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Papers by rogerio souza

Research paper thumbnail of Patchwork Girl

Research paper thumbnail of Diagnosis, Assessment, and Treatment of Non-Pulmonary Arterial Hypertension Pulmonary Hypertension

Journal of The American College of Cardiology, 2009

Research paper thumbnail of Endothelin1/Endothelin3 Ratio: A Potential Prognostic Factor of Pulmonary Arterial Hypertension

Chest, 2007

Pulmonary arterial hypertension (PAH) is a rare condition characterized by elevated pulmonary art... more Pulmonary arterial hypertension (PAH) is a rare condition characterized by elevated pulmonary artery pressure leading to right-heart failure and death. Endothelin (ET)-1 has been shown to play a significant pathogenic role in PAH. ET-3 has not yet been investigated in PAH. ET-1 and ET-3 plasma concentrations were measured in 33 PAH patients prior to any specific PAH therapy and in 9 control subjects. In PAH patients, hemodynamic parameters measured by right-heart catheterization, 6-min walk distance (6MWD), New York Heart Association (NYHA) functional class, and time until lung transplantation or death were recorded. In patients with PAH, levels of ET-1 were increased while those of ET-3 were decreased, as compared to control subjects (p < 0.005 for both comparisons). ET-1/ET-3 ratio varied little in control subjects, while it increased threefold in PAH patients (p < 0.0001). ET-1 correlated positively with right atrial pressure (RAP), indexed total pulmonary resistance, and negatively with cardiac index and venous saturation of oxygen (Svo(2)). ET-3 correlated positively with 6MWD. ET-1/ET-3 ratio correlated positively with RAP, negatively with Svo(2) and 6MWD, and was also associated with NYHA functional class. ET-1/ET-3 ratio was associated with prognosis in this sample of PAH patients treated with specific therapies. PAH is characterized by elevated ET-1 and ET-1/ET-3 ratio and decreased ET-3 plasma concentrations. All of them correlate with hemodynamic and clinical markers of disease severity. ET-1/ET-3 ratio might be a novel prognostic factor in PAH. These preliminary data should be validated in a large prospective multicenter cohort of PAH patients.

Research paper thumbnail of Platelet-derived Growth Factor Expression and Function in Idiopathic Pulmonary Arterial Hypertension

Rationale: Platelet-derived growth factor (PDGF) promotes the proliferation and migration of pulm... more Rationale: Platelet-derived growth factor (PDGF) promotes the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), and may play a role in the progression of pulmonary arterial hypertension (PAH), a condition characterized by proliferation of PASMCs resulting in the obstruction of small pulmonary arteries. Objectives: To analyze the expression and pathogenic role of PDGF in idiopathic PAH. Methods: PDGF and PDGF receptor mRNA expression was studied by real-time reverse transcription-polymerase chain reaction performed on laser capture microdissected pulmonary arteries from patients undergoing lung transplantation for idiopathic PAH. Immunohistochemistry was used to localize PDGF, PDGF receptors, and phosphorylated PDGFR-b. The effects of imatinib on PDGF-B-induced proliferation and chemotaxis were tested on human PASMCs. Measurements and Main Results: PDGF-A, PDGF-B, PDGFR-a, and PDGFR-b mRNA expression was increased in small pulmonary arteries from patients displaying idiopathic PAH, as compared with control subjects. Western blot analysis revealed a significant increase in protein expression of PDGFR-b in PAH lungs, as compared with control lungs. In small remodeled pulmonary arteries, PDGF-A and PDGF-B mainly localized to PASMCs and endothelial cells (perivascular inflammatory infiltrates, when present, showed intensive staining), PDGFR-a and PDGFR-b mainly stained PASMCs and to a lesser extent endothelial cells. Proliferating pulmonary vascular lesions stained phosphorylated PDGFR-b. PDGF-BB-induced proliferation and migration of PASMCs were inhibited by imatinib. This effect was not due to PASMC apoptosis. Conclusions: PDGF may play an important role in human PAH. Novel therapeutic strategies targeting the PDGF pathway should be tested in clinical trials.

Research paper thumbnail of Pulmonary artery distensibility in pulmonary arterial hypertension: an MRI pilot study

European Respiratory Journal, 2007

Pulmonary arterial hypertension (PAH) is a disease of the small vessels in which there is a subst... more Pulmonary arterial hypertension (PAH) is a disease of the small vessels in which there is a substantial increase in pulmonary vascular resistance leading to right ventricle failure and death. Invasive haemodynamic evaluation is mandatory not only for diagnosis confirmation but also to address prognosis and eligibility for the use of calcium-channel blockers through an acute vasodilator challenge. Noninvasive surrogate response markers to the acute vasodilator test have been sought.

