Nira Koren-Morag

Markers of increased risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke in clinical practice: The multicenter rt-PA acute stroke survey

Background—Intravenous recombinant tissue plasminogen activator (rtPA) is an effective therapy for acute ischemic stroke, but it is associated with risk of intracerebral hemorrhage (ICH). Our aim was to identify, in a large cohort of patients, readily available baseline factors that are associated with thrombolysis-related ICH. Methods and Results—In a multicenter retrospective and prospective investigation of individual data from 1205 patients treated in routine clinical practice with intravenous rtPA within 3 hours of stroke symptom onset, 72 patients (6%) developed symptomatic ICH and 86 additional patients (7%) had asymptomatic ICH identified on a routine follow-up CT. In analyses based on clinical variables alone, the main attributes associated with ICH were a history of diabetes mellitus and cardiac disease, increasing stroke severity, advancing age, use of antiplatelet agents other than aspirin before stroke onset, and elevated pretreatment mean blood pressure. In additional analyses that incorporated baseline CT and laboratory findings (in a subset of patients), the main associations were early ischemic CT changes, in particular if exceeding one third of middle cerebral artery territory; increasing stroke severity; diabetes mellitus or elevated serum glucose; and lower platelet counts. Final independent attributes associated with parenchymatous hematoma, defined by purely radiologically based criteria, were similar to those of symptomatic ICH. Conclusions—Readily available factors can identify acute ischemic stroke patients at high and low risk for rtPA-related ICH. These factors require confirmation in a prospective cohort before clinical implementation.

Reduced incidence of ischemic stroke in patients with severe factor XI deficiency.

Inherited disorders of hemostasis are natural models for investigating mechanisms of thrombosis and development of antithrombotic therapy. Because mice with total factor XI deficiency are protected against ischemic stroke and do not manifest excessive bleeding, we investigated the incidence of ischemic stroke in patients with severe inherited factor XI deficiency. Incidence of ischemic stroke in 115 patients aged 45 years or more with severe factor XI deficiency (activity less than 15 U/dL) was compared with incidence in the Israeli population as estimated from a stroke survey of 1528 patients. Adjustment for major risk factors of stroke (hypertension, diabetes mellitus, hypercholesterolemia, current smoking) was based on comparison of their prevalence in the stroke survey to an Israeli health survey of 9509 subjects. Incidence of myocardial infarction in the factor XI cohort was also recorded. After adjustment for the 4 major risk factors of ischemic stroke, the expected incidence of ischemic stroke was 8.56 compared with one observed (P = .003). The reduced 1:115 incidence of ischemic stroke contrasted with a 19:115 incidence of myocardial infarction, similar to the expected incidence. Thus, severe factor XI deficiency probably is protective against ischemic stroke but not against acute myocardial infarction.

Long-term association of brachial artery flow-mediated vasodilation and cardiovascular events in middle-aged subjects with no apparent heart disease

BACKGROUND Endothelial dysfunction is considered an important prognostic factor in atherosclerosis. The aim of this study was to detect the long-term association of peripheral vascular endothelial function and clinical outcome in healthy subjects without apparent coronary artery disease (CAD). METHODS We prospectively assessed brachial flow-mediated dilation (FMD) in 435 consecutive healthy subjects: 281 (65%) men, mean age 54+/-12 years and body mass index 28+/-4 kg/m(2). After overnight fasting and discontinuation of all medications for > or =12 h, FMD and endothelium-independent nitroglycerin-mediated vasodilation were assessed using high resolution linear array ultrasound. RESULTS Subjects were divided into 2 groups: below (n=221) and above (n=214) the median FMD of 10.7%, and were comparable regarding CAD risk factors, lipoproteins, fasting glucose, C-reactive protein, and concomitant medications, with a mean clinical follow-up of 32+/-2 months. Composite cardiovascular endpoints (all-cause mortality, non-fatal myocardial infarction, heart failure or angina pectoris hospitalization, stroke, coronary artery bypass grafting and percutaneous coronary interventions) were significantly more common in subjects with below median FMD of 10.7%, than above (11.8% vs 4.7%, p=0.007, respectively). Univariate analysis demonstrated that median FMD significantly predicted cardiovascular events [odds ratio (OR) of 2.78 and 95% CI 1.35 to 5.71 (p=0.003)]. After multivariate analysis including conventional CAD risk factors, median FMD was the best independent predictor of long-term cardiovascular adverse events [OR of 2.70 and 95% CI 1.16 to 6.32 (p=0.011)]. CONCLUSIONS Brachial artery median FMD independently predicts long-term adverse cardiovascular events in healthy subjects in addition to traditional risk factor assessment.

