European Heart Journal Supplements (2003) 5 (Supplement F), F19 F25 Cerebral involvement in hypertensive cardiovascular disease Hypertension Unit, Hospital Clinic (IDIBAPS), University of Barcelona, Barcelona, Spain KEYWORDS Angiotensin receptor blockers; Cognitive impairment; Dementia; Hypertension; Stroke; White matter lesions Stroke and dementia in hypertension are the culmination of a complex and largely silent pathogenesis that involves atherosclerosis, vascular remodelling, white matter lesions (WMLs), lacunae and microaneurysms. WMLs in apparently asymptomatic hypertensive persons are associated with incipient cognitive impairment and cardiac hypertrophy. Longitudinal studies have established a link between WMLs and future stoke, and between cognitive decline and hypertension. A small, sustained lowering of systolic/diastolic blood pressure reduces the relative risk of stroke by about 35 40%. A favourable prognosis appears to be not simply a matter of blood pressure control. Angiotensin II receptor blockers are more effective than beta-blockers in reducing the risk for stroke, dementia and left ventricular hypertrophy in hypertensive persons, despite similar reductions in blood pressure. The mechanisms of cognitive decline in hypertension are unclear, but it is known that vascular remodelling and endothelial dysfunction in small arteries are better corrected by blockade of the renin angiotensin aldosterone system (RAAS) than by beta-blockade. The role of RAAS blockade in cerebrovascular disease and its prevention will be further investigated in The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) Trial Programme. 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved Introduction The effect of hypertension on cerebral function is potentially devastating. Stroke is the third leading cause of death after heart disease, and it is a more common reason for cardiovascular death than myocardial infarction among persons with essential hypertension. 1 In addition, high blood pressure is also now recognized as a major risk factor for dementia. 2 Although attention is frequently focused on these disabling and often fatal outcomes, they are only the culmination of progressive cerebral pathology that may take many years to manifest itself in the form of measurable clinical end-points. To understand the Correspondence: Antonio Coca, MD, PhD, Professor of Medicine, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain role of hypertension in the pathogenesis of stroke and dementia, it is necessary to elucidate this complex, largely asymptomatic process to the development of overt disease. Evaluation of the development of hypertensionrelated cerebral disease remains at a comparatively early stage. One reason for this has been the difficulty of investigating disease processes within the functioning brain. The problem has been partially overcome by modern imaging techniques, but there are still major challenges. Equally importantly, the general effects of hypertension on vascular patency and endothelial function throughout the body, and the molecular mechanisms that underlie these effects, have yet to be fully elucidated. Thus, advances in cerebrovascular investigational techniques and in our basic understanding of the vascular effects of 01520-765X/03/0F0019 + 07 $35.00/0 2003 The European Society of Cardiology, Published by Elsevier Science Ltd. All rights reserved.
F20 Fig. 1 Impact of blood pressure on stroke mortality. 3 hypertension are required before the complexities of hypertensive cerebral disease may be fully understood and improvements in patient prognosis achieved. Despite these issues, important steps have recently been made in our understanding of the interaction between hypertension, vascular disease and cerebral pathology. One important advance is the finding that different classes of antihypertensive agents appear to have varying effects both on vascular patency and endothelial function, and on the risks of developing stroke and dementia. Blood pressure and cerebrovascular events Epidemiological studies have demonstrated that the risk of mortality from stroke increases with both systolic blood pressure (SBP) and diastolic blood pressure (DBP). For instance, the Multiple Risk Factor Intervention Trial (MRFIT) 3 found that a SBP of 140 159 mmhg, which according to the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure 4 is regarded as stage 1 or mild hypertension, is associated with an approximately fourfold increase in the risk of death from stroke as compared with persons who have normal blood pressure (i.e. SBP <120 mmhg; Fig. 1). In patients with severely elevated SBP (180 209 mmhg), the relative risk increases to 10.7 and if SBP is greater than 210 mmhg then a person is 24 times more likely than a normotensive person