Are There Effects of Renin–Angiotensin System Antagonists Beyond Blood Pressure Control?

Are There Effects of Renin–Angiotensin System Antagonists Beyond Blood Pressure Control? George Bakris, MD Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are recognized to reduce cardiovascular and renal morbidity and mortality, which is primarily attributed to their antihypertensive effects. Activation of the renin–angiotensin system (RAS) may also play an important role in the pathogenesis of cardiovascular and renal disease through blood pressure–independent mechanisms mediated by angiotensin II. Thus, inhibiting the RAS with either an ARB or an ACE inhibitor may confer additional benefit in people with advanced nephropathy that cannot be explained totally by reductions in blood pressure. Preclinical evidence suggests that blood pressure lowering is not solely responsible for the organ and tissue protective effects of ACE inhibitors or ARBs. Furthermore, clinical studies evaluating effects on end organs and surrogate markers have shown that these agents have blood pressure–independent effects. There is also intriguing evidence that agents in the same class may differ in their effects on renal function despite similar blood pressure control. Support for blood pressure–independent effects comes from outcome studies. Agents evaluated in such studies and that appear to have effects independent of blood pressure lowering include irbesartan, losartan, ramipril, and telmisartan. Taken together, this body of evidence indicates that the clinical benefits of ARBs and ACE inhibitors in patients with advanced nephropathy extend beyond blood pressure reduction. Therefore, although antihypertensive efficacy is of primary importance in choosing a treatment to provide cardiovascular and renal protection, consideration should be given to the effects of an agent that extend beyond blood pressure. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105[suppl]:21A–29A)

Antihypertensive agents that block activity of the renin– angiotensin system (RAS) are hypothesized to have additional cardiovascular and renal protective effects compared with other classes of blood pressure–lowering agents. There are many studies on the effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) on various organs and of improvements of surrogate markers of risk that support the hypothesis that these 2 drug classes have actions beyond blood pressure. There are some, albeit fewer, meaningfully powered outcome trials of ACE inhibitors or ARBs that show that blood pressure– independent effects on “hard” outcomes (ie, death or time to dialysis). This review examines the evidence that the beneficial effects of targeting the RAS using ACE inhibitors or ARBs cannot be attributed purely to their hemodynamic activity.

Hypertensive Diseases Unit, Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, Pritzker School of Medicine, Chicago, Illinois, USA. Statement of author disclosure: Please see the Author Disclosures section at the end of this article. This work was supported by Boehringer Ingelheim GmbH. Address for reprints: George Bakris, MD, Hypertension Center, Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, 5841 South Maryland Avenue, MC1027, Chicago, Illinois 60637. E-mail address: [email protected]. 0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.10.010

The Continuum of Cardiovascular and Kidney Disease The concept of a progressive chain of pathophysiologic changes from a cellular level to the clinical manifestations of cardiovascular and renal damage of increasing severity, ultimately resulting in end-organ damage, was introduced by Dzau and Braunwald1 in 1991. In addition to bringing about vasoconstriction and resultant hypertension, angiotensin II acting via the type 1 receptor (AT1) has many detrimental effects on the cardiovascular and renal systems and the progression of cardiovascular and chronic kidney disease (Figure 1).2 At the start of the continuum, angiotensin II induces oxidative stress and increases endothelial dysfunction in the cardiovascular system.3 Angiotensin II acting via the AT1 receptor is implicated in cardiac remodeling, fibrosis, and left ventricular hypertrophy (LVH).4 The presence of LVH and the subsequent development of diastolic and systolic dysfunction are associated with an increased risk of potentially life-threatening cardiovascular events.5 The risk factors for kidney disease and the pathophysiologic processes that contribute to its progression are the same as those for cardiovascular damage. As in the heart and the peripheral vasculature, endothelial dysfunction is an early, subclinical manifestation of kidney damage.6 The first clinically detectable evidence arising from damage to the renal endothelium is microalbuminuria caused by protein leakage across the glomerular basement membrane. www.AJConline.org