Relation Between the Metabolic Syndrome and Ischemic Stroke or Transient Ischemic Attack A Prospective Cohort Study in Patients With Atherosclerotic Cardiovascular Disease

Background and Purpose— The combination of risk factors known as the metabolic syndrome is receiving increased attention, but prospective data on the syndromes association with ischemic cerebrovascular events are scarce. We explored the relation of metabolic syndrome versus frank diabetes with first-ever ischemic stroke or transient ischemic attack (TIA) in a large cohort of patients with atherosclerotic cardiovascular disease. Methods— Patients with coronary heart disease, screened for a clinical trial, underwent an extensive medical evaluation and follow-up for cerebrovascular disease over 4.8 to 8.1 years. National Cholesterol Education Program Adult Treatment Panel III criteria were used to define the metabolic syndrome, with body mass index substituted for waist circumference. Patients with previously diagnosed diabetes or with a fasting plasma glucose level >125 mg/dL (≥7.0 mmol/L) were considered diabetic. Results— The study sample comprised 14 284 patients, of which 3703 (26%) fulfilled the criteria for the metabolic syndrome without diabetes and 3500 others (25%) the criteria for diabetes. Adjusting for stroke risk factors, patients with the metabolic syndrome without diabetes exhibited a 1.49-fold increased odds for ischemic stroke or TIA (95% confidence interval [CI], 1.20 to 1.84), whereas those with frank diabetes had a 2.29-fold increased odds (95% CI, 1.88 to 2.78). The relative odds for ischemic stroke or TIA, associated with presence of the metabolic syndrome per se, were 1.39 (95% CI, 1.10 to 1.77) in men but 2.10 (95% CI, 1.26 to 3.51) in women. Although all components of the metabolic syndrome were associated with increased risk for ischemic stroke or TIA, impaired fasting glucose and hypertension were the strongest predictors of risk. Conclusions— The presence of the metabolic syndrome, even without diabetes, in patients with pre-existing atherosclerotic vascular disease identifies patients at increased risk for ischemic stroke or TIA. The suggestion of more pronounced risk associated with the metabolic syndrome in women deserves further assessment in other cohorts.

Renal dysfunction and risk of ischemic stroke or TIA in patients with cardiovascular disease

Background: Mild renal insufficiency is increasingly recognized as an independent risk factor for cardiovascular disease. However, few data exist regarding its relation to risk of ischemic stroke. Methods: Patients with chronic coronary heart disease and measured serum creatinine levels (n = 6,685) were followed up for incident ischemic stroke or TIA over 4.8 to 8.1 years. Glomerular filtration rate was estimated by the Cockroft-Gault equation and by the four-component Modification of Diet in Renal Disease (MDRD) equation and a rate ≤60 mL/minute/1.73 m2 defined chronic kidney disease (CKD). Results: Among 6,685 patients, a quarter of patients had CKD. Adjusting for conventional risk factors and related medications, patients with CKD exhibited 1.54-fold hazard ratios (95% CI 1.13 to 2.09) of incident ischemic stroke or TIA by the Cockroft-Gault equation (1.53; 95% CI 1.16 to 2.01 by the MDRD equation). The corresponding adjusted hazard ratio associated with an increment of 1 SD in GFR was 0.71 (95% CI 0.57 to 0.88) when estimated by the Cockroft-Gault equation (0.84; 95% CI 0.75 to 0.95 estimated by the MDRD equation). Conclusions: Mild degrees of renal dysfunction are associated with increased risk of incident ischemic stroke or TIA in patients with pre-existing atherothrombotic disease. These findings expand the recommendation that patients with renal dysfunction should be considered as a high-risk group for cardiovascular disease and for ischemic stroke.

