Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Interaction between serum cholesterol levels and the renin– angiotensin system on the new onset of arterial hypertension in subjects with high-normal blood pressure Claudio Borghi, Maddalena Veronesi, Eugenio Cosentino, Arrigo F.G. Cicero, Frederick Kuria, Ada Dormi and Ettore Ambrosioni Objectives To investigate the possible interactions between serum cholesterol levels and the renin–angiotensin system on the development of stable hypertension in subjects with high-normal blood pressure (BP). Background Hypercholesterolemia increases angiotensin- II type 1 (AT 1 ) receptor density and pressor responsiveness to angiotensin II, and has been reported to contribute to the development of hypertension. The effects of elevated serum cholesterol levels on BP control might be exaggerated by concomitant activation of the renin–angiotensin system, and their combination might contribute to the development of stable hypertension. Methods We investigated the relationship between serum cholesterol levels, plasma renin activity (PRA) and the long-term development of hypertension in 66 young (age <45 years) patients with high-normal BP and elevated (> 200 mg/dl, n U 46: HC) or normal ( < — 200 mg/dl, n U 20: NC) serum cholesterol levels and in 20 normotensive, normocholesterolemic controls (C). The main outcome measure was the prospective evaluation of the 15-year incidence of stable hypertension in the different populations. Results New-onset hypertension was higher in patients with high-normal BP and HC when compared to NC patients [relative risk (RR) U 1.9; 95% confidence interval (CI), 1.1–4.3, P < 0.001] and control subjects (RR U 3.1; 95% CI U 1.4–5.3, P < 0.001). High PRA increased the overall rate of hypertension in both HC and NC. The interaction between HC and PRA was more evident in patients with borderline high cholesterol levels (200–240 mg/dl) where the adjusted relative risk of new onset of hypertension was 2.17 (95% CI 1.2–3.74; P < 0.05) in high PRA subjects and 1.17 (95% CI 0.67–2.23; P U 0.87) in subjects with normal PRA. Conclusion We support the hypothesis that the presence of hypercholesterolemia can promote the development of stable hypertension through its interaction with the circulating renin–angiotensin system in patients with high-normal blood pressure. J Hypertens 25:2051–2057 Q 2007 Lippincott Williams & Wilkins. Journal of Hypertension 2007, 25:2051–2057 Keywords: blood pressure, cholesterol, hypertension, plasma renin activity Department of Internal Medicine, University of Bologna, Bologna, Italy Correspondence to Claudio Borghi, Divisione di Medicina Interna, Policlinico S. Orsola, Via Massarenti 9, 40138 Bologna, Italy Tel: +39 051 6363243; fax: +39 051 391320; e-mail: Claudio@med.unibo.it Received 17 January 2007 Revised 20 March 2007 Accepted 17 May 2007 Introduction Hypercholesterolemia is one of the most important risk factors for cardiovascular diseases since it contributes to the development of atherosclerosis [1]. More recently, some attention has been drawn to a putative role of hypercholesterolemia in the pathogenesis of arterial hy- pertension. In particular, the proportion of patients who develop stable hypertension has been reported to be significantly increased among the subjects with hyperch- olesterolemia, in both the general population [2 – 4] and in patients with high-normal blood pressure [5]. Conversely, a pharmacological approach based on the use of choles- terol-lowering drugs in normotensive patients with hypercholesterolemia has been reported to effectively reduce the new onset of hypertension [6,7]. High serum cholesterol levels impair endothelium-dependent vaso- dilatation [8–10] and exaggerate the pressor response to stress [11] and to some vascular agonists [12], and this might contribute to the increase of blood pressure (BP) values in the hypertensive range. On the other hand, treatment with statins prevents the BP hyperreactivity induced either by mental stress or the infusion of vaso- constrictive substances [13,14], thus supporting a primary role for hypercholesterolemia in the pathogenesis of hypertensive disease. Among the possible mechanisms linking elevated serum cholesterol levels to hyperten- sion, some interactions have been suggested between hypercholesterolemia and the renin–angiotensin system (RAS). Some evidence demonstrates that hypercholes- terolemia increases the density of angiotensin-II type 1 (AT 1 ) receptors and their functional responsiveness to angiotensin-II [14–17]. Conversely, lipid-lowering therapy reverses the enhanced BP response to angioten- sin-II [18] and this occurs with a downregulation of AT 1 receptor density [16], supporting the intriguing possibility of a substantial contribution of RAS in the development of ‘hypercholesterolemia-related’ hyper- tension. In particular, we hypothesize that the presence Original article 2051 0263-6352 ß 2007 Lippincott Williams & Wilkins