Jesper K. Jensen

B-type natriuretic peptides and mortality after stroke A systematic review and meta-analysis

Objective: To measure the association of B-type natriuretic peptide (BNP) and N-terminal fragment of BNP (NT-proBNP) with all-cause mortality after stroke, and to evaluate the additional predictive value of BNP/NT-proBNP over clinical information. Methods: Suitable studies for meta-analysis were found by searching MEDLINE and EMBASE databases until October 26, 2012. Weighted mean differences measured effect size; meta-regression and publication bias were assessed. Individual participant data were used to estimate effects by logistic regression and to evaluate BNP/NT-proBNP additional predictive value by area under the receiver operating characteristic curves, and integrated discrimination improvement and categorical net reclassification improvement indexes. Results: Literature-based meta-analysis included 3,498 stroke patients from 16 studies and revealed that BNP/NT-proBNP levels were 255.78 pg/mL (95% confidence interval [CI] 105.10–406.47, p = 0.001) higher in patients who died; publication bias entailed the loss of this association. Individual participant data analysis comprised 2,258 stroke patients. After normalization of the data, patients in the highest quartile had double the risk of death after adjustment for clinical variables (NIH Stroke Scale score, age, sex) (odds ratio 2.30, 95% CI 1.32–4.01 for BNP; and odds ratio 2.63, 95% CI 1.75–3.94 for NT-proBNP). Only NT-proBNP showed a slight added value to clinical prognostic variables, increasing discrimination by 0.028 points (integrated discrimination improvement index; p < 0.001) and reclassifying 8.1% of patients into correct risk mortality categories (net reclassification improvement index; p = 0.003). Neither etiology nor time from onset to death affected the association of BNP/NT-proBNP with mortality. Conclusion: BNPs are associated with poststroke mortality independent of NIH Stroke Scale score, age, and sex. However, their translation to clinical practice seems difficult because BNP/NT-proBNP add only minor predictive value to clinical information.

Serial measurements of N-terminal pro-brain natriuretic peptide after acute ischemic stroke

Background: The exact time-course of N-terminal pro-brain natriuretic peptide (NT-proBNP) and the prognostic importance in the immediate phase of ischemic stroke have not been established. Methods: NT-proBNP was measured daily from admission to day 5 and again at 6-month follow-up in 250 consecutive patients with acute ischemic stroke. Results: NT-proBNP peaked the day after onset of symptoms (p = 0.007) followed by a decrease until day 5 (p = 0.001, ANOVA). At 6-month follow-up the difference in the level of NT-proBNP was unchanged compared to day 5 (p = 0.42). NT-proBNP levels ≧615 pg/ml at day 2 after onset of symptoms was associated with 6-month mortality. Conclusion: NT-proBNP peaks the day after onset of symptoms in patients with acute ischemic stroke. A single measurement of NT-proBNP appears to be an indicator of 6-month mortality.

Fatty Acid Binding Protein 4 Is Associated with Carotid Atherosclerosis and Outcome in Patients with Acute Ischemic Stroke

Background and Purpose Fatty acid binding protein 4 (FABP4) has been shown to play an important role in macrophage cholesterol trafficking and associated inflammation. To further elucidate the role of FABP4 in atherogenesis in humans, we examined the regulation of FABP4 in carotid atherosclerosis and ischemic stroke. Methods We examined plasma FABP4 levels in asymptomatic (n = 28) and symptomatic (n = 31) patients with carotid atherosclerosis, as well as in 202 subjects with acute ischemic stroke. In a subgroup of patients we also analysed the expression of FABP4 within the atherosclerotic lesion. In addition, we investigated the ability of different stimuli with relevance to atherosclerosis to regulate FABP4 expression in monocytes/macrophages. Results FABP4 levels were higher in patients with carotid atherosclerosis, both systemically and within the atherosclerotic lesion, with particular high mRNA levels in carotid plaques from patients with the most recent symptoms. Immunostaining of carotid plaques localized FABP4 to macrophages, while activated platelets and oxidized LDL were potent stimuli for FABP4 expression in monocytes/macrophages in vitro. When measured at the time of acute ischemic stroke, high plasma levels of FABP4 were significantly associated with total and cardiovascular mortality during follow-up, although we did not find that addition of FABP4 to the fully adjusted multivariate model had an effect on the prognostic discrimination for all-cause mortality as assessed by c-statistics. Conclusions FABP4 is linked to atherogenesis, plaque instability and adverse outcome in patients with carotid atherosclerosis and acute ischemic stroke.

Osteoprotegerin concentrations and prognosis in acute ischaemic stroke.

Abstract.  Jensen JK, Ueland T, Atar D, Gullestad L, Mickley H, Aukrust P, Januzzi JL (Odense University Hospital, Denmark; Rikshospitalet, Oslo, Norway; Massachusetts General Hospital, USA). Osteoprotegerin concentrations and prognosis in acute ischaemic stroke. J Intern Med 2010; 267: 410–417.

