Laurent Savale

Long-term response to calcium-channel blockers in non-idiopathic pulmonary arterial hypertension

AIMS To assess the acute vasodilator response and long-term response to calcium-channel blockers (CCB) in pulmonary arterial hypertension (PAH) with associated conditions. METHODS AND RESULTS The response to acute vasodilator testing [>20% decrease in mean pulmonary artery pressure (mPAP) and total pulmonary resistance] was assessed in 663 consecutive PAH patients with connective tissue disease (CTD; n = 168), portal hypertension (PoPH; n = 153), anorexigen use (n = 127), human immunodeficiency virus infection (HIV; n = 124), congenital heart disease (CHD; n = 50), and pulmonary veno-occlusive disease or capillary haemangiomatosis (PVOD/PCH; n = 41). An acute vasodilator response was observed in 13.4% of PAH-anorexigen patients, 12.2% of PVOD/PCH, 10.1% of CTD, 1.6% of HIV, 1.3% of PoPH, and was absent in CHD. A long-term response to CCB (marked haemodynamic improvement at 3-4 months and New York Heart Association functional class I or II after 1 year) was reported in 9.4% of PAH-anorexigen patients but was rare in HIV, PoPH, CTD (1.6, 0.7, and 0.6%, respectively) and absent in PVOD/PCH. All patients with a long-term CCB response were alive after 5 years; two deaths not related to PAH occurred after this time. Recent criteria for acute response based on the fall in mPAP to <40 mmHg are more specific to detect long-term responders to CCB. CONCLUSION A long-term CCB response was reported in patients with PAH associated with anorexigen use, but was rare in patients with PoPH or HIV and absent in PVOD/PCH, CHD, and the vast majority of CTD. The prognosis of long-term responders was favourable and related to the underlying cause of PAH.

Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

Background— The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib. Methods and Results— This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3–36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (⩽20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%. Conclusions— Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib.

A Hemodynamic Study of Pulmonary Hypertension in Sickle Cell Disease

BACKGROUND The prevalence and characteristics of pulmonary hypertension in adults with sickle cell disease have not been clearly established. METHODS In this prospective study, we evaluated 398 outpatients with sickle cell disease (mean age, 34 years) at referral centers in France. All patients underwent Doppler echocardiography, with measurement of tricuspid-valve regurgitant jet velocity. Right heart catheterization was performed in 96 patients in whom pulmonary hypertension was suspected on the basis of a tricuspid regurgitant jet velocity of at least 2.5 m per second. Pulmonary hypertension was defined as a mean pulmonary arterial pressure of at least 25 mm Hg. RESULTS The prevalence of a tricuspid regurgitant jet velocity of at least 2.5 m per second was 27%. In contrast, the prevalence of pulmonary hypertension as confirmed on catheterization was 6%. The positive predictive value of echocardiography for the detection of pulmonary hypertension was 25%. Among the 24 patients with confirmed pulmonary hypertension, the pulmonary-capillary wedge pressure was 15 mm Hg or less (indicating precapillary pulmonary hypertension) in 11 patients. Patients with confirmed pulmonary hypertension were older and had poorer functional capacity and higher levels of N-terminal pro-brain natriuretic peptide than other patients. In contrast, patients who had a tricuspid regurgitant jet velocity of at least 2.5 m per second without pulmonary hypertension and patients with a tricuspid regurgitant jet velocity of less than 2.5 m per second had similar clinical characteristics. CONCLUSIONS In this study of adults with sickle cell disease, the prevalence of pulmonary hypertension as confirmed on right heart catheterization was 6%. Echocardiographic evaluation alone had a low positive predictive value for pulmonary hypertension. (Funded by the French Ministry of Health and Assistance Publique-Hôpitaux de Paris; ClinicalTrials.gov number, NCT00434902.).

Pulmonary veno-occlusive disease

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension (PH) characterised by preferential remodelling of the pulmonary venules. In the current PH classification, PVOD and pulmonary capillary haemangiomatosis (PCH) are considered to be a common entity and represent varied expressions of the same disease. The recent discovery of biallelic mutations in the EIF2AK4 gene as the cause of heritable PVOD/PCH represents a major milestone in our understanding of the molecular pathogenesis of PVOD. Although PVOD and pulmonary arterial hypertension (PAH) share a similar clinical presentation, with features of severe precapillary PH, it is important to differentiate these two conditions as PVOD carries a worse prognosis and life-threatening pulmonary oedema may occur following the initiation of PAH therapy. An accurate diagnosis of PVOD based on noninvasive investigations is possible utilising oxygen parameters, low diffusing capacity for carbon monoxide and characteristic signs on high-resolution computed tomography of the chest. No evidence-based medical therapy exists for PVOD at present and lung transplantation remains the preferred definitive therapy for eligible patients. Recent advances such as discovery of the genetic basis of PVOD will pave way for future translational research http://ow.ly/YldhC

