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1 REVIEW Common pathways of hypercholesterolemia and hypertension leading to atherothrombosis: the need for a global approach in the management of cardiovascular risk factors Jos Tun 1 Abstract: In the last years there has been increasing evidence suggesting that the treatment Jos Luis Martn-Ventura 1 of cardiovascular risk factors must be done on a global rather than on a separate approach, Luis Miguel Blanco-Colio 1 because they have additive effects and share common pathways leading to atherothrombosis. Nieves Tarn 2 Of special interest is the relationship between hypertension and dyslipidemia. An excessive activity of the renin-angiotensin system (RAS), that plays an important role in hypertension, Jess Egido 1 contributes to endothelial dysfunction, vascular inammation and thrombosis. Dyslipidemia 1 Cardiology and Vascular Research induces the same effects through similar mechanisms. In fact, combined therapy with statins Departments, Fundacin Jimnez Daz, Autnoma University, Madrid, Spain; and RAS modulators shows synergic benecial effects in the treatment of atherosclerosis. Then, 2 Department of Cardiology, Hospital in the future, the traditional hypertension and dyslipidemia units should probably evolve into de Mstoles, Madrid, Spain global cardiovascular risk management Units. Also, polypills combining antihypertensive and lipid-lowering drugs will make easier the treatment of these conditions. These changes would provide us the necessary tools to treat our patients in accordance with the current strategies of cardiovascular therapy and prevention. Keywords: Angiotensin, atherosclerosis, endothelium, hypercholesterolemia, hypertension, inammation Many years ago, the Framingham study and other studies began to identify a number of different risk factors as potential causes of atherothrombotic events (Kannel et al 1961; McGill 1996). Treating these risk factors emerged then as a capital task in the ght against cardiovascular disease. However, this approach has evolved notoriously in the last years. In the initial era, cardiovascular risk factors (CRF) were assessed and treated separately, but later, the avalaible information has shown us that this work has to be done based on a global approach. Clinical studies have demonstrated that CRF act in a synergistic way. In addition, we have learned from pathophysiological studies that there are mechanistic links between the pathways through which different CRF cause atherothrombosis. In this regard, of special interest is the relationship between the pathophysiology of hypertension and dyslipidemia.We will focus on the clinical and pathophysiological data relating to the development of these two factors, to sup- port the concept of a global management of the patient with CRF. Correspondence: Jos Tun Department of Cardiology, Fundacin Jimnez Daz, Avda Reyes Catlicos 2, Combined antihypertensive and lipid lowering 28040 Madrid, Spain therapies in the clinical practice Tel +34 91 550 4816 Fax +34 91 549 7033 A large number of clinical trials has demonstrated that treatment of either hypercho- Email [email protected] lesterolemia or hypertension leads to a reduction in the incidence of cardiovascular Vascular Health and Risk Management 2007:3(4) 521526 521 2007 Dove Medical Press Limited. All rights reserved

2 Tun et al events. Also, statins and angiotensin converting enzyme infarction or fatal coronary heart disease and that of (ACE) inhibitors demonstrated an additive effect reducing the stroke, cardiovascular and coronary events. Thus, using incidence of cardiovascular events (Yusuf et al 2000; Heart statins in patients with moderately increased or even Protection Study Collaborative Group 2002). normal cholesterol levels, but at risk of cardiovascular The Anglo-Scandinavian Cardiac Outcomes Trial events because of accompanying hypertension and other (ASCOT) studies have shed new light into this mat- CRF, improved their clinical evolution. Remarkably, ter. The ASCOT-BPLA (Blood Pressure Lowering in the ASCOT-BPLA, an optimal prevention of cardio- Arm) analyzed 19,257 patients with hypertension and vascular events was reached in patients randomized to at least three other cardiovascular risk factors, which atorvastatin and the amlodipine/perindopril treatment, were randomized to therapy with amlodipine, adding with a reduction of 48% in the risk of fatal myocardial perindopril when necessary, or to atenolol, using ben- infarction and non-fatal coronary heart disease and droumethiazide as a second drug (Dahlof et al 2005). 