Journal of Human Hypertension (2002) 16, S34–S41 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh The potential role of AT1-receptor blockade in the prevention and reversal of atherosclerosis V Papademetriou Hypertension and Cardiovascular Research Clinic, VA Medical Center, Georgetown University, Washington DC, USA The renin-angiotensin system may contribute to the animal experiments, treatment with ACE inhibitors or development and progression of atherosclerosis both angiotensin AT1-receptor blockers has been shown to by increasing blood pressure and by direct effects on have anti-atherogenic effects. Studies with candesartan all phases of the atherogenic process. Genetic determi- have shown that this agent produces a dose-dependent nants of renin-angiotensin system activation, notably reduction in uptake of oxidised LDL by mouse macro- the DD genotype of angiotensin converting enzyme phages in vitro, and reduces cholesterol accumulation (ACE), are associated with an increased risk of cardio- and atherosclerosis development in the aorta of Watan- vascular events, as is increased plasma renin activity. abe rabbits. These effects were independent of changes In addition, angiotensin II has been shown to increase in blood pressure. Such findings suggest that the uptake and oxidation of low density lipoprotein AT1-receptor blockers may be beneficial in reducing (LDL) by macrophages and endothelial cells. Angioten- mortality and morbidity resulting from atherosclerotic sin II also stimulates the production of interleukin 6 and disease, and are consistent with the findings from large ␬ activates the pro-inflammatory factor nuclear factor B, outcome trials with ACE inhibitors in patients at risk of leading to expression of adhesion molecules and cardiovascular events. recruitment of monocytes and macrophages, and Journal of Human Hypertension (2002) 16, S34–S41. increases the production of pro-coagulatory factors. In doi:10.1038/sj.jhh.1001437 Keywords: AT1-receptor blockers; atherosclerosis; candesartan; irbesartan; losartan; renin-angiotensin system Introduction valuable therapeutic target for the prevention of atherosclerosis. Atherosclerosis is a complex process that may pro- gress for several decades before becoming manifest as a cardiovascular event such as myocardial infarc- Involvement of the renin-angiotensin tion. The process begins with endothelial dysfunc- system in atherogenesis tion, which leads to monocyte activation and migration into the subintimal layer, lipid oxidation There is good evidence from epidemiological, lab- and uptake, foam cell accumulation, and the forma- oratory and clinical studies that the renin-angioten- tion of fatty streaks, culminating in the development sin system contributes to atherosclerosis not only by of an atherosclerotic plaque.1,2 Thrombus formation increasing blood pressure, but also through multiple at the site of ruptured plaques, or intermittent direct effects on the arterial wall. thrombosis at intact plaques, leads ultimately to car- diovascular events. The risk of cardiovascular Effects on blood pressure events resulting from atherosclerosis is influenced by a number of well established risk factors, includ- Angiotensin II, through its action on AT1-receptors, ing hypertension,3 hypercholesterolaemia,4 dia- is a potent vasoconstrictor,7 and can also increase betes5 and smoking.6 In addition, there is increasing blood pressure indirectly through activation of the evidence that the renin-angiotensin system plays an sympathetic nervous system.8 It is well established, important role in the development and progression from studies such as the Framingham Study3 and of atherosclerosis, making this system a potentially the Multiple Risk Factors Intervention Trial (MRFIT),9 that there is a continuous relationship between elevated blood pressure and the risk of car- diovascular events, and that lowering blood pres- 10 Correspondence: Professor V Papademetriou, VA Medical Center, sure reduces the risk of such events. It appears, 50 Irving St NW, Washington DC 20422, USA however, that a certain minimum level of blood Role of angiotensin II in atherosclerosis V Papademetriou S35 pressure is necessary for atherosclerosis to develop. myocardial infarction associated with the DD geno- Atherosclerosis only occurs in high-pressure type was 2.11 (95% confidence interval 1.23–3.62, vascular beds. It does not, for example, develop in P = 0.007).13 Similarly, in a study in Japan, the DD the pulmonary circulation except in the presence of genotype occurred more commonly in patients with pulmonary hypertension, and is not seen in coronary artery disease than in healthy individuals veins, except in venous grafts in the arterial system. (58% vs 42%, respectively), and