Download Cerebral involvement in hypertensive cardiovascular disease

European Heart Journal Supplements (2003) 5 (Supplement F), F19—F25
Cerebral involvement in hypertensive
cardiovascular disease
A. Coca
Hypertension Unit, Hospital Clinic (IDIBAPS), University of Barcelona, Barcelona, Spain
KEYWORDS
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.
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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
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A. Coca
Fig. 1 Impact of blood pressure on stroke mortality.3
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 Pressure4 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
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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.
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.
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)
study13 compared the prevalence of WMLs in a
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.
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Pathogenesis of hypertensive
cerebrovascular disease
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A. Coca
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
Fig. 2 Incidence of stroke in patients with baseline white matter lesions and hypertension or normotension.15
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
Antihypertensive therapy and silent
cerebral damage
The clearly established association between
hypertension and cerebral damage raises several
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Hypertension and early cerebral
damage
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 MMSE18 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.
Cerebral involvement
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 study23 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
study23 that losartan is significantly more effective
than atenolol in regressing of left ventricular
hypertrophy, suggesting that ARBs and beta-
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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-Eur21, PROGRESS22 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 study21 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
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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
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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.
A. Coca
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.
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