François Chabot

Survival in Patients With Idiopathic, Familial, and Anorexigen-Associated Pulmonary Arterial Hypertension in the Modern Management Era

Background— Novel therapies have recently become available for pulmonary arterial hypertension. We conducted a study to characterize mortality in a multicenter prospective cohort of patients diagnosed with idiopathic, familial, or anorexigen-associated pulmonary arterial hypertension in the modern management era. Methods and Results— Between October 2002 and October 2003, 354 consecutive adult patients with idiopathic, familial, or anorexigen-associated pulmonary arterial hypertension (56 incident and 298 prevalent cases) were prospectively enrolled. Patients were followed up for 3 years, and survival rates were analyzed. For incident cases, estimated survival (95% confidence intervals [CIs]) at 1, 2, and 3 years was 85.7% (95% CI, 76.5 to 94.9), 69.6% (95% CI, 57.6 to 81.6), and 54.9% (95% CI, 41.8 to 68.0), respectively. In a combined analysis population (incident patients and prevalent patients diagnosed within 3 years before study entry; n=190), 1-, 2-, and 3-year survival estimates were 82.9% (95% CI, 72.4 to 95.0), 67.1% (95% CI, 57.1 to 78.8), and 58.2% (95% CI, 49.0 to 69.3), respectively. Individual survival analysis identified the following as significantly and positively associated with survival: female gender, New York Heart Association functional class I/II, greater 6-minute walk distance, lower right atrial pressure, and higher cardiac output. Multivariable analysis showed that being female, having a greater 6-minute walk distance, and exhibiting higher cardiac output were jointly significantly associated with improved survival. Conclusions— In the modern management era, idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension remains a progressive, fatal disease. Mortality is most closely associated with male gender, right ventricular hemodynamic function, and exercise limitation.

Proinflammatory cytokine levels are linked to death in pulmonary arterial hypertension.

To the Editor: Recent data suggest that inflammatory processes play a major role in pulmonary vascular remodelling in patients with idiopathic, heritable, and drug- or toxin-induced (ihd) pulmonary arterial hypertension (PAH) [1, 2]. Besides gaining insight into the mechanisms of PAH, understanding the link between inflammation and PAH may help to identify future therapeutic targets. Different studies have shown increased levels of cytokines in ihdPAH, including the proinflammatory cytokines interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-12p70, tumour necrosis factor (TNF)-α, monocyte chemoattractant protein-1 [2, 3], and the cytokine-like hormone leptin [4]. Advances in highly sensitive multiplex detection technologies present new opportunities to rapidly and specifically measure many cytokines using a limited sample volume [5]; the potential of combining markers rather than focusing on any single biomarker is of considerable interest [3, 6]. Using such an approach, Soon et al. [7] recently suggested that IL-2, IL-6, IL-8, IL-10 and IL-12p70 levels were associated with mortality in patients with ihdPAH. The French Network of Pulmonary Hypertension recently conducted a multicentre prospective cohort study of incident cases of PAH followed up for 3 years [8], from which a biobank of plasma stored as microstraws at -180°C was available. Therefore, we tested our prospective cohort to determine whether cytokines quantified using a highly sensitive multiplex assay predict mortality in patients with ihdPAH. Briefly, consecutive incident cases of PAH presenting at the University Pulmonary Vascular Departments in Clamart (Paris), Marseille, …

Independent Association of Urinary F2-Isoprostanes With Survival in Pulmonary Arterial Hypertension

OBJECTIVES Within the past decade, biochemical markers have emerged as attractive tools to assess pulmonary arterial hypertension (PAH) prognosis, being noninvasive and easily repeatable.The objective of this study was to determine whether biomarkers measured at initial diagnostic right-sided heart catheterization predict 3-year all-cause mortality for incident cases of PAH independently of clinical and hemodynamic parameters. METHODS Patients with incident PAH were enrolled between December 2003 and April 2006 in six centers from the French Network on Pulmonary Hypertension and followed for 3 years.Venous blood samples were taken during right-sided heart catheterization, and analyses were centralized. RESULTS Among 110 enrolled patients, 11 underwent lung or heart/lung transplantation, and 27 died during follow-up. The Kaplan-Meier estimates of survival were 91%, 78%, and 75% at 1, 2, and 3 years, respectively. Plasma big endothelin-1 (hazard ratio [HR] per 1-SD increase, 1.48; 95% CI,1.14-1.92), serum troponin T . 0.01 mg/L (HR, 2.35; 95% CI, 1.05-5.29), and urinary F 2 -isoprostanes(15-F2t -isoprostane) (HR per 1-SD increase, 1.76; 95% CI, 1.31-2.36) were associated with increased unadjusted hazard of death. In multivariate analysis adjusting for patient characteristics, the level of urinary F 2 -isoprostanes was the only biomarker that remained independently associated with increased hazard of death (HR per 1-SD increase, 1.82; 95% CI, 1.28-2.60). CONCLUSIONS This study shows that levels of urinary F 2 -isoprostane, a biomarker of lipid peroxidation,quantified at initial diagnostic right-sided heart catheterization are independently associated with mortality in a cohort of patients with incident PAH.

