High Blood Press Cardiovasc Prev

DOI 10.1007/s40292-015-0115-2

REVIEW ARTICLE

Hypertension and Stroke: Epidemiological Aspects and Clinical

Raffaele Ornello1 • Antonio Carolei1

Received: 23 April 2015 / Accepted: 1 July 2015

Abstract The strong relationship between stroke and and lost productivity [1–3]. Among modifiable risk factors
hypertension has been the object of several studies and trials. for stroke, hypertension is the most frequent both in
These studies addressed the epidemiology of stroke and developed and in developing countries. Moreover, the
hypertension, in order to estimate their worldwide distribution complex interaction between hypertension and other
and time evolution, and investigated the effects of the man- modifiable risk factors, including high cholesterol levels,
agement of hypertension on stroke outcomes. Evidences diabetes mellitus, high body mass index and smoking,
coming from these studies are essential to plan proper health greatly increases the cumulative risk for cardiovascular and
services, optimise economic resources, and estimate the cerebrovascular diseases in hypertensive patients. Thus, the
effectiveness of therapeutic strategies in primary and sec- 8th report of the Joint National Committee on Hyperten-
ondary prevention. Additional suggestions are needed to tailor sion (JNC 8) recommended a series of interventions for
the pharmacologic management of hypertension on the indi- primary and secondary prevention of hypertension [4]. The
vidual needs of patients and to select the most appropriate former are mainly based on lifestyle changes and modifi-
treatment to avoid stroke recurrences on the basis of the first- cations of high-risk habits contributing to the development
ever stroke subtype. Moreover, an increasing attention has of hypertension, while the latter are aimed at improving
been given, over the last years, to the relationship between the detection and management of hypertension once it has
presence of hypertension and the development of an end-or- developed. The ambition of these strategies is to stem the
gan brain damage leading to early cognitive dysfunctions. A global burden of cardiovascular diseases [5] and to pro-
better understanding of this relationship is the prerequisite to mote successful aging worldwide.
promote successful aging and well-being.
1.1 Epidemiology of Stroke and Hypertension
Keywords Stroke
Hypertension
Epidemiology

Cerebrovascular disease
Dementia The incidence rates of stroke range from 1.3/1000 in the
United Kingdom to 4.1/1000 in Japan [6]. Incidence is higher
in men than in women [7] and in black as compared to white
1 Introduction populations [8–12]. It progressively increases with age, with
the highest incidence rates in the oldest old [3, 13–15].
Stroke is the second leading cause of death worldwide and
Ischaemic stroke accounts for about 67–81 % of all cases,
the main cause of disability in adults, thus representing a
while intracerebral hemorrhage and subarachnoid hemor-
considerable economic burden in terms of health care costs
rhage account for 7–20 % and 1–7 % of cases respectively
[6]. Undefined strokes are responsible for a variable propor-
& Francesca Pistoia tion of cases, ranging from 2 to 15 % of all strokes [6].
francesca.pistoia@univaq.it Prevalence rates range from 1.7/1000 in the Philippines
1 to 10.2/1000 in New Zealand and there is little geograph-
Department of Biotechnological and Applied Clinical
Sciences, Neurological Institute, University of L’Aquila, ical variation with the exception of Italy and the UK, where
67100 L’Aquila, Italy prevalence is highest, probably as a result of inclusion of
 F. Pistoia et al.

