Thrombolytic proteins profiling: High-throughput activity, selectivity, and resistance assays.

Tenecteplase: A Review of Its Pharmacology and Uses.

Background Risk stratification in patients with type 2 diabetes continues to be an important priority in the management of diabetes-related morbidity and mortality. International guidelines generally recognize patients with diabetes and cardiovascular disease as high-risk patients. Risk stratification is, however, more uncertain in diabetes patients without cardiovascular disease. Micro- and macroalbuminuria have previously been identified as predictors of cardiovascular events and mortality in general cohorts of diabetes patients. However, less is known about the predictive value of albuminuria in patients with diabetes but without established cardiovascular disease. Purpose We aimed to examine the association between albuminuria level and the risk of ischemic stroke, myocardial infarction, and all-cause mortality in patients with type 2 diabetes and without a diagnosis of cardiovascular disease. Methods We linked Danish nationwide registries to identify patients with type 2 diabetes and without cardiovascular disease from May 2005 through June 2015. Based on two consecutive measurements of the urinary albumin excretion rate or albumin-to-creatinine ratio patients were stratified in categories of normoalbuminuria, microalbuminuria, and macroalbuminuria. Patients were followed for the outcomes ischemic stroke, myocardial infarction, and all-cause mortality until December 31, 2015. Five-year risk of outcomes were presented as cumulative incidence functions (with death as a competing event). Associations between albuminuria level and incidence of ischemic stroke, myocardial infarction, and all-cause mortality were evaluated with Cox proportional hazard regression adjusted for cardiovascular risk factors. Results The study population included 78,841 patients with type 2 diabetes (44.7% females, mean age 63.2). When comparing patients with microalbuminuria to patients with normoalbuminuria in an age- and sex-adjusted analysis, we found hazard ratios (HRs) of 1.45 (95% CI: 1.24–1.69), 1.45 (95% CI: 1.24–1.70), and 1.50 (95% CI: 1.39–1.61) for ischemic stroke, myocardial infarction, and all-cause mortality, respectively. Furthermore, macroalbuminuria was associated with HRs of 2.05 (95% CI: 1.70–2.48), 2.25 (95% CI: 1.86–2.71), and 2.03 (95% CI: 1.85–2.23) for ischemic stroke, myocardial infarction, and all-cause mortality, respectively. Similar results were found after adjusting for cardiovascular risk factors. Conclusions In this nationwide cohort study of patients with type 2 diabetes but without cardiovascular disease, patients with micro- and macroalbuminuria had a higher risk of incident ischemic stroke, myocardial infarction, and all-cause mortality. This finding supports that patients with micro- or macroalbuminuria should be screened regularly and followed closely in clinical practice. Moreover, these findings suggest that patients with type 2 diabetes and micro- or macroalbuminuria may benefit from intensive vascular risk reduction.

Current guideline statements for primary and secondary prevention of cardiovascular disease (CVD) rely on estimates of absolute risk of coronary events. For example, the American Heart Association guidelines on primary prevention state that persons with ≥10% risk over 10 years of myocardial infarction (MI) or coronary death should be considered for antiplatelet therapy with aspirin.1 Similarly, the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines2 state that target low-density lipoprotein level should be based on projected absolute risk of future coronary events rather than on presence or absence of specific risk factors. These guidelines state that patients at high risk of MI and coronary death, defined as an absolute 10-year risk of ≥20%, should have a target low-density lipoprotein level <100 mg/dL and should receive statin therapy if needed to achieve this goal. Stroke, however, is not included as one of the outcomes contributing to these absolute risk levels. Included in the group of patients with elevated risk, moreover, are those who already have ischemic heart disease, as well as patients deemed to be “coronary heart disease (CHD) risk equivalents,” indicating those at the same elevated risk as patients with ischemic heart disease. CHD risk equivalents include patients with diabetes mellitus, those with multiple risk factors that put them at elevated risk based on calculation of their Framingham Score, and patients with “other forms of symptomatic atherosclerotic disease.” The latter group is further defined to include those with peripheral arterial disease (PAD), abdominal aortic aneurysm (AAA), and carotid artery disease. The category of “risk equivalents” in the ATP III guidelines, however, does not include the vast majority (≈80%3) of ischemic stroke patients without carotid artery disease as cause of their stroke. Ischemic stroke is therefore notably excluded from the list of outcomes contributing to …

Objective To assess the risk of pulmonary embolism, ischaemic stroke, and myocardial infarction associated with combined oral contraceptives according to dose of oestrogen (ethinylestradiol) and progestogen.Design Observational cohort study.Setting Data...

