Background: The adaptation of the right ventricular contractility to its afterload (RV–PA coupling), best measured by the ratio of end-systolic elastance (Ees) and arterial elastance (Ea), is a key determinant for prognosis and symptomatology in pulmonary hypertension (PH). It is not completely understood whether approved PH therapies acutely affect RV–PA coupling.
Methods: We compared the acute effects of inhaled iloprost (2.5 μg) and drugs targeting the NO–cGMP pathway (inhaled NO, 10 ppm or riociguat, 1 mg) on RV contractility defined by load-independent pressure–volume relationships in patients with pulmonary arterial hypertension (n = 19, 8 and 5, respectively). Right ventricular pressures and volumes were measured using high-fidelity conductance catheters. Load-independent contractility (Ees) and afterload (Ea) were determined using either the multibeat method with preload reduction via balloon occlusion of the inferior vena cava or, in patients who not consented to this procedure, with the Valsalva maneuver and supplementary single-beat analysis. Values are reported as the mean ± SD or median and interquartile range.
Results: We observed a significant decrease of Ea in both iloprost [0.66 (0.41–0.86) vs. 0.54 (0.34–0.75) mmHg/mL] and NO/riociguat [0.56 (0.48–1.33) vs. 0.48 (0.36–1.11) mmHg/mL]. The Ees decreased with NO and riociguat [0.70 (0.51–1.04) vs. 0.59 (0.45–0.74) mmHg/mL] closely to the same extend as Ea, whereas iloprost increased Ees significantly [0.56 (0.40–0.79) vs. 0.63 (0.53–0.90) mmHg/mL]. Consequently, Ees/Ea was not affected by NO/riociguat but improved with iloprost (0.93 ± 0.44 vs. 1.46 ± 0.70). Both decreased RV volumes and increased RV ejection fraction. However, only iloprost increased stroke volume [79 (67–97) vs. 85 (73–98) mL] and cardiac output [5.7 (4.4–6.9) vs. 6.5 (5.0–7.6) L/min]. Of note, we observed no changes in the heart rate.
Conclusion: Our results strongly suggest that inhaled iloprost acutely increases ejection fraction and cardiac output by a combination of decreased afterload and increased right ventricular contractility. In patients receiving NO or riociguat, the drug-induced decrease in afterload was accompanied by a decrease in contractility, preserving RV–PA coupling.
Nils Kremer, Manuel Richter, Henning Gall, Hossein Ardeschir Ghofrani, Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany Robert Naeije, Department of Pathophysiology, Free University of Brussels Campus de la Plaine, Brussels, Belgium Werner Seeger, Khodr Tello, Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany