Claudia Dellas

Fibrinolysis for patients with intermediate-risk pulmonary embolism

BACKGROUND The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. METHODS In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. RESULTS Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P=0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42). CONCLUSIONS In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. (Funded by the Programme Hospitalier de Recherche Clinique in France and others; PEITHO EudraCT number, 2006-005328-18; ClinicalTrials.gov number, NCT00639743.).

Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease

Although plasminogen activator inhibitor 1 (PAI-1) is one of the primary regulators of the fibrinolytic system, it also has dramatic effects on cell adhesion, detachment and migration. PAI-1 also differs from other serine protease inhibitors (serpins) in that it is a trace protein in plasma, it has a short half-life in vivo, its synthesis is highly regulated, and it binds to the adhesive glycoprotein vitronectin (VN) with high affinity and specificity. These unique and diverse properties of PAI-1 probably account for the many observations in the literature that correlate abnormalities in PAI-1 gene expression with a variety of pathological conditions. In this review, we discuss the discovery, origin, properties and regulation of PAI-1, and then speculate about its potential role in vascular disease, fibrosis, obesity and the metabolic syndrome, and cancer.

Highly sensitive troponin T assay in normotensive patients with acute pulmonary embolism

AIMS To assess the role of cardiac troponin T (cTnT) levels on admission using a new, highly sensitive assay (hsTnT) in the risk assessment of normotensive patients with acute pulmonary embolism (PE). METHODS AND RESULTS We prospectively studied 156 consecutive normotensive patients with confirmed PE. The prognostic value of hsTnT at baseline was compared with the conventional cTnT troponin assay and with N-terminal pro-brain natriuretic peptide concentrations. Long-term follow-up was available for 153 patients (98.1%). Highly sensitive troponin T values ranged from 0.001 to 357.2 pg/mL [median 27.2 (25th-75th percentile 9.4-69.4) pg/mL]. Overall, 100 patients (64%) had hsTnT > or =14 pg/mL. Baseline hsTnT was higher in patients with an adverse 30-day outcome (> or =1: death, need for catecholamines, endotracheal intubation, or cardiopulmonary resuscitation) compared with an uncomplicated course [71.7 (35.5-117.9) vs. 26.4 (9.2-68.2) pg/mL; P = 0.027]. The cut-off value of 14 pg/mL showed an excellent prognostic sensitivity and negative predictive value (both 100%). In comparison, as many as 50% of the patients with an adverse early outcome would have been misclassified as low risk by cTnT (cut-off 0.03 ng/mL). Logistic regression indicated a two-fold increase in the risk of an adverse outcome for each increase of hsTnT by 1SD of the natural logarithm (P = 0.037). Patients with elevated hsTnT levels had a reduced probability of long-term survival (P = 0.029 by log-rank); by Coxs regression analysis, hsTnT was the only laboratory biomarker predicting an elevated risk of death over the long term. CONCLUSION Highly sensitive troponin T assays may be capable of improving risk stratification of non-high-risk PE.

Predictive Value of the High-Sensitivity Troponin T Assay and the Simplified Pulmonary Embolism Severity Index in Hemodynamically Stable Patients With Acute Pulmonary Embolism A Prospective Validation Study

Background— The new, high-sensitivity troponin T (hsTnT) assay may improve risk stratification of normotensive patients with acute pulmonary embolism (PE). We externally validated the prognostic value of hsTnT, and of the simplified Pulmonary Embolism Severity Index (sPESI), in a large multicenter cohort. Methods and Results— We prospectively examined 526 normotensive patients with acute PE; of those, 31 (5.9%) had an adverse 30-day outcome. The predefined hsTnT cutoff value of 14 pg/mL was associated with a high prognostic sensitivity and negative predictive value, comparable to those of the sPESI. Both hsTnT ≥14 pg/mL (OR, 4.97 [95% CI, 1.71–14.43]; P=0.003) and sPESI ≥1 point(s) (OR, 9.51 [2.24–40.29]; P=0.002) emerged, besides renal insufficiency (OR, 2.97 [1.42–6.22]; P=0.004), as predictors of early death or complications; in a multivariable model, they remained independent predictors of outcome (P=0.044 and 0.012, respectively). A total of 127 patients (24.1%) were identified as low risk by a sPESI of 0 and hsTnT <14 pg/mL; none of them had an adverse 30-day outcome. During 6-month follow-up, 52 patients (9.9%) died. Kaplan-Meier analysis illustrated that patients with hsTnT ≥14 pg/mL (P=0.001) and those with sPESI ≥1 (P<0.001) had a decreased probability of 6-month survival. Patients with sPESI of 0 and hsTnT <14 pg/mL at baseline had a 42% reduction in the risk of dying (hazard ratio, 0.58 [0.01–0.42]; P=0.005). Conclusions— The hsTnT assay and the sPESI improve risk stratification of acute PE. Combination of both modalities may yield additive prognostic information and particularly identify possible candidates for out-of-hospital treatment.

