Faculty Bibliography

Platelet activity plays a major role in hemostasis with increased platelet activity likely contributing to the pathogenesis of atherothrombosis. We sought to identify associations between platelet activity variability and platelet related genes in healthy controls. Transcriptional profiling of platelets revealed that WD-40 repeat domain 1 (WDR1), an enhancer of actin depolymerizing factor activity, is downregulated in platelet mRNA from subjects with a hyperreactive platelet phenotype. We used the human megakaryoblastic cell line MEG-01 as an in vitro model for human megakaryocytes and platelets. Stimulation of MEG-01 with thrombin reduced levels of WDR1 transcripts and protein. WDR1 knockdown (KD) in MEG-01 cells increased adhesion and spreading in both the basal and activated states, increased F-actin content, and increased the basal intracellular calcium concentration. Platelet-like particles (PLPs) produced by WDR1 KD cells were fewer in number but larger than PLPs produced from unmodified MEG-01 cells, and had significantly increased adhesion in the basal state and upon thrombin activation. In contrast, WDR1 overexpression reversed the WDR1 KD phenotype of megakaryocytes and platelet like particles. To translate the clinical significance of these findings, WDR1 expression was measured in platelet RNA from subjects with established cardiovascular disease (n=27) and age- and sex-matched controls (n=10). The WDR1 mRNA and protein level was significantly lower in subjects with cardiovascular disease. These data suggest that WDR1 plays an important role in suppressing platelet activity, where it alters the actin cytoskeleton dynamics, and downregulation of WDR1 may contribute to the platelet-mediated pathogenesis of cardiovascular disease.

BACKGROUND: Reproductive factors provide an early window into a woman's coronary heart disease (CHD) risk; however, their contribution to CHD risk stratification is uncertain. METHODS AND RESULTS: In the Women's Health Initiative Observational Study, we constructed Cox proportional hazards models for CHD including age, pregnancy status, number of live births, age at menarche, menstrual irregularity, age at first birth, stillbirths, miscarriages, infertility >/=1 year, infertility cause, and breastfeeding. We next added each candidate reproductive factor to an established CHD risk factor model. A final model was then constructed with significant reproductive factors added to established CHD risk factors. Improvement in C statistic, net reclassification index (or net reclassification index with risk categories of <5%, 5 to <10%, and >/=10% 10-year risk of CHD), and integrated discriminatory index were assessed. Among 72 982 women (CHD events, n=4607; median follow-up,12.0 [interquartile range, 8.3-13.7] years; mean [standard deviation] age, 63.2 [7.2] years), an age-adjusted reproductive risk factor model had a C statistic of 0.675 for CHD. In a model adjusted for established CHD risk factors, younger age at first birth, number of still births, number of miscarriages, and lack of breastfeeding were positively associated with CHD. Reproductive factors modestly improved model discrimination (C statistic increased from 0.726 to 0.730; integrated discriminatory index, 0.0013; P<0.0001). Net reclassification for women with events was not improved (net reclassification index events, 0.007; P=0.18); and, for women without events, net reclassification was marginally improved (net reclassification index nonevents, 0.002; P=0.04) CONCLUSIONS: Key reproductive factors are associated with CHD independently of established CHD risk factors, very modestly improve model discrimination, and do not materially improve net reclassification.

BACKGROUND: Despite overwhelming data demonstrating the efficacy of antiplatelet therapy in heart disease and stroke, data in peripheral artery disease (PAD) are less compelling. Aspirin has modest evidence supporting a reduction in cardiovascular events in patients with PAD, whereas clopidogrel monotherapy may be more effective in PAD. Ticagrelor, a potent, reversibly binding P2Y12 receptor antagonist, is beneficial in patients with acute coronary syndrome and prior myocardial infarction. The EUCLID trial is designed to address the need for effective antiplatelet therapy in PAD to decrease the risk of cardiovascular events. STUDY DESIGN: EUCLID is a randomized, double-blind, parallel-group, multinational clinical trial designed to evaluate the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events in subjects with symptomatic PAD. Subjects with established PAD will be randomized in a 1:1 fashion to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. The primary end point is a composite of cardiovascular death, myocardial infarction, or ischemic stroke. Other end points address limb events including acute leg ischemia, need for revascularization, disease progression by ankle-brachial index, and quality of life. The primary safety objective is Thrombolysis in Myocardial Infarction-defined major bleeding. Recruitment began in December 2012 and was completed in March 2014; 13,887 patients were randomized. The trial will continue until at least 1,364 adjudicated primary end points occur. CONCLUSIONS: The EUCLID study is investigating whether treatment with ticagrelor versus clopidogrel, given as antiplatelet monotherapy, will reduce the incidence of cardiovascular and limb-specific events in patients with symptomatic PAD.

Testosterone replacement therapy is recommended for men with clinical androgen deficiency with decades of evidence supporting its use for treatment of sexual, physical, and psychological consequences of male hypogonadism. In this updated review, the authors discuss the implications of testosterone deficiency and conflicting evidence regarding testosterone replacement therapy and its effects on the cardiovascular system. Based on mounting evidence, the authors conclude that testosterone therapy can be safely considered in men with appropriately diagnosed clinical androgen deficiency and concurrent cardiovascular risk factors and even manifest cardiovascular disease after a thorough discussion of potential risks and with guideline-recommended safety monitoring.

Patients with non-valvular atrial fibrillation (AF) have an elevated stroke risk that is 2-7 times greater than in those without AF. Intravenous unfractionated heparin (UFH) is commonly used for hospitalized patients with atrial fibrillation and atrial flutter (AFL) to prevent stroke. Dosing strategies exist for intravenous anticoagulation in patients with acute coronary syndromes and venous thromboembolic diseases, but there are no data to guide providers on a dosing strategy for intravenous anticoagulation in patients with AF/AFL. 996 hospitalized patients with AF/AFL on UFH were evaluated. Bolus dosing and initial infusion rates of UFH were recorded along with rates of stroke, thromboemobolic events, and bleeding events as defined by the International Society on Thrombosis and Haemostasis criteria. Among 226 patients included in the analysis, 76 bleeding events occurred. Using linear regression analysis, initial rates of heparin infusion ranging from 9.7 to 11.8 units/kilogram/hour (U/kg/h) resulted in activated partial thromboplastin times that were within therapeutic range. The median initial infusion rate in patients with bleeding was 13.3 U/kg/h, while in those without bleeding it was 11.4 U/kg/h; p = 0.012. An initial infusion rate >11.0 U/kg/h yielded an OR 1.95 (1.06-3.59); p = 0.03 for any bleeding event. Using IV heparin boluses neither increased the probability of attaining a therapeutic aPTT (56.1 vs 56.3 %; p = 0.99) nor did it significantly increase bleeding events in the study (35.7 vs 31.3 %; p = 0.48). The results suggest that higher initial rates of heparin are associated with increased bleeding risk. From this dataset, initial heparin infusion rates of 9.7-11.0 U/kg/h without a bolus can result in therapeutic levels of anticoagulation in hospitalized patients with AF/AFL without increasing the risk of bleeding.