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Background Pulmonary arterial hypertension is a rare disorder associated with poor survival. Endothelial dysfunction plays a central role in the pathogenesis and progression of pulmonary arterial hypertension. Inflammation appears to drive this dysfunctional endothelial phenotype, propagating cycles of injury and repair in genetically susceptible patients with idiopathic and disease-associated pulmonary arterial hypertension. Therapy targeting pulmonary vascular inflammation to interrupt cycles of injury and repair and thereby delay or prevent right ventricular failure and death has not been tested. Spironolactone, a mineralocorticoid and androgen receptor antagonist, has been shown to improve endothelial function and reduce inflammation. Current management of patients with pulmonary arterial hypertension and symptoms of right heart failure includes use of mineralocorticoid receptor antagonists for their diuretic and natriuretic effects. We hypothesize that initiating spironolactone therapy at an earlier stage of disease in patients with pulmonary arterial hypertension could provide additional benefits through anti-inflammatory effects and improvements in pulmonary vascular function. Methods/Design Seventy patients with pulmonary arterial hypertension without clinical evidence of right ventricular failure will be enrolled in a randomized, double-blinded, placebo-controlled trial to investigate the effect of early treatment with spironolactone on exercise capacity, clinical worsening and vascular inflammation in vivo. Our primary endpoint is change in placebo-corrected 6-minute walk distance at 24 weeks and the incidence of clinical worsening in the spironolactone group compared to placebo. At a two-sided alpha level of 0.05, we will have at least 84% power to detect an effect size (group mean difference divided by standard deviation) of 0.9 for the difference in the change of 6-minute walk distance from baseline between the two groups. Secondary endpoints include the effect of spironolactone on the change in placebo-corrected maximal oxygen consumption; plasma markers of vascular inflammation and peripheral blood mononuclear cell gene expression profiles; sympathetic nervous system activation, renin-angiotensin-aldosterone system activation and sex hormone metabolism; and right ventricular structure and function using echocardiography and novel high-resolution magnetic resonance imaging-based techniques. Safety and tolerability of spironolactone will be assessed with periodic monitoring for hyperkalemia and renal insufficiency as well as the incidence of drug discontinuation for untoward effects. Trial registration ClinicalTrials.gov: NCT01712620

severe PH, were obtained retrospectively. Changes after 3 months from baseline ( ) were compared between groups using Ttest. Results: At baseline, there were no differences between groups. After three months, SIL-treated and SIL-naive groups differed in PVR (-1,9 vs 0.2, p 0.004), cardiac output (0.55 vs -0.1 p 0.02) stroke volume: (8,91 vs -2,58 p 0,01) mean PA pressure (-5,12 vs 0,87 p 0.07) transpulmonary gradient (-4,81 vs 1,07 p 0,01)No change was observed on PAWP and right atrial pressure. SIL-treated subjects experienced improvement of NYHA class (0.3 vs 0.1,p ...) and had stable weight, in conrast to sild-naive patients.

Ventilatory Inefficiency Is Associated with Right Ventricular Dysfunction in Patients with Advanced Cardiomyopathy A.B. Methvin, S.E. Wiegers, A. Emmi, P.R. Forfia, Heart Failure and Transplant Center, University of Pennsylvania, Philadelphia, PA; University of Pennsylvania School of Medicine, Philadelphia, PA; Cardiovascular Division, Echocardiographic Laboratory, University of Pennsylvania, Philadelphia, PA

ObjectivesWe examined whether B-type natriuretic peptides (BNP) can serve as noninvasive markers of pulmonary capillary wedge pressure (PCWP) in the setting of critical illness.BackgroundThe BNP and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are highly correlated with left ventricular (LV) filling pressures in patients with depressed LV systolic function. However, their relationship to PCWP in a heterogeneous intensive care unit (ICU) population has not been established.MethodsWe prospectively studied 40 patients in the ICU requiring invasive hemodynamic monitoring. Hemodynamics were recorded simultaneously with blood sampling for BNP and NT-proBNP.ResultsThe BNP (median 420 pg/ml) and NT-proBNP (median 3,304 pg/ml) levels were markedly elevated, but weakly correlated with PCWP (BNP, r = 0.40, NT-proBNP, r = 0.32) and other cardiac parameters. Peptide levels were approximately four-fold greater in patients with impaired (estimated glomerular filtration rate [eGFR] 60 ml/min) renal function, despite similar PCWP, cardiac index, and LV ejection fraction. In addition, both BNP and NT-proBNP showed stronger correlations with PCWP in patients with preserved (BNP, r = 0.58, NT-proBNP, r = 0.73) versus impaired renal function (BNP, r = 0.48, NT-proBNP, r = 0.34). Interaction terms between eGFR and BNP (p = 0.06) and NT-proBNP (p = 0.04) suggest that eGFR modulates the relationship of these peptides to filling pressures.ConclusionsThe BNPs are markedly elevated, yet show only weak correlations to PCWP in ICU patients requiring invasive hemodynamic monitoring. Thus, a single value for BNP or NT-proBNP may not be a clinically useful noninvasive marker of filling pressures in the critically ill patient. This appears to be especially true in patients with impaired renal function.

Pulmonary arterial hypertension (PAH) is associated with a high risk for adverse outcomes. Recent quality metrics have incorporated 30 day all cause readmission (30dRead) rates; little, however, is known about the frequency and predictors of 30dRead after PAH hospitalization. We examined 30dRead