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Figure 1. The cardiovascular continuum in hypertension and the relative effects of blood pressure lowering plus ancillary actions of antihypertensive agents. GFR ⫽ glomerular filtration rate; IGT ⫽ impaired glucose tolerance; IMT ⫽ carotid intima-media thickening; LVH ⫽ left ventricular hypertrophy; TIA ⫽ transient ischemic attack. (Reprinted with permission from Blood Press.2)

Increasing levels of urinary protein are evidence of further renal damage and are a precursor of end-stage renal disease.7 Based on clinical evidence, current guidelines recognize the value of ACE inhibitors and ARBs for the treatment of hypertension to reduce cardiovascular and renal morbidity and mortality.8 –10 Although ACE inhibitors and ARBs target the RAS with differing mechanisms of action,11,12 both affect the processes that contribute to the cardiovascular and renal disease continuum. ACE inhibitors prevent the conversion of angiotensin I to angiotensin II. The decrease in tissue and circulating levels of angiotensin II that accompanies ACE inhibition affects underlying disease processes and contributes to blood pressure–independent effects. In addition, by inhibiting the action of kininase II, levels of bradykinin are increased. Bradykinin, mediated via nitric oxide, attenuates cellular damage in the ischemic heart and may exert cardiovascular and renal protection independent of blood pressure control.13,14 ARBs selectively prevent the binding of angiotensin II to the AT1 receptor.15 The AT1 receptor mediates many of the physiologic (eg, vasoconstriction) and pathophysiologic processes of angiotensin II. Moreover, circulating angiotensin II, whether formed by ACE or alternative enzymatic pathways, is able to stimulate the unopposed AT2, with the potential also to produce benefits beyond those attributable to blood pressure control. As would be expected from the common underlying pathophysiology, cardiovascular disease and renal damage often occur in tandem. Thus, studies of RAS inhibition on cardiovascular end points and renal outcomes can both yield information on the existence of blood pressure–independent effects.

pressure changes or greater changes in a given parameter than a comparator, despite similar changes in blood pressure. Such effects include the regression of LVH in rats with ramipril,16 reduction in the coronary infarct area with ramiprilat,17 and improvements in survival, prevention of cerebrovascular and renal lesions, and reductions in urinary protein levels with enalapril in salt-loaded stroke-prone spontaneously hypertensive rats.18 ACE inhibitors, but not hydralazine, have also been shown to prevent or reverse angionecrosis of the brain, heart, and kidney in animals in the absence of blood pressure changes.19 Further evidence of blood pressure–independent effects and an insight into potential mechanisms is provided by animal studies with ARBs. In stroke-prone spontaneously hypertensive rats, irbesartan resulted in greater reductions in superoxide and p22phox levels in carotid arteries than did either amlodipine or hydrochlorothiazide/hydralazine.20 The decreased superoxide production and increased nitric oxide bioavailability may potentially translate into beneficial effects on cell proliferation, apoptosis, and endothelial function. Losartan 180 mg/day prevented progression of atherosclerosis cynomolgus monkeys without significantly altering blood pressure or plasma cholesterol levels.21 Similarly, in monkeys fed a high-cholesterol diet, olmesartan medoxomil reduced the lipid deposition area on the aortic surface and intimal cross section area despite there being no decreases in mean blood pressure.22

Preclinical Evidence

A study conducted in 51 previously untreated hypertensive patients evaluated the effect of captopril 50 mg versus extended release metoprolol 50 mg on echocardiographically determined left ventricular mass index.23 Although

In studies in animals, ARBs and ACE inhibitors have effects that have been shown either to occur in the absence of blood

