Olivier Sanchez

Short-term and long-term epoprostenol (prostacyclin) therapy in pulmonary hypertension secondary to connective tissue diseases: results of a pilot study

Continuous intravenous epoprostenol improves exercise capacity, haemodynamics, and survival in severe primary pulmonary hypertension. Pulmonary hypertension can also be life-threatening in patients with connective tissue diseases. In a prospective open monocentre uncontrolled study, the effects of epoprostenol were evaluated in patients with severe pulmonary hypertension secondary to connective tissue diseases who were unresponsive to oral vasodilators (including calcium channel blockers) and continued to be in the New York Heart Association (NYHA) functional class III or IV despite conventional medical therapy. Seventeen patients received epoprostenol administered by a portable infusion pump associated with conventional therapy (oral anticoagulants, diuretics, supplemental oxygen). During the first six weeks of therapy, two (12%) patients died, of pulmonary oedema (n = 1) and severe sepsis (n = 1). In the fifteen remaining subjects, clinical and haemodynamic parameters improved significantly at six weeks. These patients were subsequently monitored for 80+/-48 (range 14-154) weeks after initiation of epoprostenol. Five (33%) patients died, of right heart failure (n = 2), severe sepsis (n = 2) or syncope (n = 1) and two patients were successfully transplanted 24 and 52 weeks after initiation of epoprostenol. Seven of the remaining eight patients had a persistent clinical improvement. Short-term epoprostenol therapy is effective in some patients with connective tissue diseases as demonstrated by better clinical status and haemodynamics at six weeks. However, this study reports several cases of early and late major complications including severe sepsis and pulmonary oedema. Additional information is needed to evaluate the benefit: risk ratio of long-term epoprostenol therapy in pulmonary hypertension secondary to connective tissue diseases.

Diagnostic accuracy of magnetic resonance imaging for an acute pulmonary embolism: results of the 'IRM-EP' study.

Summary.  Background:  Magnetic resonance imaging (MRI) has not been validated as an alternative diagnostic test to computed tomography angiography (CTA) in patients with suspicion of a pulmonary embolism (PE).

Distinct patterns of circulating endothelial cells in pulmonary hypertension

The respective abundance of circulating endothelial cells and endothelial progenitor cells may reflect the balance between vascular injury and repair. As pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) can share features of pulmonary remodelling, we postulated that the two disorders might be associated with different types of pulmonary endothelial dysfunction. We studied 25 consecutive patients undergoing cardiac catheterisation for suspected pulmonary hypertension. Nine patients had PAH, nine had CTEPH, and seven had normal pulmonary arterial pressure and served as controls. Circulating endothelial cells were isolated with CD146-coated beads. CD34+CD133+ cell and endothelial progenitor cell numbers were respectively determined by flow cytometry and cell culture, in peripheral vein and pulmonary artery blood. Plasma levels of soluble vascular endothelial growth factor (VEGF), soluble E-selectin and soluble vascular cell adhesion molecule (sVCAM) were measured by ELISA. No difference in progenitor counts or VEGF levels was found across the three groups. Compared to controls, circulating endothelial cell numbers were significantly increased in PAH but not in CTEPH, in keeping with the elevated soluble E-selectin and sVCAM levels found in PAH alone. In conclusion, PAH, in contrast to CTEPH, is associated with markers of vascular injury (circulating endothelial cells, soluble E-selectin and sVCAM) but not with markers of remodelling (endothelial progenitor cells, CD34+CD133+ cells and VEGF).

Clinical probability and alveolar dead space measurement for suspected pulmonary embolism in patients with an abnormal D‐dimer test result

Summary.  Background: Most patients with suspected pulmonary embolism (PE) have a positive D‐dimer test and undergo diagnostic imaging. Additional non‐invasive bedside tests are required to reduce the need for further diagnostic tests. Objectives: We aimed to determine whether a combination of clinical probability assessment and alveolar dead space fraction measurement can confirm or exclude PE in patients with an abnormal D‐dimer test. Methods: We assessed clinical probability of PE and alveolar dead space fraction in 270 consecutive in‐ and outpatients with suspected PE and positive D‐dimer. An alveolar dead space fraction < 0.15 was considered normal. PE was subsequently excluded or confirmed by venous compression ultrasonography, spiral computed tomography and a 3‐month follow‐up. Radiologists were unaware of the results of clinical probability and capnography. Results: PE was confirmed in 108 patients (40%). Capnography had a sensitivity of 68.5% (95% confidence interval [CI]: 58.9–77.1%) and a specificity of 81.5% (95% CI: 74.6–87.1%) for PE. Forty‐five patients (16.6%) had both a low clinical probability and normal capnography (sensitivity: 99.1%, 95% CI: 94.9–100%) and 34 patients (12.6%) had both a high clinical probability and abnormal capnography (specificity: 100%, 95% CI: 97.7–100%). Conclusion: Capnography alone does not exclude PE accurately. The combination of clinical probability and capnography accurately excludes or confirms PE and avoids further testing in up to 30% of patients.