44% in the incidence of stroke (http://www.broadshow. By the end of the trial, 78% of patients were taking the com/ascot/press-material.php). second antihypertensive drug, and the amlodipine/per- indopril regimen was superior to atenolol in terms of Dyslipidemia and hypertension all-cause mortality, stroke, total cardiovascular events share common pathways leading and procedures and new-onset diabetes. When several variables of the ASCOT-BPLA were to atherothrombosis analyzed, blood pressure reduction was not the only Three ndings are of special interest in the above-mentioned contributor to the amlodipine/perindopril decrease in data. First, a statin, a cholesterol-lowering drug, is benecial cardiovascular events (Poulter et al 2005). Interestingly, in the treatment of patients who are at risk of cardiovascular although blood pressure was the most important vari- events because of the coexistence of several risk factors for able associated with the incidence of stroke, differences atherothrombosis, even when their cholesterol levels are in HDL cholesterol were more important for coronary normal or only moderately elevated. Second, blood pres- events. Furthermore, full adjustment for these variables sure control and lipid lowering seem not to account for all as well as for bodyweight, and glucose, triglycerides, the reduction achieved by antihypertensive and statin treat- creatinine and potassium serum levels explained only ments respectively. And, third, the combination of a statin 50% and 40% of the differences in coronary and stroke and an effective antihypertensive regimen leads to the best events, respectively, leaving the remaining percent- prevention results. ages to be potentially explained by other variables not These facts suggest that the pathophysiologic pathways considered in this analysis. These data suggest that that link hypertension and dyslipidemia to atherothrombosis blood pressure reduction is not the only mediator in may share common mechanisms, and this may be similar for the benecial effect of antihypertensive drugs. Accord- other cardiovascular risk factors. This idea is supported by ingly, several vasculoprotective mechanisms have been clinical data showing that statins may diminish blood pres- demonstrated for anti-hypertensive drugs, the most sure levels (Glorioso et al 1999). However, most evidence important of which have been described for those that supporting this possibility comes from basic research. In this modulate the renin-angiotensin system (RAS). The setting, the enhanced activity of the RAS, which plays an same holds true for statins, which have been claimed important role in hypertension, can activate similar mecha- to exert a part of their benecial actions by cholesterol- nisms to dyslipidemia in endothelial dysfunction, inamma- independent mechanisms (Blanco-Colio et al 2003; tion and thrombosis. Ray et al 2005). The ASCOT-LLA (Lipid Lowering Arm), pub- Endothelial dysfunction in the crossroad lished in 2003, showed data of further interest (Sever between hypertension and dyslipidemia et al 2003). Ten thousand three-hundred ve patients All major atherothrombotic risk factors induce endo- from the ASCOT-BPLA study with total cholesterol thelial dysfunction. The key feature in this disorder is a concentrations of 6.5 mmol/L or less were randomized reduced availability of nitric oxide (NO) due to both a to atorvastatin 10 mg/d or placebo. Treatment with the decrease in its synthesis and to an enhanced degradation. statin reduced the incidence of non-fatal myocardial Hypercholesterolemia plays an important role in this setting, 522 Vascular Health and Risk Management 2007:3(4)

3 Common pathways from hypercholesterolemia and hypertension to atherothrombosis as oxidized LDL diminishes the expression of endothelial with healthy subjects, and these responses are normalized NO synthase (eNOS) (Laufs et al 1998). Furthermore, in by treatment with statins (Nickenig et al 1999). Finally, the hypercholesterolemia there is an increase of asymmetric combination of a statin and an ARB are superior to each dimethylarginine levels, an eNOS endogenous inhibitor (Ito drug alone in reducing the extent of atherosclerosis and the et al 1999). Angiotensin (Ang) II may also downregulate expression of LOX-1 and p38 MAPK in the apo-E knockout eNOS expression via protein-kinase C (Harrison et al 1995), mice (Chen et al 2006). This fact reinforces the idea of the thus leading to a decrease in NO production. In addition, interplay between the atherothrombotic pathways of the RAS both hypercholesterolemia and Ang II can participate in NO and hypercholesterolemia. degradation. Oxidized LDL contributes to oxidative stress, where superoxide anion is generated by endothelial oxidase Common pathways to inflammation enzymes. Superoxide reacts with NO yielding peroxynitrite for Ang II and dyslipidemia (ONOO-), a