Sildenafil Versus Placebo for Early Pulmonary Vascular Disease in Scleroderma (SEPVADIS): protocol for a randomized controlled trial.

BACKGROUND: Pulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (SSc). An important component of SSc patient management is early detection and treatment of PH. Recently the threshold for the diagnosis of PH has been lowered to a mean pulmonary artery pressure (mPAP) threshold of > 20 mmHg on right heart catheterization (RHC). However, it is unknown if PH-specific therapy is beneficial in SSc patients with mildly elevated pressure (SSc-MEP, mPAP 21-24 mmHg). METHODS: The SEPVADIS trial is a randomized, double-blind, placebo-controlled phase 2 trial of sildenafil in SSc-MEP patients with a target enrollment of 30 patients from two academic sites in the United States. The primary outcome is change in six-minute walk distance after 16 weeks of treatment. Secondary endpoints include change in pulmonary arterial compliance by RHC and right ventricular function by cardiac magnetic resonance imaging at 16 weeks. Echocardiography, serum N-terminal probrain natriuretic peptide, and health-related quality of life is being measured at 16 and 52 weeks. DISCUSSION: The SEPVADIS trial will be the first randomized study of sildenafil in SSc-MEP patients. The results of this trial will be used to inform a phase 3 study to investigate the efficacy of treating patients with mild elevations in mPAP. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04797286.

Right and left ventricular myocardial perfusion reserves correlate with right ventricular function and pulmonary hemodynamics in patients with pulmonary arterial hypertension.

PURPOSE: To evaluate the relationships of right ventricular (RV) and left ventricular (LV) myocardial perfusion reserves with ventricular function and pulmonary hemodynamics in patients with pulmonary arterial hypertension (PAH) by using adenosine stress perfusion cardiac magnetic resonance (MR) imaging. MATERIALS AND METHODS: This HIPAA-compliant study was institutional review board approved. Twenty-five patients known or suspected to have PAH underwent right heart catheterization and adenosine stress MR imaging on the same day. Sixteen matched healthy control subjects underwent cardiac MR imaging only. RV and LV perfusion values at rest and at adenosine-induced stress were calculated by using the Fermi function model. The MR imaging-derived RV and LV functional data were calculated by using dedicated software. Statistical testing included Kruskal-Wallis tests for continuous data, Spearman rank correlation tests, and multiple linear regression analyses. RESULTS: Seventeen of the 25 patients had PAH: 11 with scleroderma-associated PAH, and six with idiopathic PAH. The remaining eight patients had scleroderma without PAH. The myocardial perfusion reserve indexes (MPRIs) in the PAH group (median RV MPRI, 1.7 [25th-75th percentile range, 1.3-2.0]; median LV MPRI, 1.8 [25th-75th percentile range, 1.6-2.1]) were significantly lower than those in the scleroderma non-PAH (median RV MPRI, 2.5 [25th-75th percentile range, 1.8-3.9] [P = .03]; median LV MPRI, 4.1 [25th-75th percentile range, 2.6-4.8] [P = .0003]) and control (median RV MPRI, 2.9 [25th-75th percentile range, 2.6-3.6] [P < .01]; median LV MPRI, 3.6 [25th-75th percentile range, 2.7-4.1] [P < .01]) groups. There were significant correlations between biventricular MPRI and both mean pulmonary arterial pressure (mPAP) (RV MPRI: ρ = -0.59, Bonferroni P = .036; LV MPRI: ρ = -0.79, Bonferroni P < .002) and RV stroke work index (RV MPRI: ρ = -0.63, Bonferroni P = .01; LV MPRI: ρ = -0.75, Bonferroni P < .002). In linear regression analysis, mPAP and RV ejection fraction were independent predictors of RV MPRI. mPAP was an independent predictor of LV MPRI. CONCLUSION: Biventricular vasoreactivity is significantly reduced with PAH and inversely correlated with RV workload and ejection fraction, suggesting that reduced myocardial perfusion reserve may contribute to RV dysfunction in patients with PAH.