minor strokes in studies estimating prevalence [6]. Mor- be found in women in Sub-Saharan Africa, in North and
tality at 1 month from stroke onset is about 23 % and it is West India, in Turkey and in some Latin American coun-
higher for intracerebral hemorrhage (42 %) and subarach- tries [22]. Moreover, prevalence progressively increases
noid hemorrhage (32 %) than for ischemic stroke (16 %) with age in both sexes and in all investigated regions.
[6, 16]. Recently differences in incidence, prevalence and Interestingly, about two-thirds of people with hypertension
mortality have been reported between Eastern and Western are in developing countries: this is the result of the larger
Europe [17]. These discrepancies may be due to a different size of populations in these regions and of on-going life-
distribution of risk factors, with higher levels of arterial style changes [22].
hypertension and other risk factors in Eastern Europe, and Epidemiological studies are essential to better under-
to differences in the methodology of the studies [17]. stand worldwide stroke distribution and its relationship
With respect to time trends of stroke incidence and with hypertension. This is a prerequisite for planning
mortality over the last four decades, a decreased stroke proper health services, optimising economic resources, and
incidence and mortality has been observed in high-income estimating the adequacy of the therapeutic strategies of
countries as a result of advances in stroke care and sec- primary and secondary prevention. Finally, a better eval-
ondary prevention [18]. These trends have been found uation of time trends in the incidence of stroke and vascular
across all age groups, with a greater decline in people risk factors may facilitate the estimation of the expected
younger than 75 years [18]. The incidence decrease mainly number of patients with cerebrovascular disease who may
involved ischemic stroke and primary intracerebral hem- benefit from stroke units and rehabilitative services.
orrhage, while subarachnoid hemorrhage showed relatively
stable incidence rates. A similar trend has recently been 1.2 Autoregulation of Cerebral Blood Flow
observed in the population living in the L’Aquila district in
central Italy, where in the years 2011–2012 the overall A constant supply of oxygen to the brain is supported by
incidence of first-ever ischemic strokes (crude rate mechanisms of autoregulation, which keep cerebral blood
142/100,000) strongly decreased with respect to that found flow constant, within predetermined blood pressure values,
in the years 1994–1998 (crude rate 292/100,000). This despite changes in perfusion pressure. Autoregulation acts
decrease involved both ischemic and hemorrhagic strokes through modulation of peripheral vascular resistance, which
and was mainly observed in the oldest age groups (data in enables an increased flow in response to decreased perfusion
press). In the same district a considerable decrease in pressure and a decreased flow in response to increased per-
30-day and 1-year case fatality rates was observed for fusion pressure [23]. Specifically, a sudden drop in blood
ischemic stroke, with age and severity of stroke being pressure induces compensatory vasodilation, whereas a
significant predictors for mortality (data in press). On the sudden rise in blood pressure causes immediate vasocon-
other hand, an increase in stroke incidence has been striction. The lower and upper limits of autoregulation are
observed in low to middle income countries, with a twofold approximately 50–60 and 150–160 mmHg (Fig. 1). When
increase in subjects younger than 75 years and a fourfold the perfusion pressure drops or rises beyond these limits the
increase in the oldest age group [18]. Early stroke mortality cerebral blood flow becomes dependent on the pressure itself
has been reported as decreasing also in low to middle in a linear manner and the brain enters a condition of cerebral
income countries, although it remains 25 % higher than ischemia or hypertensive encephalopathy. An increase in
that observed in high-income countries [18]. oxygen extraction from the blood is able to counteract the
Hypertension is the main risk factor for cardiovascular
and cerebrovascular diseases, as recently confirmed by the
INTERHEART and the INTERSTROKE studies. These
studies assessed the contribution of several risk factors both
in high-income and low-income countries [19–21]. Among
the risk factors, hypertension is reported to be the leading
contributor to overall mortality and the third greatest cause
of lost healthy life years [19]. Overall, it has been estimated
that 26 % of the world’s adult population had hypertension
in the year 2000 and that this proportion will increase to
29 % by 2025 [22]. Prevalence rates show widespread
geographical variations with the lowest rates in Korea
(19.8 %) and the highest in Germany (55.3 %) [22].
Prevalence rates are higher in men in most of the European
countries and in the United States, while higher rates may Fig. 1 Autoregulation of cerebral blood flow
Hypertension and Stroke: Epidemiological Aspects and Clinical Evaluation

initial reduction of cerebral blood flow and to avoid the occlusion; stroke of other determined aetiology; and stroke
effects of cerebral ischemia. However, when the decrease in of undetermined aetiology [29]. On the other hand, the
perfusion exceeds the limits of this compensatory mecha- OCSP classification defines stroke, on the basis of the
nism, symptoms of ischemia occur. The physiological vascular territory involved, in total anterior circulation
mechanisms which support myogenic responses during infarct (TACI), partial anterior circulation infarct (PACI),
vasodilation and vasoconstriction are not completely posterior circulation infarct (POCI) and lacunar infarcts
understood [23]. Extrinsic innervation of arterial vessels (LACI) [30]. With regard to the community in whom this
seems not to be involved, as demonstrated by the preserva- classification was initially developed, the most frequent
tion of autoregulation in sympathetically and parasympa- ischemic stroke type was PACI (34 %) followed by LACI
thetically denervated animals [24]. On the other hand, (25 %), POCI (24 %) and TACI (17 %) [30]. LACI are
intrinsic innervation may be involved, as well as metabolic caused by an atherothrombotic or lipohyalinotic occlusion
modulation through the release of nitric oxide, adenosine and of the small penetrating branches of the middle cerebral
other vasoactive substances [25, 26]. and the vertebrobasilar artery, and are mainly localised in
Finally, in patients with chronic arterial hypertension the deep brain structures including basal ganglia, cerebral
curve is adaptively shifted toward the right and upper limits white matter, thalamus, pons, and cerebellum [31, 32].
so that cerebral blood flow starts decreasing in correspon- Lipohyalinosis is characterised by a fibrinoid necrosis of
dence with higher values of pressure fluctuations. Hence the smooth muscle of the arterial wall, followed by thick-
the doubts about the advisedness of normalising blood ening of the small-vessel wall and luminal narrowing up to
pressure values in patients with chronic arterial hyperten- occlusion, which can lead to lacunar infarcts with a
sion and a history of recent stroke, as these subjects may diameter ranging from 3 mm to 2 cm [31]. These infarcts
become too reactive to the effects of blood pressure may be asymptomatic or cause a variable combination of
reduction and might experience a recurrent stroke. motor and sensory symptoms (pure motor stroke, pure
sensory stroke, isolated sensory-motor stroke, dysarthria-
1.3 Clinical Aspects clumsy hand syndrome and ataxic hemiparesis syndrome).
The classification of strokes according to pathogenic
1.3.1 Definition and Classification of Stroke mechanisms and the vascular territories involved is
important to investigate the effects of risk factor manage-
Stroke is defined as an episode of neurological dysfunction ment, including arterial hypertension, in different subtypes
caused by focal cerebral, spinal, or retinal infarction. of acute ischemic stroke. In this respect, a recent study
Diagnosis of stroke may be supported by pathological, suggested that the effect of blood pressure–lowering
imaging, or other objective evidence of cerebral, spinal treatment may differ according to different types of acute
cord, or retinal focal ischemic injury in a defined vascular ischaemic stroke, with antihypertensive therapy having a
distribution. Alternatively, diagnosis may be supported by better effect in patients with larger infarcts (TACI or PACI)
clinical evidence of cerebral, spinal cord, or retinal focal than in patients with smaller infarcts (LACI) [33]. The
ischemic injury based on symptoms persisting C24 h or observed trend may be the consequence of long-standing
leading to death. Moreover, diagnosis is supported by the hypertension in patients with LACI resulting in the afore-
exclusion of any other brain disease which may mimic mentioned rightward shift of the autoregulatory curve and
stroke. Stroke includes cerebral infarction and cerebral the occurrence of perfusion deficits following a blood
haemorrhage, which account for about 80 and 20 % of all pressure lowering toward normal values [33]. Moreover,
cases of stroke respectively. Ischemic stroke has to be cerebral autoregulation seems to be impaired, in patients
differentiated from transient ischemic attack (TIA), the with LACI, not only in the affected hemisphere but also in
definition and classification of which has been recently the opposite one: this would lead to a disproportionate fall
updated. Specifically, according to the tissue-based defi- in cerebral perfusion after blood pressure lowering [33].
nition, TIA is defined as a transient episode of neurological This is not the case for patients with TACI and PACI,
dysfunction caused by focal brain, spinal cord, or retinal whose pathogenesis is mainly atherothrombotic or car-
ischemia without evidence of acute infarction on neu- dioembolic: these infarcts are more likely to be compli-
roimaging [27, 28]. Ischemic stroke may be classified cated by oedema development or hemorrhagic
according to the Trial of Org 10172 in Acute Stroke transformation and real benefit may be obtained from a
Treatment (TOAST) classification [29] and the Oxford moderate lowering of blood pressure [33]. In daily clinical
Community Stroke Project (OCSP) classification [30]. The practice antihypertensive medications are more likely
former denotes five subtypes of stroke depending on eti- prescribed in ischemic patients with small vessel diseases
ology: stroke caused by large-artery atherosclerosis; stroke that in patients with large arteries stenosis [34]. However,
caused by cardioembolism; stroke caused by small-vessel to date no clear guidelines orientate the use of appropriate
 F. Pistoia et al.

