The histological characterization and endothlial function in HIV positive patients presenting with acute coronary syndromes
Background There are approximately 37 million HIV-positive patients worldwide, of whom 70% live in sub-Saharan Africa. Data from developed nations suggest that acute coronary syndromes (ACS) in HIV-positive patients are more prevalent in younger patients who have a high coronary risk factor profile. In developing countries data about HIV and coronary artery disease is very sparse. Furthermore, it is unclear whether the severity and characteristics of atherosclerosis in symptomatic HIV-positive patients is similar to that found in HIV-negative patients. Methods A prospective study of all HIV-positive patients with ACS presenting to a large public hospital in Johannesburg, South Africa, was performed over 3 years (July 2012- July 2015). Firstly, intravascular ultrasound and virtual histology was used to perform a detailed analysis of the plaque characteristics and burden of atherosclerotic disease in the culprit and nonculprit arteries in this group (HIV+/ACS) of patients. Secondly, in this cohort, surrogate markers of atherosclerosis such as carotid intima media thickness (CIMT), brachial flow mediated dilatation (FMD), pulse wave velocity (PWV) and endothelial biomarkers were also measured. The latter group of measurements were then compared with two groups of 20 patients each, namely HIV-negative patients presenting with ACS (HIV-/ACS) and HIVpositive patients presenting without ACS (HIV+/no ACS). Results The mean ages of the patients were 51.1 (sd=8.1) years, 52.3 (sd=9.0) years, 36.0 (sd=6.8) years in the HIV+/ACS, HIV-/ACS and HIV+/no ACS groups, respectively (p<0.0001). In the HIV+/ACS cohort, the predominant manifestation of ACS was ST-segment elevation myocardial infarction (75%), followed by non ST-segment elevation myocardial infarction (15%) and 10% presented with unstable angina. Risk factors included smoking in 11 (55%), hypertension in 6 (30%), diabetes in 2/20 (10%), dyslipidaemia in 2 patients (10%) and 1 (5%) patient had a family history of ischaemic heart disease. The left anterior descending artery was the most common artery involved (60%). The total plaque burden in the HIV+/ACS cohort consisted of moderate plaque in 60% of patients, followed by mild plaque in 35% and severe plaque in 5% of cases. The total plaque burden was significantly higher in the proximal than in the mid portion of coronary artery (p=0.010). Furthermore, it was significantly higher in the mid than in the distal part of the coronary artery (p=0.0006). The predominant plaque morphology in the entire coronary vasculature consisted of fibrous plaque (55.4%). Fibro-fatty plaques were found in 26.6% of patients, while necrotic core plaques were present in 13.3% and dense calcific plaques were present in only 4.7%. In the culprit coronary arteries, the major plaque morphology remained fibrous plaques (56.5%), whilst fibro-fatty (21.2%), necrotic core (14.4%) and dense calcific (3.6%) plaques constituted the remainder. There was no difference in the mean CIMT of the two groups of patients with ACS. The CIMT in the group without ACS (0.50; sd=0.08 mm) was marginally but significantly lower than the CIMT of both the HIV+/ACS group (0.66; sd=0.16 mm) and the HIV-/ACS group (0.70; sd=0.06 mm), (p=0.0005 and p<0.0001, respectively). There was no evidence of arterial stiffness as measured by pulse wave velocity in all 3 groups; 4.1 (sd=1.1) m/s, 4.6 (sd=1.1) m/s and 3.9 (sd=1.1) m/s, respectively (p=0.12). Endothelial dysfunction as assessed by FMD was similar in the HIV+/ACS and the HIV/ACS patients. The HIV+/ACS patients did, however, have fewer coronary risk factors (hypertension, diabetes, dyslipidaemia) compared to the HIV-/ACS patients. Vascular cell adhesion molecule-1 (VCAM-1) levels in the two HIV-positive cohorts were significantly higher than the HIV-negative cohort. There were no significant differences in the levels of IL1 β, IL1ra, MCP-1, TNFα, P-selectin and PAI-1 between the three cohorts. Conclusion Atherosclerotic plaque in HIV-positive patients presenting with ACS is predominantly comprised of non-calcified fibrous and fibrofatty plaque. In addition, these patients have a high degree of atherosclerotic plaque burden. Surprisingly, HIV-positive patients had low carotid intima media thickness and there was no significant arterial stiffness as measured by PWV. Non-invasive investigations like FMD, CIMT and PWV did not identify patients with HIV who are at high risk of ACS. The endothelial biomarker, VCAM-1 may be a useful biomarker to identify HIV patients who have endothelial dysfunction and have increased risk of ACS.
A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfillment of the requirement for the degree of Doctor of Philosophy Johannesburg 2019