Acute coronary syndromes in black South African patients with human immunodeficiency virus infection
Becker, Anthony Charles
Background: South Africa is considered to be a country in epidemiologic transition with increasing rates of cardiovascular disease. In addition, it faces an HIV pandemic, with an estimated 5.5 million people infected and five hundred thousand HIV-related deaths annually. Current evidence suggests that patients infected with HIV are at a heightened risk for acute coronary syndromes (ACS) related to traditional cardiovascular risk factors, as well as factors related to the virus and its treatment (highly active anti-retroviral therapy (HAART)). HIV infection itself may independently predispose to coronary artery disease (CAD) by promoting endothelial dysfunction, a heightened pro-inflammatory state, dyslipidaemia and thrombosis, the aetiology of which is thought to be multifactoral in nature. Protease inhibitor (PI) therapy, as part of HAART, has the potential to induce an adverse metabolic phenotype, including: dyslipidaemia, insulin resistance, endothelial dysfunction and a prothrombotic state. The attributable risk of these factors in HIV-associated CAD and ACS is currently unknown, but it seems that the risk of ACS is increased by prolonged exposure to PI’s. No data currently exists on CAD in HIV patients not receiving HAART, which is problematic considering that this makes up the majority of patients in sub-Saharan Africa and that the combination of epidemiologic transition and HIV infection has the potential for greater cardiovascular morbidity, particularly with respect to atherothrombotic events. viii Aims: The aims of this thesis are twofold. Firstly, to confirm reports of epidemiologic transition in South Africa from a broad epidemiological perspective. Secondly, by focusing on treatment-naïve HIV positive black South Africans with ACS, it aims to determine differences compared to HIV negative patients with respect to demographics and risk factors, angiographic and treatment related factors as well as markers of thrombosis and inflammation with a view to providing more focused primary and secondary prevention. Methods: All the studies contained in this thesis were conducted in the Department of Cardiology, Chris Hani Baragwanath Hospital and adhere to the declaration of Helsinki. The first of the epidemiological studies, The Heart of Soweto (HOS) study (Chapter 3), was a prospectively designed registry that recorded epidemiologic data relating to the presentation, investigations and treatment of 1593 patients from Soweto with newly diagnosed cardiovascular disease during the year 2006. The second study (Chapter 4) was a cross sectional study of patients with ACS admitted to the Baragwanath coronary care unit over the year 2004 compared to the years 1975-1980. The HIV sub-study (chapters 5-8) was a prospective single centre study conducted from March 2004 to February 2008. During this time, 30 consecutive black HIV patients presenting with ACS (ACS+: HIV+ group) were enrolled. For each HIV patient with ACS, the first presenting non-HIV black patient with ACS was selected as a case control comparator (ACS+ : HIV- group). In addition, a second control group of 30 asymptomatic HIV patients, who were matched for age, sex and ethnicity (ACS- : HIV+ group), were recruited from the HIV clinic. The methodology used to compare the groups involved: clinical and demographic data collection, routine blood test evaluation, angiographic ix analysis and specific laboratory testing of various research blood parameters (including thrombotic screening and markers of inflammation and endothelial activation). Results: Chapter 3 presents the results of the large HOS study, which showed good evidence to support the theory of epidemiologic transition in Soweto. Adding to this data are the results of Chapter 4, which clearly demonstrate a substantial increase in the number of patients diagnosed with ACS at Baragwanath in recent years. Consistent with a population in epidemiologic transition, there was more than a ten-fold increase in the rate of coronary events over two decades, paralleled by increased rates of modifiable risk factors. Chapter 5 presents the clinical and angiographic data from the HIV sub-study. HIV patients with ACS were younger and had fewer traditional risk factors for CAD except for higher rates of smoking and lower HDL cholesterol levels. HIV patients had less atherosclerotic burden angiographically, but a higher thrombus burden in the infarct related arteries, suggesting a possible prothrombotic state. In addition, HIV patients had higher rates of in-stent restenosis of bare metal coronary stents at follow up. Chapters 6 and 7 present data on the thrombotic parameters between the groups, with Chapter 6 focusing mainly on coagulation pathways and Chapter 7 focusing on antiphospholipid antibodies (aPL). Chapter 8 presents data on levels of pro-inflammatory cytokines and endothelial activation markers. Greater evidence of thrombophilia was found in HIV patients with ACS as evidenced by lower Protein C (PC) levels, higher levels of Factor VIII and a higher inflammatory burden with greater degrees of endothelial cell activation - all of which increase thrombotic risk. Antiphospholipid antibodies were more prevalent in HIV patients but did not seem to be causal in the pathogenesis of thrombosis. x Conclusion: Soweto, a large, predominantly black urban area in South Africa, is in a state of epidemiologic transition, with an increasing prevalence of modifiable cardiovascular risk factors and ischaemic heart disease. Treatment-naïve HIV positive black patients presenting with ACS have different clinical and angiographic features compared to the HIV negative population. The patients are younger, more commonly male, with high rates of smoking, lower HDL levels and less atherosclerotic burden. However, there is a higher thrombotic burden, suggesting a prothrombotic state, which was evident by lower PC levels, higher factor VIII levels with a higher inflammatory burden and a greater degree of endothelial cell activation – all factors associated with a pro-atherogenic and prothrombotic state. The exact pathogenic role of HIV, independent of associated modifiable and non-modifiable risk factors, is difficult to determine, but may be important as a contributory factor in an already “vulnerable” patient. Importantly, we identified modifiable risk factors in the HIV group. Smoking may play a crucial role in the pathogenesis of ACS in these otherwise seemingly low risk patients and remains an important target for cardiovascular risk reduction. The role of HDL in the pathogenesis and prevention of HIV-associated CAD needs to be further defined, as does the role of drug eluting coronary stents in the prevention of in-stent restenosis. Cardiovascular risk assessment and appropriate primary prevention should be an important component in the management of HIV patients, regardless of treatment status. With the anticipated increase in CVD in South Africa, further research projects appropriate to the South African context will be vital in order to explore cost effective ways to provide primary and secondary prevention in order to effectively deal with the burden of epidemiological transition as well as the cardiovascular burden likely to be imposed by the HIV pandemic.