Strokes and their relationship to hypertension

C. John Dickinson
Purpose of review There is rapidly growing appreciation that stroke morbidity and the risk of an ischaemic stroke becoming haemorrhagic can be influenced by new information about prophylaxis, rapid diagnosis and treatment. Recent findings Strokes are strongly associated with hypertension mainly because hypertension is strongly associated with atheromatous deposits blocking or narrowing brain arteries, predisposing to local clot formation. Atheroma and its ischaemic consequences may damage cerebral arterioles and the brain tissue they supply. Cerebral infarcts are more common than spontaneous cerebral haemorrhages. High blood pressure itself cannot directly rupture cerebral blood vessels because their small size protects them and intracerebral haemorrhage usually follows previous ischaemic vascular damage. It is obvious that lowering blood pressure would reduce the risk and extent of bleeding into the brain once a break in an arteriolar wall has occurred, but it is not clear why lowering blood pressure should protect against cerebral infarction. One might expect that slowing down the rate of cerebral blood flow would give more time for local clots to form. It seems most likely that induced hypotension protects against ischaemic strokes by preventing pressure- or ischaemia-induced arteriolar spasm and by advantageous vasodilation of some of the more ischaemic territories. Added protection can be provided by coenzyme-A reductase inhibitors (statins), but probably not by antioxidants. Summary Lowering blood pressure strongly protects against ischaemic and haemorrhagic stroke. Recent work shows that more accurate and faster diagnosis of stroke pathology is urgently needed, so that appropriate treatment (e.g. with tissue plasminogen activators) can be started before local bleeding has occurred. Keywords haemorrhagic transformation, ischaemic stroke pathology, plasminogen activator therapy, statin prophylaxis
Curr Opin Nephrol Hypertens 12:9196.
#

Abbreviations ACE ARB CAT MRI SHRSP tPA

#

angiotensin-converting enzyme angiotensin receptor blocker computer-aided tomography magnetic resonance imaging spontaneously hypertensive rat: stroke prone tissue plasminogen activator

2003 Lippincott Williams & Wilkins 1062-4821

A recent review concluded that spontaneous cerebral infarction and intracerebral (not subarachnoid) haemorrhage share the same aetiology: preceding ischaemic damage to the walls of small blood vessels [1 .]. This may predispose to later bleeding. The relationship of both ischaemic and haemorrhagic strokes to hypertension is well established, but haemorrhage is not caused directly by high intravascular pressure. There has been intermittent interest in the possible role of microaneurysms, but many of these are injection artifacts [2] and have never been clearly identied as being responsible for intracerebral haemorrhage. Accurate diagnosis of the immediate cause of a stroke is now possible by imaging with computer-aided tomography (CAT) and by magnetic resonance imaging (MRI). The techniques of diffusion-weighted or perfusionweighted MRI can detect early haemorrhage [3], but even standard MRI may fail to detect small haemorrhagic infarcts [4 .]. Gradient-echo scans are more sensitive and have been recommended to exclude haemorrhage before thrombolytic therapy [5]. The presence of old microbleeds is a risk factor for later haemorrhagic transformation [6,7 .]. The appearance of parenchymal hypodensity in basal ganglia CAT may predict haemorrhagic transformation after thrombolytic treatment [8]. However, studies after acute middle cerebral artery occlusion suggest that hyperdense areas are associated with haemorrhagic transformations [9]. Resolution seems to be needed here.

Introduction

Accurate diagnosis of stroke

2003 Lippincott Williams & Wilkins.

Wolfson Institute, Queen Mary, University of London, London, UK Correspondence to Professor C. John Dickinson, Wolfson Institute of Preventive Medicine, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ, UK Tel: +44 020 7882 6219; fax: +44 020 7882 6270; e-mail: c.j.dickinson@qmul.ac.uk Current Opinion in Nephrology and Hypertension 2003, 12:9196

The aetiology of cerebral infarction

There is no question that high blood pressure is strongly associated with atheroma, especially in the cerebral circulation. Fisher [10] noted that atheroma was almost invariably present in cerebral arteries when the brain at necropsy showed the appearance of the so-called `lacunar state'. The large arteries in the neck are common sites of atheroma deposition, especially at the bifurcation of the common carotid and at the origin of
91