Research paper thumbnail of Effect of bosentan treatment on surrogate markers in pulmonary arterial hypertension

Current Medical Research and Opinion, 2005

The aim of this study was to evaluate the effect of the oral dual ET(A)/ET(B) receptor antagonist... more The aim of this study was to evaluate the effect of the oral dual ET(A)/ET(B) receptor antagonist bosentan on different surrogate markers in patients with pulmonary arterial hypertension (PAH). Prospective, open label, uncontrolled study in a University Hospital in Brazil. Fifteen PAH patients (11 females) with mean age of 40 +/- 11 years (5 in WHO functional class II, 10 in class III). All patients were investigated at baseline and after 16 weeks of bosentan treatment. We used the following surrogate markers for patients' evaluation: 6-min walk test, quality of life questionnaire (Short Form SF-36) and N-terminal proBNP (B type natriuretic peptide) fraction levels in blood. Between the evaluation at baseline and week 16, the 6-min walk test distance changed from 396 +/- 135 to 434 +/- 137 m (p < 0.05). Each of the eight domains of the SF-36 was significantly improved. Mean NT-proBNP levels were decreased from a mean of 1670 pg/mL to 1010 pg/mL (p = 0.01). The study suggests that bosentan treatment results in the improvement of different kinds of surrogate markers independently of their specificity to reflect functional capacity, quality of life and myocardial stress. It is concluded that the combined use of these different markers may be an alternative endpoint for future short duration clinical trials.

Research paper thumbnail of Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension

European Respiratory Journal, 2007

Pulmonary hypertension is characterised by a progressive increase in pulmonary arterial resistanc... more Pulmonary hypertension is characterised by a progressive increase in pulmonary arterial resistance due to endothelial and smooth muscle cell proliferation resulting in chronic obstruction of small pulmonary arteries. There is evidence that inflammatory mechanisms may contribute to the pathogenesis of human and experimental pulmonary hypertension.

Research paper thumbnail of N-terminal-pro-brain natriuretic peptide as a haemodynamic marker in idiopathic pulmonary arterial hypertension

European Respiratory Journal, 2005

Patients with idiopathic pulmonary arterial hypertension usually undergo acute vasodilator tests ... more Patients with idiopathic pulmonary arterial hypertension usually undergo acute vasodilator tests with nitric oxide (NO) for haemodynamic evaluation and therapeutical planning. The aim of this study was to evaluate the link between the variation of N-terminal (NT)-pro-brain natriuretic peptide (BNP) levels and haemodynamic parameters during the acute vasodilator test.

Research paper thumbnail of Cardiopulmonary Manifestations of Hepatosplenic Schistosomiasis

Research paper thumbnail of Portopulmonary Hypertension: Survival and Prognostic Factors

American Journal of Respiratory and Critical Care Medicine, 2008

Portopulmonary hypertension (PoPH) can be defined as elevation of pulmonary arterial pressure and... more Portopulmonary hypertension (PoPH) can be defined as elevation of pulmonary arterial pressure and pulmonary vascular resistance in the setting of portal hypertension. Survival results in PoPH are contrasting, and prognostic factors need to be identified. To analyze long-term survival in a large cohort of patients with PoPH with the aim of determining the independent variables affecting survival. We retrospectively analyzed charts of all patients referred to the French Referral Center for pulmonary arterial hypertension with the diagnosis of PoPH between 1984 and 2004. The study population comprised 154 patients; 57% male. Mean age at diagnosis was 49 +/- 11 years, 60% of patients were in New York Heart Association functional class III-IV, and mean 6-minute walk distance was 326 +/- 116 m. Hemodynamic measurements showed a mean pulmonary arterial pressure of 53 +/- 13 mm Hg, cardiac index of 2.9 +/- 0.9 L/min/m(2), and pulmonary vascular resistance of 752 +/- 377 dyn/s/cm(5). Portal hypertension was related to cirrhosis in 136 patients, with a severity assessed as follows: Child-Pugh class A 51%, Child-Pugh class B 38%, Child-Pugh class C 11%. Overall survival rates at 1, 3, and 5 yr were 88, 75, and 68%, respectively. Multivariate regression analysis individualized the presence and severity of cirrhosis and cardiac index as major independent prognostic factors. Prognosis in PoPH is mainly related to the presence and severity of cirrhosis and to cardiac function. The place of pulmonary arterial hypertension-specific therapies remains to be determined in the setting of PoPH.

Research paper thumbnail of Updated Clinical Classification of Pulmonary Hypertension

Journal of The American College of Cardiology, 2009

Research paper thumbnail of NT-proBNP as a tool to stratify disease severity in pulmonary arterial hypertension

Respiratory Medicine, 2007

The recent development of treatment modalities for patients with idiopathic pulmonary arterial hy... more The recent development of treatment modalities for patients with idiopathic pulmonary arterial hypertension has been based on the evaluation of many different markers such as functional capacity, addressed by NYHA classification, six-minute walk test (6 MWT) and hemodynamic parameters. The aim of this study was to evaluate the correlation of N-terminal fragment (NT-proBNP) with other markers in IPAH and its potential for patient stratification.