antihypertensive treatments depending on the stroke sub- Table 1 Clinical symptoms for vascular regions belonging to the
type. Unlike for ischemic stroke, there is no established carotid system
uniform classification system for intracerebral hemorrhage Internal carotid artery (ICA)
(ICH). A classification system for ICH aetiology was Monoparesis to hemiparesis
recently proposed. The system was denoted as SMASH-U Partial to full hemisensory impairment
(Structural lesion, Medication, Amyloid angiopathy, Sys- Homonymous hemianopia, impairment of speech or language,
temic/other disease, Hypertension, Undetermined). Studies agnosia
based on this classification identified hypertensive Transient monocular blindness
angiopathy as the most common aetiology (35 %), fol- Partial Bernard-Horner syndrome
lowed by amyloid angiopathy (20 %) and undetermined Anterior cerebral artery (ACA)
aetiology (21 %) [35]. The remainder of cases were caused Weakness of the opposite leg, often most prominent distally
by anticoagulation (14 %), structural lesions like caver- (foot)
nomas and arteriovenous malformations (5 %), systemic Possible weakness of the proximal muscles of the upper
pathological conditions including thrombocytopenia and extremity
blood abnormalities associated with liver cirrhosis (5 %) Possible sensory involvement and apraxia (gait)
[35]. Moreover, short and long term recurrences after the Possible cognitive impairment with grasp reflex, frontal lobe
behavioural abnormalities, transcortical aphasia (left ACA) or
index event have been reported more frequently in patients left hemineglect (right ACA)
with systemic diseases and amyloid angiopathy [36].
Middle cerebral artery (MCA)
Arterial hypertension is the main risk factor not only for
Proximal occlusion
hypertensive angiopathy but also for amyloid angiopathy
Hemiplegia and hemihypoesthesia
[35]. ICH caused by hypertensive angiopathy is commonly
Homonymous hemianopia
localised in deep areas and results from the rupture of
Contralateral paralysis of the eye
degenerated arterioles during uncontrolled hypertension.
Aphasia (dominant hemisphere)
ICH induced by amyloid angiopathy, on the other hand, is
Distal occlusion
superficial or lobar in location and results from the rupture
Hemiplegia (face and arm [ leg) and hemisensory deficit (face
of small or medium sized arteries in the cortical and lep- and arm [ leg)
tomeningeal regions [36].
Homonymous hemianopia
Contralateral gaze palsy
1.3.2 Clinical Manifestations of Stroke
Global aphasia (dominant hemisphere)
Neglect syndrome (non-dominant hemisphere)
Stroke manifestations include a wide range of clinical
symptoms depending on the affected brain region, the size
of the damaged area and the functions controlled by that
area. Main cerebrovascular regions include those belonging as a result of increased intracranial pressure and are more
to the carotid and the vertebral-basilar system. The former frequent in hemorrhagic strokes than in ischaemic strokes.
includes areas served by the internal carotid artery, the
anterior cerebral artery and the middle cerebral artery, 1.3.3 Diagnostic Approach
while the latter includes regions supplied by the vertebral
artery, the basilar artery and the posterior cerebral artery. The diagnostic approach in patients with stroke is based on
Focal symptoms of stroke, depending on the involved medical history, neurological assessment, routine investiga-
vascular region, are summarised in Tables 1 and 2. The tions and neuroimaging evaluation. Medical history is aimed
variability of clinical manifestations of stroke is also at recognising the main symptoms referred by the patient and
influenced by the effectiveness of collateral circulation, the presence of modifiable and non-modifiable risk factors in
which may maintain an acceptable level of perfusion distal order to address diagnosis and to plan adequate preventive
to the site of arterial occlusion. Collateral vessels play an strategies. The neurological assessment is mainly based on the
important role especially in the presence of an occlusive administration of the National Institutes of Health Stroke
carotid artery disease, the diagnosis of which may be Scale (NIHSS), which objectively identifies the signs of stroke
incidental or may follow a devastating cerebral infarction and quantifies the stroke-related impairment [39]. The scale
[37]. Moreover, cerebral collateral vessels show significant consists of 11 items addressing specific skills, whose
anatomical variation among individuals, contributing to the impairment is graded by a score ranging, depending on single
inter-subject variability of stroke symptoms [38]. Finally, items, from 0 (normal function) to 4 (severe impairment). The
generalised symptoms, including nausea, vomiting, head- total NIHSS score is the sum of individual scores and ranges
ache, seizures and impairment of consciousness, may occur from 0 (no stroke symptoms) to 42 (severe stroke). It is used to
Hypertension and Stroke: Epidemiological Aspects and Clinical Evaluation

