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.).

Age-adjusted high-sensitivity troponin T cut-off value for risk stratification of pulmonary embolism.

High-sensitivity troponin T (hsTnT) helps in identifying pulmonary embolism patients at low risk of an adverse outcome. In 682 normotensive pulmonary embolism patients we investigate whether an optimised hsTnT cut-off value and adjustment for age improve the identification of patients at elevated risk. Overall, 25 (3.7%) patients had an adverse 30-day outcome. The established hsTnT cut-off value of 14 pg·mL(-1) retained its high prognostic value (OR (95% CI) 16.64 (2.24-123.74); p=0.006) compared with the cut-off value of 33 pg·mL(-1) calculated by receiver operating characteristic analysis (7.14 (2.64-19.26); p<0.001). In elderly (aged ≥75 years) patients, an age-optimised hsTnT cut-off value of 45 pg·mL(-1) but not the established cut-off value of 14 pg·mL(-1) predicted an adverse outcome. An age-adjusted hsTnT cut-off value (≥14 pg·mL(-1) for patients aged <75 years and ≥45 pg·mL(-1) for patients aged ≥75 years) provided additive and independent prognostic information on top of the simplified pulmonary embolism severity index (sPESI) and echocardiography (OR 4.56 (1.30-16.01); p=0.018, C-index=0.77). A three-step approach based on the sPESI, hsTnT and echocardiography identified 16.6% of all patients as being at higher risk (12.4% adverse outcome). Risk assessment of normotensive pulmonary embolism patients was improved by the introduction of an age-adjusted hsTnT cut-off value. A three-step approach helped identify patients at higher risk of an adverse outcome who might benefit from advanced therapy.

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.

Recovery of right ventricular function after intermediate-risk pulmonary embolism: results from the multicentre Pulmonary Embolism International Trial (PEITHO)-2.

BACKGROUND: Right ventricular (RV) function plays a critical role in the pathophysiology and acute prognosis of pulmonary embolism (PE). We analyzed the temporal changes of RV function in the cohort of a prospective multicentre study investigating if an early switch to oral anticoagulation in patients with intermediate-risk PE is effective and safe. METHODS: Echocardiographic and laboratory examinations were performed at baseline (PE diagnosis), 6 days and 6 months. Echocardiographic parameters were classified into categories representing RV size, RV free wall/tricuspid annulus motion, RV pressure overload and right atrial (RA)/central venous pressure. RESULTS: RV dysfunction based on any abnormal echocardiographic parameter was present in 84% of patients at baseline. RV dilatation was the most frequently abnormal finding (40.6%), followed by increased RA/central venous pressure (34.6%), RV pressure overload (32.1%), and reduced RV free wall/tricuspid annulus motion (20.9%). As early as day 6, RV size remained normal or improved in 260 patients (64.7%), RV free wall/tricuspid annulus motion in 301 (74.9%), RV pressure overload in 297 (73.9%), and RA/central venous pressure in 254 (63.2%). At day 180, the frequencies slightly increased. The median NT-proBNP level decreased from 1448 pg/ml at baseline to 256.5 on day 6 and 127 on day 180. CONCLUSION: In the majority of patients with acute intermediate-risk PE switched early to a direct oral anticoagulant, echocardiographic parameters of RV function normalised within 6 days and remained normal throughout the first 6 months. Almost one in four patients, however, continued to have evidence of RV dysfunction over the long term.

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.

Morbidity and mortality in adults with congenital heart defects in the third and fourth life decade.

OBJECTIVES: The population of adults with congenital heart defects (ACHD) is continuously growing. Data on morbidity and mortality of ACHD are limited. This longitudinal observational study examined a group of ACHD with surgically corrected or palliated congenital heart defects (CHD) during a 15-year period. METHODS: ACHD that had participated in the initial study were invited for a follow-up examination. Mortality and hospitalization data were compared with a healthy control group. RESULTS: From 05/2017 to 04/2019 a total of 249/364 (68%) ACHD participated in the follow-up study: 21% had mild, 60% moderate and 19% severe CHD. During the observational period, 290 health incidents occurred (cardiac catheterization 37%, cardiovascular surgery 27%, electrophysiological study/ablation 20%, catheter interventional treatment 14%, non-cardiac surgery 3%). Events were more frequent in ACHD with moderate (53%) and severe (87%) compared to those with mild CHD (p < 0.001). 24 individuals died at a median age of 43 years during the observation period. 29% of them had moderate and 71% severe CHD corresponding to a mortality rate of 0%, 0.29% and 1.68% per patient-year in ACHD with mild, moderate and severe CHD. Long-term survival was significantly reduced in patients with severe CHD in comparison to individuals with mild and moderate CHD (p < 0.001). CONCLUSION: After correction or palliation of CHD, there was remarkable ongoing morbidity and mortality in ACHD patients over the 15-year observation period, particularly in individuals with moderate and severe CHD when compared with the general population. Thus, life-long special care is required for all surgically corrected or palliated ACHD patients.