Clinical Evidence: Angiotensin-Converting Enzyme Inhibitors

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both antihypertensives produced a reduction in left ventricular mass index after 12 months of treatment, the decrease achieved with captopril (13%) was more than twice that observed with metoprolol (6%, p ⬍0.01). The differences could not be attributed to the extent of the blood pressure reduction because captopril and metoprolol both brought about similar reductions in daytime and nighttime ambulatory systolic and diastolic blood pressure.23 The long-term benefit of trandolapril in reducing aortic stiffness was investigated in a substudy of the Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE) trial.24 Over a median of 52 months, trandolapril 2– 4 mg produced a modest reduction in carotid–femoral pulse wave velocity, which is a measure of aortic wall stiffness, beyond that which would be anticipated from the blood pressure lowering. The investigators speculated that a significant reduction in pulse wave velocity should result in a reduction in clinically significant cardiovascular events. However, the PEACE trial, which was likely underpowered, failed to demonstrate a statistically significant reduction in the primary end point of a composite of cardiovascular death, myocardial infarction (MI), or coronary revascularization.25 A meta-analysis of 41 comparative clinical studies, comprising 1,124 patients with and without diabetes mellitus with chronic renal disease treated with ACE inhibitors and other antihypertensive agents, was performed to establish whether there were any differences in the regression of urinary protein levels.26 This meta-analysis revealed that ACE inhibitors reduced proteinuria by 39.9% (95% confidence interval [CI], 36.8 – 42.8%) versus a reduction of only 17% (95% CI, 15.1–19.0%) with other antihypertensives, and the blood pressure lowering was 12.0% (95% CI, 11.2– 12.8%) with ACE inhibitors and 11.4% (95% CI, 11.1– 11.7%) with other antihypertensives. Thus, there appears to be a renoprotective effect with ACE inhibition that cannot be explained by simply the lowering of blood pressure. In most studies, cuff blood pressure was measured to determine the degree of hypertension and the extent of blood pressure control. Such measurements do not necessarily reflect aortic and carotid pressures, which may prove to be better predictors of cardiovascular and cerebrovascular risk, respectively.27 A recent study has shown, for example, that although enalapril 10 mg and indapamide 2.5 mg given for 8 weeks produced similar reductions in brachial systolic and diastolic blood pressure, the reduction in aortic systolic pressure was greater with enalapril.28

Clinical Evidence: Angiotensin Receptor Blockers A study of 82 patients with mild hypertension evaluated the effect of the ARB telmisartan versus the ␤-blocker carvedilol on the regression of left ventricular mass measured using both 3-dimensional echocardiography and magnetic resonance imaging.29 Patients were randomized to treatment

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with telmisartan 80 mg or carvedilol 25 mg for 44 weeks. The reductions in left ventricular mass index measuring using 3-dimensional echocardiography were 15.7% and 9.1% respectively, with telmisartan and carvedilol (p ⬍0.001). Telmisartan was also superior to carvedilol in reducing left ventricular mass index measured using magnetic resonance imaging (15.5% vs 9.6%, p ⬍0.001). The 24-hour mean ambulatory systolic and diastolic blood pressure reductions were similar in the 2 treatment groups, although the nighttime and last 6-hour mean blood pressure reductions were nonsignificantly greater with telmisartan. Further evidence for the superiority of AT1 receptor blockade over ␤-blockade on regression of LVH comes from a study comparing irbesartan with atenolol.30 Hypertensive patients with echocardiographically diagnosed LVH received either irbesartan 150 –300 mg or atenolol 50 –100 mg, with the possible addition of hydrochlorothiazide and felodipine to achieve a target diastolic blood pressure of 90 mm Hg. After 48 weeks, reductions in left ventricular mass index were 27 and 15 g/m2, respectively, but the reductions in blood pressure were similar in the 2 treatment groups. In addition, irbesartan also decreased QT dispersion and QTc dispersion, whereas atenolol had only minor effects on these parameters. The investigators concluded that the superior structural and electrical remodeling could have a beneficial effect in reducing fatal events in hypertensive patients. The recently published Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) study also suggests that the effect of telmisartan on the prevention of the transition from incipient to overt nephropathy in patients with type 2 diabetic nephropathy was independent of the blood pressure– lowering effect.31 In A Trial to Compare Telmisartan 40 mg Titrated to 80 mg Versus Losartan 100 mg in Hypertensive Type 2 Diabetic Patients with Overt Nephropathy (AMADEO), the mean reduction in the adjusted protein-to-creatinine ratio from baseline to week 52 was significantly greater for telmisartan than losartan.32 However, both treatment groups displayed similar improvements in systolic and diastolic blood pressures.