DOI: 10.1097/01.mnh.0000049804.69874.47

92

Circulation and hemodynamics

the vertebral artery. In necropsy series such lesions are strongly associated with high blood pressure [11]. So also is intracranial cerebral artery atheroma [12]. High quality MRI angiograms of extra and intracranial arterial lesions in hypertensive patients conrmed the old observations [13]. In the population-based cohort in the Rotterdam Scan study MRI-visible infarcts were more than four times as common as symptomatic infarcts [14]. An often neglected late consequence of stroke is fatigue, which appears to be associated with brain stem and thalamic lesions [15 .]. Various possible explanations for the association between hypertension and cerebral atheroma have been reviewed [16]. Most people assume that high blood pressure has caused or aggravated the atheroma [17], even though it has proved difcult consistently to verify this in experimental animals, especially in the cerebral circulation [18]. However, hypertension induced by aortic constriction accelerated atheroma deposition in the cerebral arteries of cynomolgous monkeys given an atherogenic diet [19]. Atheroma causing hypertension is well known in some situations. Renal artery stenosis is an obvious example, but it is often forgotten that stenotic cerebrovascular disease can also cause sustained hypertension [20]. There is great current interest in the possible contribution of inammation, even of infection, to the formation of atheroma and it consequences. Inammation may be specially relevant to plaque rupture and changes in endothelin function [21,22 . .]. The salt-loaded spontaneously hypertensive rat: stroke prone (SHRSP) exhibited several markers of an inammatory response some 4 weeks before a spontaneous stroke occurred [23]. Drug-induced reduction of blood pressure protects against stroke The risk of stroke is linearly and positively related to an individual's usual blood pressure. The relationship is stronger for stroke than for coronary heart disease risk. There is no evidence that there is any specic tolerated lower limit of blood pressure below which vascular risk increases [24]. The cautious lowering of blood pressure with drugs certainly protects against stroke and gives better protection than against heart attacks [25 .]. Hypotensive drugs give protection against infarcts as well as haemorrhages, but the protection is most marked against cerebral haemorrhage [26 .]. Three placebo-controlled trials (SHEP, Syst-Eur and SystChina) have all demonstrated the benets of lowering isolated systolic pressure to 160 mmHg or less in the elderly [27]. Secondary prevention against strokes is also provided by blood pressure reduction, e.g. the PROGRESS trial [28 . .].

Most evidence suggests that a systolic blood pressure at or below 140 mmHg is the optimum therapeutic target [29 .], although caution may still be needed lest the enthusiam for lowering blood pressure, especially in the elderly, should go too far [30]. More than a decade ago observations made in the prospective population-based Rotterdam cohort study suggested that very low blood pressure might increase the risk of stroke [31]. Individual examples of strokes precipitated by undue acute blood pressure reduction have been documented in the past [20]; but with increasing recognition of the need to avoid extreme and sudden blood pressure reduction such cases should rarely occur today. The generally protective effect of hypotensive drugs against ischaemic strokes seems anomalous. Why should the reduction of blood pressure, which must tend to slow down blood ow in the cerebral arteries, protect against infarction? There has never been a universally agreed or convincing answer to this question. The most likely possibility is that adequate blood pressure lowering protects against prolonged and potentially damaging cerebral arterial spasm, which can be induced both by a brief ischaemic episode and probably also by an acute rise in blood pressure. Endothelin-A can cause prolonged spasm of arterioles which lasts 12 h, thus risking subsequent ischaemic necrosis. Endothelin-1 has achieved prominence with the recent demonstration that its synthesis is inhibited by red wine [32 .]. Endothelin-induced spasm has mostly been explored in the context of subarachnoid haemorrhage, but is probably also relevant to small localized intracerebral bleeds. Sphingosine-1 phosphate derived from platelets is a factor promoting arteriolar spasm [33]. In certain experimental situations, such as endothelin-mediated arteriolar constriction in the rat after hepatic ischaemia/ reperfusion injury, the blockade of endothelin-A receptors by bosentan greatly improved tissue perfusion [34]. Bosentan also improved cerebral blood ow and was neuroprotective in experimental pneumococcal meningitis in the rat [35]. There is much evidence that an acute increase in blood pressure can cause arteriolar spasm [1 .], although that phenomenon has not so far been linked to the release of endothelins. It is safe to predict that there will be increasing interest in limiting the ill effects of cerebral infarction by the administration of endothelin antagonists or receptor blockers. Endothelin-A antagonists seem likely to be less dangerous than the intravenous administration of a thrombolytic drug to stroke patients before there has been enough time to exclude signicant haemorrhage. In addition, the endothelin-A blocker bosentan has the advantage of being active by mouth.