Growth Differentiation Factor-15 for Prognostic Assessment of Patients with Acute Pulmonary Embolism

RATIONALE Growth differentiation factor (GDF)-15 is a cytokine induced in the heart after ischemia or pressure overload. Circulating levels of GDF-15 provide independent prognostic information in patients with acute coronary syndromes or heart failure. OBJECTIVES We investigated the prognostic value of GDF-15 in acute pulmonary embolism. METHODS In a prospective cohort study, plasma levels of GDF-15 were determined by immunoradiometric assay in 123 consecutive patients with confirmed acute pulmonary embolism. MEASUREMENTS AND MAIN RESULTS GDF-15 concentrations on admission ranged from 553 to 47,274 ng/L; 101 patients (82%) had GDF-15 levels above the upper limit of normal (1,200 ng/L). Patients who experienced pulmonary embolism-related complications during the first 30 days had higher baseline levels of GDF-15 (median, 6,039 [25th to 75th percentiles, 2,778 to 19,772] ng/L) compared with those with an uncomplicated course (median, 2,036 [25th to 75th percentiles, 1,279 to 3,176] ng/L; P < 0.001). By multivariable logistic regression analysis, which included clinical characteristics, cardiac biomarkers (troponin T and NT-proBNP [N-terminal propeptide of B-type natriuretic peptide]), and echocardiographic findings, GDF-15 emerged as an independent predictor of a complicated 30-day outcome (P = 0.033). The c-statistic for GDF-15 was 0.84 (95% confidence interval, 0.76-0.90), as compared with 0.72 for cardiac troponin T, and 0.65 for NT-proBNP. The ability of troponin T, NT-proBNP, and echocardiographic findings of right ventricular dysfunction to predict the risk of a complicated 30-day outcome was enhanced by GDF-15. Furthermore, multivariable Cox regression identified baseline levels of GDF-15 as an independent predictor of long-term mortality (P < 0.001). CONCLUSIONS GDF-15 is a promising new biomarker for risk stratification of pulmonary embolism.

Elevated heart-type fatty acid-binding protein levels on admission predict an adverse outcome in normotensive patients with acute pulmonary embolism.

OBJECTIVES We assessed the predictive value of heart-type fatty acid-binding protein (H-FABP) in normotensive patients with acute pulmonary embolism (PE). BACKGROUND Risk stratification of initially normotensive patients with PE on the basis of right ventricular dysfunction or injury remains controversial. Previous studies investigating biomarkers or imaging modalities included unselected patients, some of whom presented with cardiogenic shock. METHODS We included 126 consecutive normotensive patients with confirmed PE. Complicated 30-day outcome was defined as death, resuscitation, intubation, or use of catecholamines. Long-term survival was assessed by follow-up clinical examination. RESULTS During the first 30 days, 9 (7%) patients suffered complications. These patients had higher baseline H-FABP values (median, 11.2 ng/ml [interquartile range: 8.0 to 36.8 ng/ml]) compared with patients with an uncomplicated course (3.4 ng/ml [2.1 to 4.9 ng/ml]; p < 0.001). H-FABP values were above the calculated (by receiver operating characteristic curve analysis) cutoff value of 6 ng/ml in 29 patients. Eight (28%) of them suffered complications versus 1 of 97 patients with low H-FABP (negative predictive value, 99%; p < 0.001). By logistic regression, elevated (> or =6 ng/ml) H-FABP was associated with a 36.6-fold increase in the death or complication risk. The combination of H-FABP with tachycardia was a particularly useful prognostic indicator. H-FABP also predicted long-term mortality over 499 (interquartile range: 204 to 1,166) days (hazard ratio: 3.6; 95% confidence interval: 1.6 to 8.2; p = 0.003). CONCLUSIONS The H-FABP might be a useful biomarker for risk stratification of normotensive patients with acute PE.

Inhibition of Endogenous Leptin Protects Mice From Arterial and Venous Thrombosis

Objective—Human obesity is associated with an increased risk for arterial and venous thrombosis and with elevated levels of leptin in the blood. Leptin administration promotes arterial thrombosis in mice, and leptin-deficient ob/ob mice have an attenuated thrombotic response to injury. Thus, endogenous leptin may regulate arterial and venous thrombosis in vivo. Experiments were performed to test this hypothesis. Methods and Results—A leptin-neutralizing antibody was administered intravenously into wild-type mice 15 minutes before carotid artery injury with ferric chloride. The antibody-treated mice demonstrated prolonged times to thrombotic occlusion and formed unstable, embolizing thrombi. Thus, inhibiting leptin converted the thrombotic phenotype of wild-type mice into one that closely resembled that of ob/ob mice. The effect of leptin inhibition on venous thrombosis and pulmonary embolism was also investigated. Injection of a mixture of collagen and epinephrine into the jugular vein induced fatal pulmonary embolism in >90% of the control wild-type mice but in <40% of their antibody-treated counterparts. Histological analysis revealed that the antibody significantly reduced the number of occlusive thrombi in the pulmonary vessels. Conclusions—Inhibition of circulating leptin protects against arterial and venous thrombosis in mice and possibly in hyperleptinemic obese individuals.