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 Cox's 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.

Life chances after surgery of congenital heart disease: A case-control-study of inter- and intragenerational social mobility over 15 years.

BACKGROUND: Patients of congenital heart disease surgery have good prospects for reaching old age. Against the backdrop of increasing life expectancies, the question of how well such patients are mastering daily routines and their working life emerges. In our study, the educational and occupational performance of patients over 15 years was examined. METHODS: Intergenerational social mobility (changes in social positions from the parental generation to the generation of children) was examined in terms of education, and intragenerational social mobility (changes in positions within the same generation, i.e., in individuals over their life courses) was examined in terms of occupational positions. Comparisons were made between patients and a control group drawn from the German Socio-Economic Panel (SOEP). Controls were drawn from respondents who participated in the 2004 and 2018 SOEP surveys. RESULTS: The data were from 244 out of 360 patients (68%) with complete social data from the first survey (2003-2004) and who were included in the follow-up (2017-2019), and 238 controls were drawn from the SOEP. At the time of the second survey, subjects' ages ranged from 28 to 59 years of age (M = 40.1 years). Intergenerational educational mobility did not differ between cases and controls. For intragenerational social mobility, downward changes were more frequent among controls. This latter finding may be explained by patients retiring earlier than the general population. Retirement rates increased over time, particularly among patients with severe congenital malformations. Unemployment rates were also higher among patients. CONCLUSIONS: Taken together, although a considerable proportion of patients with congenital heart disease retired prematurely or never entered the labour force, their educational and occupational careers proceeded more favourably than expected.

Early switch to oral anticoagulation in patients with acute intermediate-risk pulmonary embolism (PEITHO-2): a multinational, multicentre, single-arm, phase 4 trial.

BACKGROUND: Current guidelines recommend a risk-adjusted treatment strategy for the management of acute pulmonary embolism. This is a particular patient category for whom optimal treatment (anticoagulant treatment, reperfusion strategies, and duration of hospitalisation) is currently unknown. We investigated whether treatment of acute intermediate-risk pulmonary embolism with parenteral anticoagulation for a short period of 72 h, followed by a switch to a direct oral anticoagulant (dabigatran), is effective and safe. METHODS: We did a multinational, multicentre, single-arm, phase 4 trial at 42 hospitals in Austria, Belgium, France, Germany, Italy, Netherlands, Romania, Slovenia, and Spain. Adult patients (aged ≥18 years) with symptomatic intermediate-risk pulmonary embolism, with or without deep-vein thrombosis, were enrolled. Patients received parenteral low-molecular-weight or unfractionated heparin for 72 h after diagnosis of pulmonary embolism before switching to oral dabigatran 150 mg twice per day following a standard clinical assessment. The primary outcome was recurrent symptomatic venous thromboembolism or pulmonary embolism-related death within 6 months. The primary and safety outcomes were assessed in the intention-to-treat population. The study was terminated early, as advised by the data safety and monitoring board, following sample size adaptation after the predefined interim analysis on Dec 18, 2018. This trial is registered with the EU Clinical Trials Register (EudraCT 2015-001830-12) and ClinicalTrials.gov (NCT02596555). FINDINGS: Between Jan 1, 2016, and July 31, 2019, 1418 patients with pulmonary embolism were screened, of whom 402 were enrolled and were included in the intention-to-treat analysis (median age was 69·5 years [IQR 60·0-78·0); 192 [48%] were women and 210 [52%] were men). Median follow-up was 217 days (IQR 210-224) and 370 (92%) patients adhered to the protocol. The primary outcome occurred in seven (2% [upper bound of right-sided 95% CI 3]; p<0·0001 for rejecting the null hypothesis) patients, with all events occurring in those with intermediate-high-risk pulmonary embolism (seven [3%; upper bound of right-sided 95% CI 5] of 283). At 6 months, 11 (3% [95% CI 1-5]) of 402 patients had at least one major bleeding event and 16 (4% [2-6]) had at least one clinically relevant non-major bleeding event; the only fatal haemorrhage occurred in one (<1%) patient before the switch to dabigatran. INTERPRETATION: A strategy of early switch from heparin to dabigatran following standard clinical assessment was effective and safe in patients with intermediate-risk pulmonary embolism. Our results can help to refine guideline recommendations for the initial treatment of acute intermediate-risk pulmonary embolism, optimising the use of resources and avoiding extended hospitalisation. FUNDING: German Federal Ministry of Education and Research, University Medical Center Mainz, and Boehringer Ingelheim.