The role of C-reactive protein (CRP) as a novel plasma marker of atherothrombotic disease is currently under investigation. Previous studies have mostly related CRP to coronary heart disease, were often restricted to a case-control design, and failed to include pertinent risk factors to evaluate the joint and net effect of CRP on the outcome. We related plasma CRP levels to incidence of first ischemic stroke or transient ischemic attack (TIA) in the Framingham Study original cohort. There were 591 men and 871 women free of stroke/TIA during their 1980 to 1982 clinic examinations, when their mean age was 69.7 years. CRP levels were measured by using an enzyme immunoassay on previously frozen serum samples. Analyses were based on sex-specific CRP quartiles. Risk ratios (RRs) were derived, and series of trend analyses were performed. During 12 to 14 years of follow-up, 196 ischemic strokes and TIAs occurred. Independent of age, men in the highest CRP quartile had 2 times the risk of ischemic stroke/TIA (RR=2.0, P=0.027), and women had almost 3 times the risk (RR=2.7, P=0.0003) compared with those in the lowest quartile. Assessment of the trend in risk across quartiles showed unadjusted risk increase for men (RR=1.347, P=0.0025) and women (RR=1.441, P=0.0001). After adjustment for smoking, total/HDL cholesterol, systolic blood pressure, and diabetes, the increase in risk across CRP quartiles remained statistically significant for both men (P=0.0365) and women (P=0.0084). Independent of other cardiovascular risk factors, elevated plasma CRP levels significantly predict the risk of future ischemic stroke and TIA in the elderly.

Acute pulmonary embolism (PE) remains a dreaded and frequent cardiovascular emergency, with an estimated annual incidence of almost 200 000 cases in the United States alone.1 Despite therapeutic advances, 2 the International Cooperative Embolism Registry of 2454 patients3 reported a surprisingly high 90-day all-cause mortality of 17.4%. The cause of death in 45% of patients was PE itself. Recurrent PE, fatal or nonfatal, occurred in 8% of patients within 90 days. It is clear that a novel therapeutic pharmacological strategy with a safe and easy-to-administer agent is needed to reduce adverse outcomes from this common illness. Clinical and experimental evidence suggests that antiplatelet agents, usually overlooked in the treatment of PE, may fulfill this role by preventing the initiation and propagation of the venous thrombus and by minimizing the adverse physiological consequences of PE. Venous thrombosis has been traditionally associated with red blood cell and fibrin-rich “red clot,” whereas arterial thrombi superimposed on atherosclerotic lesions are rich in platelets, giving the appearance of “white clot.” This simple but somewhat dogmatic concept has had important therapeutic implications: “red clot” has been traditionally treated with heparin and warfarin, while platelet inhibition has been utilized for acute coronary syndromes caused by “white clot.” However, careful morphological analysis of thrombi formed in veins reveals tangled pale strands of aggregated platelets and fibrin within the mass of red blood cells.4 Experimentally …