compound which, in high amount, works as a Another important feature in the pathophysiology of ath- strong oxidant and is toxic to proteins (Ischiropoulos et al erothrombosis is inammatory cell recruitment into the 1995). On the other hand, Ang II is a powerful oxidant agent vascular wall. This phenomenom is due to the expression that increases superoxide anion production through NADH/ of adhesion and chemoattractant molecules by the endothe- NADPH in vivo an in vitro via AT1 receptors (Rajagopalan lium, which is regulated, among others, by the transcription et al 1996). Angiotensin II can generate reactive oxygen factor NF-B (Barnes et al 1997). This transcription factor species (ROS), which activate different intracellular signal- plays a key role in the atherothrombotic process, since it also ing cascades, including mitogen-activated protein kinases controls the expression of many other proinammatory and (MAPK) and the transcription factor NF-B (Hernndez- prothrombotic proteins, including that of tissue factor, the Presa et al 1997; Ushio-Fukai et al 1998). Statins are able to trigger of thrombosis in the atheroma plaque. The activation counterbalance the effect of oxidative stress, and decrease of NF-B is enhanced, among other stimuli, by ROS and the NF-B activity induced by superoxide anion (Ortego oxLDL, and inhibited by HDL (Barnes et al 1997; Xu et al et al 1999). 1999; Robbesyn et al 2003). In this regard, we have shown In the setting of endothelial dysfunction, there is an that statins decrease NF-B activity in vitro and in a rabbit increase in vascular permeability to LDL, which becomes model of atherosclerosis (Bustos et al 1998; Ortego et al oxidized in the arterial wall where the macrophages uptake 1999). However, we have also demonstrated that Ang II is them evolving into foam cells. These processes are promoted able to induce NF-B activity in cultured monocytic and by AT1 receptor activation (Keidar et al 1997). In fact, the vascular smooth muscle cells (Hernndez-Presa et al 1997). expression of the oxidized LDL receptor LOX is enhanced In this effect, Ang II-induced ROS generation may play an through AT1 activation (Morawietz et al 1999). Moreover, important role, as it was inhibited by pyrrolidinedithiocarba- the expression of this receptor is induced by LDL in vascu- mate (Ortego et al 1999). In fact, ARB treatment diminishes lar smooth muscle cells, and is enhanced in experimental free radical generation and NF-B binding in mononuclear models of atherosclerosis (Nickenig et al 1997; Warnholtz cells of healthy subjects (Dandona et al 2004). et al 1999). In addition, ACE is present in greater amounts in In addition, Ang II induces leukocyte-endothelial cell atherosclerotic plaques (Diet et al 1996). Thus, lipid-lowering interactions and upregulates the expression of several drugs are not the unique strategy to lessen these LDL-related adhesion molecules and chemoattractant cytokines, includ- biological processes. In agreement with these data, angioten- ing MCP-1 (monocyte chemoattractant protein-1), IL-6 sin receptor blockers (ARBs) have been shown to decrease (interleukin-6), and IL-8, mainly through AT1 receptors atheroma formation (Warnholtz et al 1999). (Hernandez-Presa et al 1997; Schieffer et al 2000; Ito et al According to all this evidence, multiple studies in the 2002; Riaz et al 2004). In addition, RAS inhibitors decrease literature have demonstrated that both statins and RAS in- inammation in human beings and in experimental models hibitors improve the endothelial function in human beings of atherosclerosis (Hernndez-Presa 1997, 1998; Cipollone (Mancini et al 1996; ODriscoll et al 1997; Tun et al 2004; et al 2004; Fliser et al 2004). For instance, the ARB irbe- Ceriello et al 2005). Furthermore, there is an additive effect sartan reduces macrophage inltration, and the expression of hypertension and dyslipidemia. The infusion of Ang of the proinammatory enzyme cyclooxygenase-2 (COX-2) II in patients with hypercholesterolemia increases blood and metalloproteinases in human carotid plaques (Cipollone pressure and AT1 expression more than twice as compared et al 2004). Also, olmesartan has demonstrated recently to Vascular Health and Risk Management 2007:3(4) 523