Leptin enhances the recruitment of endothelial progenitor cells into neointimal lesions after vascular injury by promoting integrin-mediated adhesion.

The adipocytokine leptin modulates vascular remodeling and neointima formation. Because endothelial progenitor cells (EPCs) participate in vascular repair, we analyzed the effects of leptin on human EPC function in vitro and in vivo. After 7 days in culture, EPCs expressed the leptin receptor and responded to leptin stimulation with increased STAT3 phosphorylation. Incubation of EPCs with leptin (at concentrations between 1 and 100 ng/mL) increased the number of EPCs adhering to vitronectin and fibronectin in a receptor-specific manner. It also enhanced the capacity of EPCs to incorporate into a monolayer of human endothelial cells and the adherence of these cells to activated platelets. Leptin upregulated alphavbeta5 and alpha4 integrin expression in EPCs, and the effects of leptin on EPC function could be prevented, at least in part, by RGD peptides and function-blocking antibodies. Intravenous injection of fluorescently labeled human EPCs into athymic nude mice shortly after vascular injury revealed that preincubation of EPCs with leptin augmented their accumulation within intimal lesions, accelerating reendothelialization and decreasing neointima formation in an alphavbeta5 and alpha4 integrin-dependent manner. Our findings suggest that leptin specifically modulates the adhesive properties and the homing potential of EPCs and may thus enhance their capacity to promote vascular regeneration in vivo.

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.

Contribution of leptin receptor N-linked glycans to leptin binding.

The extracellular domain of the human leptin receptor (Ob-R) contains 20 potential N-glycosylation sites whose role in leptin binding remains to be elucidated. We found that a mammalian cell-expressed sOb-R (soluble Ob-R) fragment (residues 22-839 of the extracellular domain) bound leptin with a dissociation constant of 1.8 nM. This binding was inhibited by Con A (concanavalin A) or wheatgerm agglutinin. Treatment of sOb-R with peptide N-glycosidase F reduced leptin binding by approximately 80% concurrently with N-linked glycan removal. The human megakaryoblastic cell line, MEG-01, expresses two forms of the Ob-R, of approx. 170 and 130 kDa molecular mass. Endo H (endoglycosidase H) treatment and cell culture with alpha-glucosidase inhibitors demonstrated that N-linked glycans are of the complex mature type in the 170 kDa form and of the high-mannose type in the 130 kDa form. Both isoforms bound leptin, but not after peptide N-glycosidase F treatment. An insect-cell-expressed sOb-R fragment, consisting of the Ig (immunoglobulin), CRH2 (second cytokine receptor homology) and FNIII (fibronectin type III) domains, bound leptin with affinity similar to that of the entire extracellular domain, but this function was abolished after N-linked glycan removal. The same treatment had no effect on the leptin-binding activity of the isolated CRH2 domain. Our findings show that N-linked glycans within Ig and/or FNIII domains regulate Ob-R function, but are not involved in essential interactions with the ligand.

Sex-specific differences in pulmonary embolism.

