The introduction of antiretroviral therapy (ART) has transformed human immunodeficiency virus (HIV) infection into a chronic disease. Pulmonary arterial hypertension (PAH) in HIV is an important cause of morbidity and mortality is thought to have the the worst prognosis of any subtype of PAH with presenting symptoms often including dyspnea and exercise limitation (ExLT), commonly attributed to other disorders. In this grant application, we propose a prospective study to understand the cardiopulmonary responses and PAH in HIV using echocardiography in conjunction with exercise magnetic resonance imaging (MRI) and cardiopulmonary testing. We further propose innovative assessment of inflammatory parameters in HIV that will provide insights into the mechanisms of cardiopulmonary dysfunction and elevated PA pressures. Our hypothesis is that HIV- ExLT patients commonly exhibit alteration in RV function/PA pressure with exercise (ExPH), with the latter phenotype representing a high-risk cohort for progression to resting PAH.
In Aim 1, we will institute a protocol of ExMR and CPT that will allow measurement of RV function, mean PA pressure (mPAP) and VO2max in response to exercise to define the prevalence and distinguish patients with abnormal exercise contractile reserve ( RVEF).
In aim 2 we will investigate longitudinal changes in resting RV volume, contractile reserve and predictors of progression with a focus on measures of CD8 T cell immune activation and exhaustion and their relationship to progression of PAH.
In aim 3, we will follow patients with established or newly diagnosed resting HIV-PAH and evaluate changes in resting RV function, volume and fibrosis and correlate these changes with alteration in invasive hemodynamic parameters at 12 months. We will attempt to delineate the predictors of progression in this patient population. Our proposal is highly responsive to RFA-HL-14-023 and will allow early identification of right heart disease, answer fundamental questions pertaining to cardiopulmonary response with exercise in HIV and lead to appropriately designed outcome trials to prevent PAH and associated functional limitations.

Public Health Relevance

Recent advances in the treatment of patients infected with the human immunodeficiency virus (HIV) have resulted in these patients living longer without overt susceptibility to opportunistic infections. Heart and lung complications are now a leading cause of disability and mortality in the HIV patient. Shortness of breath and exercise limitation (ExLT) are very common in the HIV patient owing to a high prevalence of risk factors such as smoking, lung disease and other poorly understood immune factors unrelated to the burden of the HIV virus. It is very common to miss a serious disorder called pulmonary artery hypertension (PAH) that is 2500 times more common in the HIV patient and often not diagnosed until late in the disease. We have recently provided feasibility data on a unique MRI compatible exercise platform (ExMR) that can provide high-resolution information on right ventricular (RV) function along with assessment of pulmonary artery pressure in response to exercise. In this grant application, we propose a novel use of this technology with a detailed assessment of cardiopulmonary indices to provide information on the prevalence and progression of PAH and progressive impairment in contractile function of the RV that commonly afflicts these patients. We will further analyze inflammatory variables that may predict these changes thus allowing early identification of these patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL125060-03
Application #
9420374
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Caler, Elisabet V
Project Start
2017-08-15
Project End
2019-07-30
Budget Start
2017-08-15
Budget End
2018-07-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106