Calcification of the Thoracic Aorta as Detected by Spiral Computed Tomography Among Stable Angina Pectoris Patients. Association With Cardiovascular Events and Death

Background— Calcification of the thoracic aorta is associated with atherosclerotic risk factors, yet its pathogenesis and clinical implications are not yet elucidated. The goal of the present study was to assess whether thoracic aorta calcification is associated with an increased risk of cardiovascular events and death in patients with stable angina pectoris. Methods and Results— A prospective cohort of 361 stable angina pectoris patients (307 men, 54 women; age range, 37 to 83 years) underwent chest spiral computed tomography and were evaluated for aortic calcification. We recorded the incidence of cardiovascular events and death during a 4.5- to 6-year follow-up. Aortic calcification was documented in 253 patients (70% of patients; 213 men, 40 women). Patients with aortic calcification were older (mean age, 65±7 versus 55±9 years; P<0.001), and fewer were classified as smokers (13% versus 26%; P=0.014) compared with patients without aortic calcification. Significant correlation was found between patients with and those without aortic calcification for the presence of aortic valve calcification (28% versus 11%; P<0.001), mitral annulus calcification (29% versus 4%; P<0.001), and coronary calcification as expressed by coronary calcium score. (P<0.001). During 4.5 to 6 years of follow-up, 19 patients died, all of whom were in the aortic calcification group. Age-adjusted hazard ratios for total events and cardiovascular events by aortic calcification were 2.84 (95% CI, 1.52 to 5.30; P=0.001) and 2.70 (95% CI, 1.33 to 5.47; P=0.006), respectively. In multivariable analysis, hazard ratios for total events and cardiovascular events were 2.79 (95% CI, 1.46 to 5.20; P=0.002) and 4.65 (95% CI, 1.19 to 18.26; P=0.028), respectively. Conclusions— Calcification of the thoracic aorta is age related and associated with coronary calcification and valvular calcification. Thoracic aortic calcification is associated with an increased risk of death and cardiovascular disease.

Fasting Plasma Glucose and Risk of Incident Ischemic Stroke or Transient Ischemic Attacks A Prospective Cohort Study

Background and Purpose— Diabetes and impaired fasting glucose are diagnosed based on an elevated plasma glucose level after an overnight fast. The diagnostic cutpoint of diabetes arises from the threshold for development of microvascular complications. Our aim was to examine the associations between clinical relevant categories of fasting glucose levels and the risk of incident ischemic stroke. Methods— Patients with documented coronary heart disease who were screened for inclusion in a secondary prevention clinical trial (n=13 999) were followed-up. At baseline, medical histories were obtained and plasma glucose and lipids assessed at a central study laboratory. During a 6- to 8-year follow-up period 1037 cases were identified with ischemic cerebrovascular disease, of which, after reviewing hospital records with diagnoses of cerebrovascular disease, 576 cases were verified to have had ischemic stroke or transient ischemic attacks. Results— Increasing fasting glucose level categories were positively associated with increasing age, male gender, body mass index, hypertension, total cholesterol, and triglycerides, and were inversely associated with high-density lipoprotein cholesterol and percent high-density lipoprotein of total cholesterol. In comparison with patients with fasting glucose levels of 90 to 99 mg/dL (n=3706) who constitute the largest category, the odds ratios of ischemic cerebrovascular disease, adjusting for potential confounders, were 1.47 (95% CI, 1.07 to 2.02) for fasting glucose <80, 1.22 (0.98 to 1.52) for 80 to 89, 1.27 (1.02 to 1.60) for 100 to 109, 1.60 (1.26 to 2.03) for 110 to 125, 1.82 (1.33 to 2.49) for 126 to 140, and 2.82 (2.32 to 3.43) for >140 mg/dL. Similar J-shaped associations were observed in analysis excluding patients with known diagnosis of diabetes mellitus. Conclusions— The association between fasting plasma glucose and incident ischemic cerebrovascular events in patients with pre-existing atherothrombotic disease is J-shaped. Rates increase for fasting plasma glucose levels >100 mg/dL and also for those with low fasting glucose levels. These findings may carry important implications for prevention strategies.

Usefulness of brachial artery flow-mediated dilation to predict long-term cardiovascular events in subjects without heart disease.