Interpretation of High Wedge Pressure on Exercise in Patients with Chronic Obstructive Pulmonary Disease

In a retrospective review of patients subjected to right heart catheterization, case records from 109 consecutive patients with chronic obstructive pulmonary disease (COPD) and wedge pressure ≧15 mm Hg on exercise were analyzed. Patients were separated into group 1, resting wedge pressure (Pw) <15 mm Hg and difference between Pw and right atrial pressure (Pra) change on exercise <5 mm Hg (n = 54), group 2, same Pw at rest but increase in Pw on exercise ≧5 mm Hg, being higher than that of Pra (n = 34), and group 3, Pw ≧15 mm Hg at rest (n = 21). The occurrence of left heart disease increased from group 1 to group 3 (19, 53 and 71%, respectively), and the slope of the Pw/stroke index relationship was lowest in group 3. High Pw on exercise can be explained by the pressure rise in the cardiac fossa associated with lower lobe gas trapping in group 1, which showed the most severe airflow limitation, decreased left ventricular compliance in group 2, and heart failure in group 3.

Évaluation pronostique de biomarqueurs dans l’hypertension artérielle pulmonaire: Justification et plan expérimental

CURRENT SITUATION Pulmonary arterial hypertension (PAH) is a serious disease. Its prognostic is based on the functional status quantified by the NYHA class and the 6-min walking test, and the hemodynamic data. The algorithms of treatment are solely based on the hemodynamic data and the functional status. The main objective is to test whether basal concentrations of isoprostanes, Big endotheline 1, ADMA, high sensitivity CRP, NT-Pro-BNP and cardiac troponin T are a 3-year prognostic factor in PAH using a combined criterion: death from any cause and pulmonary or cardiopulmonary transplantation. MATERIALS AND METHODS This is a multicenter, prospective, prognostic, single blinded study (plasma and urinary samples being blinded). The study started in november 2003, running for 2 years, with a 3 year follow-up for each patient. The main inclusion criterion is PAH. The data analysis will use a multivariable Cox model, taking into account the functional and hemodynamic parameters. EXPECTED RESULTS This study will determine whether any of the biomarkers tested provides additional prognostic information in PAH in addition to the functional and hemodynamic parameters.Resume Position du probleme L’hypertension arterielle pulmonaire (HTAP) est une pathologie grave dont l’evaluation du pronostic repose sur l’etude du retentissement fonctionnel et sur les donnees hemodynamiques obtenues par catheterisme. L’algorithme de prise en charge therapeutique est exclusivement base sur les donnees du catheterisme et du retentissement fonctionnel. L’objectif principal est de tester l’hypothese selon laquelle les concentrations basales d’isoprostanes, de Big endotheline 1, d’ADMA, de CRP ultrasensible, de NT-Pro-BNP et de troponine T cardiaque sont un facteur pronostique dans l’HTAP a 3 ans a l’aide d’un critere combine comprenant la mortalite et la transplantation pulmonaire ou cardio-pulmonaire. Materiel et methodes Il s’agit d’une etude multicentrique, prospective, pronostique, en simple-insu (echantillons urinaires et plasmatiques doses en aveugle). L’etude a debute en novembre 2003, avec un suivi de 3 ans prevu par patient, et une duree d’inclusion de 2 ans. Le principal critere d’inclusion est la presence d’une hypertension arterielle pulmonaire. Un modele de Cox sera mis en œuvre en analyse multivariee afin d’identifier un eventuel facteur pronostique, en tenant compte des parametres fonctionnels et hemodynamiques. Resultats attendus Cette etude prospective permettra de determiner si l’un des biomarqueurs etudies presente un interet pronostique independamment des parametres pronostiques fonctionnels et hemodynamiques connus.

