Cardiovascular disease (CVD) occurs at a younger age and with greater frequency in HIV- infected subjects. Risk factors include conventional CVD risk factors in addition to HIV-induced activation of pathophysiologic processes including oxidative stress, inflammation, thrombogenesis and immune dysregulation. We have found that circulating biomarkers that depict activation of these shared pathways are also associated with both sub-clinical CVD and with CVD events in non-HIV-infected subjects. Importantly, we have found that repair and regenerative processes are able to mitigate risk of injurious risk factors in than non-HIV infected subjects, and circulating levels progenitor cells expressing CD34 and other epitoped provide an index of an individual's regenerative potential. Thus, CVD results from a combination of injury causing vascular damage that is repaired by endogenous stem and progenitor cells. Disease does not develop or progress until the reparative processes are exhausted. Our preliminary data demonstrates reduced progenitor cell levels in HIV-infected subjects implying impaired regenerative potential in HIV. We propose to investigate HIV-induced activation of these pathway-specific injury markers and of endogenous regenerative capacity and their relationship with prevalent sub-clinical CVD, measured as carotid wall thickness and or atherosclerosis, and its progression over 2 years. As secondary endpoints we will also evaluate vascular dysfunction that will be measured as endothelial function and arterial stiffness, and their progression. Our hypothesis is that these circulating biomarkers of repair and injury will predict risk of prevalent and incident vascular disease, and monitoring of these biomarkers could in the future be used to assess CVD risk in HIV and guide preventive treatment.
The results of the project will increase the understanding of molecular and regenerative pathways and their interactions in HIV-infected subjects, and their influence on risk of presence and progression of vascular disease in this population.
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