Hypertension, cardiovascular disease and cerebral infarction are common comorbidities encountered in the HIV-infected aging population. Endothelial dysfunction is the initial step in these conditions.
The aim of the research project is to better understand the effect of long-term treated HIV infection on endothelial dysfunction and atherogenesis in older HIV-infected subjects, and the mechanisms behind these effects. The overreaching hypothesis is that in HIV-infected subjects on suppressive antiretroviral therapy, the heightened state of inflammation and immune activation will lead to increases in levels of asymmetric dimethylarginine and perturbation in arginine metabolism, which result in decrease in nitric oxide availability leading to reduced endothelial progenitor cells, endothelial dysfunctin, and worse vascular disease and atherogenesis. The causative relationships will be further investigated in interventional studies in which we hypothesize that by increasing the availability of nitric oxide, rosuvastatin with or without L-arginine supplementation, will increase endothelial progenitor cells and improve endothelial function.
In Specific Aim 1, we will conduct a longitudinal 3-year study on a well characterized cohort of 300 virologically suppressed older population who has been followed since initiation of antiretroviral therapy, and will assess the effect of inflammation and immune activation on serial measures of endothelial function, atherogenesis and vascular disease, and whether this effect is mediated by alterations in arginine metabolism and reduction in endothelial progenitor cells. Then, we will determine the effect of rosuvastatin vs. placebo (Aim 2) and rosuvastatin with or without L-arginine supplementation (Aim 3) on changes in endothelial function, endothelial progenitor cells, immune activation, insulin resistance, systemic blood pressure, and oxidized LDL. This proposal gathers an excellent group of experienced investigators in the areas of pathogenesis of arginine metabolism, HIV immune activation, HIV cardiovascular disease, and vascular imaging, and conduct these highly novel and rigorous studies in the most resource-efficient manner. .

Public Health Relevance

People living with HIV are suffering from several complications like heart disease and increased risk of stroke. These complications are linked to endothelial dysfunction that persists despite successful HIV therapy and undetectable HIV viral load. At the same time, heightened inflammation and abnormal immune activation in treated HIV are common but their relationship to endothelial dysfunction is unclear. We will use a cohort of older participants who are on long term successful HIV treatment, as well as two interventional clinical trials of statin agent with or without L-arginine to carefully and comprehensively study te mechanisms of endothelial dysfunction and possibilities of reversing it with safe readily available intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56HL126539-01
Application #
8915893
Study Section
Special Emphasis Panel (ZHL1-CSR-B (S1))
Program Officer
Ershow, Abby
Project Start
2014-09-10
Project End
2015-08-31
Budget Start
2014-09-10
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$791,529
Indirect Cost
$291,551
Name
Case Western Reserve University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106