Strokes and their relationship to hypertension Dickinson

93

Strokes in young people sometimes occur because of prothrombotic abnormalities of blood clotting such as variants of factor V (Leiden) and factor II (prothrombin). These were looked for in a series of adults having their rst stroke at an average age of 38 years. The only signicant nding among all the predisposing factors examined was increased plasma homocysteine concentration [36 .].

Other aspects of stroke prophylaxis

Many trials have compared hypotensive drugs and drug classes for stroke prophylaxis. Currently most drug combinations will include thiazide diuretics, calcium antagonists and either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). A recent large meta-analysis suggested that calcium antagonists might be less protective than most other agents [37], but another recent review of cardiovascular outcomes strongly supported the use of calcium antagonists as rst-line treatment [38]. Arguments continue. The known specic cerebral vasoconstrictive effect of angiotensin II makes a compelling theoretical case for ACE inhibitors, which can lower blood pressure with no change in cerebral blood ow [39]. When ACE inhibitors are clinically acceptable, there is suggestive evidence that captopril may be preferable to enalapril in terms of side effects [40], but strict comparisons are not available for the large number of other ACE inhibitors. ARBs are necessary for patients on ACE inhibitors who are troubled by cough, and have been shown to have signicant advantages over beta blockers [41], but critical comparative trials between the various ARBs currently available are lacking. Despite the recognized disadvantage of thiazide diuretics in reducing male potency [42], thiazides continue to be recommended and used as rstline therapy. They remain the bench-mark against which other hypotensive drugs are compared [43 .]. A sceptical reviewer might reasonably conclude that it has not yet been rmly established that one hypotensive regime or drug combination is better than another in stroke prophylaxis. An exception should probably be made in the treatment of individuals with diabetes, for whom ACE inhibitors seem particularly benecial. This is presumably because of the specic ability of ACE inhibitors to lower post-glomerular resistance and thus lower intraglomerular pressure [44,45]. Captopril seems to be better than a regime of a beta-blocker plus a thiazide [44]. ACE inhibitors have advantages in diabetic patients over many other drugs that lower blood pressure. They may even exert cardiovascular protection in addition to that simply caused by a reduction in blood pressure [46]. A longer-term aspect of stroke prophylaxis is protection against the formation of atheroma itself, the rupture of the atheromatous plaque and local clot formation, with

and without distal thromboembolism. The association between LDL-cholesterol and atheroma has been known for three decades, but the mechanisms concerned have not yet been exactly dened [47 . .]. Analysis requires taking into account the effects of a very large number of risk factors [48 . .]. One of the most important of these is alcohol consumption. Its relation to stroke risk was examined in the large EUROSTROKE project. Using serum gamma glutamyl transferase as an index of alcohol consumption, an increase of one standard deviation (29 IU/ml) increased stroke risk by 26% [49]. However, many previous studies have concluded that modest drinking (one drink per day to one per week) reduces the risk of ischaemic stroke in men. The apparent difference probably means that once a man has a signicantly increased serum gamma glutamyl transferase his drinking should be classed as `heavy'. There are many different approaches to stroke prevention, including the use of antithrombotic agents such as aspirin and clopidogrel [50 . .]. Although clopidogrel is marginally more effective than aspirin, a recent study of its cost-effectiveness in coronary disease prevention suggested that its use should probably be restricted to patients ineligible for aspirin [51]. Other prophylactic measures include ACE inhibitors, antioxidants, and the reduction of cholesterol with coenzyme A reductase inhibitors (`statins') [22 . .]. Several other benets of statin therapy have been envisaged, but not as yet precisely tested [52]. It is striking that although high blood levels of cholesterol are clearly associated with atheroma, there is very little relationship between the LDL-cholesterol concentration or its change with therapy and the degree of atheroma or atheroma growth in `almost all studies' [53 .]. Protection against stroke by cholesterol reduction and by antioxidants has been examined in a recent large doubleblind trial. Its design was described in 1999 [54] and the results were published in two recent papers [55 . .,56 .]. Stroke prophylaxis was examined in a high-risk group of subjects with arterial disease and diabetes. Compliance was approximately 85% over a 5-year treatment period. Antioxidants (vitamins C and E, plus beta carotene) had no effect on vascular events in participants, whereas those taking 40 mg a day of simvastatin (which reduced LDL-cholesterol by approximately 1.3 mmol/l) enjoyed a highly signicant reduction in the stroke rate (27%) and also in total mortality, coronary heart disease and the need for revascularization procedures. A few participants stopped taking part in the trial because of myopathic symptoms. There is no doubt that statins can cause signicant muscle disease in a few individuals (0.01%). Doctors must be prepared to stop the statin if muscles become signicantly affected, although statins are generally very well tolerated.

