The Role of Ectopic Fat and Heart Attack Risk in HIV

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.

Recent advances in biomarkers related to adipocyte health and NAFLD are of significant interest in PLWHIV. Fetuin A has been demonstrated to be associated with vascular calcification in those with obesity, NAFLD and metabolic syndrome. Adiponectin is another biomarker which is closely associated with adipocyte health and insulin resistance.

Multiparametric measures of ectopic fat (MRS, Fiborscan), cardiac structure and function (CMR), adipocyte health biomarkers (using tissue, serum and plasma) in association with CVD risk have not been studied in the same setting. We have designed this detailed cross-sectional analysis comparing PLWHIV to risk-matched general groups to inform on the role of ectopic fat in CVD in PLWHIV. This is of critical importance to gain mechanistic insight into the excess CVD risk seen in PLWHIV whilst also providing potential therapeutic targets for emerging drugs.

The increasing morbidity and mortality that CVD represents in this ageing group is of pressing concern. It represents an emerging health economic challenge for already stretched Western healthcare systems. Understanding HIV-specific mechanistic drivers of the excess CVD risk and potential therapeutic targets is therefore highly desirable. Our data and others suggest an important role for altered energy metabolism causing increased ectopic fat deposition. The development and realisation of specific therapeutics, that reduce ectopic and visceral fat, is of great interest for risk reduction strategies specifically for PLWHIV. Further understanding of the link between ectopic fat and CVD is required prior to embarking on randomised control trials for these agents. We have designed a comprehensive cross-sectional analysis investigating the associations of ectopic and visceral fat (multiple measures), intramyocardial lipid (cardiac MR spectroscopy), cardiac structure and function (CMR), biomarkers specific to energy metabolism (serum/plasma biomarkers), adipocyte health (tissue) with incident CVD (cardiovascular CT) in HIV-positive and HIV-negative / general population individuals.

The use of multiple measures of ectopic fat, including biomarkers for adipocyte health in serum and tissue, with incident CVD has not been done before. We anticipate that the data generated from this study will inform power calculations for future randomised control studies investigating the use of therapeutics on ectopic fat reduction in PLWHIV.

We have designed a cross sectional study to assess the relationship between EAT volume and CVD risk in PLWHIV and general populations. Participants will be recruited from the regional HIV service hosted by LUHFT. HIV-negative / general population participants will be recruited from those undergoing CT Coronary Angiography.

The study will involve 50 HIV-positive subjects and 50 general subjects. HIV-positive subjects will be recruited from follow up clinics and will have stable HIV disease (VL<40 copies/ml) and CD4 counts >200cells/mm3 for a minimum of 1 year. All subjects will be required to read the patient information leaflet and sign the consent form before enrolment to the study. Participants will be stratified into low (n=10), moderate (n=20) and high (n=20) risk according to traditional scoring methods. We will also include within these numbers 20 subjects with documented weight gain on INSTI regimes.