Calibrated automated thrombography demonstrates hypercoagulability in patients with idiopathic pulmonary arterial hypertension

INTRODUCTION Pathogenesis of idiopathic pulmonary arterial hypertension (iPAH) includes endothelial dysfunction and in situ thrombosis. A hypercoagulable state has also been postulated but never demonstrated. Our objective was to determine whether patients with iPAH had a hypercoagulable state using calibrated automated thrombography (CAT), a new tool to phenotype coagulation in vitro. PATIENTS AND METHODS 16 patients with iPAH and 29 controls were studied. In vitro platelet dependent coagulation phenotyping by CAT monitored the activity of thrombin generation over time. Plasma levels of soluble thrombomodulin, tissue factor pathway inhibitor (TFPI) and von Willebrand factor (VWF) were measured as endothelial biomarkers. RESULTS Endogenous thrombin potential (ETP) in the absence of activated protein C (APC) tended to be increased in patients compared to controls (1769 versus 1656 nM.min; p=0.053). ETP was higher in the presence of APC 25 nM (ETP-APC) in patients (781 versus 494 nM.min; p=0.005). Five patients had ETP-APC higher than the 95th centile of controls. Other CAT parameters (lag time, peak thrombin and time to peak) were all consistent with some degree of hypercoagulability in patients. Regarding endothelial plasma biomarkers sTM was lower (28.4 versus 40.6 μg/l, p=0.0108) in patients; TFPI antigen and activity (respectively: 14.3 versus 10.5 μg/l, p=0.0167; 1.155 versus 1.070, p=0.0021) and VWF (1300 versus 976%, p=0.0108) were higher in patients. CONCLUSION We have demonstrated that at least some patients with iPAH have a hypercoagulable phenotype.

Metalloproteinase-9 in circulating monocytes in pulmonary hypertension

The role of matrix metalloproteinases (MMPs) in pulmonary hypertension (PH) is complex as MMPs are involved in both the vascular and cardiac remodelling associated with PH. To gain insight into this problem, monocytes were isolated from pulmonary arterial blood in patients suffering from PH, related to chronic obstructive pulmonary disease (n = 6), chronic pulmonary thromboembolism (n = 3) or pulmonary arterial hypertension (n = 8). The severity of PH was associated with decreases in cardiac index (CI) and mixed venous blood oxygen saturation (SO2), and an increase in right atrial pressure (). Monocyte pro‐MMP‐9 content (zymography) was positively correlated with SO2 (r = 0.73, P < 0.05) and CI (r = 0.66, P < 0.05), and negatively with (r = 0.54, P < 0.05); there was no significant correlation with pulmonary vascular resistance. In conclusion, the pro‐MMP‐9 content of circulating monocytes was lower in the more severe forms of PH which showed heart failure suggesting that such MMP enzymatic activity reflects heart failure following pulmonary vascular and myocardial remodelling in PH.

Antiphospholipid antibodies can identify lupus patients at risk of pulmonary hypertension: A systematic review and meta-analysis☆

BACKGROUND Pulmonary hypertension (PH) is a life-threatening condition that may affect outcomes in patients with systemic lupus erythematosus (SLE). The role of antiphospholipid antibodies (aPL) on the risk of PH is controversial. Therefore our objective was to estimate the risk of PH (WHO groups 1-5) including associated pulmonary arterial hypertension (APAH, WHO group 1 only) related to aPL in patients with SLE. METHODS Systematic review and meta-analysis were performed: MEDLINE, EMBASE, Cochrane Library, congress abstracts, and reference lists of eligible studies were searched through 2015. Studies were selected if they included SLE patients with descriptions of the exposure to aPL and the outcomes (PH including APAH). Two reviewers extracted study characteristics and outcome data from published reports. Estimates were pooled using random effects models and sensitivity analyses. PROSPERO registration number: CRD42015016872. RESULTS Of 984 identified abstracts, 31 primary studies (five cohorts, 13 case-control, 13 cross-sectional) met inclusion criteria, including 4480 SLE patients. Prevalence of PH in aPL-positive vs. aPL-negative SLE patients was 12.3% vs. 7.3%, respectively. The overall pooled odds ratio (OR) for PH was 2.28 (95% CI, 1.65 to 3.15) (I2=39%). The risk of APAH was also significantly increased (OR=2.62 [95% CI, 1.11-6.15]). The risk of PH was the highest for lupus anticoagulant (OR=1.96 [95% CI, 1.31-2.92]) and IgG anticardiolipin antibodies (OR=2.64 [95% CI, 1.30-5.36]) while other antibodies were not significantly associated with PH. CONCLUSIONS Among SLE patients, aPL can identify patients at risk for PH and APAH. These findings warrant implementation of effective screening and early treatment strategies.

