The Association of Ectopic Fat and Cardiovascular Disease in People Living With HIV and General Populations: A Cross Sectional Analysis

PLWHIV have an increased risk of developing cardiovascular disease compared to risk matched HIV-negative patients. CVD is a leading cause of morbidity and mortality in PLWHIV and increasing burden on healthcare systems. One model has suggested that the median age of PLWHIV will increase from 43.9 years in 2010 to 56.6 years in 2030 with 78% being diagnosed with CVD. Traditional risk predication tools have been demonstrated to perform poorly in this patient cohort.

This increased risk may be driven by several factors. Viral related mechanisms, ART, and increased prevalence of traditional risk factors (smoking, poor diet, sedentary lifestyle) act in a synergistic fashion to enhance the cardiovascular risk seen in HIV-positive patients. Recent data has focused on the role of energy metabolism as a mechanistic driver for this excess risk. Accessory proteins from the virus and certain antiretroviral agents are known to induce adipocyte dysfunction through reduction of pre-adipocyte differentiation, muted insulin-sensitivity, increased lipolysis, and mitochondrial stress. The net effect of these changes promotes 'central' storage of energy (fatty acids) in VAT and ectopic fat, of which the principal sites are the hepatic parenchyma (NAFLD) and EAT.

Both NAFLD and EAT are increasingly recognised as risk factors for CVD in both PLWHIV and HIV-negative groups. PLWHIV are 25% more likely to develop NAFLD at normal body weights compared to HIV-negative groups. Our work, and others, have demonstrated a significant association of NAFLD in PLWHIV but less so in HIV-negative groups . EAT volume has again been demonstrated to be associated with CVD in general populations. EAT shares a common microcirculation with the epicardial coronary arteries and exerts influence on vascular function through adipokine secretion, buffering of fatty acids, and secretion of inflammatory cytokines. The close anatomical relationship between EAT and the epicardial coronary arteries may indicate a novel substrate for atherogenesis in the context of EAT dysfunction. Again, our work has demonstrated a strongly significant association between EAT volume and incident CVD.

Emerging imaging studies are utilising cardiac MRS to measure intramyocardial metabolites and associations with health and disease. Cardiac MRS provides the ability to co-localise cardiac anatomy, tissue composition and energetic performance in vivo giving the ability to study the pathophysiology and cell biology of metabolic syndrome, glucose metabolism and ectopic fat deposition. Phosphorus MRS allows quantification of calculation of phosphocreatine to ATP ratio (PCr/ATP) which is a marker of myocardial energetic state. Using phosphorus MR spectroscopy myocardial energetic substrate compromise has been found in diabetic cardiomyopathy. It has also been used to study the effects of SGLT2 inhibitors on cardiac energy substrate utilisation. Proton MR spectroscopy allows quantification of intracellular triglyceride which allows further assessment of the metabolic status of cardiac tissue. Previous work has demonstrated increased cardiac steatosis, on cardiac MR spectroscopy, in HIV-positive patients compared to HIV-negative patients . HIV-positive women increased cardiac steatosis was associated with evidence of cardiac diastolic dysfunction. The use of MRS (proton and 31-P) to study the impact of therapeutic interventions on ectopic fat has never been studied in HIV.

Cardiovascular CT is an important imaging modality with widespread clinical and research utility. It has the ability to inform on multiple metrics of CVD including total plaque volume, non-calcified plaque volume, calcium score (Agatston score), plaque morphology and stenosis grading. The use of these measures as surrogates for CVD risk has been used extensively over the last two decades. This imaging modality is of critical importance to HIV / CVD research as trials powered for CVD outcomes are not feasible.