Imagerie de l’hypertension artérielle pulmonaire

Resume Introduction La decouverte d’une hypertension arterielle pulmonaire (HTAP) impose la realisation d’un bilan etiologique rigoureux dans lequel l’imagerie occupe une place importante. Etat des connaissances La radiographie de thorax peut montrer des signes non specifiques (cardiomegalie, dilatation des arteres pulmonaires) et permet une analyse du parenchyme pulmonaire. L’echocardiographie est l’examen de depistage de reference et qui permet une evaluation de la fonction ventriculaire gauche. La scintigraphie pulmonaire de ventilation et perfusion est essentielle pour affirmer la nature post-embolique de l’HTAP. L’angioscanner thoracique helicoidal est devenu un examen incontournable. Il permet une analyse fine du parenchyme pulmonaire, des vaisseaux pulmonaires et des cavites cardiaques, la recherche d’une etiologie et la realisation d’un bilan pretherapeutique. L’imagerie par resonance magnetique permet le calcul de plusieurs parametres hemodynamiques et une analyse morphologique des cavites cardiaques et des vaisseaux pulmonaires mais necessite une evaluation plus large. Perspectives L’amelioration de la qualite des images vasculaires et le developpement de techniques complementaires en IRM permettront peut-etre le developpement de cette technique dans l’HTAP. Conclusion L’imagerie occupe une place fondamentale dans la prise en charge des patients souffrant d’HTAP.

Residual pulmonary vascular obstruction and recurrence after acute pulmonary embolism. A single center cohort study

INTRODUCTION Up to 50% of patients with pulmonary embolism (PE) present lung perfusion defects after six months of anticoagulant treatment, suggesting residual pulmonary vascular obstruction (RPVO). The risk of recurrence in patients with RPVO remains unknown. The present study aims to assess the risk of recurrent venous thromboembolism (VTE) in patients with RPVO after a first symptomatic episode of PE. METHODS Consecutive patients who survived a first objectively proven acute PE, treated for at least three months with anticoagulants, were included and followed prospectively. RPVO was defined as a pulmonary vascular obstruction of >10% on ventilation/perfusion lung scan performed at inclusion. Objectively proven VTE recurrences were registered and confirmed by an investigator unaware of the result of the ventilation/perfusion lung scan. RESULTS Among the 310 patients (median age: 61years) included in the study, 60 (19%) had RPVO. During a median follow-up of 51.3months, 66 patients (21.2%, 95% CI [17.5-26.7]) experienced recurrent VTE. In an adjusted cox proportional hazards analysis, we identified RPVO (HR 1.94; 95% CI [1.11-3.39]; p=0.026) and unprovoked PE (HR 3.56; 95% CI [1.79-7.07]; p=0.00051) as independent risk factors for recurrent VTE whereas extended anticoagulation therapy (HR 0.19; 95% CI [0.07-0.55]; p=0.00014) was associated with a low risk of recurrence. CONCLUSION The results suggest that RPVO is an independent risk factor of recurrent VTE after a first PE.

Imaging of pulmonary arterial hypertension

INTRODUCTION The investigation of pulmonary arterial hypertension (PAH) requires a rigorous aetiological assessment in which imaging modalities play an important role. BACKGROUND The chest x-ray may show non-specific signs such as cardiomegaly and dilatation of the pulmonary arteries, and also allows examination of the lung parenchyma. Echocardiography is the essential screening tool and allows evaluation of left ventricular function. Pulmonary ventilation/perfusion scanning is essential to confirm post embolic PAH. Spiral CT has become an essential examination. It allows detailed study of the lung parenchyma, the pulmonary vessels and the cardiac chambers, and also helps determine the aetiology and complete the pre-treatment assessment. Magnetic resonance imaging allows calculation of several haemodynamic parameters and morphological study of the cardiac chambers and pulmonary vessels but requires further evaluation. VIEWPOINT The improvement in the quality of vascular images and the development of complementary MRI techniques may lead to increase of this modality in the study of PAH. CONCLUSION Imaging plays a fundamental role in the management of patients suffering from PAH.