to die from a stroke. DBP is also an important and independent risk factor, but SBP is the stronger predictor of the two. 3 In keeping with this observation, pulse pressure, which is the difference between SBP and DBP, is also an important independent risk factor for mortality due to stroke. The epidemiological evidence of the close association between blood pressure and stroke is strongly supported by the findings of comparative clinical studies. This was recently illustrated by a meta-analysis of the incidence of stroke and myocardial infarction in 11 large-scale prospective hypertension trials published between 1991 and 2000, involving 59 550 randomized patients with elevated SBP and DBP or with isolated systolic hypertension. 1 Within this extensive hypertensive population, there were 2553 reports of stroke and 1927 myocardial infarctions. Clinical trials data also demonstrate that the relative risk of stroke is reduced when blood pressure is controlled using antihypertensive drugs. A meta-analysis of 14 comparative trials reported between 1965 and 1986 and involving 37 000 individuals showed that a sustained reduction in DBP of 5 6 mmhg over 5 years was associated with a 42% reduction in relative risk of stroke. 5 A more recent evaluation of three large trials (Systolic Hypertension in the Elderly Program [SHEP], 6 Systolic hypertension Europe [Syst-Eur] 7 and Systolic Hypertension in China [Syst-China] 8 ) found a relative risk reduction for stroke of 37% when a decline in SBP of 10 12 mmhg was sustained for 3 5 years. 9 The cerebrovascular benefits of reducing blood pressure are not confined to those with moderateto-severe hypertension. The prognosis is improved across the full spectrum, including mild, borderline hypertension and high-normal blood pressure. This is particularly well illustrated in the prevention of secondary stroke, in which the Perindopril protection against Recurrent Stroke Study (PROGRESS) 10 showed that reduction in
Cerebral involvement blood pressure resulted in a lower incidence of stroke even in patients with mean of SBP/DBP 136/79 mmhg. The second major brain disease associated with hypertension is dementia. Here, too, hypertension has a direct, causal and highly predictive relationship to the development of cerebral damage. The impact of hypertension on the development of dementia was established by a longitudinal study of the elderly conducted in Göteborg. 2 A total of 382 patients aged 70 years at baseline were followed up with psychiatric and physical examinations over a 15-year period. The study found that there was a strong correlation between both SBP and DBP at the age of 70 years and the development of dementia at age 79 85 years. Thus, hypertension has a detrimental effect not only on the cerebrovascular system but also on cognitive function. Pathogenesis of hypertensive cerebrovascular disease Stroke is the end-point arising from a complex progression of structural and functional changes within the brain that are driven by hypertension. In general, these changes are insidious and remain silent until they manifest as serious clinical events. These include microaneurysms, which may culminate in haemorrhagic stroke, and atherosclerosis, vascular remodelling, white matter lesions (WMLs) and lacunae, which may lead to ischaemic stroke. 11 Cognitive impairment, a forerunner of frank dementia and a marker of cerebrovascular risk, is a potentially measurable manifestation of the evolving brain pathology. 12 The duration of the silent phase of hypertensive cerebral pathogenesis may vary and is dependent on the severity of the hypertension and the presence of other risk factors, such as smoking and age. The impact of hypertension on brain function should be addressed as early as possible during the silent phase in order to avoid the debilitating consequences of cerebrovascular disease and cognitive impairment. WMLs are an early manifestation of hypertension-related cerebrovascular damage. Frequently identified using magnetic resonance imaging (MRI) as confluent periventricular hyperintensities, they are not usually associated with overt symptomatology. 