Pulmonary vascular disorders in portal hypertension.

The wide spectrum of pulmonary vascular disorders in liver disease and portal hypertension ranges from the hepatopulmonary syndrome characterized by intrapulmonary vascular dilatations, to pulmonary hypertension (portopulmonary hypertension), in which pulmonary vascular resistance is elevated. Since hepatopulmonary syndrome and portopulmonary hypertension have been reported in patients with nonhepatic portal hypertension, the common factor that determines their development must be portal hypertension. The clinical presentations are very different, with gas exchange impairment in the hepatopulmonary syndrome and haemodynamic failure in portopulmonary hypertension. The severity of hepatopulmonary syndrome seems to parallel the severity of liver failure, whereas no simple relationship has been identified between hepatic impairment and the severity of portopulmonary hypertension. Resolution of hepatopulmonary syndrome is common after liver transplantation, which has an uncertain effect in portopulmonary hypertension. The pathophysiology of both syndromes may involve vasoactive mediators and angiogenic factors.

Platelet-derived growth factor expression in primary pulmonary hypertension: comparison of HIV seropositive and HIV seronegative patients.

Primary pulmonary hypertension (PPH) is characterized by intimal fibrosis and cell proliferation (including fibroblasts, smooth muscle and endothelial cells) in the distal pulmonary arterial tree. Considerable interest has been generated by recent reports of PPH in human immunodeficiency virus (HIV)-1-infected individuals. Although the lack of evidence for a pulmonary artery infection has suggested that in such cases HIV may act through mediator release rather than by direct endothelial infection, the mechanisms underlying HIV-associated PPH remain poorly defined. Platelet-derived growth factor (PDGF) has the ability to induce smooth muscle cell and fibroblast proliferation and migration. Given these considerations, we have attempted to document a possible role for PDGF in PPH occurring in HIV seropositive and seronegative patients. Using semiquantitative polymerase chain reaction (PCR), PDGF A-chain messenger ribonucleic acid (mRNA) expression was analysed in surgical lung biopsies from 13 HIV seronegative patients and one HIV seropositive patient, all displaying severe PPH. In parallel, lung samples from two patients with HIV-1-associated PPH were studied by immunohistochemistry and in situ hybridization. Results were compared to those obtained in three HIV-1-infected individuals with no pulmonary complication (as demonstrated by clinical, radiological, bacteriological, and necropsy findings) and five control lung biopsies. As compared to controls, PDGF A-chain mRNA expression is elevated in lung biopsies from patients displaying PPH (p=0.029). In HIV-1-associated PPH, interstitial perivascular cells expressing PDGF A-chain mRNA and protein could be detected by in situ hybridization and immunohistochemistry, respectively. Platelet-derived growth factor expression is elevated in lung biopsies of patients displaying primary pulmonary hypertension. Growth factors such as platelet-derived growth factor may play a part in the initiation and/or progression of primary pulmonary hypertension.

[Favorable outcome of a severe carcinoid cardiopathy after complete resection of the primary ovarian tumor]. / Evolution favorable d'une cardiopathie carcinoïde sévère après résection complète de la tumeur ovarienne responsable.

Carcinoid heart disease induced by a primary ovarian carcinoid tumor is very uncommon but offers the opportunity to study its specific outcome. Indeed, unlike to other carcinoid syndromes that occur in the setting of liver metastasis, a complete removal of the primary carcinoid ovarian tumor is often possible in such cases. We report a case of severe carcinoid heart disease secondary to a carcinoid ovarian tumor. Its interest is related to the exhaustive assessment of the cardiopathy and its complete regression after removal of the ovarian tumor. This outcome emphasizes the need for a as complete as possible reduction of humoral secretions in carcinoid heart disease by medical or surgical therapies before discussing valve replacement surgery.

Prognostic value of pulmonary hypertension in patients with chronic interstitial lung disease referred for lung or heart-lung transplantation.