Atherothrombosis is the major pathophysiological process responsible for the occurrence of severe ischemic events in patients with cardiovascular diseases. In the United States, atherothrombosis strongly influenced mortality in 2004: One in 2.8 deaths was due to CVD, 1 in 5 deaths to coronary heart disease, and 1 in 17 deaths to stroke.1 Because cardiovascular disease is a progressive and systemic disease, long-term antithrombotic therapies that effectively target the entire arterial vasculature and modulate the key components responsible for thrombus generation are essential to improve patient outcomes. Because platelet activation is determined by multiple receptor-mediated signaling pathways, clinical studies have evaluated the efficacy of multidrug administration in the prevention of atherothrombotic complications.2,3 The major concern with these therapies is the critical balance between anti-ischemic effect and bleeding risk. This review summarizes our understanding of the role of combination antiplatelet therapies in the treatment and prevention of atherothrombosis. Platelet activation and aggregation play a pivotal role in the generation of occlusive thrombus at the site of coronary arterial plaque rupture. In addition, platelets influence various endothelial and inflammatory responses during the initiation and progression of atherosclerosis. Under normal conditions, anucleate circulating platelets are in a quiescent state. Healthy vascular endothelium prevents adhesion and activation of platelets by producing antithrombotic factors such as CD39 (ectoADPase), prostaglandin I2, nitric oxide, heparin, matrix metalloproteinase-9, protein S, and thrombomodulin.3,4 Endothelial activation and denudation and frank atherosclerotic plaque rupture expose the subendothelial matrix and release prothrombotic factors during acute coronary syndromes (ACS) and percutaneous interventions. These processes result in localized platelet adhesion and platelet activation. After adhesion to the exposed subendothelial matrix, platelets are activated by shear and the soluble agonists thromboxane A2 (TxA2), ADP, and thrombin. TxA2 is produced from arachidonic acid, which originates from membrane phospholipids and …

Use of proton pump inhibitors (PPIs) has been associated with cardiovascular disease amongst patients not on antiplatelet therapy. The associations of PPI use, duration and dose, with risk of first-time ischemic stroke and myocardial infarction (MI) are poorly understood. All Danish individuals with no prior history of MI or stroke, who had an elective upper gastrointestinal endoscopy performed between 1997 and 2012, were identified from nationwide registries. We used multiple Poisson regression to test associations with current PPI use and its dose and used multiple cause-specific Cox regression and g-formula methods to analyze long-term use. Amongst 214998 individuals, during a median follow-up of 5.8years, there were 7916 ischemic strokes and 5608 MIs. Current PPI exposure was associated with significantly higher rates of both ischemic stroke (Hazard ratio (HR) 1.13; 95% confidence interval (CI) 1.08-1.19) and MI (HR 1.31, CI 1.23-1.39) after adjusting for age, sex, comorbidities and concomitant medication. High-dose PPI was associated with increased rates of ischemic stroke (HR 1.31, CI 1.21-1.42) and MI (HR 1.43, CI 1.30-1.57). Histamine H2 receptor antagonists (H2RAs) use was not significantly associated with ischemic stroke (HR 1.02, CI 0.84-1.24) or MI (HR 1.15, CI 0.92-1.43). Long-term users of PPIs, compared with nonusers, had a 29% (CI 5%-59%) greater absolute risk of ischemic stroke and a 36% (CI 7%-73%) greater risk of MI within a 6-month period. Use of PPIs was associated with increased risks of first-time ischemic stroke and MI, particularly amongst long-term users and at high doses.

Albuminuria and Risk of Cardiovascular Events and Mortality in a General Population of Patients with Type 2 Diabetes Without Cardiovascular Disease: A Danish Cohort Study

A 66-year-old man with a recent prosthetic knee infection, status post–prosthesis removal, was admitted with recurrent septic arthritis. On his seventh hospital day, as he was signing his discharge paperwork, he developed acute respiratory distress. On physical examination, he was tachycardic to 118 beats/min, relatively hypotensive from 144/78 mm Hg earlier in the day to 94/54 mm Hg, and hypoxemic, with an oxygen saturation of 94% on a 100% nonrebreather facemask. The ECG showed sinus tachycardia. An urgent contrast-enhanced chest computed tomogram (CT) demonstrated large saddle pulmonary embolism (PE) and severe right ventricular (RV) enlargement, with an RV diameter-to-left ventricular (LV) diameter ratio of 1.8 (Figure 1). The patient was administered a bolus of intravenous unfractionated heparin followed by a continuous infusion. An urgent bedside transthoracic echocardiogram showed severe RV dilation, moderate-to-severe pulmonary hypertension, and RV pressure overload as suggested by systolic deviation of the interventricular septum toward the LV (Figure 2). The Vascular Medicine and Cardiac Surgery services were consulted for consideration of advanced therapies. Because of concern for major bleeding associated with fibrinolytic therapy in the setting of recent major surgery, surgical pulmonary embolectomy was recommended. Figure 1. Contrast-enhanced chest computed tomogram (CT) demonstrating acute pulmonary embolism (PE) in a 66-year-old man who developed sudden dyspnea, severe hypoxemia, and relative hypotension. Coronal views demonstrating a large, dense filling defect straddling the bifurcation of the main pulmonary artery consistent with saddle PE ( A ) and extending into the right and left main pulmonary arteries (arrows, B ). Axial view demonstrating a right ventricular (RV) diameter of 4.8 cm in comparison with 2.6 cm for the left ventricle (LV; RV-to-LV diameter ratio of 1.8; normal <0.9) consistent with severe RV enlargement ( C ). Figure 2. Transthoracic echocardiogram, apical 4-chamber view, demonstrating right ventricular (RV) and right atrial (RA) dilation and RV pressure overload with interventricular septal …

