November 12, 2018 – A DCRI substudy identified proteins that may differentiate diastolic dysfunction in HIV patients from non-HIV individuals.
As antiretroviral therapy has transformed HIV from a potentially fatal disease to a chronic one, persons living with HIV (PLHIV) may develop more cardiovascular risk factors and CV-related morbidity and mortality, even with viral suppression, than those not infected by HIV.
“Antiretrovirals have shifted the epidemiology of heart failure in HIV from systolic to diastolic dysfunction (DD), putting PLHIV at a higher risk for cardiovascular disease,” said the DCRI’s Svati Shah, MD, MHS. “The question has been what are the mechanisms?”
On Monday at the American Heart Association’s Scientific Sessions 2018 in Chicago, Shah presented her research on proteomics that identify inflammatory, lipid, and cell proliferative pathways in diastolic dysfunction in HIV. Her presentation was a substudy of the CHART (Characterizing Heart Function on Antiretroviral Therapy) clinical trial that recently enrolled 195 healthy PLHIV through the National Heart, Lung, and Blood Institute’s Heart Failure Network.
“With a goal of looking deeply at these patients, we used proteomic profiling technologies to test CHART blood samples and locate the novel biomarkers and potential mechanisms underlying DD in PLHIV,” Shah said. “Both cardiac fibrosis and inflammation have been proposed as key mechanisms in PLHIV underlying cardiovascular disease and heart failure with preserved ejection fraction (HFpEF), but those mechanisms had not been well understood.”
After assaying 977 unique protein biomarkers, Shah and her colleagues determined that cardiac fibrotic pathways (as represented by extracellular matrix proteins) rather than inflammatory pathways were the strong differentiators of DD in PLHIV. “We believe these biomarkers can help identify those PLHIV who have DD and are at risk of developing HFpEF or diastolic heart failure.”
Shah’s team also used STRING bioinformatics tools to analyze which pathways may be “overrepresented” in the data. The extra cellular matrix, which is the core component of cardiac fibrosis, was overrepresented in the significant proteins, Shah said.
“This reinforces other findings that it is not just one protein but several proteins in that pathway that are significant in the development of DD in PLHIV,” she said. “The beauty of these relatively new technologies is the ability to measure so many proteins in very small amounts of blood. It’s like a liquid biopsy, and with such high specificity that we can be confident of what we are measuring.”
“Basically, we are measuring the stiffness of the heart, which is, at a simple level, what DD is,” Shah said. “These proteins essentially show us how cells talk to each other and how they become stiff and cause cardiovascular disease. Going forward, we plan to compare these results to a non-HIV infected group and to perform longitudinal assessments.”
Shah said this may be the first time anyone has been able to look at this many plasma proteins at one time.
“We may also be the first to use high throughput large-scale proteomic profiling to get this comprehensive and unbiased view of the diverse biological pathways underlying DD in PLHIV,” she said.
In addition to Shah, DCRI contributors included Lydia Coulter Kwee, Steven McNulty, and Adrian Hernandez.