Table 2 Clinical symptoms for vascular regions belonging to the the management of patients with acute spontaneous
vertebral-basilar system intracerebral hemorrhage (Table 3) [40–42]. Indeed, the
Vertebral artery (VA) association between the proper management of hyperten-
Vertigo, nausea, vomiting, dysphagia sion and the reduction of stroke risk has been long well
Ipsilateral cerebellar ataxia known. The INDANA (INdividual Data ANalysis of
Ipsilateral Horner’s syndrome Antihypertensive intervention trials) project analysed the
Ipsilateral facial sensory loss with contralateral body pain and effects of blood pressure lowering medications in survivors
temperature loss of stroke or TIA, and showed that the treatment was able to
Basilar artery (BA) prevent approximately 30 % of stroke recurrences [43].
Sensory or motor deficit on one side of the face and the opposite This data is in line with that reported by a metanalysis,
side of the body which suggested that the risk decrease was mainly due to
Dizziness, vertigo, and nystagmus the reduction of systolic blood pressure and that vascular
Variable involvement of cranial nerves prevention was associated positively with the magnitude by
Possible locked-in syndrome: quadriplegia, lower cranial nerve which blood pressure was reduced [44]. Moreover, the
paralysis, anarthria reduction in the risk of stroke after blood pressure lowering
Posterior cerebral artery (MCA) seemed to be consistent across sexes, stroke subtypes and
Homonymous hemianopia or quadrantanopia territories, and for fatal and nonfatal events, with greater
Dyslexia and dyscalculia (dominant hemisphere) benefits from larger blood pressure reductions [45]. Whe-
Parietal lobe syndrome (non-dominant hemisphere) ther prevention of stroke recurrence depends on drug class
Hemisensory deficit and occasionally thalamic syndrome is still debated: the Heart Outcomes Prevention Evaluation
(sensory loss with spontaneous pain) (HOPE) Study suggested that treatment with ramipril for a
Cortical blindness and behavioural changes (bilateral occlusion) 4.5-year period caused a 32 % reduction of the relative risk
for stroke [46]. Moreover, the benefits were sustained over
orientate treatments, to quantify neurological improvement or time as confirmed by the Heart Outcomes Prevention
deterioration and to screen patients who are eligible for Evaluation-TOO (HOPE-TOO) study, which provided an
thrombolysis. Routine investigations are useful to exclude any additional 2.6 year follow-up for patients receiving the
systemic diseases which may mimic a stroke and to evaluate treatment [47]. Similarly, the Perindopril Protection
the general medical condition of the patients. Prompt neu- Against Recurrent Stroke Study (PROGRESS) showed, in
roimaging evaluation is mandatory to distinguish between patients with previous stroke or TIA, a 28 % risk reduction
vascular and non-vascular lesions, to differentiate ischemia of stroke following combined treatment with perindopril
from hemorrhage, to identify the site and the extent of the and indapamide [48]. The risk reduction was greater for
lesion, and to investigate stroke pathogenesis. Finally, addi- hemorrhagic stroke (50 %) than for ischemic stroke
tional examinations allow investigation of the physiopatho- (24 %). Moreover, the relative risk reduction for all strokes
logical mechanisms responsible for stroke: ultrasound was greater among participants treated with combination
scanning of carotid and vertebral arteries is needed to exclude therapy (43 %) as compared to those treated with
the presence of a critical narrowing of the large arteries; perindopril alone (5 %), with a similar pattern observed for
transcranial ultrasonography and computed tomography and/ ischemic stroke (relative risk reduction after combination
or magnetic resonance angiography are used to identify therapy 36 vs 6 % after single-drug therapy) and for
intracranial artery stenosis or aneurysms and other vascular hemorrhagic stroke (relative risk reduction after combina-
malformations; transthoracic and transesophageal echocar- tion therapy 76 vs 1 % after single-drug therapy). This
diography are needed to detect cardiac wall and chamber suggested that the overall blood pressure reduction, rather
abnormalities, residual patent foramen ovale or valve disor- than the independent effects of single treatments, is the
ders which may be the source of emboli in cardioembolic main mechanism of secondary prevention for both
stroke; electrocardiographic monitoring is required to reveal ischemic and hemorrhagic strokes [48]. Further evidence
the presence of paroxysmal atrial fibrillation. was provided by the Morbidity and Mortality After Stroke,
Eprosartan Compared with Nitrendipine for Secondary
1.4 Management of Hypertension and Risk Prevention (MOSES) study, which compared an angio-
of Stroke tensin II type 1 receptor antagonist with a calcium antag-
onist in secondary stroke prevention. This study showed
A regular blood pressure monitoring and appropriate comparable blood pressure reduction with the two treat-
treatment of hypertension has been strongly recommended ments and a greater reduction of the combined primary end
in the most recent guidelines for primary and secondary point, which was total mortality and all cardiovascular and
prevention of ischemic stroke as well as in guidelines for cerebrovascular events, in the eprosartan group as
 F. Pistoia et al.