94

Circulation and hemodynamics

As ischaemic damage of cerebral arterioles is the basic cause of most strokes, haemorrhagic or not, there is an obvious case to be made for anti-clotting prophylaxis and for thrombolysis in established stroke. The continuous monitoring of strokes by a portable 2 MHz Doppler technique showed that treatment with a tissue plasminogen activator (tPA) can lead to rapid clot dissolution and recanalization within approximately 45 min, but this was observed in only approximately 30% of treated patients [57]. The timing of treatment is crucial. Thrombolysis within the rst 3 h of an acute stroke produced a better outcome than in a control population [58 .,59,60 .], but there is unfortunately no doubt that thrombolytic drugs favour haemorrhagic transformation. This becomes progressively more likely as time passes [61,62]. The previous use of aspirin may be especially risky when combined with tPA administration [58 .,63], as also is the previous use of heparin [64]. The original enthusiasm for the treatment of strokes with a tPA (e.g. alteplase) has waned slightly after some adverse experiences and criticisms [65 .], but it has been equally robustly defended [60 .]. Some protection may be afforded by combining tPA with lubeluzole [66]. A selective glycine receptor antagonist has also been reported to be neuroprotective [67]. Another potential treatment of stroke is the use of spironolactone to antagonize aldosterone. This has been observed to reduce experimental infarct size in SHRSPs [68]. Increased matrix metalloproteinase is found after cerebral infarction in animal models [69], and there is current interest in the possible use of matrix metalloproteinase inhibitors in acute stroke in humans [70]. At present, we are in the situation that more potentially neuroprotective drugs are being developed than there has been time for their crucial testing in long-term trials. Unfortunately, most eligible patients do not receive tPA because they do not reach hospital soon enough. One of the saddest recent reports was that tPA treatment was withheld in many cases because of the apparent mildness of the stroke, yet many of these patients did very badly in the end `bringing into question the decision not to treat' [71]. The timing and speed of giving thrombolytic therapy is evidently important [61]. Giving intravenous tPA within 3 h of the onset of a stroke appears from the available evidence to do more good than harm [72]. It appears to speed up the recanalization of strokes and reduces long-term dependency [73 .].

The treatment of acute stroke

and haemorrhages. There is current excitement that further studies in rats may identify a `stroke gene' [74]. After local reduction in cerebral perfusion in SHRSPs, ACE inhibition appeared to have a better effect on cerebral arteriolar function than beta-blockade [75]. As already mentioned, the transformation of an ischaemic stroke into a haemorrhage in SHRSPs seems to be strongly inuenced by matrix metalloproteinase enzymes [70,76,77], and there is current interest in the possibilities of designing specic blocking drugs for use in humans. By selective inbreeding, a SHRSP that goes into the malignant phase has been created. It has a much increased heart rate associated with the onset of stroke [78].

Current therapeutic recommendations

`Most patients with acute stroke should not be treated with unfractionated heparin or other rapidly acting anticoagulants after stroke. The prevention of deep vein thrombosis and pulmonary embolism among bedridden patients is the only established indication for early anticoagulation after acute ischaemic stroke' [64]. However, there is a growing consensus in treating acute stroke that a thrombolytic regime can be benecial if signicant haemorrhage can be excluded, and thrombolysis can be started within 3 h of the rst symptoms. At present the possible use of endothelin antagonists is potentially exciting and the results of controlled trials are awaited.

