Dichotomous effects of exposure to bivalirudin in patients undergoing percutaneous coronary intervention on protease-activated receptor-mediated platelet activation.

Bivalirudin is a direct thrombin inhibitor that is increasingly used in percutaneous coronary intervention (PCI) and has been previously shown to lack inherent platelet activation. Thrombin works through activation of protease activated receptor-1 (PAR1) and PAR4 on human platelets to initiate signaling cascades leading to platelet aggregation. Despite the increasing usage of bivalirudin, the effects on platelet function have not been well defined. Bivalirudin exposure during PCI was therefore assessed for its potential short-term effects on washed platelet function through PAR1 and PAR4. Bivalirudin significantly inhibited low-dose thrombin-mediated platelet aggregation, dense granule secretion, integrin αIIbß3 activation and Rap1 activation and high dose thrombin-mediated dense granule secretion and Rap1 activation. Exposure to bivalirudin did not alter PAR1 or 4 agonist peptide (PAR1-AP or PAR4-AP) induced aggregation, dense granule secretion, integrin glycoprotein IIbIIIa activation or Rap1 activation. However, exposure to bivalirudin significantly potentiated surface expression of P-selectin following stimulation with high dose thrombin and PAR1-AP, and both low and high dose PAR4-AP. Hence, our data are the first to show that exposure to bivalirudin increased P-selectin expression with certain conditions demonstrating that bivalirudin can increase inherent platelet activity.

Weight loss and related behavior changes among lesbians.

Overweight and obesity are known risk factors for several modifiable, if not preventable diseases. Growing evidence suggests that lesbians may have higher rates of obesity than other women. This study was designed to describe weight loss and behavior changes related to food choices and exercise habits among lesbians who participated in a predominantly lesbian, mainstream, commercial weight loss program. Behavioral changes were recorded in exercise, quality of food choices, and number of times dining out. Although there were several limitations based on sample size and heterogeneity, the impact of a lesbian-supportive environment for behavior change was upheld.

3T magnetic resonance imaging accurately depicts radiofrequency ablation zones in a blood-perfused bovine liver model.

PURPOSE: To determine if noncontrast T1-weighted (T1W) images from 3T magnetic resonance (MR) imaging accurately depict radiofrequency (RF) ablation zones as determined macroscopically and microscopically in a blood-perfused bovine liver model. MATERIALS AND METHODS: Three-dimensional (3D) gradient-recalled echo (GRE) T1W images were obtained on a 3T MR imaging scanner after RF ablations (n = 14) of in vitro blood-perfused bovine livers. The resulting central hypointense and peripheral hyperintense signal regions were measured and compared with the inner tan and outer red zones of the gross specimen. Corresponding ablated hepatic tissue samples were examined microscopically and stained with nicotinamide adenine dinucleotide phosphate (NADPH) to assess for the presence or absence of NADPH diaphorase activity. Bootstrap two-sample hypothesis tests were used to compare MR imaging, gross, and histopathologic measurements. RESULTS: The MR imaging inner ablation zone had a mean radius of 0.80 cm (range 0.33-1.14 cm); the inner zone plus the outer ablation zone had a mean radius of 1.40 cm (range 1.01-1.74 cm). Comparison of the measurements of the inner ablation zone on MR imaging versus the gross specimen showed equivalence (95% confidence interval [CI] -0.122 cm, 0.223 cm). Comparison of the measurements of the outer ablation zone on MR imaging versus the gross and histologic specimens also showed equivalence (95% CI -0.095 cm, 0.244 cm, and -0.146 cm, 0.142 cm). CONCLUSIONS: Noncontrast 3D GRE T1W 3T MR imaging accurately depicts the RF ablation zones in a blood-perfused bovine liver model and can be used as a noninvasive means to assess the 3D morphologic characteristics of RF ablation lesions in the model.

Suboptimal inhibition of platelet cyclooxygenase-1 by aspirin in metabolic syndrome.

