A founder EIF2AK4 mutation causes an aggressive form of pulmonary arterial hypertension in Iberian Gypsies.

Pulmonary arterial hypertension (PAH) is a pathological condition characterized by a persistent and progressive elevation of pulmonary vascular resistance with devastating consequences if untreated. In the past recent years, several genes have been related to PAH, however, the molecular defect remains unknown in a significant proportion of patients with familial PAH (∼20%). During the past few years, we have observed that PAH shows a particular behavior in Iberian Gypsies, with more aggressive course and frequently affecting multiple members of the same family. We studied five Gypsy families in whom at least one individual from each family developed a severe form of PAH and in whom no mutation had been identified in the common genes. We applied SNP-array-based homozygosity mapping in three families and obtained, among others, one of which included the gene EIF2AK4, recently reported in patients with PAH from group-1' pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH). Subsequently, we sequenced EIF2AK4 and found a homozygous mutation in all five families: c.3344C>T(p.P1115L). The majority of our patients required early lung transplantation. Hence, this mutation appeared with a more severe phenotype than previously reported for other EIF2AK4 mutations. The finding of this novel mutation is important for genetic counseling and calculation of population recurrence risks.

Prognostic significance of tricuspid annular displacement in normotensive patients with acute symptomatic pulmonary embolism.

BACKGROUND: Tricuspid annular plane systolic excursion (TAPSE) is an emerging prognostic indicator in patients with acute symptomatic pulmonary embolism (PE). METHODS AND RESULTS: We prospectively examined 782 normotensive patients with PE who underwent echocardiography in a multicenter study. As compared with patients with a TAPSE of > 1.6 cm, those with a TAPSE of ≤ 1.6 cm had increased systolic pulmonary artery pressure (53.7 ± 16.7 mmHg vs. 40.0 ± 15.5 mmHg, P < 0.001), right ventricle (RV) end-diastolic diameter (3.5 ± 0.8 cm vs. 3.0 ± 0.6 cm, P < 0.001), and RV to left ventricle end-diastolic diameter ratio (1.0 ± 0.3 vs. 0.8 ± 0.2, P < 0.001), and a higher prevalence of RV free wall hypokinesis (68% vs. 11%, P < 0.001). Patients with a TAPSE of ≤ 1.6 cm at the time of PE diagnosis were significantly more likely to die from any cause (hazard ratio [HR] 2.3; 95% confidence interval [CI] 1.2-4.7; P = 0.02) and from PE (HR 4.4; 95% CI 1.3-15.3; P = 0.02) during follow-up. In an external validation cohort of 1326 patients with acute PE enrolled in the international multicenter Registro Informatizado de la Enfermedad TromboEmbólica, a TAPSE of ≤ 1.6 cm remained a significant predictor of all-cause mortality (HR 2.1; 95% CI 1.3-3.2; P = 0.001) and PE-specific mortality (HR 2.5; 95% CI 1.2-5.2; P = 0.01). CONCLUSIONS: In normotensive patients with PE, TAPSE reflects right ventricular function. For these patients, TAPSE is independently predictive of survival.

Thrombolytic therapy and outcome of patients with an acute symptomatic pulmonary embolism.

BACKGROUND: While the primary therapy for most patients with a pulmonary embolism (PE) consists of anticoagulation, the efficacy of thrombolysis relative to standard therapy remains unclear. METHODS: In this retrospective cohort study of 15,944 patients with an objectively confirmed symptomatic acute PE, identified from the multicenter, international, prospective, Registro Informatizado de la Enfermedad TromboEmbólica (RIETE registry), we aimed to assess the association between thrombolytic therapy and all-cause mortality during the first 3 months after the diagnosis of a PE. After creating two subgroups, stratified by systolic blood pressure (SBP) (< 100 mm Hg vs. other), we used propensity score-matching for a comparison of patients who received thrombolysis to those who did not in each subgroup. RESULTS: Patients who received thrombolysis were younger, had fewer comorbid diseases and more signs of clinical severity compared with those who did not receive it. In the subgroup with systolic hypotension, analysis of propensity score-matched pairs (n = 94 pairs) showed a non-statistically significant but clinically relevant lower risk of death for thrombolysis compared with no thrombolysis (odds ratio [OR] 0.72; 95% confidence interval [CI], 0.36-1.46; P = 0.37). In the normotensive subgroup, analysis of propensity score-matched pairs (n = 217 pairs) showed a statistically significant and clinically meaningful increased risk of death for thrombolysis compared with no thrombolysis (OR 2.32; 95% CI, 1.15-4.68; P = 0.018). When we imputed data for missing values for echocardiography and troponin tests in the group of normotensive patients, we no longer detected the increased risk of death associated with thrombolytic therapy. CONCLUSIONS: In normotensive patients with acute symptomatic PE, thrombolytic therapy is associated with a higher risk of death than no thrombolytic therapy. In hemodynamically unstable patients, thrombolytic therapy is possibly associated with a lower risk of death than no thrombolytic therapy. However, study design limitations do not imply a causal relationship between thrombolytics and outcome.