Acknowledgements

The author is grateful for the helpful criticisms of Malcolm Law and Nick Wald. The author has no nancial interests in any of the drugs and treatments discussed in this review.

Papers of particular interest, published within the annual period of review, have been highlighted as: . of special interest .. of outstanding interest

References and recommended reading

1
.

Dickinson CJ. Why are strokes related to hypertension? Classic studies and hypotheses revisited. J Hypertens 2001; 19:15151521. A review providing the background to recent work relating hypertension to the common aetiology of cerebal haemorrhage and infarction. 2 Challa VR, Moody DM, Bell MA. The CharcotBouchard aneurysms controversy: impact of a new histologic technique. J Neuropathol Exp Neurol 1992; 51:264271. Tong DC, Adami A, Moseley ME, Marks MP. Prediction of hemorrhagic transformation following acute stroke: role of diffusion- and perfusionweighted magnetic resonance imaging. Arch Neurol 2001; 58:587593.

Comparative studies of stroke

The large cerebral arteries of the SHRSP are narrower than those in WistarKyoto control rats. Like hypertensive humans, SHRSPs get spontaneous cerebral infarcts

Nighoghossian N, Hermier M, Berthezene Y, et al. Early diagnosis of hemorrhagic transformation: diffusion/perfusion-weighted MRI versus CT scan. Cerebrovasc Dis 2002; 11:151156. MRI adds extra weight to CAT scan in stroke diagnosis. 4
.

Strokes and their relationship to hypertension Dickinson

5 Lin DD, Filippi CG, Steever AB, Zimmerman RD. Detection of intracranial hemorrhage: comparison between gradient-echo images and b(0) images obtained from diffusion-weighted echo-planar sequences. Am J Neuroradiol 2002; 22:12751281. Nighoghossian N, Hermier M, Adeleine P, et al. Old microbleeds are a potential risk factor for cerebral bleeding after ischemic stroke: a gradientecho T2 weighted brain MRI study. Stroke 2002; 33:735742.