Table 3 Recommendations for the management of blood pressure in primary and secondary prevention of stroke and in the management of
acute spontaneous intracerebral hemorrhage [40–42]
Recommendations from the management of blood pressure (BP) in the primary prevention of stroke
Regular BP screening and appropriate treatment of patients with hypertension, including lifestyle modification and pharmacological therapy,
are recommended (Class I; Level of Evidence A)
Annual screening for high BP and health-promoting lifestyle modification are recommended for patients with prehypertension (SBP of 120
to 139 mm Hg or DBP of 80 to 89 mm Hg) (Class I; Level of Evidence A)
Patients who have hypertension should be treated with antihypertensive drugs to a target BP of\140/90 mm Hg (Class I; Level of Evidence
A)
Successful reduction of BP is more important in reducing stroke risk than the choice of a specific agent, and treatment should be
individualized on the basis of other patient characteristics and medication tolerance (Class I; Level of Evidence A)
Self-measured BP monitoring is recommended to improve BP control. (Class I; Level of Evidence A)
Recommendations from the management of blood pressure (BP) in patients with previous stroke or transient ischemic attack (TIA)
Initiation of BP therapy is indicated for previously untreated patients with ischemic stroke or TIA who, after the first several days, have an
established BP C140 mm Hg systolic or C90 mm Hg diastolic (Class I; Level of Evidence B). Initiation of therapy for patients with BP
\140 mm Hg systolic and \90 mm Hg diastolic is of uncertain benefit (Class IIb; Level of Evidence C)
Resumption of BP therapy is indicated for previously treated patients with known hypertension for both prevention of recurrent stroke and
prevention of other vascular events in those who have had an ischemic stroke or TIA and are beyond the first several days (Class I; Level of
Evidence A)
Goals for target BP level or reduction from pretreatment baseline are uncertain and should be individualized, but it is reasonable to achieve a
systolic pressure \140 mm Hg and a diastolic pressure \90 mm Hg (Class IIa; Level of Evidence B). For patients with a recent lacunar
stroke, it might be reasonable to target a systolic BP of \130 mm Hg (Class IIb; Level of Evidence B)
Recommendations from the management of blood pressure (BP) in patients with acute spontaneous intracerebral hemorrhage (ICH)
For ICH patients presenting with SBP between 150 and 220 mm Hg and without contraindication to acute BP treatment, acute lowering of
SBP to 140 mm Hg is safe (Class I; Level of Evidence A) and can be effective for improving functional outcome (Class IIa; Level of
Evidence B)
For ICH patients presenting with SBP [220 mm Hg, it may be reasonable to consider aggressive reduction of BP with a continuous
intravenous infusion and frequent BP monitoring (Class IIb; Level of Evidence C)