Endothelial dysfunction is considered an important prognostic factor in atherosclerosis. To determine the long-term association of brachial artery flow-mediated dilation (FMD) and adverse cardiovascular (CV) events in healthy subjects, we prospectively assessed brachial FMD in 618 consecutive healthy subjects with no apparent heart disease, 387 men (63%), and mean age 54 ± 11 years. After overnight fasting and discontinuation of all medications for ≥12 hours, FMD was assessed using high-resolution linear array ultrasound. Subjects were divided into 2 groups: FMD ≤11.3% (n = 309) and >11.3% (n = 309), where 11.3% is the median FMD, and were comparable regarding CV risk factors, lipoproteins, fasting glucose, C-reactive protein, concomitant medications, and Framingham 10-year risk score. In a mean clinical follow-up of 4.6 ± 1.8 years, the composite CV events (all-cause mortality, nonfatal myocardial infarction, hospitalization for heart failure or angina pectoris, stroke, coronary artery bypass grafting, and percutaneous coronary interventions) were significantly more common in subjects with FMD ≤11.3% rather than >11.3% (15.2% vs 1.2%, p = 0.0001, respectively). Univariate analysis demonstrated that the median FMD significantly predicted CV events (odds ratio 2.78, 95% CI 1.35 to 5.71, p <0.001). Multivariate analysis, controlling for traditional CV risk factors, demonstrated that median FMD was the best independent predictor of long-term CV adverse events (odds ratio 2.93, 95% CI 1.28 to 6.68, p <0.001). In conclusion, brachial artery median FMD independently predicts long-term adverse CV events in healthy subjects with no apparent heart disease in addition to those derived from traditional risk factor assessment.

Systemic dysregulation of CEACAM1 in melanoma patients.

It was previously shown that CEACAM1 on melanoma cells strongly predicts poor outcome. Here, we show a statistically significant increase of serum CEACAM1 in 64 active melanoma patients, as compared to 48 patients with no evidence of disease and 37 healthy donors. Among active patients, higher serum CEACAM1 correlated with LDH values and with decreased survival. Multivariate analysis with neutralization of LDH showed that increased serum CEACAM1 carries a hazard ratio of 2.40. In vitro, soluble CEACAM1 was derived from CEACAM1(+), but neither from CEACAM1(−) melanoma cells nor from CEACAM1(+) lymphocytes, and directly correlated with the number of CEACAM1(+) melanoma cells. Production of soluble CEACAM1 depended on intact de novo protein synthesis and secretion machineries, but not on metalloproteinase function. An unusually high percentage of CEACAM1(+) circulating NK and T lymphocytes was demonstrated in melanoma patients. CEACAM1 inhibited killing activity in functional assays. CEACAM1 expression could not be induced on lymphocytes by serum from patients with high CEACAM1 expression. Further, expression of other NK receptors was impaired, which collectively indicate on a general abnormality. In conclusion, the systemic dysregulation of CEACAM1 in melanoma patients further denotes the role of CEACAM1 in melanoma and may provide a basis for new tumor monitoring and prognostic platforms.

Impact of Acute Caffeine Ingestion on Endothelial Function in Subjects With and Without Coronary Artery Disease

Although coffee is a widely used, pharmacologically active beverage, its impact on the cardiovascular system is controversial. To explore the effect of acute caffeine ingestion on brachial artery flow-mediated dilation (FMD) in subjects without coronary artery disease (CAD; controls) and patients with CAD, we prospectively assessed brachial artery FMD in 40 controls and 40 age- and gender-matched patients with documented stable CAD on 2 separate mornings 1 week to 2 weeks apart. After overnight fasting, discontinuation of all medications for ≥12 hours, and absence of caffeine for >48 hours, participants received capsules with caffeine 200 mg or placebo. One hour after drug ingestion, participants underwent brachial artery FMD and nitroglycerin-mediated dilation (NTG) using high-resolution ultrasound. As expected, patients with CAD were more often diabetic, hypertensive, obese, dyslipidemic, and smoked more than controls (p <0.01 for all comparisons). Aspirin, Clopidogrel, angiotensin-converting enzyme inhibitors, β blockers, and statins were significantly more common in patients with CAD than in controls (p <0.01 for all comparisons). At baseline, FMD, but not NTG, was significantly lower in patients with CAD compared to controls. Acute caffeine ingestion significantly increased FMD (patients with CAD 5.6 ± 5.0% vs 14.6 ± 5.0%, controls 8.4 ± 2.9% vs 18.6 ± 6.8%, p <0.001 for all comparisons) but not NTG (patients with CAD 13.0 ± 5.2% vs 13.8 ± 6.1%, controls 12.9 ± 3.9% vs 13.9 ± 5.8%, p = NS for all comparisons) and significantly decreased high-sensitivity C-reactive protein (patients with CAD 2.6 ± 1.4 vs 1.4 ± 1.2 mg/L, controls 3.4 ± 3.0 vs 1.2 ± 1.0 mg/L, p <0.001 for all comparisons) in the 2 groups compared to placebo. In conclusion, acute caffeine ingestion significantly improved endothelial function assessed by brachial artery FMD in subjects with and without CAD and was associated with lower plasma markers of inflammation.