Different Mechanisms of Increased Luminal Stenosis After Arterial Injury in Mice Deficient for Urokinase- or Tissue-Type Plasminogen Activator

Background—Tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) are thought to play critical roles in vascular remodeling after injury, with tPA mediating intravascular clot lysis and uPA modulating cell migration within the vessel wall. In human vascular disease, however, thrombus organization and neointimal formation are closely interrelated processes. This study examines the differential roles of tPA and uPA in these processes in mice. Methods and Results—Carotid artery injury and thrombosis were induced in wild-type (WT), uPA-deficient (uPA−/−), and tPA-deficient (tPA−/−) mice with the use of ferric chloride. The expression of uPA and tPA was significantly upregulated in the vessel wall of WT mice 1 week after injury, and compared with WT mice, uPA−/− and tPA−/− mice had lower carotid patency rates after injury. At 3 weeks, only 55% of uPA−/− mouse vessels were patent compared with 81% in tPA−/− mice and 100% in WT mice (P =0.014). Morphometric analysis of injured arterial segments revealed severe luminal stenosis (62±28%) in uPA−/− mice compared with their tPA−/− (16±12%) and WT (6.3±3.6%, P <0.001) counterparts. Moreover, although the vascular walls of WT mice and, particularly, tPA−/− mice developed a cell-rich multilayered neointima and media, the lumen of uPA−/− vessels remained obstructed with acellular unorganized thrombotic material, and their medial areas did not expand. Conclusions—These results indicate that the roles of uPA and tPA in the arterial response to injury are different and more complex than previously assumed and emphasize the critical role of thrombus organization and resolution in neointimal formation and vascular pathology.

Validation of N-terminal pro-brain natriuretic peptide cut-off values for risk stratification of pulmonary embolism

The optimal N-terminal pro-brain natriuretic peptide (NT-proBNP) cut-off value for risk stratification of pulmonary embolism remains controversial. In this study we validated and compared different proposed NT-proBNP cut-off values in 688 normotensive patients with pulmonary embolism. During the first 30 days, 28 (4.1%) patients reached the primary outcome (pulmonary embolism-related death or complications) and 29 (4.2%) patients died. Receiver operating characteristic analysis yielded an area under the curve of 0.70 (0.60–0.80) for NT-proBNP. A cut-off value of 600 pg·mL−1 was associated with the best prognostic performance (sensitivity 86% and specificity 50%) and the highest odds ratio (6.04 (95% CI 2.07–17.59), p=0.001) compared to the cut-off values of 1000, 500 or 300 pg·mL−1. Using multivariable logistic regression analysis, NT-proBNP ≥600 pg·mL−1 had a prognostic impact on top of that of the simplified Pulmonary Embolism Severity Index and right ventricular dysfunction on echocardiography (OR 4.27 (95% CI 1.22–15.01); p=0.024, c-index 0.741). The use of a stepwise approach based on the simplified Pulmonary Embolism Severity Index, NT-proBNP ≥600 pg·mL−1 and echocardiography helped optimise risk assessment. Our findings confirm the prognostic value of NT-proBNP and suggest that a cut-off value of 600 pg·mL−1 is most appropriate for risk stratification of normotensive patients with pulmonary embolism. NT-proBNP should be used in combination with a clinical score and an imaging procedure for detecting right ventricular dysfunction. Stepwise approach based on sPESI, NT-proBNP and echocardiography for pulmonary embolism risk stratification http://ow.ly/tsMud

Heart-type fatty acid-binding protein for risk assessment of chronic thromboembolic pulmonary hypertension

Heart-type fatty acid-binding protein (H-FABP) is a reliable marker of myocardial injury and was recently identified as a predictor of outcome in acute pulmonary embolism. The aim of the present study was to investigate the prognostic value of H-FABP in chronic thromboembolic pulmonary hypertension (CTEPH). In total, 93 consecutive patients with CTEPH were studied. During long-term follow-up (median duration 1,260 days, interquartile range (IQR) 708–2,460 days), 46 (49%) patients had an adverse outcome, defined as CTEPH-related death, lung transplantation or persistent pulmonary hypertension after pulmonary endarterectomy (PEA). Baseline H-FABP levels in plasma ranged from 0.69–24.3 ng·mL−1 (median (IQR) 3.41 (2.28–4.86) ng·mL−1). Cox regression analysis revealed a hazard ratio of 1.10 (95% confidence interval 1.04–1.18) for each increase of H-FABP by 1 ng·mL−1, and continuous elevations of H-FABP emerged as an independent predictor of adverse outcome by multivariable analysis. PEA was performed in 52 patients and favourably affected the long-term outcome. Kaplan–Meier analysis revealed that patients with baseline H-FABP concentrations >2.7 ng·mL−1, the median value of the biomarker in the surgically treated population, had a lower probability of event-free survival after PEA. Heart-type fatty acid-binding protein is a promising novel biomarker for risk stratification of patients with chronic thromboembolic pulmonary hypertension.