95

26 Klungel OH, Kaplan RC, Heckbert SR, et al. Control of blood pressure and risk . of stroke among pharmacologically treated hypertensive patients. Stroke 2002; 31:420424. A contribution to the choice of hypotensive therapy, giving evidence for the greater protective benefit of thiazide diuretics compared with beta-blockers, calcium antagonists, and ACE inhibitors. 27 Wang JG, Staessen JA. The benefit of treating isolated systolic hypertension. Curr Hypertens Rep 2001; 3:333339. 28 PROGRESS Collaborative Group. Randomised trial of a perindopril-based . . blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358:10331041. A well-designed trial based on intention-to-treat high-risk patients with cerebrovascular disease, which shows the benefit of lowering blood pressure. 29 Hansson L. How far should we lower blood pressure in the elderly? Cardiovasc . Drug Ther 2002; 15:275279. A useful and wide-ranging discussion of many aspects of hypotensive protection in older people. 30 Bulpitt C, Fletcher A, Beckett N, et al. Hypertension in the Very Elderly Trial (HYVET): protocol for the main trial. Drug Aging 2002; 18:151164. 31 Voko Z, Bots ML, Hofman A, et al. J-shaped relation between blood pressure and stroke in treated hypertensives. Hypertension 1999; 34:11811185. 32 Corder R, Douthwaite JA, Lees DM, et al. Endothelin-1 synthesis reduced by . red wine. Nature 2001; 414:863864. A contribution to solving the `French paradox'. 33 Tosaka M, Okajima F, Hashiba Y, et al. Sphingosine 1-phosphate contracts canine basilar arteries in vitro and in vivo: possible role in pathogenesis of cerebral vasospasm. Stroke 2002; 32:29132919. 34 Uhlmann D, Uhlmann S, Loffler BM, et al. Pharmacologic regulation of postischemic sinusoidal diameters in rats a new approach for reducing hepatic ischemia/reperfusion injury. Clin Hemorheol Microcirc 2002; 24:233 246. 35 Pfister LA, Tureen JH, Shaw S, et al. Endothelin inhibition improves cerebral blood flow and is neuroprotective in pneumococcal meningitis. Ann Neurol 2002; 47:329333. 36 Madonna P, de Stefano V, Coppola A, et al. Hyperhomocysteinemia and other . inherited prothrombotic conditions in young adults with a history of ischemic stroke. Stroke 2002; 33:5156. Hyperhomocystinaemia was the only factor that identified young patients with ischaemic stroke. 37 Pahor M, Psaty BM, Alderman MH, et al. Health outcomes are associated with calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomised controlled trials. Lancet 2000; 356:19491954. 38 De Leeuw PW, Birkenhager WH. The effects of calcium channel blockers on cardiovascular outcomes: a review of randomised controlled trials. Blood Press 2002; 11:7178. 39 Paulson OB, Waldemar G. ACE inhibitors and cerebral blood flow. J Hum Hypertens 1990; 4 (Suppl. 4):6972. 40 Testa MA, Anderson RB, Nackley JF, Hollenberg NK. Quality of life and antihypertensive therapy in men. A comparison of captopril with enalapril. The Quality-of-Life Hypertension Study Group. N Engl J Med 1993; 328:907 913. 41 Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan for Endpoint Reduction For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359:9951003. 42 Opie LH. Diuretic downsides but in low doses they still seem among the best authenticated antihypertensives. Cardiovasc Drug Ther 2002; 14:407 409. 43 Klungel OH, Heckbert SR, Longstreth WT Jr, et al. Antihypertensive drug . therapies and the risk of ischemic stroke. Arch Intern Med 2002; 161:3743. See also Ref. [26 .]. 44 Niskanen L, Hedner T, Hansson L, et al. Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/beta-blocker-based treatment regimen: a subanalysis of the Captopril Prevention Project. Diabet Care 2002; 24:20912096. 45 Opie LH, Schall R. Evidence-based evaluation of calcium channel blockers for hypertension: equality of mortality and cardiovascular risk relative to conventional therapy. J Am Coll Cardiol 2002; 39:315322. 46 Sleight P, Yusuf S, Pogue J, et al. Heart Outcomes Prevention Evaluation, HOPE. Blood-pressure reduction and cardiovascular risk in HOPE study. Lancet 2002; 358:21302131.

Kidwell CS, Saver JL, Villablanca JP, et al. Magnetic resonance imaging detection of microbleeds before thrombolysis: an emerging application. Stroke 2002; 33:9598. UCLA experience in the detection of microbleeds before thrombolytic therapy. Detection of microbleeds is a signal that thrombolytic therapy is potentially dangerous. 7
.

Dubey N, Bakshi R, Wasay M, Dmochowski J. Early computed tomography hypodensity predicts hemorrhage after intravenous tissue plasminogen activator in acute ischemic stroke. J Neuroimag 2002; 11:184188. Nakano S, Iseda T, Kawano H, et al. Hyperdensity on computed tomography after intra-arterial reperfusion acute middle cerebral artery occlusion: incidence and clinical significance. Stroke 2002; 32:20422048.

10 Fisher CM. Lacunes: small, deep cerebral infarcts. Neurology (Minneap) 1965; 15:774784. 11 Dickinson CJ, Thomson AD. A post mortem study of the main cerebral arteries with special reference to their possible role in blood pressure regulation. Clin Sci 1960; 19:513538. 12 Baker AB, Resch JA, Loewenson RB. Hypertension and cerebral atherosclerosis. Circulation 1969; 39:701710. 13 Belichenko OI, Abramova NN, Arabidze GG, et al. Magnetic resonance tomography and magnetic resonance angiography in the clinical diagnosis of extra- and intracranial arterial pathology in patients with arterial hypertension [in Russian]. Vistnik Rentgenol Radiolog 1994; 3:2528. 14 Vermeer SE, Koudstaal PJ, Oudkerk M, et al. Prevalence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study. Stroke 2002; 33:2125. 15 Staub F, Bogousslavsky J. Fatigue after stroke: a major but neglected issue. . Cerebrovasc Dis 2001; 12:7581. A useful reminder of a neglected topic. 16 Bondjers G, Glukhova M, Hansson GK, et al. Hypertension and atherosclerosis: cause and effect, or two effects with one unknown cause? Circulation 1991; 84 (Suppl. VI):VI-2VI-16. 17 Chobanian AV. Vascular effects of systemic hypertension. Am J Cardiol 1992; 69:3E7E. 18 Chobanian AV. The influence of hypertension and other hemodynamic factors in atherogenesis. Progr Cardiovasc Dis 1983; 26:177196. 19 Hollander W, Prusty S, Kemper T, et al. The effects of hypertension on cerebral atherosclerosis in the cynomolgus monkey. Stroke 1993; 24:1218 1226. 20 Dickinson CJ. Neurogenic hypertension. London: Chapman and Hall; 1991. 21 Rader DJ. Inflammatory markers of coronary risk. N Engl J Med 2000; 343:11791182. 22 Gorelick PB. Stroke prevention therapy beyond antithrombotics: unifying . . mechanisms in ischemic stroke pathogenesis and implications for therapy: an invited review. Stroke 2002; 33:862875. A fully referenced up-to-date review of stroke prevention therapy in the light of recent work suggesting an inflammatory aetiology for atheroma, concentrating particularly on stroke prevention with statins, ACE inhibitors and vitamins. 23 Sironi L, Tremoli E, Miller I, et al. Acute-phase proteins before cerebral ischemia in stroke-prone rats: identification by proteomics. Stroke 2002; 32:753760. 24 MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part I. Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335:765774. 25 Ruilope LM, Schiffrin EL. Blood pressure control and benefits of antihyperten. sive therapy: does it make a difference which agents we use? Hypertension 2002; 38:537542. Without coming to a final conclusion, the authors usefully review the preventive value of various hypotensive agents.

96

Circulation and hemodynamics

61 Madden K. Optimal timing of thrombolytic therapy in acute ischaemic stroke. CNS Drug 2002; 16:213218. 62 Kidwell CS, Saver JL, Carneado J, et al. Predictors of hemorrhagic transformation in patients receiving intra-arterial thrombolysis. Stroke 2002; 33:717724. 63 Saloheimo P, Juvela S, Hillbom M. Use of aspirin, epistaxis, and untreated hypertension as risk factors for primary intracerebral hemorrhage in middleaged and elderly people. Stroke 2002; 32:399404. 64 Adams HP Jr. Emergent use of anticoagulation for treatment of patients with ischemic stroke. Stroke 2002; 33:856861. 65 Lenzer J. Alteplase for stroke: money and optimistic claims buttress the `brain . attack' campaign. BMJ 2002; 324:723726. A strongly prejudiced argument against the use of a tPA thrombolytic agent, suggesting that it is over-promoted. See also Refs [58 .] and [60 .]. 66 Grotta J, and the Combination Therapy Stroke Trial Investigators. Combination Therapy Stroke Trial: recombinant tissue-type plasminogen activator with/without lubeluzole. Cerebrovasc Dis 2002; 12:258263. 67 Reggiani A, Pietra C, Arban R, et al. The neuroprotective activity of the glycine receptor antagonist GV150526: an in vivo study by magnetic resonance imaging. Eur J Pharmacol 2002; 419:147153. 68 Dorrance AM, Osborn HL, Grekin R, Webb RC. Spironolactone reduces cerebral infarct size and EGF-receptor mRNA in stroke-prone rats. Am J Physiol (Regul Integr Compar Physiol) 2001; 281:R944R950. 69 Montaner J, Alvarez-Sabin J, Molina CA, et al. Matrix metalloproteinase expression is related to hemorrhagic transformation after cardioembolic stroke. Stroke 2001; 32:27622767. 70 Lapchak PA, Chapman DF, Zivin JA. Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke. Stroke 2000; 31:30343040. 71 Barber PA, Zhang J, Demchuk AM, et al. Why are stroke patients excluded from TPA therapy? An analysis of patient eligibility. Neurology 2002; 56:10151020. 72 Petty MA, Wettstein JG. Elements of cerebral microvascular ischaemia. Brain Res Brain Res Rev 2002; 36:2334. 73 Molina CA, Montaner J, Abilleira S, et al. Time course of tissue plasminogen . activator-induced recanalization in acute cardioembolic stroke: a casecontrol study. Stroke 2002; 32:28212827. Intravenous tPA is associated with early recanalization of occluded cerebral arteries causing stroke. 74 Kirsch T, Wellner M, Luft FC, et al. Altered gene expression in cerebral capillaries of stroke-prone spontaneously hypertensive rats. Brain Res 2002; 910:106115. 75 Chillon JM, Baumbach GL. Effects of an angiotensin-converting enzyme inhibitor and a beta-blocker on cerebral arteriolar dilatation in hypertensive rats. Hypertension 2002; 37:13881393. 76 Sumii T, Lo EH. Involvement of matrix metalloproteinase in thrombolysisassociated hemorrhagic transformation after embolic focal ischemia in rats. Stroke 2002; 33:831836. 77 Guerrini U, Sironi L, Tremoli E, et al. New insights into brain damage in stroke-prone rats: a nuclear magnetic imaging study. Stroke 2002; 33:825 830. 78 Tabuchi M, Umegaki K, Ito T, et al. Disturbance of circadian rhythm in heart rate, blood pressure and locomotive activity at the stroke-onset in malignant stroke-prone spontaneously hypertensive rats. Jap J Pharmacol 2002; 85:197202.