Research paper thumbnail of Intravenous Epoprostenol in Inoperable Chronic Thromboembolic Pulmonary Hypertension

Journal of Heart and Lung Transplantation, 2007

Background: Pulmonary thromboendarterectomy may be a cure for patients with chronic thromboemboli... more Background: Pulmonary thromboendarterectomy may be a cure for patients with chronic thromboembolic pulmonary hypertension (CTEPH) with proximal obstruction. Conversely, short-term prognosis is poor for inoperable CTEPH patients with distal obstruction. Vascular remodeling lesions can be found in lungs of patients with CTEPH. Little is known about epoprostenol therapy in inoperable distal CTEPH patients.

Research paper thumbnail of Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases

European Respiratory Journal, 2008

The aim of the present study was to describe a large cohort of fenfluramineassociated pulmonary a... more The aim of the present study was to describe a large cohort of fenfluramineassociated pulmonary arterial hypertension (fen-PAH) and its possible prognostic markers.

Research paper thumbnail of Clinical Outcomes of Pulmonary Arterial Hypertension in Carriers of BMPR2 Mutation

American Journal of Respiratory and Critical Care Medicine, 2008

Rationale: Activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) mutation is a ca... more Rationale: Activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) mutation is a cause of hereditary hemorrhagic telangiectasia (HHT) and/or heritable pulmonary arterial hypertension (PAH). Objectives: To describe the characteristics of patients with PAH carrying an ACVRL1 mutation. Methods: We reviewed clinical, functional, and hemodynamic characteristics of 32 patients with PAH carrying an ACVRL1 mutation, corresponding to 9 patients from the French PAH Network and 23 from literature analysis. These cases were compared with 370 patients from the French PAH Network (93 with a bone morphogenetic protein receptor type 2 [BMPR2] mutation and 277 considered as idiopathic cases without identified mutation). Distribution of mutations in the ACVRL1 gene in patients with PAH was compared with the HHT Mutation Database. Measurements and Main Results: At diagnosis, ACVRL1 mutation carriers were significantly younger (21.8 6 16.7 yr) than BMPR2 mutation carriers and noncarriers (35.7 6 14.9 and 47.6 6 16.3 yr, respectively; P , 0.0001). In seven of the nine patients from the French PAH Network, PAH diagnosis preceded manifestations of HHT. ACVRL1 mutation carriers had better hemodynamic status at diagnosis, but none responded to acute vasodilator challenge and they had shorter survival when compared with other patients with PAH despite similar use of specific therapies. ACVRL1 mutations in exon 10 were more frequently observed in patients with PAH, as compared with what was observed in the HHT Mutation Database (33.3 vs. 5%; P , 0.0001). Conclusions: ACVRL1 mutation carriers were characterized by a younger age at PAH diagnosis. Despite less severe initial hemodynamics and similar management, these patients had worse prognosis compared with other patients with PAH, suggesting more rapid disease progression.

Research paper thumbnail of Long term imatinib treatment in pulmonary arterial hypertension

Research paper thumbnail of Cardiopulmonary Manifestations of Hepatosplenic Schistosomiasis

Circulation, 2009

Background -Schistosomiasis is a highly prevalent disease with Ͼ200 million infected people. Pulm... more Background -Schistosomiasis is a highly prevalent disease with Ͼ200 million infected people. Pulmonary hypertension is one of the pulmonary manifestations in this disease, particularly in its hepatosplenic presentation. The aim of this study was to determine the prevalence of pulmonary hypertension in schistosomiasis patients with the hepatosplenic form of the disease. Methods and Results -All patients with hepatosplenic schistosomiasis followed up at the gastroenterology department of our university hospital underwent echocardiographic evaluation to search for pulmonary hypertension. Patients presenting with systolic pulmonary artery pressure Ͼ40 mm Hg were further evaluated through right heart catheterization. Our study showed an 18.5% prevalence of patients with elevated systolic pulmonary artery pressure at echocardiography. Invasive hemodynamics confirmed the presence of pulmonary hypertension in 7.7% (95% confidence interval, 3.3 to 16.7) of patients, with a prevalence of precapillary (arterial) pulmonary hypertension of 4.6% (95% confidence interval, 1.5 to 12.7). Conclusions -Our study reinforces the role of echocardiography as a screening tool in the investigation of pulmonary hypertension, together with the need for invasive monitoring for a proper diagnosis. We conclude that hepatosplenic schistosomiasis may account for one of the most prevalent forms of pulmonary hypertension worldwide, justifying the development of further studies to evaluate the effect of specific pulmonary hypertension treatment in this particular form of the disease.