Acute Pulmonary Venous Thromboembolic Disease

Venous thromboembolism (VTE) is a common disease considered to be the result of the interaction between patient-related and setting-related risk factors. Several diagnostic algorithms combining clinic

Fibrinogen and the Prediction of Residual Obstruction Manifested after Pulmonary Embolism Treatment

Residual pulmonary vascular obstruction (RPVO) and chronic thromboembolic pulmonary hypertension (CTEPH) are both long-term complications of acute pulmonary embolism, but it is unknown whether RPVO can be predicted by variants of fibrinogen associated with CTEPH. We used the Akaike information criterion to select the best predictive models for RPVO in two prospectively followed cohorts of acute pulmonary embolism patients, using as candidate variables the extent of the initial obstruction, clinical characteristics and fibrinogen-related data. We measured the selected models’ goodness of fit by analysis of deviance and compared models using the Chi-squared test. RPVO occurred in 29 (28.4%) out of 102 subjects in the first cohort and 46 (25.3%) out of 182 subjects in the second. The best-fit predictive model derived in the first cohort (p=0.0002) and validated in the second cohort (p=0.0005) implicated fibrinogen Bβ-chain monosialylation in the development of RPVO. When the derivation procedure excluded clinical characteristics, fibrinogen Bβ-chain monosialylation remained a predictor of RPVO in the best-fit predictive model (p=0.00003). Excluding fibrinogen characteristics worsened the predictive model (p=0.03). Fibrinogen Bβ-chain monosialylation, a common structural attribute of fibrin, helped predict RPVO after acute pulmonary embolism. Fibrin structure may contribute to the risk of developing RPVO. Fibrinogen helps predict residual pulmonary vascular obstruction after pulmonary embolism: results from the PROMPT study http://ow.ly/G7pY30m2HU6

096 Endothelin-1 expression and effects on pulmonary artery smooth muscle cells in idiopathic pulmonary arterial hypertension (IPAH)

Background Endothelin 1 (ET-1) has been implicated in the development of pulmonary arterial hypertension (PAH) and asso-ciated with pulmonary vascular remodeling. ET-1 synthesis is increased in lungs from patients with PAH and ET-1 receptor anta-gonists clinically improve patients with PAH. However, the mecha-nisms by which ET-1 affects the pulmonary vessels and the respective roles of ET-A and ET-B receptors in PAH remain a mat-ter of debate. Methods We investigate in lung specimens, pulmonary artery smooth muscle cells (PA-SMCs) and endothelial cells (PA-ECs) from 8 PAH patients and 8 controls: (i) ET-1 pulmonary expression, (ii) ET-1 synthesis by both cultured PA-SMCs and PA-ECs, (iii) the effects of ET-1 on PA-SMCs growth and migration, (iiii) the respective role and distribution of ET-A and ET-B receptor subtypes. Results We found that ET-1 synthesis was more marked in lungs from patients with PAH. ET-1 content in the medium was 32-35 fold higher in PA-ECs than in PA-SMCs. In both cell types, ET-1 synthesis was higher in PAH as compared to controls. ET-1 synthesis by PA-SMCs was markedly increased when the cells was stimulated by serotonin. This effect was abolished by fluoxe-tine a serotonin transporter inhibitor. Receptor density in cultured PA-SMCs was 2.3 fold higher in PAH patients than in controls. ET-A receptors predominate over ET-B from both PAH and controls. ET-1 had a weak mitogenic and migratory effect on PA-SMCs. The growth effect was mediated by ET-A, the migratory effect was due to activation of both ET-A and ET-B receptors. These effects was more pronounced in cells from PAH than in controls. Conclusion ET-1, ET-A and ET-B receptors expression are ele-vated in lungs and pulmonary vascular cells from patients with PAH and participate to pulmonary vascular remodelling. These results support the hypothesis that antagonizing endothelin receptors may reduce pulmonary vascular remodelling in PAH patients.