Statin treatment prevents the development of pulmonary arterial hypertension in a nonhuman primate model of HIV-associated PAH

Whitney Rabacal,Emily Rayens,Karen A Norris,Patrick Whang,Finja Schweitzer,Rebecca Tarantelli,Viviana Cobos Jimenez,Judy A Outwater

doi:10.1038/s41598-019-55301-9

Whitney Rabacal, Emily Rayens + Show 6 more

Open Access

https://doi.org/10.1038/s41598-019-55301-9

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Journal: Scientific Reports	Publication Date: Dec 1, 2019
Citations: 11	License type: open-access

Affiliation: University of Georgia

Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by pulmonary vascular remodeling, elevated pulmonary arterial pressure, and right heart failure. Human immunodeficiency virus (HIV)-infected individuals have a higher incidence of PAH than the non-HIV infected population and evidence suggests a role for systemic and pulmonary inflammation in the pathogenesis of HIV-associated PAH. Due to their pleiotropic effects, including immune-modulatory and anti-inflammatory effects, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been considered for the treatment of PAH, with conflicting results. The effects of statins on HIV-associated PAH have not been specifically evaluated. We have developed a non-human primate (NHP) model of HIV-associated PAH that closely mimics HIV-PAH using simian immunodeficiency virus (SIV)-infected rhesus macaques (Macaca mulatta). We determined that treatment of healthy macaques with atorvastatin prior to and throughout SIV infection prevented the development of SIV-associated PAH. Additionally, SIV-infected macaques that initiated atorvastatin treatment during the early chronic disease stage had reduced incidence of PAH compared to untreated animals. Statin treatment reduced inflammatory mediators TGF-β, MIP-1α, and TNF-α and the numbers of CD14dimCD16+ non-classical monocytes, and CD14+CCR7−CD163−CD206+ alveolar macrophages previously shown to be associated with SIV-PAH. These results support the concept that statins reduce inflammatory processes that contribute to PAH and may provide a safe and effective prophylactic strategy for the prevention of PAH in HIV-infected individuals.

Highlights

Pulmonary arterial hypertension (PAH) is a subgroup of pulmonary hypertension that includes idiopathic PAH and heritable forms, as well as PAH associated with congenital heart disease, connective tissue disease, portal hypertension, human immunodeficiency virus (HIV) and other infections[1]
To determine if statin therapy in healthy macaques could alter the incidence or progression of simian immunodeficiency virus (SIV)-PAH, atorvastatin treatment was initiated in a cohort of nonhuman primate (NHP) 1 week prior to SIV infection (Fig. 1a, SIV/Statin Group 2; Extended Data Fig. 1) and maintained on drug throughout infection
Hemodynamics were measured by serial right heart catheterizations at baseline (BL), 6 months post-infection (6 mpi), and at terminal

Summary

Introduction

Pulmonary arterial hypertension (PAH) is a subgroup of pulmonary hypertension that includes idiopathic PAH and heritable forms, as well as PAH associated with congenital heart disease, connective tissue disease, portal hypertension, human immunodeficiency virus (HIV) and other infections[1]. MPAP of monkey 24–16 decreased to 21.2 mmHg. We further tested whether statin treatment initiated following SIV infection could prevent the development of PAH or alter progression (Fig. 1, SIV/Statin Group 3; Extended Data Fig. 1).

Results

Conclusion