Research paper thumbnail of Acute vasodilator test in pulmonary arterial hypertension: Evaluation of two response criteria

Vascular Pharmacology, 2005

The rationale for the acute vasodilator test in idiopathic pulmonary arterial hypertension (IPAH)... more The rationale for the acute vasodilator test in idiopathic pulmonary arterial hypertension (IPAH) is to identify patients who have a 11 vasoreactive component that justifies the use of non-selective vasodilators. We tested the ability of two different response criteria to identify 12 such patients studying 34 patients with IPAH. The hemodynamic data from the right heart catheterization were collected at baseline and post-13 administration of inhaled nitric oxide. We describe the results obtained by two different response criteria: (A) a 20% decrease in indexed 14 pulmonary vascular resistance (PVRi) and in mean pulmonary artery pressure(PAPm)(classic criterion); (B) a fall in PAPm of at least 10 mm 15 Hg to a pressure level of 40 mm Hg or lower(revised criterion).

Research paper thumbnail of Platelet-derived Growth Factor Expression and Function in Idiopathic Pulmonary Arterial Hypertension

American Journal of Respiratory and Critical Care Medicine, 2008

Rationale: Platelet-derived growth factor (PDGF) promotes the proliferation and migration of pulm... more Rationale: Platelet-derived growth factor (PDGF) promotes the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), and may play a role in the progression of pulmonary arterial hypertension (PAH), a condition characterized by proliferation of PASMCs resulting in the obstruction of small pulmonary arteries. Objectives: To analyze the expression and pathogenic role of PDGF in idiopathic PAH. Methods: PDGF and PDGF receptor mRNA expression was studied by real-time reverse transcription-polymerase chain reaction performed on laser capture microdissected pulmonary arteries from patients undergoing lung transplantation for idiopathic PAH. Immunohistochemistry was used to localize PDGF, PDGF receptors, and phosphorylated PDGFR-b. The effects of imatinib on PDGF-B-induced proliferation and chemotaxis were tested on human PASMCs. Measurements and Main Results: PDGF-A, PDGF-B, PDGFR-a, and PDGFR-b mRNA expression was increased in small pulmonary arteries from patients displaying idiopathic PAH, as compared with control subjects. Western blot analysis revealed a significant increase in protein expression of PDGFR-b in PAH lungs, as compared with control lungs. In small remodeled pulmonary arteries, PDGF-A and PDGF-B mainly localized to PASMCs and endothelial cells (perivascular inflammatory infiltrates, when present, showed intensive staining), PDGFR-a and PDGFR-b mainly stained PASMCs and to a lesser extent endothelial cells. Proliferating pulmonary vascular lesions stained phosphorylated PDGFR-b. PDGF-BB-induced proliferation and migration of PASMCs were inhibited by imatinib. This effect was not due to PASMC apoptosis. Conclusions: PDGF may play an important role in human PAH. Novel therapeutic strategies targeting the PDGF pathway should be tested in clinical trials.

Research paper thumbnail of Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation

Rationale: Activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) mutation is a ca... more Rationale: Activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) mutation is a cause of hereditary hemorrhagic telangiectasia (HHT) and/or heritable pulmonary arterial hypertension (PAH). Objectives: To describe the characteristics of patients with PAH carrying an ACVRL1 mutation. Methods: We reviewed clinical, functional, and hemodynamic characteristics of 32 patients with PAH carrying an ACVRL1 mutation, corresponding to 9 patients from the French PAH Network and 23 from literature analysis. These cases were compared with 370 patients from the French PAH Network (93 with a bone morphogenetic protein receptor type 2 [BMPR2] mutation and 277 considered as idiopathic cases without identified mutation). Distribution of mutations in the ACVRL1 gene in patients with PAH was compared with the HHT Mutation Database. Measurements and Main Results: At diagnosis, ACVRL1 mutation carriers were significantly younger (21.8 6 16.7 yr) than BMPR2 mutation carriers and noncarriers (35.7 6 14.9 and 47.6 6 16.3 yr, respectively; P , 0.0001). In seven of the nine patients from the French PAH Network, PAH diagnosis preceded manifestations of HHT. ACVRL1 mutation carriers had better hemodynamic status at diagnosis, but none responded to acute vasodilator challenge and they had shorter survival when compared with other patients with PAH despite similar use of specific therapies. ACVRL1 mutations in exon 10 were more frequently observed in patients with PAH, as compared with what was observed in the HHT Mutation Database (33.3 vs. 5%; P , 0.0001). Conclusions: ACVRL1 mutation carriers were characterized by a younger age at PAH diagnosis. Despite less severe initial hemodynamics and similar management, these patients had worse prognosis compared with other patients with PAH, suggesting more rapid disease progression.

Research paper thumbnail of Patchwork Girl

Research paper thumbnail of Diagnosis, Assessment, and Treatment of Non-Pulmonary Arterial Hypertension Pulmonary Hypertension

Journal of The American College of Cardiology, 2009

Research paper thumbnail of Endothelin1/Endothelin3 Ratio: A Potential Prognostic Factor of Pulmonary Arterial Hypertension

Chest, 2007

Pulmonary arterial hypertension (PAH) is a rare condition characterized by elevated pulmonary art... more Pulmonary arterial hypertension (PAH) is a rare condition characterized by elevated pulmonary artery pressure leading to right-heart failure and death. Endothelin (ET)-1 has been shown to play a significant pathogenic role in PAH. ET-3 has not yet been investigated in PAH. ET-1 and ET-3 plasma concentrations were measured in 33 PAH patients prior to any specific PAH therapy and in 9 control subjects. In PAH patients, hemodynamic parameters measured by right-heart catheterization, 6-min walk distance (6MWD), New York Heart Association (NYHA) functional class, and time until lung transplantation or death were recorded. In patients with PAH, levels of ET-1 were increased while those of ET-3 were decreased, as compared to control subjects (p < 0.005 for both comparisons). ET-1/ET-3 ratio varied little in control subjects, while it increased threefold in PAH patients (p < 0.0001). ET-1 correlated positively with right atrial pressure (RAP), indexed total pulmonary resistance, and negatively with cardiac index and venous saturation of oxygen (Svo(2)). ET-3 correlated positively with 6MWD. ET-1/ET-3 ratio correlated positively with RAP, negatively with Svo(2) and 6MWD, and was also associated with NYHA functional class. ET-1/ET-3 ratio was associated with prognosis in this sample of PAH patients treated with specific therapies. PAH is characterized by elevated ET-1 and ET-1/ET-3 ratio and decreased ET-3 plasma concentrations. All of them correlate with hemodynamic and clinical markers of disease severity. ET-1/ET-3 ratio might be a novel prognostic factor in PAH. These preliminary data should be validated in a large prospective multicenter cohort of PAH patients.

Research paper thumbnail of Platelet-derived Growth Factor Expression and Function in Idiopathic Pulmonary Arterial Hypertension

Rationale: Platelet-derived growth factor (PDGF) promotes the proliferation and migration of pulm... more Rationale: Platelet-derived growth factor (PDGF) promotes the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), and may play a role in the progression of pulmonary arterial hypertension (PAH), a condition characterized by proliferation of PASMCs resulting in the obstruction of small pulmonary arteries. Objectives: To analyze the expression and pathogenic role of PDGF in idiopathic PAH. Methods: PDGF and PDGF receptor mRNA expression was studied by real-time reverse transcription-polymerase chain reaction performed on laser capture microdissected pulmonary arteries from patients undergoing lung transplantation for idiopathic PAH. Immunohistochemistry was used to localize PDGF, PDGF receptors, and phosphorylated PDGFR-b. The effects of imatinib on PDGF-B-induced proliferation and chemotaxis were tested on human PASMCs. Measurements and Main Results: PDGF-A, PDGF-B, PDGFR-a, and PDGFR-b mRNA expression was increased in small pulmonary arteries from patients displaying idiopathic PAH, as compared with control subjects. Western blot analysis revealed a significant increase in protein expression of PDGFR-b in PAH lungs, as compared with control lungs. In small remodeled pulmonary arteries, PDGF-A and PDGF-B mainly localized to PASMCs and endothelial cells (perivascular inflammatory infiltrates, when present, showed intensive staining), PDGFR-a and PDGFR-b mainly stained PASMCs and to a lesser extent endothelial cells. Proliferating pulmonary vascular lesions stained phosphorylated PDGFR-b. PDGF-BB-induced proliferation and migration of PASMCs were inhibited by imatinib. This effect was not due to PASMC apoptosis. Conclusions: PDGF may play an important role in human PAH. Novel therapeutic strategies targeting the PDGF pathway should be tested in clinical trials.

Research paper thumbnail of Pulmonary artery distensibility in pulmonary arterial hypertension: an MRI pilot study

European Respiratory Journal, 2007

Pulmonary arterial hypertension (PAH) is a disease of the small vessels in which there is a subst... more Pulmonary arterial hypertension (PAH) is a disease of the small vessels in which there is a substantial increase in pulmonary vascular resistance leading to right ventricle failure and death. Invasive haemodynamic evaluation is mandatory not only for diagnosis confirmation but also to address prognosis and eligibility for the use of calcium-channel blockers through an acute vasodilator challenge. Noninvasive surrogate response markers to the acute vasodilator test have been sought.