compared to the nitrendipine group [49]. Divergent results greater occurrence of adverse events without an increase in
have been found in the Valsartan Antihypertensive Long- benefit in patients receiving the therapeutic regimen [54].
term Use Evaluation (VALUE) study which, although A lack of advantages from combination therapies was also
reporting a more pronounced effect of amlodipine as shown in the Aliskiren Trial in Type 2 Diabetes Using
compared to valsartan in blood pressure lowering [50], Cardiovascular and Renal Disease Endpoints (ALTI-
showed similar effects in secondary stroke prevention for TUDE). The addition of aliskiren to standard therapy with
the two treatments [51]. Comparisons have also been per- renin-angiotensin system blockade was reported to be less
formed to evaluate the effects of different diuretics in the beneficial than treatment with single agents for the pre-
prevention of cardiovascular and cerebrovascular diseases. vention of major cardiovascular events including nonfatal
A recent meta-analysis compared the effects of strokes [55]. The Telmisartan Randomised AssessmeNt
hydrochlorothiazide with those of chlorthalidone, and Study in ACE iNtolerant subjects with cardiovascular
showed a greater effectiveness of the latter in preventing Disease (TRANSCEND) investigated the tolerability of
cardiovascular events including stroke [52]. The advan- telmisartan in patients unable to tolerate ACE inhibitors.
tages from using combined regimens were also investi- Although well-tolerated, telmisartan modestly reduced the
gated by the Anglo-Scandinavian Cardiac Outcomes Trial- risk of cardiovascular death, myocardial infarction, or
Blood Pressure Lowering Arm (ASCOT-BPLA), which stroke in treated patients [56]. Other studies of interest
compared the effectiveness of the association of amlodip- focused on the management of resistant arterial hyperten-
ine and perindopril with that of atenolol and ben- sion, which is defined as failure to achieve a blood pressure
droflumethiazide, showing better effects with the former goal of \140/90 mmHg despite treatment with C3 differ-
treatment [53]. Further evidence came from the Ongoing ent classes of antihypertensive medication at the maximum
Telmisartan Alone and in combination with Ramipril tolerated dose and including a diuretic. These trials showed
Global Endpoint Trial (ONTARGET), which compared the some success with different pharmacological and non-
effects of a combination therapy, based on ramipril and pharmacological treatments including endothelin A antag-
telmisartan, with single-drug therapies. The trial found a onists, aldosterone antagonists, catheter-based renal
Hypertension and Stroke: Epidemiological Aspects and Clinical Evaluation

