High Blood Press Cardiovasc Prev DOI 10.1007/s40292-015-0115-2

REVIEW ARTICLE

Hypertension and Stroke: Epidemiological Aspects and Clinical Evaluation Francesca Pistoia1 • Simona Sacco1 • Diana Degan1 • Cindy Tiseo1 Raffaele Ornello1 • Antonio Carolei1



Received: 23 April 2015 / Accepted: 1 July 2015 Ó Springer International Publishing Switzerland 2015

Abstract The strong relationship between stroke and hypertension has been the object of several studies and trials. These studies addressed the epidemiology of stroke and hypertension, in order to estimate their worldwide distribution and time evolution, and investigated the effects of the management of hypertension on stroke outcomes. Evidences coming from these studies are essential to plan proper health services, optimise economic resources, and estimate the effectiveness of therapeutic strategies in primary and secondary prevention. Additional suggestions are needed to tailor the pharmacologic management of hypertension on the individual needs of patients and to select the most appropriate treatment to avoid stroke recurrences on the basis of the firstever stroke subtype. Moreover, an increasing attention has been given, over the last years, to the relationship between the presence of hypertension and the development of an end-organ brain damage leading to early cognitive dysfunctions. A better understanding of this relationship is the prerequisite to promote successful aging and well-being.

and lost productivity [1–3]. Among modifiable risk factors for stroke, hypertension is the most frequent both in developed and in developing countries. Moreover, the complex interaction between hypertension and other modifiable risk factors, including high cholesterol levels, diabetes mellitus, high body mass index and smoking, greatly increases the cumulative risk for cardiovascular and cerebrovascular diseases in hypertensive patients. Thus, the 8th report of the Joint National Committee on Hypertension (JNC 8) recommended a series of interventions for primary and secondary prevention of hypertension [4]. The former are mainly based on lifestyle changes and modifications of high-risk habits contributing to the development of hypertension, while the latter are aimed at improving detection and management of hypertension once it has developed. The ambition of these strategies is to stem the global burden of cardiovascular diseases [5] and to promote successful aging worldwide. 1.1 Epidemiology of Stroke and Hypertension

Keywords Stroke  Hypertension  Epidemiology  Cerebrovascular disease  Dementia

1 Introduction Stroke is the second leading cause of death worldwide and the main cause of disability in adults, thus representing a considerable economic burden in terms of health care costs & Francesca Pistoia [email protected] 1

Department of Biotechnological and Applied Clinical Sciences, Neurological Institute, University of L’Aquila, 67100 L’Aquila, Italy

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 populations [8–12]. It progressively increases with age, with the highest incidence rates in the oldest old [3, 13–15]. Ischaemic stroke accounts for about 67–81 % of all cases, while intracerebral hemorrhage and subarachnoid hemorrhage account for 7–20 % and 1–7 % of cases respectively [6]. Undefined strokes are responsible for a variable proportion of cases, ranging from 2 to 15 % of all strokes [6]. Prevalence rates range from 1.7/1000 in the Philippines to 10.2/1000 in New Zealand and there is little geographical variation with the exception of Italy and the UK, where prevalence is highest, probably as a result of inclusion of