Research paper thumbnail of Effect of bosentan treatment on surrogate markers in pulmonary arterial hypertension

Current Medical Research and Opinion, 2005

The aim of this study was to evaluate the effect of the oral dual ET(A)/ET(B) receptor antagonist... more The aim of this study was to evaluate the effect of the oral dual ET(A)/ET(B) receptor antagonist bosentan on different surrogate markers in patients with pulmonary arterial hypertension (PAH). Prospective, open label, uncontrolled study in a University Hospital in Brazil. Fifteen PAH patients (11 females) with mean age of 40 +/- 11 years (5 in WHO functional class II, 10 in class III). All patients were investigated at baseline and after 16 weeks of bosentan treatment. We used the following surrogate markers for patients' evaluation: 6-min walk test, quality of life questionnaire (Short Form SF-36) and N-terminal proBNP (B type natriuretic peptide) fraction levels in blood. Between the evaluation at baseline and week 16, the 6-min walk test distance changed from 396 +/- 135 to 434 +/- 137 m (p < 0.05). Each of the eight domains of the SF-36 was significantly improved. Mean NT-proBNP levels were decreased from a mean of 1670 pg/mL to 1010 pg/mL (p = 0.01). The study suggests that bosentan treatment results in the improvement of different kinds of surrogate markers independently of their specificity to reflect functional capacity, quality of life and myocardial stress. It is concluded that the combined use of these different markers may be an alternative endpoint for future short duration clinical trials.

Research paper thumbnail of Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension

European Respiratory Journal, 2007

Pulmonary hypertension is characterised by a progressive increase in pulmonary arterial resistanc... more Pulmonary hypertension is characterised by a progressive increase in pulmonary arterial resistance due to endothelial and smooth muscle cell proliferation resulting in chronic obstruction of small pulmonary arteries. There is evidence that inflammatory mechanisms may contribute to the pathogenesis of human and experimental pulmonary hypertension.

Research paper thumbnail of N-terminal-pro-brain natriuretic peptide as a haemodynamic marker in idiopathic pulmonary arterial hypertension

European Respiratory Journal, 2005

Patients with idiopathic pulmonary arterial hypertension usually undergo acute vasodilator tests ... more Patients with idiopathic pulmonary arterial hypertension usually undergo acute vasodilator tests with nitric oxide (NO) for haemodynamic evaluation and therapeutical planning. The aim of this study was to evaluate the link between the variation of N-terminal (NT)-pro-brain natriuretic peptide (BNP) levels and haemodynamic parameters during the acute vasodilator test.

Research paper thumbnail of Cardiopulmonary Manifestations of Hepatosplenic Schistosomiasis

Research paper thumbnail of Portopulmonary Hypertension: Survival and Prognostic Factors

American Journal of Respiratory and Critical Care Medicine, 2008

Portopulmonary hypertension (PoPH) can be defined as elevation of pulmonary arterial pressure and... more Portopulmonary hypertension (PoPH) can be defined as elevation of pulmonary arterial pressure and pulmonary vascular resistance in the setting of portal hypertension. Survival results in PoPH are contrasting, and prognostic factors need to be identified. To analyze long-term survival in a large cohort of patients with PoPH with the aim of determining the independent variables affecting survival. We retrospectively analyzed charts of all patients referred to the French Referral Center for pulmonary arterial hypertension with the diagnosis of PoPH between 1984 and 2004. The study population comprised 154 patients; 57% male. Mean age at diagnosis was 49 +/- 11 years, 60% of patients were in New York Heart Association functional class III-IV, and mean 6-minute walk distance was 326 +/- 116 m. Hemodynamic measurements showed a mean pulmonary arterial pressure of 53 +/- 13 mm Hg, cardiac index of 2.9 +/- 0.9 L/min/m(2), and pulmonary vascular resistance of 752 +/- 377 dyn/s/cm(5). Portal hypertension was related to cirrhosis in 136 patients, with a severity assessed as follows: Child-Pugh class A 51%, Child-Pugh class B 38%, Child-Pugh class C 11%. Overall survival rates at 1, 3, and 5 yr were 88, 75, and 68%, respectively. Multivariate regression analysis individualized the presence and severity of cirrhosis and cardiac index as major independent prognostic factors. Prognosis in PoPH is mainly related to the presence and severity of cirrhosis and to cardiac function. The place of pulmonary arterial hypertension-specific therapies remains to be determined in the setting of PoPH.

Research paper thumbnail of Updated Clinical Classification of Pulmonary Hypertension

Journal of The American College of Cardiology, 2009

Research paper thumbnail of NT-proBNP as a tool to stratify disease severity in pulmonary arterial hypertension

Respiratory Medicine, 2007

The recent development of treatment modalities for patients with idiopathic pulmonary arterial hy... more The recent development of treatment modalities for patients with idiopathic pulmonary arterial hypertension has been based on the evaluation of many different markers such as functional capacity, addressed by NYHA classification, six-minute walk test (6 MWT) and hemodynamic parameters. The aim of this study was to evaluate the correlation of N-terminal fragment (NT-proBNP) with other markers in IPAH and its potential for patient stratification.

