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Korean Circ J. 2018 Sep;48(9):839-853. English. Original Article. https://doi.org/10.4070/kcj.2017.0394
Kim KH , Kim HK , Chan SY , Kim YJ , Sohn DW .
Division of Cardiology, Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea.
Division of Cardiology, Department of Internal Medicine, Cardiovascular Center, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea. cardiman73@gmail.com
Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh Medical Center (UPMC) and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Abstract

Background and Objectives

Macitentan (MAC) reduces morbidity and mortality among advanced-stage pulmonary arterial hypertension (PAH) patients. However, data regarding the histopathologic and hemodynamic benefits of MAC treatment at an early stage of PAH is lacking.

Methods

One week after monocrotaline (MCT) injection, rats were randomly assigned to MAC (n=16), MAC combined with sildenafil (SIL) (MAC+SIL, n=16), or normal saline (MCT, n=16). Twelve sham rats (Sham) were included for comparison. Right ventricular (RV) systolic function was assessed via echocardiography as the RV fractional area change (RV-FAC). An invasive pressure-volume analysis using a Millar conductance catheter was performed 7 weeks after MCT injection. Rats were subsequently euthanized for histopathologic analysis.

Results

RV-right atrial pressure gradient on echocardiography was significantly increased 3 weeks after MCT injection, but was maintained in the Sham. RV-FAC was less deteriorated in the MAC, compared to that in the MCT (44±3% vs. 25±7%, p < 0.05), and the co-administration of SIL showed no additional benefit (45±8%, p > 0.05 vs. the MAC). On invasive hemodynamic analyses, RV end-systolic (196±78 µL) and end-diastolic volumes (310±86 µL), pulmonary artery systolic pressure (89±7.2 mmHg), and end-systolic pressure-volume relationship (−254±25.1) were significantly worse in the MCT vs. in the MAC (101±45 µL, 235±55 µL, 40±10.5 mmHg, and −145±42.1, respectively) and MAC+SIL (109±47 µL, 242±46 µL, 38±9.2 mmHg, and −151±39.2, respectively) (all p < 0.05). However, the MAC and MAC+SIL did not differ (all p > 0.05). On histopathology, both RV and lung fibrosis were significantly reduced in the MAC and MAC+SIL vs. in the MCT (all p < 0.05); the 2 treatment groups did not differ.

Conclusions

MAC treatment at an earlier stage significantly attenuated experimental PAH progression hemodynamically and histopathologically.

Copyright © 2019. Korean Association of Medical Journal Editors.