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minor strokes in studies estimating prevalence [6]. Mortality at 1 month from stroke onset is about 23 % and it is higher for intracerebral hemorrhage (42 %) and subarachnoid hemorrhage (32 %) than for ischemic stroke (16 %) [6, 16]. Recently differences in incidence, prevalence and mortality have been reported between Eastern and Western Europe [17]. These discrepancies may be due to a different distribution of risk factors, with higher levels of arterial hypertension and other risk factors in Eastern Europe, and to differences in the methodology of the studies [17]. With respect to time trends of stroke incidence and mortality over the last four decades, a decreased stroke incidence and mortality has been observed in high-income countries as a result of advances in stroke care and secondary prevention [18]. These trends have been found across all age groups, with a greater decline in people younger than 75 years [18]. The incidence decrease mainly involved ischemic stroke and primary intracerebral hemorrhage, while subarachnoid hemorrhage showed relatively stable incidence rates. A similar trend has recently been observed in the population living in the L’Aquila district in central Italy, where in the years 2011–2012 the overall incidence of first-ever ischemic strokes (crude rate 142/100,000) strongly decreased with respect to that found in the years 1994–1998 (crude rate 292/100,000). This decrease involved both ischemic and hemorrhagic strokes and was mainly observed in the oldest age groups (data in press). In the same district a considerable decrease in 30-day and 1-year case fatality rates was observed for ischemic stroke, with age and severity of stroke being significant predictors for mortality (data in press). On the other hand, an increase in stroke incidence has been observed in low to middle income countries, with a twofold increase in subjects younger than 75 years and a fourfold increase in the oldest age group [18]. Early stroke mortality has been reported as decreasing also in low to middle income countries, although it remains 25 % higher than that observed in high-income countries [18]. 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

be found in women in Sub-Saharan Africa, in North and West India, in Turkey and in some Latin American countries [22]. Moreover, prevalence progressively increases with age in both sexes and in all investigated regions. Interestingly, about two-thirds of people with hypertension are in developing countries: this is the result of the larger size of populations in these regions and of on-going lifestyle changes [22]. Epidemiological studies are essential to better understand worldwide stroke distribution and its relationship with hypertension. This is a prerequisite for planning proper health services, optimising economic resources, and estimating the adequacy of the therapeutic strategies of primary and secondary prevention. Finally, a better evaluation of time trends in the incidence of stroke and vascular risk factors may facilitate the estimation of the expected number of patients with cerebrovascular disease who may benefit from stroke units and rehabilitative services. 1.2 Autoregulation of Cerebral Blood Flow A constant supply of oxygen to the brain is supported by mechanisms of autoregulation, which keep cerebral blood flow constant, within predetermined blood pressure values, despite changes in perfusion pressure. Autoregulation acts through modulation of peripheral vascular resistance, which enables an increased flow in response to decreased perfusion pressure and a decreased flow in response to increased perfusion pressure [23]. Specifically, a sudden drop in blood pressure induces compensatory vasodilation, whereas a sudden rise in blood pressure causes immediate vasoconstriction. The lower and upper limits of autoregulation are approximately 50–60 and 150–160 mmHg (Fig. 1). When the perfusion pressure drops or rises beyond these limits the cerebral blood flow becomes dependent on the pressure itself in a linear manner and the brain enters a condition of cerebral ischemia or hypertensive encephalopathy. An increase in oxygen extraction from the blood is able to counteract the

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 effects of cerebral ischemia. However, when the decrease in perfusion exceeds the limits of this compensatory mechanism, symptoms of ischemia occur. The physiological mechanisms which support myogenic responses during vasodilation and vasoconstriction are not completely understood [23]. Extrinsic innervation of arterial vessels seems not to be involved, as demonstrated by the preservation of autoregulation in sympathetically and parasympathetically denervated animals [24]. On the other hand, intrinsic innervation may be involved, as well as metabolic modulation through the release of nitric oxide, adenosine and other vasoactive substances [25, 26]. Finally, in patients with chronic arterial hypertension the curve is adaptively shifted toward the right and upper limits so that cerebral blood flow starts decreasing in correspondence with higher values of pressure fluctuations. Hence the doubts about the advisedness of normalising blood pressure values in patients with chronic arterial hypertension and a history of recent stroke, as these subjects may become too reactive to the effects of blood pressure reduction and might experience a recurrent stroke. 1.3 Clinical Aspects 1.3.1 Definition and Classification of Stroke Stroke is defined as an episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction. Diagnosis of stroke may be supported by pathological, imaging, or other objective evidence of cerebral, spinal cord, or retinal focal ischemic injury in a defined vascular distribution. Alternatively, diagnosis may be supported by clinical evidence of cerebral, spinal cord, or retinal focal ischemic injury based on symptoms persisting C24 h or leading to death. Moreover, diagnosis is supported by the exclusion of any other brain disease which may mimic stroke. Stroke includes cerebral infarction and cerebral haemorrhage, which account for about 80 and 20 % of all cases of stroke respectively. Ischemic stroke has to be differentiated from transient ischemic attack (TIA), the definition and classification of which has been recently updated. Specifically, according to the tissue-based definition, TIA is defined as a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia without evidence of acute infarction on neuroimaging [27, 28]. Ischemic stroke may be classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification [29] and the Oxford Community Stroke Project (OCSP) classification [30]. The former denotes five subtypes of stroke depending on etiology: stroke caused by large-artery atherosclerosis; stroke caused by cardioembolism; stroke caused by small-vessel

occlusion; stroke of other determined aetiology; and stroke of undetermined aetiology [29]. On the other hand, the OCSP classification defines stroke, on the basis of the vascular territory involved, in total anterior circulation infarct (TACI), partial anterior circulation infarct (PACI), posterior circulation infarct (POCI) and lacunar infarcts (LACI) [30]. With regard to the community in whom this classification was initially developed, the most frequent ischemic stroke type was PACI (34 %) followed by LACI (25 %), POCI (24 %) and TACI (17 %) [30]. LACI are caused by an atherothrombotic or lipohyalinotic occlusion of the small penetrating branches of the middle cerebral and the vertebrobasilar artery, and are mainly localised in deep brain structures including basal ganglia, cerebral white matter, thalamus, pons, and cerebellum [31, 32]. Lipohyalinosis is characterised by a fibrinoid necrosis of the smooth muscle of the arterial wall, followed by thickening of the small-vessel wall and luminal narrowing up to occlusion, which can lead to lacunar infarcts with a diameter ranging from 3 mm to 2 cm [31]. These infarcts may be asymptomatic or cause a variable combination of motor and sensory symptoms (pure motor stroke, pure sensory stroke, isolated sensory-motor stroke, dysarthriaclumsy hand syndrome and ataxic hemiparesis syndrome). The classification of strokes according to pathogenic mechanisms and the vascular territories involved is important to investigate the effects of risk factor management, including arterial hypertension, in different subtypes of acute ischemic stroke. In this respect, a recent study suggested that the effect of blood pressure–lowering treatment may differ according to different types of acute ischaemic stroke, with antihypertensive therapy having a better effect in patients with larger infarcts (TACI or PACI) than in patients with smaller infarcts (LACI) [33]. The observed trend may be the consequence of long-standing hypertension in patients with LACI resulting in the aforementioned rightward shift of the autoregulatory curve and the occurrence of perfusion deficits following a blood pressure lowering toward normal values [33]. Moreover, cerebral autoregulation seems to be impaired, in patients with LACI, not only in the affected hemisphere but also in the opposite one: this would lead to a disproportionate fall in cerebral perfusion after blood pressure lowering [33]. This is not the case for patients with TACI and PACI, whose pathogenesis is mainly atherothrombotic or cardioembolic: these infarcts are more likely to be complicated by oedema development or hemorrhagic transformation and real benefit may be obtained from a moderate lowering of blood pressure [33]. In daily clinical practice antihypertensive medications are more likely prescribed in ischemic patients with small vessel diseases that in patients with large arteries stenosis [34]. However, to date no clear guidelines orientate the use of appropriate

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antihypertensive treatments depending on the stroke subtype. Unlike for ischemic stroke, there is no established uniform classification system for intracerebral hemorrhage (ICH). A classification system for ICH aetiology was recently proposed. The system was denoted as SMASH-U (Structural lesion, Medication, Amyloid angiopathy, Systemic/other disease, Hypertension, Undetermined). Studies based on this classification identified hypertensive angiopathy as the most common aetiology (35 %), followed by amyloid angiopathy (20 %) and undetermined aetiology (21 %) [35]. The remainder of cases were caused by anticoagulation (14 %), structural lesions like cavernomas and arteriovenous malformations (5 %), systemic pathological conditions including thrombocytopenia and blood abnormalities associated with liver cirrhosis (5 %) [35]. Moreover, short and long term recurrences after the index event have been reported more frequently in patients with systemic diseases and amyloid angiopathy [36]. Arterial hypertension is the main risk factor not only for hypertensive angiopathy but also for amyloid angiopathy [35]. ICH caused by hypertensive angiopathy is commonly localised in deep areas and results from the rupture of degenerated arterioles during uncontrolled hypertension. ICH induced by amyloid angiopathy, on the other hand, is superficial or lobar in location and results from the rupture of small or medium sized arteries in the cortical and leptomeningeal regions [36]. 1.3.2 Clinical Manifestations of Stroke 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 to the carotid and the vertebral-basilar system. The former includes areas served by the internal carotid artery, the anterior cerebral artery and the middle cerebral artery, while the latter includes regions supplied by the vertebral artery, the basilar artery and the posterior cerebral artery. Focal symptoms of stroke, depending on the involved vascular region, are summarised in Tables 1 and 2. The variability of clinical manifestations of stroke is also influenced by the effectiveness of collateral circulation, which may maintain an acceptable level of perfusion distal to the site of arterial occlusion. Collateral vessels play an important role especially in the presence of an occlusive carotid artery disease, the diagnosis of which may be incidental or may follow a devastating cerebral infarction [37]. Moreover, cerebral collateral vessels show significant anatomical variation among individuals, contributing to the inter-subject variability of stroke symptoms [38]. Finally, generalised symptoms, including nausea, vomiting, headache, seizures and impairment of consciousness, may occur

Table 1 Clinical symptoms for vascular regions belonging to the carotid system Internal carotid artery (ICA) Monoparesis to hemiparesis Partial to full hemisensory impairment Homonymous hemianopia, impairment of speech or language, agnosia Transient monocular blindness Partial Bernard-Horner syndrome Anterior cerebral artery (ACA) Weakness of the opposite leg, often most prominent distally (foot) Possible weakness of the proximal muscles of the upper extremity Possible sensory involvement and apraxia (gait) Possible cognitive impairment with grasp reflex, frontal lobe behavioural abnormalities, transcortical aphasia (left ACA) or left hemineglect (right ACA) Middle cerebral artery (MCA) Proximal occlusion Hemiplegia and hemihypoesthesia Homonymous hemianopia Contralateral paralysis of the eye Aphasia (dominant hemisphere) Distal occlusion Hemiplegia (face and arm [ leg) and hemisensory deficit (face and arm [ leg) Homonymous hemianopia Contralateral gaze palsy Global aphasia (dominant hemisphere) Neglect syndrome (non-dominant hemisphere)

as a result of increased intracranial pressure and are more frequent in hemorrhagic strokes than in ischaemic strokes. 1.3.3 Diagnostic Approach The diagnostic approach in patients with stroke is based on medical history, neurological assessment, routine investigations and neuroimaging evaluation. Medical history is aimed at recognising the main symptoms referred by the patient and the presence of modifiable and non-modifiable risk factors in order to address diagnosis and to plan adequate preventive strategies. The neurological assessment is mainly based on the administration of the National Institutes of Health Stroke Scale (NIHSS), which objectively identifies the signs of stroke and quantifies the stroke-related impairment [39]. The scale consists of 11 items addressing specific skills, whose impairment is graded by a score ranging, depending on single items, from 0 (normal function) to 4 (severe impairment). The total NIHSS score is the sum of individual scores and ranges 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 vertebral-basilar system Vertebral artery (VA) Vertigo, nausea, vomiting, dysphagia Ipsilateral cerebellar ataxia Ipsilateral Horner’s syndrome Ipsilateral facial sensory loss with contralateral body pain and temperature loss Basilar artery (BA) Sensory or motor deficit on one side of the face and the opposite side of the body Dizziness, vertigo, and nystagmus Variable involvement of cranial nerves Possible locked-in syndrome: quadriplegia, lower cranial nerve paralysis, anarthria Posterior cerebral artery (MCA) Homonymous hemianopia or quadrantanopia Dyslexia and dyscalculia (dominant hemisphere) Parietal lobe syndrome (non-dominant hemisphere) Hemisensory deficit and occasionally thalamic syndrome (sensory loss with spontaneous pain) Cortical blindness and behavioural changes (bilateral occlusion)

orientate treatments, to quantify neurological improvement or deterioration and to screen patients who are eligible for thrombolysis. Routine investigations are useful to exclude any systemic diseases which may mimic a stroke and to evaluate the general medical condition of the patients. Prompt neuroimaging evaluation is mandatory to distinguish between vascular and non-vascular lesions, to differentiate ischemia from hemorrhage, to identify the site and the extent of the lesion, and to investigate stroke pathogenesis. Finally, additional examinations allow investigation of the physiopathological mechanisms responsible for stroke: ultrasound scanning of carotid and vertebral arteries is needed to exclude the presence of a critical narrowing of the large arteries; transcranial ultrasonography and computed tomography and/ or magnetic resonance angiography are used to identify intracranial artery stenosis or aneurysms and other vascular malformations; transthoracic and transesophageal echocardiography are needed to detect cardiac wall and chamber abnormalities, residual patent foramen ovale or valve disorders which may be the source of emboli in cardioembolic stroke; electrocardiographic monitoring is required to reveal the presence of paroxysmal atrial fibrillation. 1.4 Management of Hypertension and Risk of Stroke A regular blood pressure monitoring and appropriate treatment of hypertension has been strongly recommended in the most recent guidelines for primary and secondary prevention of ischemic stroke as well as in guidelines for

the management of patients with acute spontaneous intracerebral hemorrhage (Table 3) [40–42]. Indeed, the association between the proper management of hypertension and the reduction of stroke risk has been long well known. The INDANA (INdividual Data ANalysis of Antihypertensive intervention trials) project analysed the effects of blood pressure lowering medications in survivors of stroke or TIA, and showed that the treatment was able to prevent approximately 30 % of stroke recurrences [43]. This data is in line with that reported by a metanalysis, which suggested that the risk decrease was mainly due to the reduction of systolic blood pressure and that vascular prevention was associated positively with the magnitude by which blood pressure was reduced [44]. Moreover, the reduction in the risk of stroke after blood pressure lowering seemed to be consistent across sexes, stroke subtypes and territories, and for fatal and nonfatal events, with greater benefits from larger blood pressure reductions [45]. Whether prevention of stroke recurrence depends on drug class is still debated: the Heart Outcomes Prevention Evaluation (HOPE) Study suggested that treatment with ramipril for a 4.5-year period caused a 32 % reduction of the relative risk for stroke [46]. Moreover, the benefits were sustained over time as confirmed by the Heart Outcomes Prevention Evaluation-TOO (HOPE-TOO) study, which provided an additional 2.6 year follow-up for patients receiving the treatment [47]. Similarly, the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) showed, in patients with previous stroke or TIA, a 28 % risk reduction of stroke following combined treatment with perindopril and indapamide [48]. The risk reduction was greater for hemorrhagic stroke (50 %) than for ischemic stroke (24 %). Moreover, the relative risk reduction for all strokes was greater among participants treated with combination therapy (43 %) as compared to those treated with perindopril alone (5 %), with a similar pattern observed for ischemic stroke (relative risk reduction after combination therapy 36 vs 6 % after single-drug therapy) and for hemorrhagic stroke (relative risk reduction after combination therapy 76 vs 1 % after single-drug therapy). This suggested that the overall blood pressure reduction, rather than the independent effects of single treatments, is the main mechanism of secondary prevention for both ischemic and hemorrhagic strokes [48]. Further evidence was provided by the Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention (MOSES) study, which compared an angiotensin II type 1 receptor antagonist with a calcium antagonist in secondary stroke prevention. This study showed comparable blood pressure reduction with the two treatments and a greater reduction of the combined primary end point, which was total mortality and all cardiovascular and 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 have been found in the Valsartan Antihypertensive Longterm Use Evaluation (VALUE) study which, although reporting a more pronounced effect of amlodipine as compared to valsartan in blood pressure lowering [50], showed similar effects in secondary stroke prevention for the two treatments [51]. Comparisons have also been performed to evaluate the effects of different diuretics in the prevention of cardiovascular and cerebrovascular diseases. A recent meta-analysis compared the effects of hydrochlorothiazide with those of chlorthalidone, and showed a greater effectiveness of the latter in preventing cardiovascular events including stroke [52]. The advantages from using combined regimens were also investigated by the Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm (ASCOT-BPLA), which compared the effectiveness of the association of amlodipine and perindopril with that of atenolol and bendroflumethiazide, showing better effects with the former treatment [53]. Further evidence came from the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), which compared the effects of a combination therapy, based on ramipril and telmisartan, with single-drug therapies. The trial found a

greater occurrence of adverse events without an increase in benefit in patients receiving the therapeutic regimen [54]. A lack of advantages from combination therapies was also shown in the Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE). The addition of aliskiren to standard therapy with renin-angiotensin system blockade was reported to be less beneficial than treatment with single agents for the prevention of major cardiovascular events including nonfatal strokes [55]. The Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) investigated the tolerability of telmisartan in patients unable to tolerate ACE inhibitors. Although well-tolerated, telmisartan modestly reduced the risk of cardiovascular death, myocardial infarction, or stroke in treated patients [56]. Other studies of interest focused on the management of resistant arterial hypertension, which is defined as failure to achieve a blood pressure goal of \140/90 mmHg despite treatment with C3 different classes of antihypertensive medication at the maximum tolerated dose and including a diuretic. These trials showed some success with different pharmacological and nonpharmacological treatments including endothelin A antagonists, aldosterone antagonists, catheter-based renal

Hypertension and Stroke: Epidemiological Aspects and Clinical Evaluation

denervation procedures and carotid baroreceptor stimulation devices [57]. Finally, some studies demonstrated that specific drug interventions might confer benefits beyond those related to the blood pressure reduction. For instance, some antihypertensive drugs exert additional beneficial effects in stroke prevention by decreasing blood pressure variability while others play a relevant role in reversing or improving left ventricular hypertrophy. The role of blood pressure variability in stroke pathogenesis and prognosis have been confirmed by several studies including a substudy of the Systolic Hypertension in Europe (Syst-Eur) Trial in elderly hypertensive patients [58]. This study showed that an increased night-time systolic blood pressure variability was an independent risk factor for stroke while daytime systolic blood pressure variability was not of prognostic value [58]. This observation was confirmed by more recent studies highlighting the relationship between short-term and long-term blood pressure variability and the occurrence of cardiovascular events [59, 60]. Moreover, a recent cohort study showed that, among patients with a previous transient ischemic attack, a more pronounced systolic blood pressure variability was associated with a higher risk of stroke [61]. Similarly, patients showing wide blood pressure fluctuations during the acute phase of ischemic stroke have been reported to have a poor outcome at 1 and 3 months following the index event [62]. In this light, a recent meta-analysis suggested that the different effect of antihypertensive drugs on individual blood pressure variability may account for their different potential in preventing stroke [63]. Specifically, a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT-BPLA) and of the Medical Research Council (MRC) trial proposed that the different effect of calcium-channel blockers and beta blockers on blood pressure variability may be responsible for the greater effectiveness of the former in reducing the risk of stroke in hypertensive patients [64]. All these observations suggest that the most effective blood-pressure-lowering drugs in preventing cardiovascular morbidity and mortality are those able to reduce both mean blood pressure and blood pressure variability [64]. Similarly, other drugs, belonging to the angiotensin-II type 1-receptor antagonists class, may exert their beneficial effects in cardiovascular and cerebrovascular prevention by promoting the regression of left ventricular hypertrophy, which is a well-known blood-pressure-independent predictor for cerebrovascular events [65]. In this respect, the Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE) showed the greater effectiveness of losartan, as compared to atenolol, in reducing the rate of fatal and nonfatal stroke and ascribed this superiority also to its protective effects towards left ventricular hypertrophy [66, 67]. All the reported data

about the prevention of cardiovascular events suggest that combinations of drugs with different modes of action are more effective than combinations of drugs with a similar mode of action, as the latter are more likely to increase adverse events without improving outcomes. Moreover, multiple non hemodynamic pleomorphic benefits may contribute to the overall effects of some treatments. These include enhancing angiogenesis, inhibiting platelet aggregation, increasing nitric oxide production and reducing carotid intima-media thickness, vascular permeability and epinephrine-mediated platelet aggregation. 1.5 Hypertension and End-Organ Brain Damage Recently special attention has been paid to the role of hypertension as a contributor to the end-organ brain damage associated with a decline in cognitive function. Much evidence suggests that increased systolic blood pressure is linearly associated with markers of cerebral white matter microstructural damage in healthy young adults [68]. The above injury mainly involves the anterior corpus callosum, the inferior fronto-occipital fasciculi, and the fibres that project from the thalamus to the superior frontal gyrus. In addition, a reduced grey-matter volumes in Brodmann’s area 48 on the medial surface of the temporal lobe and in Brodmann’s area 21 of the middle temporal gyrus is observed [68]. This damage may lead to what is known as unsuccessful ageing, characterised by impairment in specific cognitive domains such as those subserving language, executive functions and visuospatial memory. Hypertension may lead to the development of white-matter lesions by accelerating the progression of arterial ageing measured as arterial stiffness. This suggests that the effects of hypertension go beyond those traditionally associated with stroke and that early preventive strategies are essential to stem end-organ brain damage. In fact, although it is not clear whether this brain damage is reversible or can be slowed by the use of antihypertensive treatments, early control of blood pressure in young subjects is recommended in order to avoid subtle myelin injury and decreased cognitive performance [69]. Contradictory results have been reported for older age groups, where aggressive antihypertensive treatment is not even associated with a later favourable cognitive outcome. Some studies in elderly subjects showed that midlife hypertension is a risk factor for late-life cognitive impairment [70, 71] whereas others suggested that hypertension may contribute to cognitive decline and dementia only when longstanding and developing in early age [72]. Thus, the protective effect of antihypertensive therapy against dementia and stroke-related cognitive decline in the elderly is still debated, as a certain level of blood pressure seems to be necessary for older adults to maintain cerebral perfusion

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and to preserve cognitive abilities [72]. Recently, an association between cognitive deterioration and blood pressure variability has also been proposed [73]. Autonomic dysfunctions and increased arterial stiffness associated with blood pressure variability may play a role in the development and progression of cognitive decline with advancing age [73]. Taken together, these data suggest that individual considerations, including the age of the patient and the presence of other risk factors and comorbidities, are essential in order to understand the risk–benefit relationship of medication and to plan tailored medical approaches.

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Hypertension and Stroke: Epidemiological Aspects and Clinical Evaluation.

The strong relationship between stroke and hypertension has been the object of several studies and trials. These studies addressed the epidemiology of...
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