Research paper thumbnail of Intravenous Epoprostenol in Inoperable Chronic Thromboembolic Pulmonary Hypertension

Journal of Heart and Lung Transplantation, 2007

Background: Pulmonary thromboendarterectomy may be a cure for patients with chronic thromboemboli... more Background: Pulmonary thromboendarterectomy may be a cure for patients with chronic thromboembolic pulmonary hypertension (CTEPH) with proximal obstruction. Conversely, short-term prognosis is poor for inoperable CTEPH patients with distal obstruction. Vascular remodeling lesions can be found in lungs of patients with CTEPH. Little is known about epoprostenol therapy in inoperable distal CTEPH patients.

Research paper thumbnail of Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases

European Respiratory Journal, 2008

The aim of the present study was to describe a large cohort of fenfluramineassociated pulmonary a... more The aim of the present study was to describe a large cohort of fenfluramineassociated pulmonary arterial hypertension (fen-PAH) and its possible prognostic markers.

Research paper thumbnail of Clinical Outcomes of Pulmonary Arterial Hypertension in Carriers of BMPR2 Mutation

American Journal of Respiratory and Critical Care Medicine, 2008

Rationale: Activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) mutation is a ca... more Rationale: Activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) mutation is a cause of hereditary hemorrhagic telangiectasia (HHT) and/or heritable pulmonary arterial hypertension (PAH). Objectives: To describe the characteristics of patients with PAH carrying an ACVRL1 mutation. Methods: We reviewed clinical, functional, and hemodynamic characteristics of 32 patients with PAH carrying an ACVRL1 mutation, corresponding to 9 patients from the French PAH Network and 23 from literature analysis. These cases were compared with 370 patients from the French PAH Network (93 with a bone morphogenetic protein receptor type 2 [BMPR2] mutation and 277 considered as idiopathic cases without identified mutation). Distribution of mutations in the ACVRL1 gene in patients with PAH was compared with the HHT Mutation Database. Measurements and Main Results: At diagnosis, ACVRL1 mutation carriers were significantly younger (21.8 6 16.7 yr) than BMPR2 mutation carriers and noncarriers (35.7 6 14.9 and 47.6 6 16.3 yr, respectively; P , 0.0001). In seven of the nine patients from the French PAH Network, PAH diagnosis preceded manifestations of HHT. ACVRL1 mutation carriers had better hemodynamic status at diagnosis, but none responded to acute vasodilator challenge and they had shorter survival when compared with other patients with PAH despite similar use of specific therapies. ACVRL1 mutations in exon 10 were more frequently observed in patients with PAH, as compared with what was observed in the HHT Mutation Database (33.3 vs. 5%; P , 0.0001). Conclusions: ACVRL1 mutation carriers were characterized by a younger age at PAH diagnosis. Despite less severe initial hemodynamics and similar management, these patients had worse prognosis compared with other patients with PAH, suggesting more rapid disease progression.

Research paper thumbnail of Long term imatinib treatment in pulmonary arterial hypertension

Research paper thumbnail of Cardiopulmonary Manifestations of Hepatosplenic Schistosomiasis

Circulation, 2009

Background -Schistosomiasis is a highly prevalent disease with Ͼ200 million infected people. Pulm... more Background -Schistosomiasis is a highly prevalent disease with Ͼ200 million infected people. Pulmonary hypertension is one of the pulmonary manifestations in this disease, particularly in its hepatosplenic presentation. The aim of this study was to determine the prevalence of pulmonary hypertension in schistosomiasis patients with the hepatosplenic form of the disease. Methods and Results -All patients with hepatosplenic schistosomiasis followed up at the gastroenterology department of our university hospital underwent echocardiographic evaluation to search for pulmonary hypertension. Patients presenting with systolic pulmonary artery pressure Ͼ40 mm Hg were further evaluated through right heart catheterization. Our study showed an 18.5% prevalence of patients with elevated systolic pulmonary artery pressure at echocardiography. Invasive hemodynamics confirmed the presence of pulmonary hypertension in 7.7% (95% confidence interval, 3.3 to 16.7) of patients, with a prevalence of precapillary (arterial) pulmonary hypertension of 4.6% (95% confidence interval, 1.5 to 12.7). Conclusions -Our study reinforces the role of echocardiography as a screening tool in the investigation of pulmonary hypertension, together with the need for invasive monitoring for a proper diagnosis. We conclude that hepatosplenic schistosomiasis may account for one of the most prevalent forms of pulmonary hypertension worldwide, justifying the development of further studies to evaluate the effect of specific pulmonary hypertension treatment in this particular form of the disease.