Early Impact of Prescription Omega-3 Fatty Acids on Platelet Biomarkers in Patients with Coronary Artery Disease and Hypertriglyceridemia

Background: Prescription omega-3-acid ethyl esters (PO-3A) have been tested for outcome benefits in patients with coronary artery disease (CAD), arrhythmias and heart failure. Some evidence suggests that PO-3A may exert their benefit via inhibiting platelets. We tested the hypothesis that PO-3A may inhibit platelet activity in patients with documented stable CAD, beyond the antiplatelet properties of aspirin and statins. Methods: Thirty patients with documented CAD and triglycerides over 250 mg/dl treated with aspirin (70–160 mg/daily) and statins (simvastatin equivalence dose: 5–40 mg/daily) were randomized 1:1:1 to Omacor™ 1 g/day (DHA/EPA ratio 1.25:1.0), Omacor 2 g/day, or a placebo for 2 weeks. Platelet tests including aggregometry and flow cytometry and cartridge analyzer readings were performed at baseline and at 1 and 2 weeks following PO-3A therapy. Results: ADP-induced platelet aggregation (p = 0.037), GP IIb/IIIa antigen (p = 0.031) and activity (p = 0.024), and P-selectin (p = 0.041) were significantly reduced after PO-3A, while platelet/endothelial cell adhesion molecule (p = 0.09), vitronectin receptor (p = 0.16), formation of platelet-monocyte microparticles (p = 0.19) and the VerifyNow IIb/IIIa test (p = 0.27) only exhibited nonsignificant trends suggestive of reduced platelet activity. Finally, collagen- and arachidonic acid-induced aggregation, closure time with the PFA-100 device and expression of thrombospondin (CD36), GP Ib (CD42b), LAMP-3 (CD63), LAMP-1 (CD107a), CD40-ligand (CD154), GP37 (CD165), and PAR-1 receptor intact (SPAN 12) and cleaved (WEDE-15) epitopes were not affected by 2 weeks of PO-3A. Conclusion: Independently of the dose and already at 1 week, short-term therapy with PO-3A provided a modest reduction of platelet activity biomarkers, despite concomitant aspirin and statin therapy, when compared to a placebo. The effect of PO-3A is unique, differs from other known antiplatelet agents and suggests potential pleiotropism. These preliminary randomized data call for confirmation in prospective studies.

Comparison of Usefulness of Exercise Testing Versus Coronary Computed Tomographic Angiography for Evaluation of Patients Suspected of Having Coronary Artery Disease

In patients suspected of having coronary artery disease (CAD), we compared the diagnostic sensitivity and specificity of exercise testing using ST-segment changes alone and ST-segment changes, angina pectoris, and hemodynamic variables compared to coronary computed tomographic angiography (CTA). Quantitative invasive coronary angiography was the reference method (>50% coronary lumen reduction). A positive exercise test was defined as the development of significant ST-segment changes (> or =1 mV measured 80 ms from the J-point), and the occurrence of one or more of the following criteria: ST-segment changes > or =1 mV measured 80 ms from the J-point, angina pectoris, ventricular arrhythmia (the occurrence of > or =3 premature ventricular beats), and > or =20 mm Hg decrease in systolic blood pressure during the test. Positive results on CTA were defined as a coronary lumen reduction of > or =50%. In 100 patients (61 +/- 9 years old, 50% men, and 29% prevalence of significant CAD), the diagnostic sensitivity and specificity of exercise testing using ST-segment changes was 45% (95% confidence interval 53% to 87%) and 63% (95% confidence interval 61% to 84%), respectively. However, the inclusion of all test variables yielded a sensitivity of 72% (95% confidence interval 53% to 87%) and a specificity of 37% (95% confidence interval 26% to 49%). The diagnostic sensitivity of 97% (95% confidence interval 82% to 100%) and specificity of 80% (95% confidence interval 69% to 89%) for CTA, however, were superior to any of the exercise test analysis strategies. In conclusion, in patients suspected of having CAD, the diagnostic sensitivity of exercise testing significantly improves if all test variables are included compared to using ST-segment changes exclusively. Furthermore, the superior diagnostic performance of CTA for the detection and exclusion of significant CAD might favor CTA as the first-line diagnostic test in patients suspected of having CAD.

Soluble CXCL16 and long-term outcome in acute ischemic stroke

OBJECTIVE CXCL16 is a chemokine involved in atherosclerosis by promoting inflammation, lipid accumulation and matrix degradation. The level of circulating CXCL16 has been proposed as a predictor of long-term mortality in acute coronary syndromes. We studied plasma CXCL16 in acute ischemic stroke and examined associations with long-term mortality following the acute event. METHODS CXCL16 samples were obtained from 244 patients with acute ischemic stroke (age: 69±13 years) daily from presentation to day 5 and at half a year after the stroke. Patients with overt ischemic heart disease and atrial fibrillation were excluded. The patients were followed for 47 months, with all-cause and cardiovascular (CV) mortality as end-points. RESULTS At follow-up, 72 patients had died with 43 due to CV causes. Plasma CXCL16 was stably elevated in the first days after the acute event followed by a marked decrease after 6 months. In patients who subsequently suffered an adverse outcome, CXCL16 levels at 4 days after the initial event were elevated and were moderately associated with mortality. The increase in CXCL16 from day 1 to 4 was a predictor for all-cause and, in particular, CV mortality even after adjustment in the multivariate analysis for established risk factors such as age, the presence of heart/renal failure, troponin, C-reactive protein and stroke severity. CONCLUSIONS An increase in plasma CXCL16 during the first days after the initial event is associated with an adverse outcome in patients with acute ischemic stroke, supporting the potential pathogenic role of CXCL16 in atherosclerosis and vascular remodelling as well as their major clinical consequences.