13 Nevertheless, the link between WMLs and hypertension is clear. The Atherosclerosis Risk In Communities (ARIC) study 13 compared the prevalence of WMLs in a F21 clinically mixed population of over 1900 patients aged 55 72 years. The study found that, whereas 8% of normotensive individuals had WMLs, the overall frequency among hypertensive individuals was 17%. Among those patients in whom blood pressure was controlled, the incidence was 14%. Moreover, the frequency of WMLs was 24% in treated, but uncontrolled hypertensive persons. Hypertension is not the only cause of WMLs; age is an independent and confounding factor that must be considered. A study conducted in Rotterdam found that, among the 36 individuals between the ages of 65 and 69 years evaluated, 89% had no WMLs and only 8% and 3%, respectively, had moderate and severe lesions identified by MRI. 14 By contrast, successively older cohorts had increasing frequency and severity of lesions, such that among the 26 individuals aged between 80 and 84 years 27% had moderate lesions and a further 27% had severe lesions. These findings were independent of blood pressure, indicating that the overall aetiology of WMLs is complex and multifactorial, despite the importance of hypertension as a major risk factor for their development. The clinical significance of WMLs lies in their strong association with both stroke and cognitive impairment. Their relationship with stroke was recently illustrated in a study conducted by Kario and coworkers, 15 who compared the incidence of stroke in persons with or without baseline WMLs. After a mean follow-up period of 42 months, the incidence of stroke in those with baseline WMLs was 13.5%, compared with 2.3% in those with no baseline lesions, representing a sixfold increase in relative risk (Fig. 2). The incidence of stroke was relatively low (<4%) in individuals who were hypertensive without WMLs at baseline and in those who were normotensive with lesions at baseline. However, in those with WMLs and who were hypertensive at baseline, the incidence of stroke was in excess of 17%. The simultaneous occurrence of these two factors, therefore, places individuals at an increased risk for stroke. One interpretation of these findings is that the occurrence of WMLs in hypertensive persons represents a progression in the evolving pathology that culminates in overt stroke. An association has been also established between WMLs and cognitive impairment. In the Cardiovascular Health Study, 16 Mini Mental State Examination (MMSE) scores were compared in 3301 persons older than 65 years with or without silent WMLs. In both male and female participants there was a strong correlation between the severity of WMLs, measured using an 8-point grading scale, and the mean MMSE score.
F22 Fig. 2 Incidence of stroke in patients with baseline white matter lesions and hypertension or normotension. 15 Hypertension and early cerebral damage The existence of a period of silent cerebral damage of variable length in hypertensive individuals raises the question of whether high blood pressure has deleterious effects during the early stages of disease, years or even decades before the occurrence of major clinical endpoints. This possibility was recently investigated in a study that determined the cerebral effects of hypertension in comparatively young patients between the ages of 50 and 60 years. 12 The study was conducted in 66 patients (41 males and 25 females) with previously untreated mild-tomoderate hypertension. At baseline there was no clinical evidence of cerebral or cardiovascular disease in any of the patients studied, who were not diabetic, whose daily alcohol intake was 30 g or less and who did not have carotid atheromatosis with greater than 50% stenosis. A brain MRI scan and 24-h ambulatory blood pressure monitoring were performed in all of the enrolled patients. The MRI scans revealed that 27 (41%) had grade 1 or 2 WMLs. 12 The presence of lesions was not dependent on sex, age, body mass index or smoking. However, there was a statistically significant positive correlation between the presence of WMLs and clinic SBP, DBP and pulse pressure. The correlation between WMLs and blood pressure was even stronger when mean 24-h SBP, DBP and pulse pressure were considered (Fig. 3). Moreover, not only the occurrence of WMLs, but also their severity was directly related to mean ambulatory blood pressures, with higher mean 24-h Fig. 3 Correlation between silent white matter lesions (WMLs) and mean 24-hour ambulatory systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) in hypertensive persons. 12 SBP, DBP and pulse pressure being observed in the patients with grade 2 lesions than in patients without WMLs. Echocardiography also showed that the occurrence of WMLs was associated with increased thickness of the posterior wall and intraventricular septum, increased left ventricular mass index and increased relative wall thickness ratio. 17 These observations suggest a close relationship between damage to the heart and that to the brain in association with elevated blood pressure. As a systemic and pervasive disease, one would expect hypertension to exert similar pathological effects on different organ systems, and the findings of Sierra et al. 12,17 are consistent with this proposition. The Wechsler Memory Scale is a more sensitive and subtle test than the MMSE 18 and is better suited to the detection of early impairment. Unpublished data showed that there was no correlation between the presence of WMLs, adjusted for age and education, and working memory as assessed by backward digit span, logical memory or visual memory tests. However, the presence of WMLs did predict a deficit in attention as assessed by forward digit span test. 19 Thus, in relatively young, asymptomatic hypertensive persons, WMLs correlated not only with the severity of hypertension but also with deleterious cardiac changes and declining cognitive performance. Antihypertensive therapy and silent cerebral damage The clearly established association between hypertension and cerebral damage raises several