Outcomes Trials Although the preclinical and clinical evidence outlined above suggests that RAS blockade involves cardiovascular and renoprotective mechanism(s) other than blood pressure control, this may not necessarily manifest as an effect on the hard end points used in outcome trials. Nevertheless, some evidence suggests that targeting the RAS can confer longterm cardiovascular and/or renal benefit. A trial of 6,038 patients aged 65– 84 years with hypertension studied the patients for a median of 4.1 years.33 Initiation of antihypertensive treatment involving ACE inhibitors in these older subjects, particularly men, appears to lead to better outcomes, with a lower incidence of all car-

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diovascular deaths or death from any cause (hazard ratio, 0.89; 95% CI, 0.79 –1.00) than treatment with diuretic agents. This was despite reductions of blood pressure of 26/12 mm Hg at year 5 of the study, regardless of the antihypertensive treatment received. In a review of placebo-controlled trials with ACE inhibitors—the Prevention of Atherosclerosis with Ramipril Trial (PART-2), the Quinapril Ischemic Event Trial (QUIET), the Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT), the Heart Outcomes Prevention Evaluation (HOPE) study, and the Perindopril Protection Against Recurrent Secondary Stroke (PROGRESS)—it has been questioned whether ACE inhibitor therapy has a benefit in primary or secondary prevention of stroke beyond blood pressure reduction.34 The investigators concluded that the only study supporting a blood pressure–independent effect of an ACE inhibitor on stroke was the HOPE study. In HOPE, the reduction in the risk of stroke (and MI) was larger than would have been inferred from the reduction in blood pressure.35 The HOPE study was not a blood pressure–independent trial. However, a high proportion of patients received drugs that could lower blood pressure and lower cardiovascular risk, with the result that blood pressure was well controlled at study entry. The populations in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) comprised patients at increased cardiovascular risk who did not have heart failure and who had similar characteristics to patients in the HOPE trial.35–37 In ONTARGET and TRANSCEND, the mean blood pressure at baseline was 142/82 mm Hg, similar to the entry blood pressure of 139/79 mm Hg in HOPE, and within the normal range.38 After a 3-week run-in period in which the safety and tolerability of the treatments were tested, mean blood pressures at randomization were reduced to 134/77 mm Hg in ONTARGET and 135/78 mm Hg in TRANSCEND.38 In the ONTARGET study, after a median follow-up of 56 months, the primary outcome of death from cardiovascular causes, MI, stroke, or hospitalization for heart failure was similar for telmisartan and ramipril (16.7% vs 16.5%; relative risk, 1.01; 95% CI, 0.94 –1.09), whereas telmisartan was better tolerated than ramipril and resulted in fewer treatment discontinuations.36 Meta-analysis has shown that there are differences between ACE inhibitors and other classes of antihypertensive agents in their effects on major cardiovascular events. The Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC), using data from 29 prospectively designed randomized trials involving 162,341 subjects, demonstrated that ACE inhibitors reduced blood pressure to a lesser extent than calcium antagonists or diuretics.39 Nevertheless, there were no differences in the incidence of total major cardiovascular events with the different classes of antihypertensives (Figure 2).40