Interindividual variation in the ability of aspirin to inhibit platelet cyclooxygenase-1 (COX-1) could account for some on-treatment cardiovascular events. Here, we sought to determine whether there are clinical phenotypes that are associated with a suboptimal pharmacological effect of aspirin. In a prospective, 2-week study, we evaluated the effect of aspirin (81 mg) on platelet COX-1 in 135 patients with stable coronary artery disease by measuring serum thromboxane B(2) (sTxB(2)) as an indicator of inhibition of platelet COX-1. A nested randomized study compared enteric-coated with immediate-release formulations of aspirin. We found that sTxB(2) was systematically higher among the 83 patients with metabolic syndrome than among the 52 patients without (median: 4.0 versus 3.02 ng/mL; P=0.013). Twelve patients (14%) with metabolic syndrome, but none without metabolic syndrome, had sTxB(2) levels consistent with inadequate inhibition of COX (sTxB(2) ≥13 ng/mL). In linear regression models, metabolic syndrome (but none of its individual components) significantly associated with higher levels of log-transformed sTxB(2) (P=0.006). Higher levels of sTxB(2) associated with greater residual platelet function measured by aggregometry-based methods. Among the randomized subset, sTxB(2) levels were systematically higher among patients receiving enteric-coated aspirin. Last, urinary 11-dehydro thromboxane B(2) did not correlate with sTxB(2), suggesting that the former should not be used to quantitate aspirin's pharmacological effect on platelets. In conclusion, metabolic syndrome, which places patients at high risk for thrombotic cardiovascular events, strongly and uniquely associates with less effective inhibition of platelet COX-1 by aspirin.

Pentoxifylline lowers plasminogen activator inhibitor 1 levels in obese individuals: a pilot study.

Plasminogen activator inhibitor 1 (PAI-1), the primary inhibitor of fibrinolysis and C-reactive protein (CRP), is a predictor of myocardial infarction. Both are upregulated by tumor necrosis factor-alpha (TNF-α) within the obese population. This pilot study tested the hypothesis that TNF-α blockade with pentoxifylline lowers PAI-1 and high-sensitivity CRP (hsCRP) in obese individuals. Twenty participants were treated with pentoxifylline for 8 weeks. A proportional odds model was used to compare the change in PAI-1 and CRP in the pentoxifylline and placebo groups. Plasminogen activator inhibitor 1, but not hsCRP levels, decreased over the 8-week period of the study (P = .025 and P = NS). There was significant dropout of participants due to drug tolerability. These findings suggest that these markers of cardiovascular risk are differentially regulated in obesity and that PAI-1 levels can be reduced by pentoxifylline in this population.

Circulating neuregulin-1ß levels vary according to the angiographic severity of coronary artery disease and ischemia.

BACKGROUND: Coronary artery disease (CAD) is the leading killer in the United States. Patients with severe CAD and ischemia have worse prognosis. Therefore expansion of biomarker research, to identify at-risk individuals and explain the complex biology between cardiovascular growth factors and atherosclerosis is needed. Neuregulin-1ß (NRG-1ß) is a myocardial stress activated growth and survival factor released from endocardial and endothelial cells. NRG-1ß is essential for cardiovascular development and a regulator of angiogenesis. We postulated that plasma and serum levels of NRG-1ß would vary in relation to CAD severity and the presence of stress-induced ischemia. METHODS: We measured serum and plasma levels of NRG-1ß and vascular endothelial growth factor (VEGF) in 60 patients undergoing cardiac catheterization. CAD severity was calculated from angiographic results using a modified Duke jeopardy score. RESULTS: Serum NRG-1ß (sNRG-1ß), plasma NRG-1ß (pNRG-1ß), serum VEGF, and plasma VEGF were detectable in the majority of patients. The pNRG-1ß levels were approximately two-fold higher than sNRG-1ß. Both sNRG-1ß and pNRG-1ß correlated inversely with CAD severity. pNRG-1ß levels were statistically higher in patients with stress-induced ischemia denoted by a positive myocardial perfusion imaging study that correlated with angiographic findings (P=0.02). CONCLUSION: Both sNRG-1ß and pNRG-1ß correlated inversely with angiographic severity of CAD. pNRG-1ß levels were two-fold higher than serum and were higher in patients with stress-induced ischemia. Therefore we conclude that plasma is the optimal source for the further exploration of the biological significance of NRG-1ß as a biomarker of CAD severity and ischemia.

In vitro blood-perfused bovine liver model: a physiologic model for evaluation of the performance of radiofrequency ablation devices.