Shortened Telomeres in Circulating Leukocytes of Patients with Chronic Obstructive Pulmonary Disease

RATIONALE Telomere length is considered a marker for biological aging. Chronic obstructive pulmonary disease (COPD) may be associated with premature aging. OBJECTIVES To test the hypothesis that patients with COPD experience accelerated telomere shortening and that inflammation is linked to this process. METHODS We measured telomere length, using a quantitative polymerase chain reaction-based method, and plasma levels of various cytokines in 136 patients with COPD, 113 age- and sex-matched smokers, and 42 nonsmokers with normal lung function. MEASUREMENTS AND MAIN RESULTS Median (range) telomere length ratio was significantly lower in patients with COPD (0.57 [0.23-1.18]) than in control smokers (0.79 [0.34-1.58]) or nonsmokers (0.85 [0.38-1.55]) (P < 0.001). The difference remained highly significant when using logistic regression analysis adjusted for age, sex, and tobacco exposure. Both females and males with COPD had shorter telomere length than same-sex control subjects. Telomere length was related to age in patients and control subjects but was shorter in patients than in control subjects in all age groups. No relationship was found between telomere length and tobacco exposure in patients or control subjects, with no difference between control smokers and nonsmokers. In patients with COPD, telomere length was related to PaO2 (P < 0.001) and PaCO2 (P < 0.001) but not to lung function parameters or the BODE Index. Patients with COPD also had elevated plasma levels of various cytokines, interleukin-6 correlating negatively with telomere length (P < 0.001). CONCLUSIONS Given that in vivo telomere length reflects cellular turnover and exposure to oxidative and inflammatory damage, our data support accelerated aging in COPD.

Portopulmonary Hypertension : Survival and Prognostic Factors

RATIONALE 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. OBJECTIVES To analyze long-term survival in a large cohort of patients with PoPH with the aim of determining the independent variables affecting survival. METHODS 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. MEASUREMENTS AND MAIN RESULTS 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. CONCLUSIONS 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.

Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study

Patients with severe pulmonary arterial hypertension (PAH) in New York Heart Association (NYHA) functional class (FC) III/IV have a poor prognosis, despite survival benefits being demonstrated with intravenous epoprostenol. In this pilot study, the efficacy and safety of a triple combination therapy regimen in patients with severe PAH was investigated. Data from newly diagnosed NYHA FC III/IV PAH patients (n=19) initiated on upfront triple combination therapy (intravenous epoprostenol, bosentan and sildenafil) were collected retrospectively from a prospective registry. Significant improvements in 6-min walk distance and haemodynamics were observed after 4 months’ triple combination therapy in 18 patients (p<0.01); 17 patients had improved to NYHA FC I or II. One patient was not included in the month 4 assessment (due to an emergency lung transplant in month 3). At the final evaluation (mean±sd 32±19 months), all 18 patients had sustained clinical and haemodynamic improvement. Overall survival estimates for the triple combination cohort were 100% at 1, 2 and 3 years. Expected survival calculated from the French equation was 75% (95% CI 68–82%), 60% (95% CI 50–70%) and 49% (95% CI 38–60%) at 1, 2 and 3 years, respectively. This pilot study provides preliminary evidence of the long-term benefits of upfront triple combination therapy in patients with severe PAH. Upfront triple combination therapy shows promising long-term efficacy in severe pulmonary arterial hypertension http://ow.ly/tKgHX

HIV-associated pulmonary arterial hypertension: survival and prognostic factors in the modern therapeutic era.