Evidence from studies of advanced proteinuric kidney disease also indicates that ACE inhibitors have effects independent of blood pressure. In patients with type 1 diabetes, captopril treatment was associated with a 50% reduction in the risk of the combined end point of death, dialysis, and transplantation compared with placebo.41 This reduction was independent of the difference in blood pressure between the groups. The African American Study of Kidney Disease and Hypertension (AASK) trial revealed that ramipril conferred greater benefit than metoprolol in blacks with nephrosclerosis, although blood pressure control was similar with both drugs The trial was conducted in 1,094 patients with hypertensive renal disease (glomerular filtration rate of 20 – 65 mL/min per 1.73 m2) who were studied for 3– 6.4 years.42 Analysis revealed that compared with metoprolol, ramipril treatment resulted in a slower decrease in glomerular filtration rate and delayed the onset of a significant decrease in glomerular filtration rate, end-stage renal disease, or death, and decreased urinary protein excretion. The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, which showed the long-term benefit of losartan over atenolol on cardiovascular end points, also demonstrated that was there was a greater lowering of urinary albumin levels in patients with diabetes receiving losartan.43 The LIFE study was specifically designed to maximize blood pressure control by the use of additional antihypertensive therapy (apart from ACE inhibitors, other ARBs, or other ␤-blockers). The superiority of losartan was shown with similar blood pressure control between the losartan- and atenolol-based treatment arms.44 In the TRANSCEND study, in which telmisartan was compared with standard care, the primary end point (superiority on a composite of death from cardiovascular causes, MI, stroke, or hospitalization for heart failure) was not met.37 Telmisartan, however, significantly reduced the risk of the end point that was used in the HOPE study (a composite of cardiovascular death, MI, or stroke).37 The TRANSCEND investigators noted that, after adjusting for the differences in blood pressure, “a large proportion of the benefits of telmisartan may be independent of blood pressure lowering.”37 It is also worth noting that the tolerability of an agent is important. The ONTARGET study demonstrated that the better tolerability of telmisartan resulted in fewer treatment discontinuations than with ramipril. Compliance with a therapy is vital if benefit is to be gained from it, whether that benefit is a result of antihypertensive actions or blood pressure–lowering effects. The Irbesartan Diabetic Nephropathy Trial (IDNT)45 and the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL)46 studies provide evidence of renal protection with ARB therapy in patients with type 2 diabetes and further support a blood pressure– independent effect of treatments that target the RAS. In the IDNT study, irbesartan significantly reduced the primary end point (a composite of a doubling of serum creatinine

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Figure 2. Angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists (CA) compared with placebo and more or less intensive blood pressure (BP)–lowering regimens. BB ⫽ ␤-blockers; CI ⫽ confidence interval; D ⫽ diuretics; p homog ⫽ p value by ␹2 test of homogeneity; RR ⫽ relative risk. *Overall mean BP difference during follow-up in group assigned the first-listed treatment compared with the second-listed treatment. (Reprinted with permission from Arch Intern Med.40)

concentration, development of end-stage renal disease, or death from any cause) by 23% compared with a reduction of 23% in amlodipine-treated patients.45 The difference was driven by the reductions in serum creatinine concentration and development of end-stage renal disease but was not explained by differences in the blood pressures that were achieved during the study. In the RENAAL study, which

used the same end point as the IDNT study, losartan resulted in a 16% risk reduction compared with placebo.46 There was a small time-averaged difference in trough blood pressure between the losartan and placebo groups. On correction for the difference in blood pressure, the renal protection conferred by losartan exceeded that attributable to the small differences in blood pressure.

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Figure 3. The relative risk for the primary renal outcome (composite of dialysis, doubling of serum creatinine, and death) in subgroups treated with telmisartan or ramipril in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) trial. CI ⫽ confidence interval; eGFR ⫽ estimated glomerular filtration rate. (Reprinted with permission from Lancet.48)