the relative risk of Furthermore, in patients with aortic coarctation, myocardial infarction associated with the DD atherosclerosis is confined to the proximal segment, genotype was 2.81 (1.79–4.41, P Ͻ 0.001);14,15 in where pressure is high, and does not occur distal to other Asian populations, the relative risk was 1.88 the site of coarctation. The level of blood pressure (1.43–2.48, P Ͻ 0.001).12 In a large case-control required for atherosclerosis to develop has not been study, involving 2267 male German caucasians, established. In the Hypertension Optimal Treatment there was a strong association between the presence (HOT) Study, the lowest incidence of major cardio- of the DD genotype and the risk of coronary artery vascular events (non-fatal stroke or myocardial disease, particularly in individuals without other infarction, and cardiovascular death) was seen at risk factors.16 mean systolic and diastolic blood pressures of 138.5 mm Hg and 82.6 mm Hg, respectively, and the Plasma renin activity: There is a well established lowest risk of cardiovascular death at pressures of relationship between elevated plasma renin activity 138.8 mm Hg and 86.5 mm Hg, respectively.11 and the risk of cardiovascular disease. In one study, for example, plasma renin activity was determined before starting antihypertensive treatment in 1717 Evidence for direct effects of the renin-angiotensin patients with mild-to-moderate hypertension.17 Dur- system on atherogenesis ing the subsequent 8 years of antihypertensive ther- Several lines of evidence suggest that the renin- apy, a total of 27 myocardial infarctions occurred in angiotensin system directly influences the risk of these patients. After adjustment for age, gender and atherogenesis (Table 1). race, the incidence of myocardial infarction in patients with high plasma renin activity at baseline Genetic determinants of renin-angiotensin system was 14.7/1000 person-years, compared with activation: Variations in the angiotensin con- 5.6/1000 person-years among those with normal verting enzyme (ACE) genotype have been shown to renin levels, and 2.8/1000 person-years in those be associated with an increased risk of cardiovascu- with low plasma renin activity. Similarly, all-cause lar events. The most extensively studied of these mortality was markedly higher among patients with variations is ACE I/D polymorphism.12 This is high plasma renin activity than in those with normal characterised by the presence (I) or absence (D) of a or low renin activity (9.3, 5.3 and 3.9/1000 person- 287 base pair sequence within intron 16 of the ACE years, respectively). Multivariate analysis showed gene, and the D allele is associated with increased that elevated plasma renin activity was a powerful ACE activity; in most populations, the DD genotype independent risk factor for myocardial infarction, is associated with plasma ACE activity approxi- but the risk was increased still further when other mately 20 times higher than that observed in indi- risk factors were present (Figure 1). viduals with the DI genotype, and 40 times higher than in those with the II genotype.12 Studies in Anti-ischaemic effects: Large outcome studies with countries with genetically homogeneous popu- ACE inhibitors have consistently shown that these lations have shown that the DD genotype is associa- agents reduce cardiovascular mortality and mor- ted with an approximately two to three-fold increase bidity in high-risk patients.18–23 In addition, how- in the risk of cardiovascular events. For example, in ever, these studies have shown that ACE inhibitor a study in Turkey involving patients with previous therapy reduces the incidence of recurrent myocar- myocardial infarction, the relative risk of dial infarction, by approximately 7–9% each year (Figure 2). This finding suggests that ACE inhibitors have anti-ischaemic effects, probably related to Table 1 Evidence for involvement of the renin angiotensin system in atherosclerosis stabilisation of atherosclerotic plaques. • Association of DD ACE genotype with risk of ischaemic Presence of ACE in atherosclerotic plaques: Recent events studies show that ACE is abundant at sites of athero- • Relationship between plasma renin activity and risk of sclerosis. In one study, for example, endarterectomy ischaemic events specimens were obtained from 24 patients with sev- • Anti-ischaemic effects of renin-angiotensin system ere occlusive carotid artery disease, and ACE mRNA blockade and protein were localised by in situ hybridisation • Presence of ACE in atherosclerotic plaques and immunohistochemistry.24 ACE was localised in • Multiple atherogenic actions of angiotensin II in the intima, and the degree of staining increased as experimental models lesions became more complex;