Abnormal immune activation and fibrosis of epicardial adipose tissue in people living with HIV: results from the PIECVIH study

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Abstract Background Increased Epicardial Adipose Tissue (EAT) volume has been associated with increased risk of CAD in people living with HIV (PLWH). However, the underlying mechanisms remain unknown. Purpose We conducted the PIECVIH study to compare EAT properties in relation with CAD between PLWH and HIV-negative patients, all undergoing coronary artery bypass graft (CABG). Methods The PIECVIH study is a cross sectional prospective study performed in a single center enrolling 11 ART-controlled PLWH and 11 matched (age ± 3 years and sex) HIV-negative patients requiring CABG. During surgery, EAT and thoracic subcutaneous fat samples were taken. Gene expression was analyzed in samples with sufficient mRNA quality (7 PLWH and 7 HIV− for subcutaneous fat, 9 PLWH and 8 HIV− samples for EAT). The expression of 30 genes, mainly related to inflammation, immune activation, fibrosis and adipokines, was evaluated and related to the expression of the reference gene 18S. Results The mean age of the cohort was 59.8 years (100% male). The cardiovascular risk profile was quite similar between both groups including 66% smokers, 64% hypercholesterolemia, 36% hypertriglyceridemia and 56% hypertension. However, HIV− subjects had a higher prevalence of diabetes (73% vs 18%, p=0.002) and a higher body mass index than HIV− (23,2 vs 27.5 kg/m2, p=0.017). The level of gene expression of all tested genes was not different between PLWH and HIV− subjects in subcutaneous fat. Conversely, in EAT, the relative expression of IL-6 and CCL2 was 3–5-fold higher in samples issued from PLWH than from HIV−: respectively 0.46 vs 0.13 (p=0.03) and 1.13 vs 0.24 (p=0.03). Moreover, only in EAT, and only in PLWH, the expression of the chemokines CCL2 and CCL5 and of the macrophage immune activation markers (CD68, CD163, CD206), was globally related to the expression of genes involved into fibrosis: collagen genes (COL1A1, COL3A1, COL3A1, COL6A2, COL6A3), TGFB, LOX (lysyl-oxidase) and ASAH1 (acid ceraminidase). Only in EAT and only in PLWH, the expression of IGF1 and CES (carboxylesterase 1), two genes associated with increased cardiovascular risk, was related to the expression of genes associated with immune activation, fibrosis and vascularization (VEGFA). Only in PLWH, the Gensini score, evaluating the severity of CAD, was associated with EAT expression of collagen 6 and of the CV risk factors IGF1 and CES. Conclusion In very high CV risk subjects undergoing CABG, inflammation/immune activation of EAT was higher in PLWH as compared to controls. In EAT of PLWH, immune activation was strongly associated with fibrosis stressing for a dysfunctional EAT. Moreover, the severity of CAD, as addressed by the Gensini score, was associated with collagen 6 expression, a deleterious collagen in the context of EAT fibrosis. We propose that in PLWH, altered EAT immune profile and fibrosis could be responsible for reported accelerated CAD. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): French Agency for Research on AIDS and Viral Hepatitis

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