Stimulant and Polysubstance use, Inflammation and Sex Effects on Myocardial Disease in HIV (SPISE) - PROJECT SUMMARY/ABSTRACT Heart failure (HF) and other cardiovascular diseases (CVDs) constitute a leading cause of death in people with HIV (PWH). Compared to people without HIV, PWH have greater HF risk and we have shown that the difference in risk may be greater in women than men. However, traditional HIV and CVD risk factors do not fully explain the higher HF risk. Notably, symptomatic HF is often preceded by subclinical changes in left ventricular structure and function detectable by echocardiography (echo), and even sooner by cardiac magnetic resonance imaging (CMR). Recognizing myocardial disease determinants and the mechanistic contributors early in the disease process is imperative to identify targets for HF prevention and treatment in PWH. Controlled stimulants like cocaine and methamphetamine are known cardiotoxins, but their role in myocardial remodeling among PWH is unclear. Stimulant use is higher among PWH than the general population, yet stimulant use is poorly assessed in large HIV and CVD studies. It is either pooled with other substances or lacks details about patterns of use, level of exposure, and synergistic influences with other substances – hampering our ability to understand the potentially outsized role of stimulant use in the pathogenesis of HIV and myocardial disease in PWH. We propose “Stimulant and Polysubstance use, Inflammation, and Sex Effects on Myocardial Disease in HIV (SPISE)” a research program within the Multicenter AIDS Cohort Study (MACS)/Women’s Interagency HIV Study (WIHS) Combined Cohort Study. Our findings from WIHS suggest that sustained (and not any) self-reported substance use is associated with cardiac dysfunction, and sustained cannabis may have a protective effect, emphasizing a need to assess substance use patterns and different influences of multiple substances. Furthermore, women with HIV who reported prior cocaine use may have a larger HIV-1 reservoir than never users, even after adjusting for ART adherence, which could explain persistent viremia in some women with implications to inflammation and epigenetic maladaptation. SPISE’s overarching research goal is to rigorously characterize substance use patterns (using serial urine drug toxicology measures and self-report) and determine its effect on structural heart disease and myocardial disease through the longitudinal SPICE-echo and prospective SPICE-CMR studies, respectively; whether DNA methylation and the inflammatory proteome mediates these effects; and how HIV and sex influence the pathways. SPISE will establish a transdisciplinary infrastructure to comprehensively investigate the biological basis of substance-associated myocardial disease at multiple points of the mechanistic pathway. Our findings will be shared with the scientific community to stimulate and sustain research in substance use and HIV. SPISE has the potential to transform current research paradigms that do not consider independent stimulant use effects, promote new approaches for implementation research that acknowledge the importance of substance use patterns, inform biomedical and behavioral interventions that are sex-specific, and direct resource-intensive risk reduction strategies to those PWH who use substances and are at highest CVD risk.
