Effective HIV treatment with antiretroviral therapy (ART) has shifted the spectrum of morbidity and mortality to non-infectious complications such as cardiovascular disease (CVD). To date HIV-CVD research has largely been conducted in western countries where atherosclerotic coronary heart disease (CHD) is the predominant pathology. However, nearly 80% of the global CVD burden exists in developing nations and 70% of the global HIV epidemic exists in sub-Saharan Africa, where hypertension and non-CHD related heart failure (HF) are the predominant CVD pathologies. Our central hypothesis is that sub-Saharan Africans with HIV infection are at increased risk for HF despite ART. This risk is mediated, in part, via structural changes to the myocardium characterized by end-organ inflammation and fibrosis. This biology is exacerbated by advancing age, may be accelerated by hypertension, and occurs in the absence of atherosclerotic ischemic CHD. Prior to advancing CVD prevention strategies in sub-Saharan Africa, we will use this R21 exploratory proposal to characterize the independent effects of treated HIV disease and advancing age on structural changes to myocardium. We will also explore the potential underlying mechanisms with an emphasis on the contribution of monocyte subsets reflecting greater inflammation and migration that potentiate pro-fibrotic M2 tissue macrophages. The unique CVD risk factor profile in sub-Saharan Africa will influence this biology, and limits the generalizability of data from high-income countries. We propose to evaluate myocardial changes by HIV status and age, by studying 4 groups of participants (n=50 in each): a) HIV+ on ART age ?50, b) HIV+ on ART age <50, c) HIV- age ?50, and d) HIV- age<50. We will exclude those with known CHD, structural heart disease, TB, or opportunistic infections. Participants will have comprehensive assessments of myocardial structure and function (and coronary ischemic disease) via cardiovascular magnetic resonance (CMR) imaging, as well as vascular stiffness and immunologic studies. We hypothesize that ART-treated HIV+ persons will have increased myocardial fibrosis (diffuse), tissue inflammation and diastolic dysfunction, and the adverse effects of HIV infection and older age (e.g., age >50 years old) on myocardial structure and dysfunction will be additive. Potential mechanisms that may, in part, mediate the effect of HIV status and/or age on myocardial abnormalities include arterial stiffness, systemic inflammation and an expansion of monocyte phenotypes indicative of a shift toward M2 pro-fibrotic tissue macrophages. In sum, our findings will inform a possible paradigm shift in our understanding of HIV-CVD complications and guide research to improve the quality of life for older HIV+ patients in sub-Saharan Africa.

Public Health Relevance

SUMMARY (Public Health Relevance) This is a collaborative project between US investigators (MMRF and University of Minnesota) and South African (SA) investigators (University of Cape Town) to study the phenotype and pathogenesis of cardiovascular disease (CVD) among older HIV-positive persons in South Africa. Findings from this project will explore the independent effects of treated HIV infection and advanced age on myocardial disease, identify potential treatment targets for prevention strategies, and expand our understanding of HIV-CVD pathogenesis in a region of the world where the majority of the HIV epidemic resides.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL137435-02
Application #
9625152
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ketema, Fassil
Project Start
2018-01-15
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Minneapolis Medical Research Fdn, Inc.
Department
Type
DUNS #
068195064
City
Minneapolis
State
MN
Country
United States
Zip Code
55415