Cerebral involvement important issues relating to antihypertensive treatment. The first is whether the use of antihypertensives can prevent not only stroke, but also cognitive impairment and dementia. A second key question is whether different classes of antihypertensive drugs are likely to have the same effects on these end-points. Several studies have addressed these issues. These include the dementia substudies of SHEP, 20 Syst-Eur 21, PROGRESS 22 and the Losartan Intervention For Endpoint reduction in hypertension study (LIFE). 23 A post hoc analysis of the Study on COgnition and Prognosis in the Elderly (SCOPE) will also consider these questions. 24 In the Syst-Eur study 21 more than 2900 patients with isolated systolic hypertension (seated SBP 160 219 mmhg, DBP <95 mmhg) were evaluated, 1417 of whom received placebo and 1485 were given active antihypertensive treatment based on the calcium channel blocker nitrendipine. The incidence of dementia after a 2-year follow-up period was 1.8% in the placebo group, but less than 0.9% in the patients receiving active treatment (P=0.05). Extrapolation of these findings translated into the prevention of 19 cases of dementia if 1000 hypertensive patients were treated with antihypertensive drugs for 5 years. By contrast, in the SHEP study, 20 which also was conducted in patients with isolated systolic hypertension, the antihypertensive treatment was based on a diuretic. In that study, the incidence of dementia in the active treatment group was 1.6% and there was no significant difference between this and the 1.9% incidence recorded in the placebo group. The cognitive evaluations, however, were biased toward the null effect by differential dropout. This might well have obscured the detection of a protective effect of treatment on the cognitive and functional decline in older hypertensive adults. Further evidence for the positive impact of antihypertensive is provided by PROGRESS. 22 In that study the angiotensinconverting enzyme (ACE) inhibitor perindopril was found to have a favourable effect. Over the 4-year period of follow-up, the relative risks of dementia with stroke and cognitive decline with or without stroke were reduced if an ACE inhibitor was given rather than placebo. The beneficial effect was noted in hypertensive patients and in nonhypertensive persons with a history of stroke or transient ischaemic attack. Taken together, these findings suggest that calcium channel blockers and other agents that target the renin angiotensin aldosterone system (RAAS) reduce the risk for dementia in hypertensive patients. This variation in cerebral protection implies that the mechanisms involved F23 Fig. 4 Effect of atenolol and losartan based treatment of patients with left ventricular hypertrophy on fatal and nonfatal stroke. 22 ITT=intent to treat; RR=relative risk. Reprinted with permission from Elsevier (Lancet 2002;359:995 1003). may be, at least in part, independent of the effects on blood pressure and are not shared by other antihypertensive drug classes, such as betablockers and the diuretic hydrochlorothiazide. In particular, angiotensin II receptor blockade may play an important role in neuroprotection, neuroregeneration, preservation of cerebral haemodynamics and protection against ischaemia. 25 These differences between the effects of different classes of antihypertensive on the risk of cerebral disease are not limited to cognitive function. The LIFE study 23 showed that the incidence of stroke is reduced more by losartan, an angiotensin II receptor blocker (ARB), than by the beta-blocker atenolol, although the reductions in blood pressure were comparable (Fig. 4). In that large-scale trial, in which over 9000 patients with left ventricular hypertrophy were treated for up to 4.8 years, the adjusted relative risk reduction for fatal or non-fatal stroke in patients given ARB-based treatment was 25% as compared with patients who received the beta-blocker-based treatment. The benefits of ARB-based treatment over atenolol were even more marked in a subgroup of patients with isolated systolic hypertension (SBP 160 200 mmhg, DBP <90 mmhg). 26 Protection against cerebrovascular end-points conferred by certain antihypertensive agents may result from direct beneficial effects on vascular structure and endothelial function in addition to control of blood pressure. Such a possibility is consistent with a further finding from the LIFE study 23 that losartan is significantly more effective than atenolol in regressing of left ventricular hypertrophy, suggesting that ARBs and beta-
