A pilot study of the effect of spironolactone therapy on exercise capacity and endothelial dysfunction in pulmonary arterial hypertension: study protocol for a randomized controlled trialReportar como inadecuado




A pilot study of the effect of spironolactone therapy on exercise capacity and endothelial dysfunction in pulmonary arterial hypertension: study protocol for a randomized controlled trial - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Trials

, 14:91

First Online: 02 April 2013Received: 19 December 2012Accepted: 14 March 2013DOI: 10.1186-1745-6215-14-91

Cite this article as: Elinoff, J.M., Rame, J.E., Forfia, P.R. et al. Trials 2013 14: 91. doi:10.1186-1745-6215-14-91

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

KeywordsMagnetic resonance imaging Microarray Mineralocorticoid receptor antagonist Neurohormonal axis Pulmonary arterial hypertension Right ventricular function Vascular inflammation AbbreviationsACEangiotensin-converting enzyme

Crcreatinine

DSMBData Safety and Monitoring Board

ECGelectrocardiography

eGFRestimate glomerular filtration rate

HIVhuman immunodeficiency virus

IL-1βinterleukin-1 beta

IL1RL1interleukin-1 receptor-like 1

IL-6interleukin-6

IL-7interleukin-7

IL-8interleukin-8

IPAHidiopathic pulmonary arterial hypertension

IVCDintraventricular conduction delay

Kpotassium

labslaboratory tests

LMMlinear mixed model

LVleft ventricular

MCP-1monocyte chemotactic protein-1

METmetabolic equivalent, MPH, miles per hour

MRmineralocorticoid receptor

MRImagnetic resonance imaging

NFκBnuclear factor kappa B

NHLBINational Heart, Lung, and Blood Institute

NIHNational Institutes of Health

NRnuclear receptor

NSAIDsnonsteroidal anti-inflammatory drugs

NT-proBNPN-terminal pro-brain natriuretic peptide

NYHANew York Heart Association

PAECspulmonary artery endothelial cells

PAHpulmonary arterial hypertension

PBMCsperipheral blood mononuclear cells

PCRpolymerase chain reaction

PHpulmonary hypertension

PVCspremature ventricular contractions

RNAribonucleic acid

RVright ventricular

sCD40Lsoluble CD40 ligand

sICAM-1soluble intercellular adhesion molecule 1

sVCAM-1soluble vascular cell adhesion molecule 1

TNFαtumor necrosis factor alpha

VCO2carbon dioxide production

VEventilation

VO2oxygen uptake

WHOWorld Health Organization.

Electronic supplementary materialThe online version of this article doi:10.1186-1745-6215-14-91 contains supplementary material, which is available to authorized users.

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Autor: Jason M Elinoff - J Eduardo Rame - Paul R Forfia - Mary K Hall - Junfeng Sun - Ahmed M Gharib - Khaled Abd-Elmoniem -

Fuente: https://link.springer.com/







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