D-dimer levels and 15-day outcome in acute pulmonary embolism. Findings from the RIETE Registry.

BACKGROUND: A number of variables have been evaluated for risk stratification in patients with acute pulmonary embolism (PE). Whereas increased D-dimer levels have been associated with mortality at 3 months, its role in predicting short-term outcome (the period of time during which any therapeutic decision has to be taken) remains unclear. METHODS: RIETE is an ongoing, prospective registry of consecutive patients with acute venous thromboembolism. We assessed the prognostic value of D-dimer levels at baseline, measured with an automated latex agglutination test (IL Test D-dimer), on the 15-day outcome in patients with acute PE. Overall mortality, fatal PE and major bleeding rates were compared by quartile. RESULTS: As of February 2008, 1707 patients with acute PE underwent D-dimer testing. Of these, 72 patients (4.2%) died during the first 15 days, 11 (0.6%) had recurrent PE, and 29 (1.7%) had major bleeding. Overall mortality increased with increasing D-dimer levels, from 2.7% in the first quartile (< 1050 ng mL(-1)) to 7.0% in the fourth quartile (>or= 4200 ng mL(-1)). The rates of fatal PE and major bleeding also increased. On multivariate analysis, patients with D-dimer levels in the fourth quartile had an increased risk for overall death (odds ratio, 1.8; 95% CI, 1.1-3.2), fatal PE (odds ratio, 2.0; 95% CI, 1.0-3.8) or major bleeding (odds ratio, 3.2; 95% CI, 1.5-7.0). CONCLUSIONS: PE patients with D-dimer levels in the fourth quartile had an increased incidence of overall death, fatal PE and major bleeding within 15 days both before and after multivariate adjustment.

Use of venous thromboembolism prophylaxis for surgical patients: a multicentre analysis of practice in Spain.

OBJECTIVE: To assess the use of venous thromboembolism prophylaxis in surgical patients. DESIGN: Retrospective multicentre study. SETTING: Eight acute-care teaching hospitals with more than 400 beds, Spain. PATIENTS: Medical records of all consecutive patients undergoing operations in the general surgical and trauma and orthopaedic services during the month of April, 1997, were randomly selected. INTERVENTION: The sample size for each type of operation (general, trauma-orthopaedic) was calculated from the number of operations done at each hospital (with an absolute precision of 5%, and an alpha error of 5%) and the prevalence of the use of venous thromboembolism prophylaxis obtained from a random sample of 50 records (25 from patients in general surgery and 25 from patients in orthopaedic surgery) from each centre. MAIN OUTCOME MEASURES: Appropriate and inappropriate pharmacological prophylaxis defined according to a combination of risk categories for venous thromboembolism, doses of antithrombotic agents given, time of starting prophylaxis, and its duration. RESULTS: A total of 1848 medical records (general surgery, n = 1025; trauma-orthopaedic surgery, n = 823) were included. Physical methods (elastic stockings, intermittent pneumatic compression) were used in only 0.3% of patients. Pharmacological prophylaxis consisted of low molecular weight heparin in 99% of cases. The percentage given heparin-based prophylaxis was 54%. Overall, appropriate prophylaxis was given in 1175 patients (64%). Use of thromboprophylaxis ranged from 27% to 70% among the participating hospitals. Prophylaxis was more likely to be appropriate in orthopaedic patients (577, 70%) than in general surgical patients (598, 58%) in both the high and moderate risk categories. CONCLUSIONS: Given the large variability between the participating hospitals, more specific protocols and recommendations about prophylaxis of thromboembolism in surgical patients are needed.