4 Tun et al diminish plasma levels of C reactive protein, TNF-, IL-1 atherosclerotic plaques (Toschi et al 1997). Platelets and MCP-1 in patients with arterial hypertension and micro- express AT1 receptors, and ACE inhibitors and ARBs inammation (Fliser et al 2004). have been demonstrated to inhibit platelet aggregration With regard to statins, there is a huge amount of infor- (James et al 1988; Crabos et al 1993; Schieffer et al mation showing that they may downregulate the NF-B 2004). Also, losartan works as a competitive antagonist pathway, decreasing the expression of adhesion molecules, of thromboxane A2, a compound derived from COX- chemoattractant cytokines, that of the proinflammatory 1 activity which induces platelet aggregation (Corriu enzyme COX-2 and plasma levels of several inammatory et al 1995). Statins also interfere with these pathways, markers (Bustos et al 1998; Hernndez-Presa et al 1998; as they diminish platelet aggregation, thromboxane A2 Ortego et al 1999; Blanco-Colio et al 2003). In this regard, synthesis and thrombin-induced tissue factor expression we have demonstrated that atorvastatin decreases NF-B in endothelial cells (Davi et al 1992; Notarbartolo et al activity, MCP-1 expression and macrophage inltration in 1995; Eto et al 2002). Moreover, Ang II induces tissue human atherosclerotic plaques in only one month of treatment factor expression in human monocytes via the protein (Martn-Ventura et al 2005). Of interest, the expression of kinase C pathway, and ARBs decrease tissue factor metalloproteinases is enhanced by Ang II in smooth muscle activity in hypertensive patients (Koh et al 2004; He cells and reduced by statins (Luan et al 2003; Luchtefeld et al 2006). Also, RAS is involved in the regulation of et al 2005). Furthermore, statins are able to inhibit the Ang the endogenous brinolytic system. Ang II induces the II-induced expression of MCP-1 and IL-8 in vascular smooth expression of the inhibitor of spontaneous thrombolysis muscle cells (Ortego et al 1999; Ito et al 2002), conrming PAI-1 (plasminogen activator inhibitor type 1), and the interaction between the inammatory pathways triggered RAS inhibitors decrease PAI-1 plasma levels, which by dyslipidemia and the RAS. Finally, the combination of are enhanced following a myocardial infarction (Wright atorvastatin and irbesartan reduced C-reactive protein and et al 1994; Koh et al 2004). Moreover, ACE inhibitors IL-6 levels more effectively than each of two drugs alone in block bradykinin degradation, and this peptide induces diabetic patients (Ceriello et al 2005). the expression of t-PA (tissue plasminogen activator) There are other crosslinks between RAS and statins in (Vaughan et al 1995). Similarly, statins increase the inammation. Vascular permeability is augmented by Ang synthesis of t-PA and decrease PAI-1 (Essig et al 1998; II via AT1 receptors, while it is decreased by statins (Bonetti Bourcier et al 2000). Very recently, we have observed et al 2002; Victorino et al 2002). Ang II and dyslipidemia that intensive treatment with atorvastatin after an share also their effects on brosis, the part of the inam- acute coronary syndrome enhances the expression of matory process that repairs the damaged tissue, but that in annexin II, a receptor for tissue plasminogen activator atherosclerosis also results in plaque growth. In this sense, and plasminogen, in circulating monocytes (Tun the expression of PDGF (platelet-derived growth factor), et al 2007). In conclusion, Ang II and dyslipidemia TGF-1 (transforming growth factor-1) and CTGF (connec- also act through common mechanisms to promote tive tissue growth factor), that mediate the growth-promot- thrombus formation, which is ultimately responsible for ing effect of Ang II, is reduced not only by ARBs and ACE acute ischemic events in atherothrombosis. Combining inhibitors, but also by statins (Grandaliano et al 1993; Wong adequately RAS modulators with statins may reduce et al 1997; Kim et al 2000; Iwanciw et al 2003; Ruprez et al the probabilities of developing cardiovascular events 2003). Moreover, these drugs are able to decrease Ang II- by interfering with these actions. induced expression of CTGF (Iwanciw et al 2003). Clinical implications Lipids, RAS and thrombosis Several pathways of the essential biological processes in Thrombosis is a critical component of the atheroscle- atherothrombosis are shared by dyslipidemia and Ang II, rotic disorder, and leads to acute coronary syndromes and these mechanisms are targets for RAS modulators and ischemic stroke. It begins with platelet adhesion and statins. Then, the isolated approach to the treatment and aggregation, followed by activation of the coagu- of separated risk factors for atherothrombosis seems to be lation cascade. Tissue factor activation is the rst step over, since evidence from basic and clinical research clearly of the cascade coagulation in vascular thrombosis, and indicates that the pathways by which multiple risk factors this factor is present in the lipid core component of the lead to this disorder are strongly interrelated. In fact, cur- 524 Vascular Health and Risk Management 2007:3(4)

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