F24 blockers have differential effects on vascular remodelling. Direct evidence for differential actions of a beta-blocker and an ARB on remodelling of blood vessels recently emerged from a prospective study of 15 hypertensive patients with a mean age of 50±2 years. 27 These patients had good blood pressure control (SBP/DBP 131/84 mmhg) after 1 year of atenolol-based treatment. When switched to an irbesartan-based regimen for 1 year, similar blood pressure control (SBP/DBP 129/85 mmhg) was achieved. The study evaluated remodelling by collecting subcutaneous biopsies of gluteal small arteries (150 300 µm diameter) at the end of the atenolol- and irbesartan-based treatments. Treatment with atenolol did not significantly change the media to lumen ratio. However, following 1 year of irbesartan treatment, the mean arterial medial width to lumen ratio had significantly decreased from 8.44 to 6.46 (P<0.01). The study also assessed the impact of treatment on endothelial function. 27 Compared with arteries from normotensive individuals, the maximal relaxation response to acetylcholine was reduced both before the start and end of atenolol treatment to 81%, but after irbesartan treatment the maximal response increased to 95% of that in arteries from normotensive individuals. Further evaluation of the importance of the renin angiotensin aldosterone system Data are accumulating that blockade of the RAAS is clinically beneficial in hypertension-related cerebral disease not only as a result of a reduction in blood pressure, but also through enhanced endothelial function and vascular remodelling. It is likely that these effects are highly important in the ability of these agents to prevent stroke, dementia and progression of silent WMLs in hypertensive patients across a wide spectrum of ages and severity of hypertension. The relationship between RAAS blockade and cerebrovascular disease will be put further to the test in The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) Trial Programme (see the report by Sleight in the present supplement). The primary end-point of this international, multicentre study, involving 29 400 high-risk hypertension patients who will be followed up for up to 5.5 years, will be a composite of cardiovascular death, myocardial infarction, stroke or hospitalization for congestive heart failure. There are a variety of secondary endpoints, including cognitive decline and dementia. The results of The ONTARGET Trial Programme, in which two alternative strategies for RAAS interruption (ACE inhibition and angiotensin II receptor blockade) are being investigated when used alone and in combination, will provide more detailed characterization of the relationship between RAAS-targeting antihypertensive medications and the progression of cerebral pathology in hypertensive patients. Conclusion Stroke and dementia are the two major clinical outcomes of hypertension-related cerebrovascular disease that can reduce the quality of life of the patient and their immediate family. However, it is now clear that they are not sudden events, but the culmination of a progressive, insidious and initially silent disease process. Before the development of frank dementia or overt stroke, early cognitive impairment is a common feature. In hypertension there is undoubtedly a close relationship between early and largely silent cerebral disease, including WMLs and incipient cognitive impairment, and wider damage of the cardiovascular system, most notably left ventricular hypertrophy. This is consistent with the proposition that vascular remodelling, driven by similar pathogenic processes to those that underlie left ventricular hypertrophy, may play a role in the development of the cerebrovascular complications of hypertension. The use of antihypertensive drugs reduces the risk for both fatal and non-fatal stroke and appears, on the basis of trials data, to delay the progression of cognitive decline and dementia. The fact that stroke and dementia are merely the end results of a progressive disease process rather than sudden events emphasizes the critical importance of early and aggressive intervention to control blood pressure, even in younger patients who are otherwise well and have no other abnormal cardiovascular or cerebrovascular signs. Data are now emerging that suggest that the cerebroprotective effects of antihypertensive agents differ between drug classes and are not achieved by pressure-dependent mechanisms alone. The blockade of the RAAS using an ARB is more effective than beta-blockade in preventing stroke, and further evidence suggests that ARBs are more effective than beta-blockers in preserving endothelial function and preventing pathological remodelling of small blood vessels. There is no decisive evidence as yet, however, that