Usefulness of Natriuretic Peptide Testing for Long-Term Risk Assessment Following Acute Ischemic Stroke

Acute-phase levels of B-type natriuretic peptide (BNP) and the N-terminal fragment of the BNP prohormone (NT-pro-BNP) have been associated with mortality when measured in patients with an acute ischemic stroke; however, data regarding the longer-term value of NT-pro-BNP for long-term prognostication after ischemic stroke are limited. Two hundred sixteen patients (mean age 67 +/- 13 years) with acute ischemic stroke were seen 6 months after index admission at which time a structured evaluation including measurement of plasma NT-pro-BNP was performed. Patients were followed for 45 months, with all-cause mortality as the clinical end point. Median NT-pro-BNP concentration for the entire group was 147 pg/ml (10th to 90th percentiles 37 to 869). At follow-up 45 patients (21%) had died. NT-pro-BNP concentrations were significantly higher in decedents (308 pg/ml, 10th to 90th percentiles 74 to 2,279) than in the 171 survivors (132 pg/ml, 10th to 90th percentiles 35 to 570, p <0.001). Patients with NT-pro-BNP < or =147 pg/ml had a significantly improved survival rate on univariate analysis (p <0.001). In multivariate analysis after adjustment for age, stroke severity, heart and renal failures, levels of NT-pro-BNP were an independent predictor of mortality >6 months after stroke (adjusted hazard ratio 1.5, 95% confidence interval 1.1 to 1.9, p = 0.005). In conclusion, NT-pro-BNP concentrations measured during the stable phase after acute ischemic stroke are strongly predictive of long-term mortality.

Highly Sensitive Troponin T in Patients with Acute Ischemic Stroke

Background: Newly developed troponin assays have superior diagnostic and prognostic performance in acute coronary syndrome (ACS), when compared to conventional troponin assays; however, highly sensitive troponin has not been evaluated in patients with acute ischemic stroke. Methods: Highly sensitive troponin T (hsTnT) was measured daily during the first 4 days in 193 consecutive patients with acute ischemic stroke without overt ACS or atrial fibrillation. The patients were previously tested normal with a fourth-generation TnT assay. The patients were followed for 47 months, with all-cause and cardiovascular mortality end-points. Results: A total of 33.7% of the patients had hsTnT levels >14 ng/l following admission. Patients with increased hsTnT were older, had decreased hemoglobin levels and increased creatinine, NT-proBNP and CRP levels. hsTnT concentrations at admission were significantly higher in decedents than in survivors. After adjustment for stroke severity, C-reactive protein, age, NT-proBNP and prior heart and/or renal failure, hsTnT levels were not a significant predictor of long-term all-cause or cardiovascular mortality. Conclusion: Elevated levels of hsTnT are frequently present in patients with acute ischemic stroke previously tested normal with a fourth-generation TnT assay. hsTnT did not provide additional prognostic information in these subjects.

Activated Leukocyte Cell Adhesion Molecule and Prognosis in Acute Ischemic Stroke

Background and Purpose— Biomarkers predicting mortality and functional outcome in stroke may be clinically helpful in identification of patients likely to benefit from intervention. Activated leukocyte cell adhesion molecule (ALCAM) is upregulated during neuroinflammation; we investigated whether ALCAM concentrations are associated with long-term mortality after ischemic stroke. Methods— In 244 patients with acute ischemic stroke (age 69±13 years), samples of ALCAM were obtained serially from presentation to Day 5 and after 6 months. Patients with overt ischemic heart disease and atrial fibrillation were excluded. The patients were followed for 47 months with all-cause and cardiovascular mortality as end points. Results— At follow-up, 72 patients (29%) had died, 43 due to cardiovascular causes. Patients with ALCAM in the fourth quartile (>46.8 ng/mL) at admission had a significantly poorer survival rate on univariate analysis (P<0.001); other time points did not add further but provided similar prognostic information. In multivariate analysis, after adjustment for age, stroke severity, C-reactive protein levels, troponin T levels, and heart and/or renal failure, ALCAM levels above the fourth quartile remained an independent predictor of long-term mortality (adjusted hazard ratio, 2.05; 95% CI, 1.11 to 3.76; P=0.021) and cardiovascular mortality (adjusted hazard ratio, 2.54; 95% CI, 1.06 to 6.07; P=0.028). Conclusions— ALCAM levels measured at admission of acute ischemic stroke are associated with long-term mortality.