INTRODUCTION: Sex-specific differences regarding risk factors, symptoms and prognosis have been reported for several cardiovascular diseases. For patients with pulmonary embolism (PE), sex-specific data are limited and inconsistent. We aimed to investigate sex-specific differences in PE. MATERIALS AND METHODS: Over a 10-year period (01/2003-09/2013), patients with confirmed PE were enrolled in a prospective single-centre cohort study. RESULTS: We prospectively examined 569 PE patients (55.9% women). Men more often had cancer (20.7% vs. 13.5%, p = 0.024) and unprovoked PE (61.0% vs. 47.5%, p = 0.001) while women more frequently presented with risk factors for venous thromboembolism such as older age (median, 71 [IQR, 55-79] vs. 67 [53-75] years, p = 0.008), surgery/trauma/immobilisation (38.4% vs. 29.5%, p = 0.026) and sex-hormone therapy (14.8% vs. 0.8%, p < 0.001). Overall, 84 patients (14.8%) had an adverse 30-day outcome and 43 (7.6%) died within 30 days; outcomes did not differ between males and females and were not influenced by the patients' sex. Risk stratification markers and models such as right ventricular dysfunction on TTE/CT, cardiac troponin, sPESI, Bova score and 2014 ESC guidelines algorithm predicted adverse outcome in normotensive female patients only, while tachycardia, hypoxia, NT-proBNP and modified FAST score were able to predict an adverse outcome in both sexes. Using sex-specific biomarker cut-off values, the 2014 ESC guidelines algorithm was able to predict adverse outcome in both sexes. CONCLUSIONS: The 30-day adverse outcomes did not differ between male and female PE patients and were not influenced by the patients' sex despite sex-specific differences in the prognostic performance of risk stratification markers/models.

Quality of life and functional limitations after pulmonary embolism and its prognostic relevance.

BACKGROUND: While the importance of patients' quality of life (QoL) in chronic cardiac or pulmonary disease is uncontroversial, the burden of an acute pulmonary embolism (PE) on QoL has received little attention thus far. OBJECTIVES: We aimed to validate the German PEmb-QoL questionnaire, identify associations between QoL and clinical/functional parameters, and investigate the prognostic relevance of QoL for long-term survival in survivors of an acute PE episode. PATIENTS/METHODS: Patients were invited for a clinical follow-up visit including assessment of QoL using the German PEmb-QoL questionnaire 6 months after an objectively confirmed PE at a single center. Internal consistency reliability, construct-related validity, and regressions between PEmb-QoL and clinical patient-characteristics were assessed using standard scale construction techniques. RESULTS: Overall, 101 patients [median age, 69 ([interquartile range] IQR 57-75) years; women, 48.5%] were examined 208 (IQR 185-242) days after PE. Internal consistency reliability and construct-related validity of the PEmb-QoL questionnaire were acceptable. As many as 47.0% of patients reported dyspnea, 27.5% had right ventricular (RV) dysfunction on transthoracic echocardiography (TTE), and 25.3% were diagnosed with post-PE impairment (PPEI) at 6-month follow-up. Furthermore, 15.9% of patients were diagnosed with depression 6 months after an acute PE. The QoL was affected by dyspnea, preexisting pulmonary disease, and PPEI, and a reduced QoL was associated with an increased risk for long-term mortality after an observation period of 3.6 years. CONCLUSIONS: The German PEmb-QoL questionnaire is a reliable instrument for assessing QoL 6 months after PE. The QoL was affected by dyspnea, preexisting pulmonary disease, and PPEI and was associated with long-term mortality.

Incomplete echocardiographic recovery at 6 months predicts long-term sequelae after intermediate-risk pulmonary embolism. A post-hoc analysis of the Pulmonary Embolism Thrombolysis (PEITHO) trial.

INTRODUCTION: Symptoms and functional limitation are frequently reported by survivors of acute pulmonary embolism (PE). However, current guidelines provide no specific recommendations on which patients should be followed after acute PE, when follow-up should be performed, and which tests it should include. Definition and classification of late PE sequelae are evolving, and their predictors remain to be determined. METHODS: In a post hoc analysis of the Pulmonary Embolism Thrombolysis (PEITHO) trial, we focused on 219 survivors of acute intermediate-risk PE with clinical and echocardiographic follow-up 6 months after randomisation as well as over the long term (median, 3 years after acute PE). The primary outcome was a composite of (1) confirmed chronic thromboembolic pulmonary hypertension (CTEPH) or (2) 'post-PE impairment' (PPEI), defined by echocardiographic findings indicating an intermediate or high probability of pulmonary hypertension along with New York Heart Association functional class II-IV. RESULTS: Confirmed CTEPH or PPEI occurred in 29 (13.2%) patients, (6 with CTEPH and 23 with PPEI). A history of chronic heart failure at baseline and incomplete or absent recovery of echocardiographic parameters at 6 months predicted CTEPH or PPEI at long-term follow-up. CONCLUSIONS: CTEPH or PPEI occurs in almost one out of seven patients after acute intermediate-risk PE. Six-month echocardiographic follow-up may be useful for timely detection of late sequelae.