PURPOSE: To describe an in vitro blood-perfused bovine liver model for the testing of radiofrequency (RF) ablation devices and compare the performance of a specific RF ablation device in the model relative to three other biologic models. MATERIALS AND METHODS: Fresh bovine livers were used to create three in vitro models: blood-perfused, Krebs-Henseleit (KH) solution-perfused, and nonperfused. The perfused models were connected to a heart-lung machine via the portal vein and perfused with heparinized autologous blood or KH solution under physiologic conditions. Six swine were used as in vivo liver models. A cluster electrode and RF ablation system was operated in impedance mode for 12 minutes in all models. Ablated livers were sectioned, with long- and short-axis measurements of the ablations obtained, and statistical analysis was performed. RESULTS: A total of 39, 23, 17, and 12 ablations were performed in 14, 6, 5, and 6 blood-perfused bovine livers, KH solution-perfused bovine livers, nonperfused bovine livers, and in vivo porcine livers, respectively. On cut specimens, the average diameters of ablation zones were 4.00 cm (95% CI, 3.88-4.13) in blood-perfused livers, 4.34 cm (95% CI, 4.14-4.50) in KH solution-perfused livers, 4.67 cm (95% CI, 4.50-4.83) in nonperfused livers, and 3.56 cm (95% CI, 3.26-3.83) in in vivo porcine livers. In all models, the ablation zone diameters were normally distributed. CONCLUSIONS: In the in vitro blood-perfused bovine liver model, the size of ablations produced by an RF ablation device are closer in size to those seen in porcine liver in vivo compared with the lesions produced in KH solution-perfused or nonperfused bovine liver.

User perspectives on the usability of a regional health information exchange.

OBJECTIVE: We assessed the usability of a health information exchange (HIE) in a densely populated metropolitan region. This grant-funded HIE had been deployed rapidly to address the imminent needs of the patient population and the need to draw wider participation from regional entities. DESIGN: We conducted a cross-sectional survey of individuals given access to the HIE at participating organizations and examined some of the usability and usage factors related to the technology acceptance model. MEASUREMENTS: We probed user perceptions using the Questionnaire for User Interaction Satisfaction, an author-generated Trust scale, and user characteristic questions (eg, age, weekly system usage time). RESULTS: Overall, users viewed the system favorably (ratings for all usability items were greater than neutral (one-sample Wilcoxon test, p<0.0014, Bonferroni-corrected for 35 tests). System usage was regressed on usability, trust, and demographic and user characteristic factors. Three usability factors were positively predictive of system usage: overall reactions (p<0 0.01), learning (p<0.05), and system functionality (p<0.01). Although trust is an important component in collaborative relationships, we did not find that user trust of other participating healthcare entities was significantly predictive of usage. An analysis of respondents' comments revealed ways to improve the HIE. CONCLUSION: We used a rapid deployment model to develop an HIE and found that perceptions of system usability were positive. We also found that system usage was predicted well by some aspects of usability. Results from this study suggest that a rapid development approach may serve as a viable model for developing usable HIEs serving communities with limited resources.

Modulators of normal electrocardiographic intervals identified in a large electronic medical record.

BACKGROUND: Traditional electrocardiographic (ECG) reference ranges were derived from studies in communities or clinical trial populations. The distribution of ECG parameters in a large population presenting to a healthcare system has not been studied. OBJECTIVE: The purpose of this study was to define the contribution of age, race, gender, height, body mass index, and type 2 diabetes mellitus to normal ECG parameters in a population presenting to a healthcare system. METHODS: Study subjects were obtained from the Vanderbilt Synthetic Derivative, a de-identified image of the electronic medical record (EMR), containing more than 20 years of records on 1.7 million subjects. We identified 63,177 unique subjects with an ECG that was read as "normal" by the reviewing cardiologist. Using combinations of natural language processing and laboratory and billing code queries, we identified a subset of 32,949 subjects without cardiovascular disease, interfering medications, or abnormal electrolytes. The ethnic makeup was 77% Caucasian, 13% African American, 1% Hispanic, 1% Asian, and 8% unknown. RESULTS: The range that included 95% of normal PR intervals was 125-196 ms, QRS 69-103 ms, QT interval corrected with Bazett formula 365-458 ms, and heart rate 54-96 bpm. Linear regression modeling of patient characteristic effects reproduced known age and gender effects and identified novel associations with race, body mass index, and type 2 diabetes mellitus. A web-based application for patient-specific normal ranges is available online at http://biostat.mc.vanderbilt.edu/ECGPredictionInterval. CONCLUSION: Analysis of a large set of EMR-derived normal ECGs reproduced known associations, found new relationships, and established patient-specific normal ranges. Such knowledge informs clinical and genetic research and may improve understanding of normal cardiac physiology.