denervation procedures and carotid baroreceptor stimula- about the prevention of cardiovascular events suggest that
tion devices [57]. Finally, some studies demonstrated that combinations of drugs with different modes of action are
specific drug interventions might confer benefits beyond more effective than combinations of drugs with a similar
those related to the blood pressure reduction. For instance, mode of action, as the latter are more likely to increase
some antihypertensive drugs exert additional beneficial adverse events without improving outcomes. Moreover,
effects in stroke prevention by decreasing blood pressure multiple non hemodynamic pleomorphic benefits may
variability while others play a relevant role in reversing or contribute to the overall effects of some treatments. These
improving left ventricular hypertrophy. The role of blood include enhancing angiogenesis, inhibiting platelet aggre-
pressure variability in stroke pathogenesis and prognosis gation, increasing nitric oxide production and reducing
have been confirmed by several studies including a sub- carotid intima-media thickness, vascular permeability and
study of the Systolic Hypertension in Europe (Syst-Eur) epinephrine-mediated platelet aggregation.
Trial in elderly hypertensive patients [58]. This study
showed that an increased night-time systolic blood pressure 1.5 Hypertension and End-Organ Brain Damage
variability was an independent risk factor for stroke while
daytime systolic blood pressure variability was not of Recently special attention has been paid to the role of
prognostic value [58]. This observation was confirmed by hypertension as a contributor to the end-organ brain dam-
more recent studies highlighting the relationship between age associated with a decline in cognitive function. Much
short-term and long-term blood pressure variability and the evidence suggests that increased systolic blood pressure is
occurrence of cardiovascular events [59, 60]. Moreover, a linearly associated with markers of cerebral white matter
recent cohort study showed that, among patients with a microstructural damage in healthy young adults [68]. The
previous transient ischemic attack, a more pronounced above injury mainly involves the anterior corpus callosum,
systolic blood pressure variability was associated with a the inferior fronto-occipital fasciculi, and the fibres that
higher risk of stroke [61]. Similarly, patients showing wide project from the thalamus to the superior frontal gyrus. In
blood pressure fluctuations during the acute phase of addition, a reduced grey-matter volumes in Brodmann’s
ischemic stroke have been reported to have a poor outcome area 48 on the medial surface of the temporal lobe and in
at 1 and 3 months following the index event [62]. In this Brodmann’s area 21 of the middle temporal gyrus is
light, a recent meta-analysis suggested that the different observed [68]. This damage may lead to what is known as
effect of antihypertensive drugs on individual blood pres- unsuccessful ageing, characterised by impairment in
sure variability may account for their different potential in specific cognitive domains such as those subserving lan-
preventing stroke [63]. Specifically, a substudy of the guage, executive functions and visuospatial memory.
Anglo-Scandinavian Cardiac Outcomes Trial Blood Pres- Hypertension may lead to the development of white-matter
sure Lowering Arm (ASCOT-BPLA) and of the Medical lesions by accelerating the progression of arterial ageing
Research Council (MRC) trial proposed that the different measured as arterial stiffness. This suggests that the effects
effect of calcium-channel blockers and beta blockers on of hypertension go beyond those traditionally associated
blood pressure variability may be responsible for the with stroke and that early preventive strategies are essential
greater effectiveness of the former in reducing the risk of to stem end-organ brain damage. In fact, although it is not
stroke in hypertensive patients [64]. All these observations clear whether this brain damage is reversible or can be
suggest that the most effective blood-pressure-lowering slowed by the use of antihypertensive treatments, early
drugs in preventing cardiovascular morbidity and mortality control of blood pressure in young subjects is recom-
are those able to reduce both mean blood pressure and mended in order to avoid subtle myelin injury and
blood pressure variability [64]. Similarly, other drugs, decreased cognitive performance [69]. Contradictory
belonging to the angiotensin-II type 1-receptor antagonists results have been reported for older age groups, where
class, may exert their beneficial effects in cardiovascular aggressive antihypertensive treatment is not even associ-
and cerebrovascular prevention by promoting the regres- ated with a later favourable cognitive outcome. Some
sion of left ventricular hypertrophy, which is a well-known studies in elderly subjects showed that midlife hyperten-
blood-pressure-independent predictor for cerebrovascular sion is a risk factor for late-life cognitive impairment [70,
events [65]. In this respect, the Cardiovascular morbidity 71] whereas others suggested that hypertension may con-
and mortality in the Losartan Intervention For Endpoint tribute to cognitive decline and dementia only when long-
reduction in hypertension study (LIFE) showed the greater standing and developing in early age [72]. Thus, the pro-
effectiveness of losartan, as compared to atenolol, in tective effect of antihypertensive therapy against dementia
reducing the rate of fatal and nonfatal stroke and ascribed and stroke-related cognitive decline in the elderly is still
this superiority also to its protective effects towards left debated, as a certain level of blood pressure seems to be
ventricular hypertrophy [66, 67]. All the reported data necessary for older adults to maintain cerebral perfusion
 F. Pistoia et al.

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