In a meta-analysis of 49 studies (6,181 participants), in which many of the studies were small and of variable quality, ARBs were found to be as effective as ACE inhibitors in reducing proteinuria.47 Examination of the ONTARGET study indicates that ARBs and ACE inhibitors have broadly similar effects on renal end points.36,48 The incidence of renal outcomes (a composite of dialysis, doubling of serum creatinine, and death) was comparable for telmisartan and ramipril (Figure 3), although the increase in urinary albumin excretion was significantly less with telmisartan than ramipril.48 In interpreting renal data from this trial, it is worth noting that it was not powered for renal outcomes, the data on kidney function were limited, a predetermined protocol was not used to evaluate the requirement for dialysis, and these data were assessed post hoc. Furthermore, most subjects had normal kidney function. It is uncertain whether a difference exists in the blood pressure–independent effects of ACE inhibitors and ARBS. An analysis by the BPLTTC—which examined data from 26 large-scale trials comparing an ACE inhibitor or an ARB with placebo or another antihypertensive class— concluded that there are similar blood pressure– dependent effects of ACE inhibitors and ARBs on the risk of stroke, coronary artery disease, and heart failure (Figure 4).49 In the case of

ACE inhibitors, but not ARBs, the data appear to suggest that there is a blood pressure–independent effect on reducing the risk of major coronary disease events.49 However, BPLTTC acknowledged that the confidence intervals were wider for ARBs than for ACE inhibitors, which may have excluded the existence of a modest effect. Moreover, a retrospective cohort study using a population database of around 1.4 million subjects aged ⱖ65 years suggested that ARBs offer a similar reduction in acute coronary syndrome outcomes in elderly patients with atherosclerosis, diabetes, or heart failure.50

Conclusion The reduction in cardiovascular and renal morbidity and mortality achieved with ACE inhibitors and ARBs is well recognized. Blood pressure control with these agents is largely responsible for these cardiovascular and renal benefits, but blood pressure–independent mechanisms are also implicated. Angiotensin II plays an important role in the pathogenesis of cardiovascular and renal disease through effects that extend beyond blood pressure. Evidence that ARBs and ACE inhibitors confer additional benefit that

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Figure 4. Meta-analysis of trials comparing angiotensin-converting enzyme inhibitor (ACE-I) with angiotensin receptor blocker (ARB)– based regimens for cardiovascular outcomes. CAD ⫽ coronary artery disease; CI ⫽ confidence interval; ELITE II ⫽ Evaluation of Losartan in the Elderly–II; OPTIMAAL ⫽ Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan; VALIANT ⫽ Valsartan in Acute Myocardial Infarction. (Reprinted with permission from J Hypertens.49)

cannot be explained totally by reduction of blood pressure comes largely from animal studies. Clinical outcome studies in people with advanced proteinuric nephropathy clearly show a benefit of ARBs and ACE inhibitors to a greater extent than seen just with blood pressure control with other classes of agents. Agents that have been investigated in outcome studies and for which there are indications of effects independent of blood pressure lowering include irbesartan, losartan, ramipril, and telmisartan. Thus, the potential for multiple interventions provided by ARBs or ACE inhibitors within the continuum of cardiovascular and renal disease appears to offer clinical benefits. In choosing a therapy to provide protection against cardiovascular or renal disease, consideration should be given to agents whose actions extend beyond blood pressure lowering.

Author Disclosures The author who contributed to this article has disclosed the following industry relationship: George Bakris, MD, is a consultant for Boehringer Ingelheim.

Acknowledgment Writing and editorial assistance was provided by Ann Ralph, PhD, of PAREXEL MMS, which was contracted by Boehringer Ingelheim for these services. The author(s) meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE) and were fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development. The authors received no compensation related to the development of the manuscript. 1. Dzau V, Braunwald E. Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement. Am Heart J 1991;121:1244 –1263. 2. Ruilope L, Kjeldsen SE, De La Sierra A, Mancia G, Ruggenenti P, Stergious GS, Bakris GL, Giles TD. The kidney and cardiovascular risk–implications for management: a consensus statement from the European Society of Hypertension. Blood Press 2007;16:72–79. 3. Muller G, Goettsch C, Morawietz H. Oxidative stress and endothelial dysfunction. Hamostaseologie 2007;27:5–12. 4. Zhu YC, Zhu YZ, Lu N, Wang MJ, Wang YX, Yao T. Role of angiotensin AT1 and AT2 receptors in cardiac hypertrophy and cardiac remodelling. Clin Exp Pharmacol Physiol 2003;30:911–918. 5. Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in

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