BACKGROUND: The purpose of this study was to identify precise and reliable prognostic parameters in patients affected by serious chronic interstitial lung disease, who were undergoing screening for lung or heart-lung transplantation. METHODS: Hemodynamic and respiratory function parameters of 67 patients (43 with idiopathic pulmonary fibrosis, 18 with histiocytosis X, and 6 with lymphangioleiomyomatosis) undergoing clinical screening for lung transplantation. RESULTS: Statistical analysis showed that hemodynamic and respiratory function parameters in patients affected by histiocytosis X and idiopathic pulmonary fibrosis were not related to survival time. Moreover, the degree of pulmonary hypertension showed no correlation between respiratory function parameters in all the groups of diseases examined. Patients affected with histiocytosis X, even with higher degrees of pulmonary hypertension, had a better survival rate (p < 0.0005) compared with patients with idiopathic pulmonary fibrosis. CONCLUSIONS: Hemodynamic and respiratory parameters obtained during the clinical screening for lung transplantation do not predict survival and cannot be used as prognostic indicators.

Medical management of primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is a poorly understood, progressive disease that is characterized by elevation of pulmonary artery pressure and vascular resistance, leading to right ventricular failure and death within 2-3 yrs after diagnosis. Based upon the concept that vasoconstriction and thrombotic occlusion of resistance vessels precipitate this process, vasodilator therapy and anticoagulation have become the main strategies for improving survival in these patients. Whereas, a few years ago, medical therapy of primary pulmonary hypertension was perceived as a bridging therapy to lung or heart lung transplantation, modes of therapy are being clinically tested at this time to offer an alternative to the surgical treatment of this disease. However, no selective pulmonary vasodilator is yet available. Therefore, and because of the potential hazards of vasodilator treatment, standardized haemodynamic testing is performed prior to initiation of vasodilator treatment. In this update, the currently available compounds both for haemodynamic testing and chronic therapy, their mode of action, method of administration and efficacy are reviewed.

Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group.

BACKGROUND: Recently, a cluster of patients was observed in France in whom primary pulmonary hypertension developed in patients exposed to derivatives of fenfluramine in appetite suppressants (anorexic agents), which are used for weight control. We investigated the potential role of anorexic agents and other suspected risk factors for primary pulmonary hypertension. METHODS: In a case-control study, we assessed 95 patients with primary pulmonary hypertension from 35 centers in France, Belgium, the United Kingdom, and the Netherlands and 355 controls recruited from general practices and matched to the patients' sex and age. RESULTS: The use of anorexic drugs (mainly derivatives of fenfluramine) was associated with an increased risk of primary pulmonary hypertension (odds ratio with any anorexic-drug use, 6.3; 95 percent confidence interval, 3.0 to 13.2). For the use of anorexic agents in the preceding year, the odds ratio was 10.1 (95 percent confidence interval, 3.4 to 29.9). When anorexic drugs were used to a total of more than three months, the odds ratio was 23.1 (95 percent confidence interval, 6.9 to 77.7). We also confirmed an association with several previously identified risk factors: a family history of pulmonary hypertension, infection with the human immunodeficiency virus, cirrhosis, and use of cocaine or intravenous drugs. CONCLUSIONS: The use of anorexic drugs was associated with the development of primary pulmonary hypertension. Active surveillance for this disease should be considered, particularly since their use is expected to increase in the near future.

Clinical significance of the pulmonary vasodilator response during short-term infusion of prostacyclin in primary pulmonary hypertension.

BACKGROUND: The short-term vasodilator response to prostacyclin (PGI2) in patients with primary pulmonary hypertension (PPH) is not only unpredictable but also extremely variable in magnitude. In this retrospective study, we attempted to evaluate in a nonselected population of patients with PPH the degree of vasodilatation achieved during short-term infusion of PGI2 and to investigate whether patients with PPH differed in terms of baseline characteristics and prognoses, according to the level of vasodilatation achieved during initial testing with PGI2. METHODS AND RESULTS: Between 1984 and 1992, 91 consecutive patients with PPH underwent catheterization of the right side of the heart with a short-term vasodilator trial with PGI2 (5 to 10 ng.kg-1.min-1). According to the level of vasodilatation achieved during PGI2 infusion, patients were divided into three groups: nonresponding (NR, n = 40), moderately responding (MR, n = 42), and highly responding (HR, n = 9) patients. All three groups were defined by a decrease in total pulmonary resistance index (TPRi) of < 20%, between 20% and 50%, and > 50%, respectively, relative to control values. Prolonged oral vasodilator therapy was subsequently started only in MR and HR patients. All patients had long-term oral anticoagulant therapy. The survival rate at 2 years (transplant recipients excluded) was significantly higher in HR patients compared with NR and MR patients (62% versus 38% and 47% survivors, respectively; P < .05). Comparisons between groups showed no significant differences in baseline hemodynamics or clinical characteristics except for a longer time between onset of symptoms and diagnosis (ie, first catheterization) of PPH in HR patients than in NR and MR patients (71 +/- 61 versus 35 +/- 34 and 21 +/- 21 months, respectively; P < .05). CONCLUSIONS: In this study, patients with PPH exhibiting a decrease in TPRi > 50% during short-term PGI2 challenge at the time of diagnosis had longer disease evolutions and better prognoses than patients with a lower vasodilator response.

