Rationale: Pulmonary arterial hypertension (PAH) related to systemic sclerosis (SSc) has a poorer prognosis compared with other forms of PAH for reasons that remain unexplained. Objectives: To identify risk factors of mortality in a well-characterized cohort of patients with PAH related to systemic sclerosis (SSc-PAH). Methods: Seventy-six consecutive patients with SSc (64 women and 12 men; mean age 61 6 11 yr) were diagnosed with PAH by heart catheterization in a single center, starting in January 2000, and followed over time. Kaplan-Meier estimates were calculated and mortality risk factors were analyzed. Measurements and Main Results: Forty (53%) patients were in World Health Organization functional class III or IV. Mean pulmonary artery pressure was 41 6 11 mm Hg, pulmonary vascular resistance (PVR) was 8.6 6 5.6 Wood units, and cardiac index was 2.4 6 0.7 L/min/m 2 . Median follow-up time was 36 months, with 42 deaths observed. Survival estimates were 85%, 72%, 67%, 50%, and 36% at 1, 2, 3, 4, and 5 years, respectively. Multivariate analysis identified PVR (hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.03-1.18; P , 0.01), stroke volume index (HR, 0.94; 95% CI, 0.89-0.99; P 5 0.02), and pulmonary arterial capacitance (HR, 0.43; 95% CI, 0.20-0.91; P 5 0.03) as strong predictors of survival. An estimated glomerular filtration rate less than 60 ml/min/1.73 m 2 portended a threefold risk of mortality. Conclusions: Our results suggest that specific components of right ventricular dysfunction and renal impairment contribute to increased mortality in SSc-PAH. Understanding the mechanisms of right ventricular dysfunction in response to increased afterload should lead to improved targeted therapy in these patients.

The aim of this study was to examine the causes and outcomes of hospitalisation in patients with pulmonary arterial hypertension (PAH).205 consecutive hospitalisations occurring between 2000 and 2009 in 90 PAH patients were studied. The leading causes for hospitalisation were right heart failure (RHF; 56%), infection (16%) and bleeding disorders (8%). For patients with RHF, in-hospital mortality was 14% overall, 46% for patients receiving inotropes and 48% for those admitted to the intensive care unit. The predictors for in-hospital mortality were the presence of connective tissue disease (CTD) (OR 4.92), systolic blood pressure ,100 mmHg (OR 4.32) and Na f136 mEq?L -1 (OR 4.29). Mortality after discharge was 13, 26 and 35% at 3, 6 and 12 months, respectively. World Health Organization functional class prior to admission, renal dysfunction, Charlson comorbidity index, and the presence of CTD were all predictors of mortality after discharge. Hyponatraemia and low systolic blood pressure upon admission and underlying CTD are the main prognostic factors for in-hospital mortality in patients with PAH admitted for RHF. The shortterm outcomes after discharge are poor and remarkably worse in patients with underlying CTD or renal impairment. Early recognition of these factors may guide decisions regarding more aggressive therapy, including consideration for lung transplantation.KEYWORDS: Connective tissue diseases, heart failure, hospital mortality, right ventricular dysfunction, scleroderma, systemic P ulmonary arterial hypertension (PAH) remains a disease with high morbidity and mortality rates despite recent advances in therapy and overall improved survival. PAH is usually progressive, with right ventricular dysfunction being the leading cause of death. Patients often require hospitalisation during the course of their disease, typically for bouts of right heart failure (RHF). In addition, complications related to treatment itself, including PAH-specific therapy, anticoagulation and long-standing indwelling catheters, constitute other potential causes of hospitalisation.In contrast with left heart failure (LHF), the course and outcomes of acute or decompensated RHF have been seldom described [1,2]. Several features differentiate RHF secondary to severe PAH from LHF and make management of RHF particularly challenging. While aggressive diuresis is usually required in both LHF and RHF, the large increase in transpulmonary gradient due to a fixed resistance in the pulmonary vasculature in PAH complicates the treatment of RHF. In addition, right ventricular-left ventricular interdependence often leads to left ventricular dysfunction with low cardiac output and consequent systemic hypotension in RHF, which may require the use of vasopressor and inotropic agents. These haemodynamic perturbations may be further complicated by decreased myocardial perfusion from compromised coronary flow due to right ventricle overload. Ultimately, these processes can lead to distal organ dysfunction and irreversible haemodynamic col...

Background: Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH.

Rationale: Pulmonary arterial hypertension (PAH) is a medically incurable disease resulting in death from right ventricular (RV) failure. Both pulmonary vascular and RV remodeling are linked to dynamic changes in the microvasculature. Therefore, we hypothesized that circulating angiostatic factors could be linked to outcomes and represent novel biomarkers of disease severity in PAH.Objectives: We sought to determine the relationship of a potent angiostatic factor, endostatin (ES), with disease severity and mortality in PAH. Furthermore, we assessed genetic predictors of ES expression and/or function and their association with outcomes in PAH.Methods: We measured levels of serum ES in two independent cohorts of patients with PAH. Contemporaneous clinical data included New York Heart Association functional class, 6-minutewalk distance, invasive hemodynamics, and laboratory chemistries.Measurements and Main Results: Serum ES correlated with poor functional status, decreased exercise tolerance, and invasive hemodynamics variables. Furthermore, serum ES was a strong predictor of mortality. A loss-of-function, missense variant in the gene encoding ES, Col18a1, was linked to lower circulating protein and was independently associated with reduced mortality.Conclusions: Our data link increased expression of ES to disease severity in PAH and demonstrate a significant relationship with adverse outcomes. Circulating ES levels can be genetically influenced, implicating ES as a genetically determined modifier of disease severity impacting on survival. These observations support serum ES as a potential biomarker in PAH with the capacity to predict poor outcomes. More importantly, this study implicates Col18a1/ES as a potential new therapeutic target in PAH.

N-terminal pro-brain natriuretic peptide (NT-proBNP) is a marker of neurohormonal activation that is useful in the diagnosis and prognosis of various forms of pulmonary arterial hypertension (PAH). We sought to characterise and compare NT-proBNP in a cohort of PAH related to systemic sclerosis (PAH-SSc) and idiopathic PAH (IPAH) patients.NT-proBNP levels, collected from PAH-SSc and IPAH patients followed prospectively, were compared and correlated with haemodynamic variables. Cox proportional hazard models were created to assess the predictive value of NT-proBNP.98 patients (55 PAH-SSc, 43 IPAH) were included. Haemodynamics were similar, except for lower mean pulmonary arterial pressure in PAH-SSc. NT-proBNP levels were significantly higher in PAH-SSc (3,419¡3,784 versus 1,393¡1,633 pg?mL -1 ; p,0.01) and were more closely related to haemodynamics in PAH-SSc than IPAH. 28 patients died. NT-proBNP predicted survival (hazard ratio (HR) 3.18; p,0.01) in the overall cohort; however, when stratified by group, predicted survival only in PAH-SSc (HR 3.07, p,0.01 versus 2.02, p50.29 in IPAH). This is the first description showing NT-proBNP levels are 1) significantly higher in PAH-SSc than IPAH despite less severe haemodynamic perturbations, and 2) stronger predictors of survival in PAH-SSc, suggesting that neurohormonal regulation may differ between PAH-SSc and IPAH. Future studies to define pertinent mechanisms are warranted.