Research paper thumbnail of Acute vasodilator test in pulmonary arterial hypertension: Evaluation of two response criteria

Vascular Pharmacology, 2005

The rationale for the acute vasodilator test in idiopathic pulmonary arterial hypertension (IPAH)... more The rationale for the acute vasodilator test in idiopathic pulmonary arterial hypertension (IPAH) is to identify patients who have a 11 vasoreactive component that justifies the use of non-selective vasodilators. We tested the ability of two different response criteria to identify 12 such patients studying 34 patients with IPAH. The hemodynamic data from the right heart catheterization were collected at baseline and post-13 administration of inhaled nitric oxide. We describe the results obtained by two different response criteria: (A) a 20% decrease in indexed 14 pulmonary vascular resistance (PVRi) and in mean pulmonary artery pressure(PAPm)(classic criterion); (B) a fall in PAPm of at least 10 mm 15 Hg to a pressure level of 40 mm Hg or lower(revised criterion).

Research paper thumbnail of Platelet-derived Growth Factor Expression and Function in Idiopathic Pulmonary Arterial Hypertension

American Journal of Respiratory and Critical Care Medicine, 2008

Rationale: Platelet-derived growth factor (PDGF) promotes the proliferation and migration of pulm... more Rationale: Platelet-derived growth factor (PDGF) promotes the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), and may play a role in the progression of pulmonary arterial hypertension (PAH), a condition characterized by proliferation of PASMCs resulting in the obstruction of small pulmonary arteries. Objectives: To analyze the expression and pathogenic role of PDGF in idiopathic PAH. Methods: PDGF and PDGF receptor mRNA expression was studied by real-time reverse transcription-polymerase chain reaction performed on laser capture microdissected pulmonary arteries from patients undergoing lung transplantation for idiopathic PAH. Immunohistochemistry was used to localize PDGF, PDGF receptors, and phosphorylated PDGFR-b. The effects of imatinib on PDGF-B-induced proliferation and chemotaxis were tested on human PASMCs. Measurements and Main Results: PDGF-A, PDGF-B, PDGFR-a, and PDGFR-b mRNA expression was increased in small pulmonary arteries from patients displaying idiopathic PAH, as compared with control subjects. Western blot analysis revealed a significant increase in protein expression of PDGFR-b in PAH lungs, as compared with control lungs. In small remodeled pulmonary arteries, PDGF-A and PDGF-B mainly localized to PASMCs and endothelial cells (perivascular inflammatory infiltrates, when present, showed intensive staining), PDGFR-a and PDGFR-b mainly stained PASMCs and to a lesser extent endothelial cells. Proliferating pulmonary vascular lesions stained phosphorylated PDGFR-b. PDGF-BB-induced proliferation and migration of PASMCs were inhibited by imatinib. This effect was not due to PASMC apoptosis. Conclusions: PDGF may play an important role in human PAH. Novel therapeutic strategies targeting the PDGF pathway should be tested in clinical trials.

Research paper thumbnail of Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation

Rationale: Activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) mutation is a ca... more Rationale: Activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) mutation is a cause of hereditary hemorrhagic telangiectasia (HHT) and/or heritable pulmonary arterial hypertension (PAH). Objectives: To describe the characteristics of patients with PAH carrying an ACVRL1 mutation. Methods: We reviewed clinical, functional, and hemodynamic characteristics of 32 patients with PAH carrying an ACVRL1 mutation, corresponding to 9 patients from the French PAH Network and 23 from literature analysis. These cases were compared with 370 patients from the French PAH Network (93 with a bone morphogenetic protein receptor type 2 [BMPR2] mutation and 277 considered as idiopathic cases without identified mutation). Distribution of mutations in the ACVRL1 gene in patients with PAH was compared with the HHT Mutation Database. Measurements and Main Results: At diagnosis, ACVRL1 mutation carriers were significantly younger (21.8 6 16.7 yr) than BMPR2 mutation carriers and noncarriers (35.7 6 14.9 and 47.6 6 16.3 yr, respectively; P , 0.0001). In seven of the nine patients from the French PAH Network, PAH diagnosis preceded manifestations of HHT. ACVRL1 mutation carriers had better hemodynamic status at diagnosis, but none responded to acute vasodilator challenge and they had shorter survival when compared with other patients with PAH despite similar use of specific therapies. ACVRL1 mutations in exon 10 were more frequently observed in patients with PAH, as compared with what was observed in the HHT Mutation Database (33.3 vs. 5%; P , 0.0001). Conclusions: ACVRL1 mutation carriers were characterized by a younger age at PAH diagnosis. Despite less severe initial hemodynamics and similar management, these patients had worse prognosis compared with other patients with PAH, suggesting more rapid disease progression.