Subcutaneous low-molecular-weight heparin fragmin versus intravenous unfractionated heparin in the treatment of acute non massive pulmonary embolism: an open randomized pilot study.

Low-molecular-weight heparins have been extensively investigated in the treatment of deep venous thrombosis but limited data are available concerning their use in pulmonary embolism. In an open, pilot, randomized study, we compare the safety and efficacy of Fragmin, a low-molecular-weight heparin with those of unfractionated heparin in 60 patients with non massive pulmonary embolism (Miller Index < 20). Thirty one patients received unfractionated heparin intravenously and 29 received a fixed dose of 120 Anti-Xa IU/kg of Fragmin administered subcutaneously twice a day for 10 days. There was no pulmonary embolism recurrence nor major bleeding in either group during the treatment period. The decrease in pulmonary vascular obstruction on perfusion lung scan between day 0 and day 10 was 17 +/- 13% in the Fragmin group and 16 +/- 13% in the heparin group (NS). These results indicate that Fragmin may be a safe and effective treatment of submassive pulmonary embolism.

Increased plasma serotonin in primary pulmonary hypertension.

PURPOSE: Pulmonary hypertension can occur in patients who have disorders associated with altered platelet serotonin storage, including collagen vascular disease and platelet storage pool disease. We tested the hypothesis that primary pulmonary hypertension (PPH) may be also associated with impaired handling of serotonin by platelets, resulting in increased plasma serotonin levels. PATIENTS AND METHODS: We used radioenzymatic assays to measure serotonin in platelets and plasma and serotonin released during in vitro platelet aggregation in 16 patients with PPH, and in 16 normal controls matched for age and sex. Six patients were restudied after heart-lung transplantation to determine whether serotonin abnormalities persisted after pulmonary arterial pressure returned to normal. RESULTS: Patients had decreased platelet serotonin concentration (1.8 +/- 0.6 x 10(-18) mol/platelet versus 3.2 +/- 0.2 x 10(-18) mol/platelet in controls; P < 0.01) and increased plasma serotonin concentration (30.1 +/- 9.2 x 10(-9) mol/L versus 0.6 +/- 0.1 x 10(-9) mol/L in controls; P < 0.001). Serotonin released during in vitro platelet aggregation was higher in patients than in controls. After heart-lung transplantation, platelet serotonin concentrations remained decreased and plasma levels remained increased. CONCLUSIONS: Abnormal handling of serotonin by platelets leading to an increase in plasma serotonin occurs in PPH. The persistent decrease in platelet storage of serotonin after heart-lung transplantation suggests that this platelet abnormality is not secondary to PPH.

Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is characterized by the proliferation of smooth-muscle cells, fibroblasts, and endothelial cells in the walls of small pulmonary arteries. In order to evaluate a role for proinflammatory cytokines in this process, we studied the concentration of interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF alpha) in the serum of 29 patients with severe PPH referred to our center for lung transplantation. Results were compared with those obtained in 15 normal controls and nine patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD-PH). TNF alpha serum levels were within the normal range in each group. This contrasted with increased IL-1 beta serum levels in severe PPH (118 +/- 36 pg/ml, mean +/- SEM) as compared with controls (3 +/- 1 pg/ml, p < 0.001) or COPD-PH patients (3 +/- 1 pg/ml, p < 0.001). IL-6 serum concentrations were also higher in severe PPH (66 +/- 20 pg/ml) than in controls (14 +/- 6 pg/ml, p < 0.01). This study demonstrates increased serum levels of IL-1 beta and IL-6 in severe PPH, and suggests a role for proinflammatory cytokines in PPH.

Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension. A dose-response study and comparison with prostacyclin.