Absence of leptin resistance in platelets from morbidly obese individuals may contribute to the increased thrombosis risk in obesity.

Clinical studies have shown that elevated leptin levels are an independent cardiovascular risk factor. However, little is known about the existence of platelet resistance to leptin in the setting of obesity. We examined the effects of leptin on platelet aggregation in morbidly obese subjects (n = 40; BMI, 41.6 +/- 1.1 kg/m2; leptin, 49.7 +/- 3.4 ng/ml) in comparison to normal-weight controls (n = 36; BMI, 23.3 +/- 0.4 kg/m2; leptin, 6.5 +/- 0.7 ng/ml). The aggregatory response to increasing concentrations of adenosine diphosphate (ADP) (2, 3, 4, and 5 microM) was significantly increased in platelets from obese compared to lean donors, reflecting a left shift in the dose-response curve. Plasma leptin levels, but not BMI, were significantly higher in subjects with stronger (above the median) compared to weaker (below the median) platelet aggregation at all ADP concentrations tested. In further experiments, stimulation (preincubation) with leptin (500 ng/ml) promoted ADP-induced platelet aggregation by approximately 25%, and there was no difference between platelets from obese and those from lean donors regarding the responsiveness to leptin (p = 0.99). Western blotting revealed that leptin induced phosphorylation of JAK2 and STAT3 to a similar extent in platelets from both groups. Expression of potential mediators of leptin resistance (SOCS3 and PTP1B) also did not differ in platelets from obese and control subjects. In conclusion, our data indicate that platelets from obese donors show increased aggregatory response to ADP, and that this might partly be the consequence of increased circulating leptin levels. Platelets from obese donors are not resistant to the enhancing effects of leptin on ADP-induced platelet aggregation.

Quantification of pulmonary regurgitation and prediction of pulmonary valve replacement by echocardiography in patients with congenital heart defects in comparison to cardiac magnetic resonance imaging.

Pulmonary regurgitation (PR) is common in patients with congenital heart defects (CHD) and contributes to morbidity and mortality in the long-term. We investigated in this retrospective analysis whether readily accessible echocardiographic parameters are useful for quantification of PR and for predicting pulmonary valve replacement (PVR) in comparison to the gold-standard phase contrast (PC) flow measurements from cardiovascular magnetic resonance (CMR). Continuous wave (CW) Doppler and colour flow images in echocardiograms from 53 patients with CHD were analysed. Slope and jet-to-RVOT ratio correlated significantly with CMR-assessed regurgitation fraction (RF), whereas pressure half time (PHT) showed an inverse correlation. Patients with mild PR in CMR had significantly higher PHT, lower slope and jet-to-RVOT ratio than patients with moderate or severe regurgitation. The AUC regarding PR severity was 0.778 for PHT (95% CI, 0.649-0.907; P = 0.007 for CMR-RF ≤ 35%), 0.744 for slope (95% CI, 0.603-0.885; P = 0.017 for CMR-RF > 35%) and 0.652 for jet-to-RVOT ratio (95% CI, 0.473-0.860; P = 0.168 for CMR-RF > 35%). The optimal cut-off values calculated from ROC analysis were 95 ms for PHT and 4.9 m/s2 for slope. In logistic regression analysis, slope emerged as the most valuable parameter for predicting the indication for PVR (OR 12.9, 95% CI, 1.8-90.9, P = 0.010). In conclusion, echocardiographic assessment of PR was feasible. Both parameters, PHT and in particular slope, were predictors for PVR. Thus, echocardiography appears appropriate in the management of patients with PR.

Lack of urokinase plasminogen activator promotes progression and instability of atherosclerotic lesions in apolipoprotein E-knockout mice.