Objectives:To examine baseline characteristics and outcome, and to determine variables affecting survival in patients with pulmonary arterial hypertension (PAH) associated with HIV infection (PAH-HIV) in the modern era of highly-active antiretroviral therapy (HAART) and specific PAH therapy. Design:Retrospective review of data from PAH-HIV patients without other associated risk factors for PAH, and comparison with previous series. Methods:Data were reviewed for 77 consecutive patients treated at the French Reference Centre for Pulmonary Hypertension between October 2000 and January 2008. Results were expressed as median [1st–3rd quartile] values. Results:At diagnosis of PAH, 81% patients were on HAART, 79% had a CD4+ count more than 200 cells/μl and 49% had undetectable HIV load. New York Heart Association functional class assessment was II (22%), III (69%), and IV (9%). Six-minute walk distance (6MWD) was 375 [288–421] m, and pulmonary vascular resistance was 689 [524–852] dyn s/cm5. All patients received HAART irrespective of HIV disease stage. Specific PAH therapy was started in 50 patients and led to improvements in 6MWD and haemodynamic parameters. In patients who did not receive specific PAH therapy, 6MWD improved but haemodynamics did not change. Overall survival rate was 88% at 1 year and 72% at 3 years. On multivariate analysis, cardiac index more than 2.8 l/min per m2 and CD4+ lymphocyte count more than 200 cells/μl were independent predictors of survival. Conclusion:In patients with PAH-HIV, HAART seems unable to improve haemodynamic parameters. Prognosis in PAH-HIV is mainly related to CD4+ lymphocyte count and cardiac function.

Role for Interleukin-6 in COPD-Related Pulmonary Hypertension

BACKGROUND Pulmonary artery remodeling triggered by alveolar hypoxia is considered the main mechanism of pulmonary hypertension (PH) in COPD patients. We hypothesized that the risk for PH in COPD is increased by an elevation in the proinflammatory cytokines interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), and IL-1beta, as well as by specific genetic polymorphisms of these cytokines. METHODS We assessed cytokine plasma levels and the polymorphisms G(-174)C IL-6, C(-511)T IL-1beta, and A(-2518)G MCP-1 in 148 COPD patients (recruited at two centers) with right heart catheterization data and 180 control subjects including smokers and nonsmokers. Human pulmonary artery smooth muscle cells (PA-SMCs) were cultured for IL-6 messenger RNA assays under normoxic and hypoxic conditions. RESULTS Patients with PH (mean pulmonary artery pressure [PAP], >or= 25 mm Hg) had lower Pao(2) and higher plasma IL-6 values than those without PH; there were no differences in terms of pulmonary function test results or CT scan emphysema scores. Plasma IL-6 correlated with mean PAP (r = 0.39; p < 0.001) and was included in a multiple stepwise regression analysis, with mean PAP as the dependent variable. In patients with the IL-6 GG genotype, the mean PAP value was significantly higher and PH was more common than in CG or CC patients (adjusted odds ratio, 4.32; 95% confidence interval, 1.96 to 9.54). Exposure to 4 h of hypoxia led to an about twofold increase in IL-6 messenger RNA in cultured human PA-SMCs. CONCLUSIONS Inflammation, most likely involving IL-6, may contribute substantially to PH complicating COPD.

RhoA and Rho kinase activation in human pulmonary hypertension: role of 5-HT signaling.

RATIONALE The complex and multifactorial pathogenesis of pulmonary hypertension (PH) involves constriction, remodeling, and in situ thrombosis of pulmonary vessels. Both serotonin (5-HT) and Rho kinase signaling may contribute to these alterations. OBJECTIVES To investigate possible links between the 5-HT transporter (5-HTT) and RhoA/Rho kinase pathways, as well as their involvement in the progression of human and experimental PH. METHODS Biochemical and functional analyses of lungs, platelets, and pulmonary artery smooth muscle cells (PA-SMCs) from patients with idiopathic PH (iPH) and 5-HTT overexpressing mice. MEASUREMENTS AND MAIN RESULTS Lungs, platelets, and PA-SMCs from patients with iPH were characterized by marked elevation in RhoA and Rho kinase activities and a strong increase in 5-HT binding to RhoA indicating RhoA serotonylation. The 5-HTT inhibitor fluoxetine and the type 2 transglutaminase inhibitor monodansylcadaverin prevented 5-HT-induced RhoA serotonylation and RhoA/Rho kinase activation, as well as 5-HT-induced proliferation of PA-SMCs from iPH patients that was also inhibited by the Rho kinase inhibitor fasudil. Increased Rho kinase activity, RhoA activation, and RhoA serotonylation were also observed in lungs from SM22-5-HTT(+)mice, which overexpress 5-HTT in smooth muscle and spontaneously develop PH. Treatment of SM22-5-HTT(+) mice with either fasudil or fluoxetine limited PH progression and RhoA/Rho kinase activation. CONCLUSIONS RhoA and Rho kinase activities are increased in iPH, in association with enhanced RhoA serotonylation. Direct involvement of the 5-HTT/RhoA/Rho kinase signaling pathway in 5-HT-mediated PA-SMC proliferation and platelet activation during PH progression identify RhoA/Rho kinase signaling as a promising target for new treatments against PH.