To investigate the capacity of the pulmonary vascular bed to acutely vasodilate, we examined in 35 consecutive patients with primary pulmonary hypertension (PPH), the hemodynamic effects of incremental inhalation periods of an air-NO mixture at different concentrations (10, 20, and 40 ppm), and compared them with those of an acute infusion of prostacyclin (PGI2). An individual pulmonary vasodilator response was defined by a fall in total pulmonary resistance (TPR) > or = 30% relative to mean TPR baseline value. Thirteen patients were responders and 22 were nonresponders to both drugs, and they did not significantly differ in overall baseline characteristics except for mean right atrial pressure (p < 0.03). In responders, both drugs produced similar individual vasodilator response. Changes in mean pulmonary arterial pressure and TPR observed during NO and PGI2 were closely correlated (r2 = 0.9, p < 0.001, and r2 = 0.7, p < 0.01, respectively). The vasodilator response to NO was not concentration-related with a maximal effect obtained at 10 ppm. Combination of both drugs did not lead to any additive vasodilator response. Unlike PGI2, NO did not induce any systemic effect, no adverse reaction, but a moderate increase in methemoglobin. Inhaled NO at low dose (10 ppm) appears to be an effective, safe, and reliable substitute for PGI2 in screening for acute pulmonary vasodilator responsiveness during therapeutic assessment of patients with PPH.

Surgical management of unresolved pulmonary embolism. A personal series of 72 patients.

Chronic thromboembolic pulmonary hypertension (CT-E PH) is a rare and aberrant outcome of acute pulmonary embolism. Because it has become a potentially curable form of pulmonary hypertension, the frequency of recognized cases has increased. We report a case series of 72 patients with CT-E PH evaluated in our institution between 1984 and 1993, and discuss diagnostic clues and therapeutic approaches. All patients complained of dyspnea on exertion, a history of acute thromboembolic event, and lung murmurs were found in 60% and 17% of patients, respectively. The presence of a disorder of coagulation was found in 30% of the patients tested, the most common abnormality being lupus anticoagulant. The key noninvasive study for diagnosis was the lung perfusion scan which showed at least one segmental or larger perfusion defect in all patients. Pulmonary angiography confirmed the diagnosis in all cases, and sometimes associated to intravascular ultrasound imaging, established the feasibility of thromboendarterectomy. Medical therapy included the use of long-term oral anticoagulant, and in the case of lower limb venous thrombosis, inferior vena cava filtration. Finally two surgical procedures were discussed in selected patients: thromboendarterectomy and lung transplantation. Since 1988, eight patients have benefited from lung transplantation (six patients are still alive), and 11 patients underwent thromboendarterectomy which was successful in 9 patients with a dramatic functional and hemodynamic improvement.

[Morphological and functional study of pulmonary arteries by MRI]. / Etude morphologique et fonctionnelle des artères pulmonaires par l'IRM.

This article presents an exhaustive review of MRI in the assessment of the pulmonary arteries (sequences, normal results, clinical signs of the main diseases). Its current preferential indications are: the study of the main pulmonary artery trunks (primary tumours, proximal embolism, caliber abnormalities, anatomical relations with central tumours), the assessment and post-treatment follow-up of pulmonary arterial malformations. Angio-MRI is currently being developed and, in the near future, should allow the reliable diagnosis of pulmonary embolism and will therefore be indicated alongside spiral computed tomography. MRI also allows functional assessment of the right circulation (measurements of circulatory velocity and flow rates). It should rapidly become an examination of choice in the haemodynamic follow-up of patient with pulmonary hypertension and transplant recipients and as an evaluation tool for new drugs.

[Pulmonary arterial hypertension of chronic thromboembolic origin; therapeutic indications]. / Hypertension artérielle pulmonaire d'origine thrombo-embolique chronique; indications thérapeutiques.

Chronic thromboembolic pulmonary hypertension is a rare complication of acute pulmonary embolism. The therapeutic approach to the disease is addressed, based on a series of 81 patients referred to our department between 1984 and 1993. Medical treatment associates long-term anticoagulant therapy and, in some cases, inferior vena cava interruption. Two surgical procedures are available in selected patients: lung transplantation and pulmonary thrombo-endareterectomy. Lung transplantation has been performed in 8 patients since 1988 with 6 survivors with a maximal follow-up of 5 years. Twelve patients underwent pulmonary thromboendareterectomy with in 9 patients a dramatic functional and haemodynamic improvement. Chronic thromboembolism should be systematically investigated as the cause of pulmonary hypertension considering that in selected cases, curative surgery is possible.