47 Keaney JF Jr. Atherosclerosis: from lesion formation to plaque activation and . . endothelial dysfunction. Mol Aspect Med 2002; 21:99166. A comprehensive and massive review of the pathogenetic sequence of atheroma formation and endothelial dysfunction. 48 Tegos TJ, Kalodiki E, Daskalopoulou SS, Nicolaides AN. Stroke: epidemiology, . . clinical picture, and risk factors Part I of III. Angiology 2002; 51:793808. A large review of the epidemiology of stroke and its risk factors. 49 Bots ML, Salonen JT, Elwood PC, et al. Gamma-glutamyltransferase and risk of stroke: the EUROSTROKE project. J Epidemiol Commun Health 2002; 56 (Suppl. 1):i25i29. 50 Jarvis B, Simpson K. Clopidogrel: a review of its use in the prevention of . . atherothrombosis. Drugs 2002; 60:347377. A comprehensive and important review of the use of this ADP receptor antagonist, which rates its protective effect as good as aspirin and also confers benefit in addition to that of aspirin, with fewer adverse events. 51 Gaspoz J-M, Coxson PG, Goldman PA, et al. Cost effectiveness of aspirin, clopidogrel, or both for secondary prevention of coronary heart disease. N Engl J Med 2002; 346:18001806. 52 Hornung RS. Reducing cholesterol and atherosclerosis. Q J Med 2002; 95:339341. 53 Ravnskov U. Is atherosclerosis caused by high cholesterol? Q J Med 2002; . 95:397403. A worthwhile review of the intellectual distance between cholesterol concentrations and the formation of atheroma. 54 MRC/BHF Heart Protection Study Collaborative Group . MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at risk of coronary heart death: early safety and efficacy experience. Eur Heart J 1999; 20:725741. 55 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection . . Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360:722. A large trial whose design was described in Ref. [54], with an unequivocal result showing that high-risk individuals taking 40 mg simvastatin a day obtain substantial and highly significant protection against strokes as well as heart attacks. 56 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection . Study of antioxidant vitamin supplementation in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360:2333. The other arm of Ref. [55 .], showing no benefit at all from antioxidant vitamin supplementation. 57 Alexandrov AV, Demchuk AM, Felberg RA, et al. High rate of complete recanalization and dramatic clinical recovery during tPA infusion when continuously monitored with 2 MHz intracranial doppler monitoring. Stroke 2000; 31:610614. 58 Larrue V, von Kummer R, Muller A, Bluhmki E. Risk factors for severe . hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the EuropeanAustralasian Acute Stroke Study (ECASS II). Stroke 2002; 32:438441. A useful discussion of the risk factors for stroke and the benefits of early thrombolytic therapy. See also Refs [60] and [65 .]. 59 Albers GW, Clark WM, Madden KP, Hamilton SA. ATLANTIS trial: results for patients treated within 3 hours of stroke onset. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. Stroke 2002; 33:493 496. 60 Saver JL, Kidwell CS, Starkman S. Commentary: thrombolysis in stroke: it . works. BMJ 2002; 324:727729. A strong rebuttal of the criticisms against the use of thrombolytic tPA therapy. See . . also Refs [58 ] and [65 ].