 1.39 to 3.88, respectively) with adjustment for baseline levels of age, sex, education, and baseline use of medications. The CBC group demonstrated a significant reduction in global CHD risk, whereas no reduction was seen in the EPC group (P<0.0001). CONCLUSIONS: Eliminating known barriers may not be sufficient to reduce CHD risk in primary care settings. An alternative community care model that addresses barriers may be a more effective way to ameliorate CHD risk in high-risk black families.

Adult↗

PubMed2005

Skin tissue cholesterol assay correlates with presence of coronary calcium.

BACKGROUND: Keratinocytes maintain cholesterol homoeostasis using LDL and HDL-scavenger receptor pathways implicated in atherosclerosis. We tested whether skin tissue cholesterol (SkTC) is associated with subclinical atherosclerosis, assessed using carotid intima-medial thickness (IMT) and coronary artery calcification (CAC). METHODS: Two hundred and twenty two subjects were recruited from the Baltimore site of the Multi-Ethnic Study of Atherosclerosis (MESA). Baseline MESA examination included fasting blood collection, IMT measurement by B-mode ultrasound and CAC determination by helical CT. SkTC was measured using the Cholesterol 1, 2, 3 kit (IMI Inc., Canada). RESULTS: SkTC was significantly higher if CAC was present in Caucasians (p = 0.04) but not African-Americans. SkTC was not significantly correlated with IMT in either group. Using multiple logistic regression adjusting for age, sex and serum lipids, a 1-standard deviation higher SkTC was associated with 187% higher odds of the presence of CAC in Caucasians (p < 0.01) but no significant difference in odds for African-Americans. In subjects in whom CAC was present, the extent of CAC was not related to the SkTC in multiple linear regressions. CONCLUSIONS: SkTC was associated with the presence of CAC independently of serum lipids/lipoproteins in Caucasians but not African-Americans. SkTC may provide a useful indicator of subclinical atherosclerosis in Caucasians.

Black or African American↗

PubMed2005

Long-term hormone replacement therapy does not cause increased platelet activation.

BACKGROUND: Observational studies have shown apparently lower ischemic coronary disease risk in postmenopausal women receiving hormone replacement therapy (HRT). However, several recent studies have shown an increase in ischemic cardiac events when HRT is initiated in postmenopausal women with known coronary artery disease. It is postulated that estrogen may result in increased platelet aggregation. METHODS: We evaluated platelet activation, as measured by flow cytometric analysis using P selectin and PAC1 as activation markers, and aggregation, as measured by standard platelet aggregation using platelet-rich plasma, in 27 postmenopausal women (17 HRT, 10 placebo) who were participants in 2 placebo-controlled randomized angiographic trials evaluating the effect of HRT on coronary atherosclerosis or saphenous vein graft disease. All women had received HRT or placebo for >2 years and were on aspirin therapy. The estrogen component was either conjugated equine estrogen or 17beta-estradiol. RESULTS: Patients on HRT and those on placebo had comparable degrees of platelet aggregation when measured using various doses of agonists (adenosine diphosphate and epinephrine). There were no significant differences in levels of platelet activation measured by flow cytometry. CONCLUSION: We conclude that long-term HRT does not appear to cause increased platelet activation and aggregation in women with coronary artery disease. There may be increased platelet activation in the early period after HRT initiation; however, this was not assessed in this study.

Aged↗

PubMed2005

Sex differences in left ventricular function in older persons with mild hypertension.

BACKGROUND: Epidemiologic studies suggest that women are at increased risk of developing heart failure secondary to hypertension. Other studies have documented sex differences in left ventricular systolic and diastolic function in the presence of pressure overload states such as seen in aortic stenosis and hypertension. It is less clear if sex differences are present among older persons with mild hypertension. METHODS: One hundred seven healthy subjects, aged 55 to 75 years, with blood pressures ranging from 130 to 159 mm Hg systolic and/or 85 to 99 mm Hg diastolic, were examined by standard echocardiography and the newer modalities of tissue Doppler and color M-mode imaging. RESULTS: Women had a lower peak mitral annular systolic velocity (Sm), 8.9 (95% CI 8.4-9.5) cm/s versus 10.2 (95% CI 9.6-11.0) cm/s, (P < .01) than men. Among women, increasing age was associated with a reduction in diastolic function. For every decade of age, peak early mitral annular diastolic velocity (Em) declined by 1.6 cm/s (P < .01), mitral inflow velocity of propagation (Vp) declined by 26% (P < .01), E/Vp ratio increased by 20% (P = .03), and E/Em ratio increased by 11% (P = .04) in women. No age-associated changes were seen in men. CONCLUSIONS: As revealed by newer echocardiographic imaging modalities, women with mild hypertension showed greater reductions in systolic and diastolic function as they aged compared with men. Our findings are consistent with the increased risk older women have of developing heart failure because of hypertension.

Age Factors↗

PubMed2004

Hormone therapy and antioxidant vitamins do not improve endothelial vasodilator function in postmenopausal women with established coronary artery disease: a substudy of the Women's Angiographic Vitamin and Estrogen (WAVE) trial.

We measured flow-mediated dilation (FMD) by high-resolution brachial ultrasound in 61 women who participated in the Women's Angiographic Vitamin and Estrogen (WAVE) trial, a randomized controlled trial. There were no significant differences in the baseline demographics of women receiving hormone therapy (0.625 mg/day of conjugated equine estrogen plus 2.5mg of medroxyprogesterone acetate for women who had not had a hysterectomy) or placebo; or vitamins (400 IU of Vitamin E and 500 mg of Vitamin C twice daily) or placebo. Baseline FMD was impaired in all subjects (3.3+/-7.6%). Neither hormone therapy (4.1+/-5.2% at baseline, 4.2+/-5.0% at 3 months, and 4.1+/-6.5% at 34 months) nor antioxidant vitamins (3.0+/-8.3% at baseline; 3.5+/-4.6% at 3 months; 3.1+/-7.6% at 34 months) improved FMD (all p-values=NS). Endothelium-independent vasodilation, induced by nitroglycerin (NTG) was similar at baseline and was not affected by either therapy. In univariate and multivariate analysis, neither hormone therapy nor antioxidant vitamins were associated with FMD. Women with established coronary artery disease have impaired flow-mediated vasodilation of the brachial artery that does not improve after 3 months or up to 34 months of treatment with postmenopausal hormone therapy or antioxidant vitamins.

Aged↗