Urokinase plasminogen activator (uPA) is strongly expressed in atherosclerotic lesions, but the overall effect of the protease on plaque composition and growth remains controversial. In the present study, apolipoprotein E-deficient (apoE(-/-)) mice were intercrossed with mice which were lacking the uPA gene (doubleknockout; DKO). In ferric chloride-induced carotid artery lesions in chow-fed mice, uPA deficiency increased neointimal size (P = 0.015) and luminal stenosis (P = 0.014), while reducing media thickness (P = 0.002). A lack of uPA also increased the size of and the luminal obstruction from atherosclerotic plaques at the coronary and brachiocephalic arteries of apoE(-/-) mice. Plaques were characterised by a higher fibrinogen/fibrin content and a decrease in cellularity and collagen content. When apoE(-/-) and DKO mice were analysed as a single group, a significant correlation was found between the alpha-actin (smooth muscle cell) and collagen content of atherosclerotic lesions (r = 0.554; P < 0.05), and a negative correlation existed between the alpha-actin and fibrin/fibrinogen immunopositive area (r = -0.791; P < 0.001). Further analysis of brachiocephalic atherosclerosis, a predilection site for plaque rupture in the apoE(-/-) mouse, revealed signs of plaque vulnerability, including a reduced cap-to-intima ratio (0.21 +/- 0.04 vs. 0.37 +/- 0.05; P = 0.03) and more frequent detection of intraplaque haemorrhage (56% vs. 13%; P < 0.01) and buried fibrous caps (1.8 +/- 0.5 vs. 0.5 +/- 0.2; P = 0.02) in DKO compared to apoE(-/-) mice. These results indicate that, at least at (patho)physiologic concentrations, uPA is essential for maintaining the cellularity and collagen content and, possibly, the stability of lesions, both by preventing excessive intramural fibrin accumulation and by facilitating cell migration and invasion.

Leptin signalling and leptin-mediated activation of human platelets: importance of JAK2 and the phospholipases Cgamma2 and A2.

Leptin enhances agonist-induced platelet aggregation, and human platelets have been reported to express the leptin receptor. However, the pathways and mediators lying downstream of leptin binding to platelets remain, with few exceptions, unknown. In the present study, we sought to gain further insight into the possible role of leptin as a platelet agonist. Stimulation of platelets with leptin promoted thromboxane generation and activation of alpha(IIb)beta(3), as demonstrated by PAC-1 binding. Furthermore, it increased the adhesion to immobilised fibrinogen (p<0.001) and induced cytoskeletal rearrangement of both platelets and Meg01 cells. Leptin time- and dose-dependently phosphorylated the intracellular signalling molecules JAK2 and STAT3, although the importance of STAT3 for leptin-induced platelet activation remains to be determined. Important intracellular mediators and pathways activated by leptin downstream of JAK2 were found to include phosphatidylinositol-3 kinase, phospholipase Cgamma2 and protein kinase C, as well as the p38 MAP kinase-phospholipase A(2) axis. Accordingly, incubation with the specific inhibitors AG490, Ly294002, U73122, and SB203580 prevented leptin-mediated platelet activation. These results help delineate biologically relevant leptin signalling pathways in platelets and may improve our understanding of the mechanisms linking hyperleptinaemia to the increased thrombosis risk in human obesity.

Plasminogen activator inhibitor-1 from bone marrow-derived cells suppresses neointimal formation after vascular injury in mice.

OBJECTIVE: To investigate the ability of bone marrow (BM)-derived cells to modulate neointimal growth after injury by expressing plasminogen activator inhibitor-1 (PAI-1). METHODS AND RESULTS: We performed BM transplantation (BMT) in lethally irradiated wild-type (WT) and PAI-1(-/-) mice. Three weeks after carotid injury with ferric chloride, analysis of Y-chromosome DNA expression in the vessel wall of female hosts revealed that 20.8+/-6.0% of the cells in the neointima and 37.6+/-5.7% of those in the media were of BM origin. Lack of PAI-1 in either the host or the donor cells did not affect recruitment of BM-derived cells into sites of vascular injury. The neointima consisted predominantly of smooth muscle cells, and a proportion of these cells expressed PAI-1. Overall, lack of PAI-1 was associated with enhanced neointimal formation. However, importantly, BMT(WT-->PAI-1(-/-)) mice exhibited reduced neointimal area (P=0.05) and luminal stenosis (P=0.04) compared with BMT(PAI-1(-/-)-->PAI-1(-/-)) mice. Although PAI-1-expressing cells were shown to be present in BMT(WT-->PAI-1(-/-)) lesions, these mice did not exhibit detectable levels of the inhibitor in the circulation, suggesting that local production of PAI-1 by cells in the neointima and media was sufficient to reduce luminal stenosis. CONCLUSIONS: PAI-1 from BM-derived cells appears capable of suppressing neointimal growth after vascular injury.