Lack of Transcription Factor p53 Exacerbates Elastase-Induced Emphysema in Mice

The transcription factor p53 is overexpressed in the lung of patients with emphysema, but it remains unclear if it has a deleterious or protective effect in disease progression. We investigated the role of p53 in the elastase-induced emphysema model and the molecular underlining mechanisms. Wild-type (WT) and p53(-/-) mice were instilled with pancreatic porcine elastase. We quantified emphysema (morphometric analysis), chemokine (C-C motif) ligand 2 (CCL2), and TNF-α in bronchoalveolar lavage (BAL) (ELISA), oxidative stress markers [heme oxygenase 1 (HO1), NAD(P)H dehydrogenase quinone 1 (NQO1), and quantitative RT-PCR], matrix metalloproteinase 12 (MMP12) expression, and macrophage apoptosis (cleaved caspase-3, immunofluorescence). p53 gene expression was up-regulated in the lung of elastase-instilled mice. p53 deletion aggravated elastase-induced emphysema severity, pulmonary inflammation (macrophage and neutrophil numbers and CCL2 and TNF-α levels in BAL), and lung oxidative stress. These findings, except for the increase in CCL2, were reproduced in WT mice transplanted with p53(-/-) bone marrow cells. The increased number of macrophages in p53(-/-) mice was not a consequence of reduced apoptosis or an excess of chemotaxis toward CCL2. Macrophage expression of MMP12 was higher in p53(-/-) mice compared with WT mice after elastase instillation. These findings provide evidence that p53(-/-) mice and WT mice grafted with p53(-/-) bone marrow cells are more prone to developing elastase-induced emphysema, supporting a protective role of p53, and more precisely p53 expressed in macrophages, against emphysema development. The pivotal role played by macrophages in this phenomenon may involve the MMP12-TNF-α pathway.

Three-Dimensional Echocardiography for the Assessment of Right Ventriculo-Arterial Coupling

Background: The analysis of right ventriculo‐arterial coupling (RVAC) from pressure‐volume loops is not routinely performed. RVAC may be approached by the combination of right heart catheterization (RHC) pressure data and cardiac magnetic resonance (CMR)–derived right ventricular (RV) volumetric data. RV pressure and volume measurements by Doppler and three‐dimensional echocardiography (3DE) allows another way to approach RVAC. Methods: Ninety patients suspected of having pulmonary hypertension underwent RHC, 3DE, and CMR (RHC mean pulmonary artery pressure [mPAP] 37.9 ± 11.3 mm Hg; range, 15–66 mm Hg). Three‐dimensional (3D) echocardiography was performed in 30 normal patients (echocardiographic mPAP 18.4 ± 3.1 mm Hg). Pulmonary artery (PA) effective elastance (Ea), RV maximal end‐systolic elastance (Emax), and RVAC (PA Ea/RV Emax) were calculated from RHC combined with CMR and from 3DE using simplified formulas including mPAP, stroke volume, and end‐systolic volume. Results: Three‐dimensional echocardiographic and RHC‐CMR measures for PA Ea (3DE, 1.27 ± 0.94; RHC‐CMR, 0.71 ± 0.52; r = 0.806, P < .001), RV Emax (3DE, 0.72 ± 0.37; RHC‐CMR, 0.38 ± 0.19; r = 0.798, P < .001), and RVAC (3DE, 2.01 ± 1.28; RHC‐CMR, 2.32 ± 1.77; r = 0.826, P < .001) were well correlated despite a systematic overestimation of 3DE elastance parameters. Among the whole population, 3D echocardiographic PA Ea and 3D echocardiographic RVAC but not 3D echocardiographic RV Emax were significantly lower in patients with mPAP < 25 mm Hg (n = 41) than in others (n = 79). Among the 90 patients who underwent RHC, 3D echocardiographic PA Ea and 3D echocardiographic RVAC but not 3D echocardiographic RV Emax increased significantly with increasing levels of pulmonary vascular resistance. Conclusions: Three‐dimensional echocardiography–derived PA Ea, RV Emax, and RVAC correlated well with the reference RHC‐CMR measurements. Ea and RVAC but not Emax were significantly different between patients with different levels of afterload, suggesting failure of the right ventricle to maintain coupling in severe pulmonary hypertension. HIGHLIGHTS3D echo‐derived PA Ea, RV Emax, RVAC are correlated with those derived from RHC‐CMR.3D echo‐derived PA Ea and RVAC are significantly lower in patients with mPAP <25 mm Hg.3D echo‐derived PA Ea and RVAC increase significantly with severity of PH.3D echo‐derived RV Emax is not significantly influenced by levels of afterload.