Abstract
BackgroundPulmonary 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/DesignSeventy 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 registrationClinicalTrials.gov: NCT01712620
Highlights
Pulmonary arterial hypertension is a rare disorder associated with poor survival
Patients with pulmonary arterial hypertension (PAH) without right ventricular (RV) failure on either no medical therapy or stable medical therapy for at least 4 weeks will be recruited to the National Institutes of Health (NIH) Clinical Center for a randomized, double-blinded, placebocontrolled study of early treatment with spironolactone to investigate the effect of treatment on exercise capacity, clinical worsening and vascular inflammation in vivo
In a recent pilot study comparing peripheral blood mononuclear cells (PBMCs) expression profiles from 10 patients with PAH with 10 age, genderand race-matched controls, we identified 321 differentially regulated genes at a 20% false discovery rate
Summary
Epidemiology and natural history The vascular injury-induced forms of pulmonary hypertension (PH), collectively referred to as pulmonary arterial hypertension (PAH), are distinct from other causes of PH such as left-sided heart failure, parenchymal lung disease with hypoxemia and chronic thromboembolic disease (Table 1) [1]. Pathophysiology of pulmonary arterial hypertension and the role of endothelial inflammation The initial mechanisms responsible for the development of IPAH and other forms of PAH remain incompletely understood. Spironolactone, a combined MR and androgen receptor antagonist, improves endothelial dysfunction in patients with left-sided heart failure [19,20,21], rheumatoid arthritis [22], and in women with polycystic ovarian syndrome [23], suggesting a possible mechanism for its clinical efficacy in these patient populations. Initiating therapy with spironolactone at an earlier stage of disease in patients with PAH is a novel approach to treatment and could provide benefits through anti-inflammatory mechanisms and improvements in endothelial function that might alter the natural history of PAH. We are actively investigating the molecular mechanisms that mediate the anti-inflammatory activity of spironolactone and the relative contributions of MR, androgen receptor and progesterone receptor, as well as NRindependent effects
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