Major Ongoing Stroke Trials

Major Ongoing Stroke Trials

Diabetes is a metabolic disorder that is diagnosed when the fasting and/or postload glucose level rises above well-established thresholds. These thresholds were chosen because they identified people at particularly high risk for retinopathy based on epidemiological data. These data also have shown that people with diabetes and poorly controlled glucose levels have higher risks of retinopathy than people with diabetes and well-controlled glucose levels.1,2 Moreover, recent studies have shown that the relationship between chronically elevated glucose levels (as measured by A1c) and retinal disease is not confined to people with diabetes and is apparent (although less marked) in people with high glucose levels that are below the diabetes cutoffs such as those with impaired glucose tolerance and/or impaired fasting glucose.3–5 Thus, there is a progressive relationship between glycemia and retinopathy that extends below glucose thresholds for diabetes. Article p 812 Clearly, diabetes also is a risk factor for many other serious chronic diseases, including cardiovascular disease.6 Indeed, a recent meta-analysis of large prospective studies comprising 450 000 people showed that men and women with diabetes are 2 and 3 times more likely, respectively, to die of coronary heart disease than men and women without diabetes.7 Other studies have shown that the degree of glucose elevation measured by A1c, fasting glucose, or postload glucose is progressively related to the incidence of cardiovascular outcomes in people with established diabetes and in people without diabetes after adjustment for age and varying numbers of other risk factors.8–15 Moreover, several studies that recruited people from both ambulatory and hospitalized settings suggest that there may be a stronger relationship between glycemia and incident cardiovascular outcomes in people without diabetes than in people with diabetes.8,9,15–17 Such a discrepancy may occur because in people with established diabetes, markers of …

Cardiovascular diseases (CVDs) are a major source of morbidity and mortality worldwide. Despite a decline of ≈30% over the past decade, heart disease remains the leading killer of Americans.1 For rare and familial forms of CVD, we are increasingly recognizing single-gene mutations that impart relatively large effects on individual phenotype. Examples include inherited forms of cardiomyopathy, arrhythmias, and aortic diseases. However, the prevalence of monogenic disorders typically accounts for a small proportion of the total CVD observed in the population. CVDs in the general population are complex diseases, with several contributing genetic and environmental factors. Although recent progress in monogenic disorders has occurred, we have seen a period of intense investigation to identify the genetic architecture of more common forms of CVD and related traits. Genomics serves several roles in cardiovascular health and disease, including disease prediction, discovery of genetic loci influencing CVD, functional evaluation of these genetic loci to understand mechanisms, and identification of therapeutic targets. For single-gene CVDs, progress has led to several clinically useful diagnostic tests, extending our ability to inform the management of afflicted patients and their family members. However, there has been little progress in developing genetic testing for complex CVD because individual common variants have only a modest impact on risk. The study of the genomics of complex CVDs is further challenged by the influence of environmental variables, phenotypic heterogeneity, and pathogenic complexity. Characterization of the clinical phenotype requires consideration of the clinical details of the diseases and traits under study. This update expands the prior scientific statement on the relevance of genetics and genomics for the prevention and treatment of CVDs.2 In the earlier report, we focused on the current status of the field, which consisted of predominantly family-based linkage studies and single-gene or mendelian mutations of relatively large phenotypic effect …

Vasculocentricity Versus Cerebrocentricity: What Stroke-Related Baroreceptor Reflex Sensitivity Changes Might Be Telling Us