Cerebral involvement ARBs are more effective than other classes of antihypertensive agents in preventing cognitive decline. Further mechanistic studies, as well as clinical studies, such as the ONTARGET Trial Programme, are required to produce a definitive answer. References 1. Kjeldsen SE, Julius S, Hedner T, et al. Stroke is more common than myocardial infarction in hypertension: analysis based on 11 major randomized intervention trials. Blood Press 2001;10:190 2. 2. Skoog I, Lernfelt B, Landahl S, et al. 15-year longitudinal study of blood pressure and dementia. Lancet 1996;347: 1141 5. 3. Multiple Risk Factor Intervention Trial Research Group. Mortality after 10 1/2 years for hypertensive participants in the Multiple Risk Factor Intervention Trial. Circulation 1990;82:1616 28. 4. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 2003;289:2560 72. 5. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. Part 2: short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990;335:827 38. 6. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1991;265:3255 64. 7. Staessen JA, Fagard R, Thijs L, et al. Randomised doubleblind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350:757 64. 8. Wang JG, Staessen JA, Gong L, et al. Chinese trial on isolated systolic hypertension in the elderly. Arch Intern Med 2000;160:211 20. 9. Staessen JA, Wang JG, Thijs L, et al. Overview of the outcome trials in older patients with isolated systolic hypertension. J Hum Hypertens 1999;13:859 63. 10. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358:1033 41. 11. Sierra C. Cerebral white matter lesions in essential hypertension. Curr Hypertens Rep 2001;3:429 33. 12. Sierra C, de La Sierra A, Mercader J, et al. Silent cerebral white matter lesions in middle-aged essential hypertensive patients. J Hypertens 2002;20:519 24. 13. Liao D, Cooper L, Cai J, et al. Presence and severity of cerebral white matter lesions and hypertension, its treatment, and its control. The ARIC Study. Atherosclerosis Risk in Communities Study. Stroke 1996;27:2262 70. F25 14. Breteler MM, van Swieten JC, Bots ML, et al. Cerebral white matter lesions, vascular risk factors, and cognitive function in a population-based study: the Rotterdam Study. Neurology 1994;44:1246 52. 15. Kario K, Shimada K, Schwartz JE, et al. Silent and clinically overt stroke in older Japanese subjects with white-coat and sustained hypertension. J Am Coll Cardiol 2001;38: 238 45. 16. Longstreth WT Jr, Manolio TA, Arnold A, et al. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study. Stroke 1996;27:1274 82. 17. Sierra C, de la Sierra A, Pare JC, et al. Correlation between silent cerebral white matter lesions and left ventricular mass and geometry in essential hypertension. Am J Hypertens 2002;15:507 12. 18. Derrer DS, Howieson DB, Mueller EA, et al. Memory testing in dementia: how much is enough? J Geriatr Psychiatry Neurol 2001;14:1 6. 19. Sierra C, de la Sierra A, Salamero M, et al. Silent cerebral white matter lesions and cognitive function in middle-aged essential hypertensive patients. Hypertension 2002;40: 423. 20. Di Bari M, Pahor M, Franse LV, et al. Dementia and disability outcomes in large hypertension trials: lessons learned from the systolic hypertension in the elderly program (SHEP) trial. Am J Epidemiol 2001;153:72 8. 21. Forette F, Seux ML, Staessen JA, et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 1998;352:1347 51. 22. Tzourio C, Anderson C, Chapman N, et al. Effects of blood pressure lowering with perindopril and indapamide on dementia and cognitive decline in patients with cardiovascular disease. Arch Intern Med 2003;163:1069 75. 23. Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995 1003. 24. Lithell H, Hansson L, Skoog I, et al. The Study of Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003;21:875 86. 25. Culman J, Blume A, Gohlke P, et al. The renin angiotensin system in the brain: possible therapeutic implications for AT(1)-receptor blockers. J Hum Hypertens 2002;16(suppl 3):S64 70. 26. Kjeldsen SE, Dahlof B, Devereux RB, et al. Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: a Losartan Intervention for Endpoint Reduction (LIFE) substudy. JAMA 2002;288:1491 8. 27. Schiffrin EL, Park JB, Pu Q. Effect of crossing over hypertensive patients from a beta-blocker to an angiotensin receptor antagonist on resistance artery structure and on endothelial function. J Hypertens 2002;20:71 8.