Quantification of hemodynamics in primary pulmonary hypertension with magnetic resonance imaging.

The aims of this study were first to analyze pulmonary flow differences between patients with primary pulmonary hypertension (PPH) and volunteers, and second to determine whether magnetic resonance (MR) 3D Fourier encoding velocity imaging is capable of assessing hemodynamics in PPH. Pulmonary and aortic flows were quantified with MR imaging in 13 patients with PPH confirmed by right heart catheterization (RHC) within the same week and in 10 volunteers. MR pulmonary antegrade velocities, acceleration time (defined as the time from the onset of flow to the peak velocity), and arterial distensibility (maximal surface-minimal surface/minimal surface) were significantly different in patients (p < 0.05). MR pulmonary and aortic flow volumes correlated well with each other in the two populations (r = 0.98). Agreement between MR and RHC data was low: for the right cardiac output (mean difference) the 95% confidence interval was -0.88 to -0.22 L/min and for the right stroke volume 2.83 to 9.71 ml. However, the high coefficient correlations found between the two techniques showed that MR data could be used as indicators of right hemodynamics. 3D Fourier encoding-velocity sequence is a reliable noninvasive flow measurement method for the quantification of right hemodynamics in patients with PPH.

Double lung transplantation in situs inversus with Kartagener's syndrome. Paris-Sud University Lung Transplant Group.

En bloc double lung transplantation with bilateral bronchial anastomoses was successfully performed in three patients with complete situs inversus and end-stage Kartagener's syndrome. Dextrocardia was not a technical problem for institution of cardiopulmonary bypass, but a large azygos vein draining the systemic venous return was systematically preserved. The major technical difficulty was restoration of airway continuity, because patients with situs inversus have an inverse direction and length of the main stem bronchi. The right and left main bronchi of the recipients were approached in the aortocaval sinus and transected approximately at 1.5 cm from the carina. The donor right main stem bronchus was divided at its origin and the donor left main stem bronchus was divided proximal to the upper lobe takeoff. The different bronchial angulation was not an obstacle, and airway continuity was reestablished twice with an end-to-end anastomosis and once with a telescopic technique. Because of the midline position of the left atrium and pulmonary artery, the anastomoses with the respective recipient's structures were made as in patients with situs solitus. One patient required a right lower lobectomy because the position of the right side of the heart interfered with lobar expansion. One patient died of obliterative bronchiolitis 36 months after the operation. The remaining two are alive and doing well after 48 and 6 months, respectively.

[Pulmonary arterial hypertension of chronic thrombo-embolic origin. 70 patients]. / Hypertension artérielle pulmonaire d'origine thrombo-embolique chronique. 70 malades.

OBJECTIVES: Chronic thrombo-embolic pulmonary hypertension is a rare and aberrant outcome of acute pulmonary embolism. Because it has become a potentially curable form of pulmonary hypertension, the frequency of recognized cases has increased. We report a case series of 70 patients with chronic thromboembolic pulmonary hypertension evaluated in our institution between 1984 and 1993, and discuss diagnostic clues and therapeutic approaches. RESULTS: All patients complained of dyspnoea on exertion. A history of acute thrombo-embolic events and lung murmurs were found in 60% and 17% of patients respectively. Coagulation disorders were found in 30% of the patients tested; the most common abnormality was lupus anticoagulant. The key non-invasive study for diagnosis was the lung perfusion scan which showed at least one segmental or wider perfusion defects in all patients. Pulmonary angiography confirmed the diagnosis in all cases and, sometimes associated with intravascular ultrasound imaging, established the feasibility of thromboendarterectomy. Medical therapy included the use of long-term oral anticoagulant, and in case of lower limb venous thrombosis, inferior vena cava filtration. Finally two surgical procedures were discussed in selected patients: thromboendarterectomy and lung transplantation. Since 1988, eight patients have benefited from lung transplantation (six patients are still alive) and 11 patients underwent thromboendarterectomy which was successful in 9 patients leading to dramatic functional and haemodynamic improvement. CONCLUSION: Chronic thrombo-embolic pulmonary hypertension is a severe, sometimes fatal, disease which can be successfully treated by pulmonary thromboendartectomy and lung transplantation.