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Neurology India
Medknow Publications on behalf of the Neurological Society of India
ISSN: 0028-3886 EISSN: 1998-4022
Vol. 50, Num. s1, 2002, pp. S15-S20
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Neurology India, Vol. 50, (Suppl. 1), Dec, 2002,
pp. S15-S20
Vascular Biology and Stroke
M.C.Wong, H.M. Chang
Department of Neurology,
Singapore General Hospital,
National Neurosciences Centre, Singapore.
Correspondence to : Dr. M.C. Wong, Department of
Neurology, Singapore General Hospital, Singapore.
Code Number: ni02158
Summary
The pathophysiology of
stroke is complex and involves an abnormal interaction between
vessel wall and platelets. Of late many genetic and environmental
factors impinging on the
vessel wall have been identified which may determine the
susceptibility of an individual to
stroke. These include elevated homocysteine levels, chronic
chalymydial and periodontal
infection, plaque characteristics and genetic susceptibility.
Intervention with HMG CO
enzyme A reductase inhibitors, Angiotensin Enzyme Inhibitors and
vitamins have been
shown to offer protection.
Key words :
Vascular biology,
Stroke.
Introduction
Advances in understanding vascular pathobiology
hold promise for the stroke field. Recent studies have
shed light on vascular disease mechanisms, opened up
new avenues for categorization and risk stratification,
as well as improved therapies for patients with stroke,
or at increased risk of stroke. The reader is directed to
substantive reviews,1-6 this article briefly highlights
five rapidly evolving areas of vascular biology,
relevant to stroke physicians.
Metabolism and Diet
Individual genetic and metabolic differences, lifestyle
and diet impact vascular disease risk. One illustrative
model of multiple complex disease interactions is
homocysteine metabolism. Elevated homocysteine
levels are associated with cardiovascular disease and
stroke.7-13 Pathophysiologic mechanisms currently
implicated include endothelial dysfunction,
impairment of vascular nitric oxide response,
prothrombotic platelet and coagulation factor
responses.14-17 Homocysteine metabolism varies with
cystathione beta-synthase and methylenetetrahydrofolate
reductase (MTHFR) activity. Emerging genetic data suggests that allelic variation
of these enzymes may account for differences in
homocysteine metabolism, including response to
methionine loading.18 Lifestyle factors, including
smoking, alcohol intake and concurrent illnesses such
as renal failure can alter homocysteine levels.7,8
Vitamin supplementation, particularly for those
deficient in folic acid, Vit B6 and B12 has shown
promise for improving a suboptimal diet,
homocysteine metabolism, and reduction of stroke
and cardiovascular risk.19- 23
Role of Inflammation
Inflammation plays a major role in the atherosclerotic
process.24 Macrophages and T lymphocytes
contribute to fatty streak formation. Inflammation and
free radical damage alter endothelial permeability
with influx and oxidation of low density lipoprotein
cholesterol, increased leucocyte and platelet adhesion,
cytokine and growth factor stimulation with smooth
muscle cell proliferation, and arterial wall
'remodelling'. Plaque destabilization can be
precipitated by continued inflammation with
expression of cell adhesion molecules, ingress of
inflammatory cells surrounding an expanded lipid
laden necrotic core, further cytokine release, matrix
metalloproteinase activation and plaque rupture.25, 26
Infection and inflammation are increasingly
recognized to contribute to vascular disease.27-36
Epidemiologic studies implicate infections and
inflammation as more common in the week
antecedent to stroke onset.37-39 Bacterial and viral
infections were both associated with increased risk of
acute ischemic stroke. Periodontal disease has also
been highlighted, as a risk factor for stroke, and is
amenable to treatment.40-42 Specific agents such as
Chlamydia pneumoniae43-54 can infect endothelial
cells and macrophages, and have been detected in
plaques. Cytomegalovirus,55 Helicobacter Pylori,56-58
and other agents are under investigation for playing a
role to promote the atherosclerotic process.
Statins
The 'Statin' drugs are HMG-CoA (3-hydroxy-
3-methylglutaryl coenzyme A) reductase inhibitors
and these reduce cholesterol synthesis. In addition to
their lipid lowering effects, they augment endothelial
nitric oxide synthase activity and have antioxidant
properties, including reduced LDL oxidation. Adverse
effects include hepatotoxicity, myopathy and others.
In experimental stroke models, statins have been
shown to facilitate blood flow preservation, reduce
cytokine induced inflammation and infarct size. In
addition to their lipid lowering effects, statins appear
to benefit endothelial function, stabilise plaques
thereby reducing rupture and have a range of
pleiotrophic effects, which have variously been
termed as anti-inflammatory, antithrombotic and
antiatherosclerotic effects.59-66 The efficacy of statins
to reduce risk of stroke has been demonstrated in a
number of clinical trials and this effect has been
shown to extend to groups with relatively low lipid
levels also.67-80
Angiotensin Converting Enzyme Inhibition
Amongst modifiable risk factors for stroke,
hypertension is pre-eminent. Stroke risk rises
proportionately with blood pressure levels. Long term
lowering of blood pressure by 10 mm Hg (systolic)
and 5 mm Hg (diastolic) is estimated to reduce
absolute stroke risk by about 2% annually.81-86
Unfortunately, sustained adequate control of
hypertension is uncommon in most countries,87-91 and
many strokes occur in individuals without
hypertension, or who have mildly elevated blood
pressure.
Angiotensin converting enzyme inhibitors (ACE-I) act
on the renin-angiotensin-aldosterone system by
inhibiting angiotensin-converting enzyme, thus,
reducing conversion of angiotensin I to angiotensin II.
Angiotensin II is a vasoconstrictor, stimulates
aldosterone release and raises blood pressure.92 In
addition, angiotensin II induces smooth muscle
hypertrophy, stimulates LDL oxidation and impairs
endothelial function.93,94 Adverse effects of ACE-I
therapy include azotemia, hyperkalemia and cough
associated with reduced bradykinin metabolism.
Following ACE-I therapy, changes in resistance
arterioles, reduction of arteriolar collagen and
improvement of endothelial function and vascular
compliance have been described.95-100 In clinical
trials, ACE-I has been shown to reduce stroke risk, as
well as cardiovascular outcomes; including for nonhypertensives.101-107
Profiling the Individual and his Vasculature
Epidemiologic type studies have highlighted some
differences in stroke patterns between different races.
Extracranial cerebrovascular disease is common
amongst the Caucasian population in the West, but
intracranial disease and small vessel stroke appear to
be the most common pattern amongst the ethnic
Chinese population in Asia. Whilst the
pathophysiologic basis for these observations is
lacking, molecular genetic studies may give us new
insights into stroke predisposition. Examples of
genomic studies include examining allelic differences
in the MTHFR,108-110 ACE,111-115 other genes,6,116-
119 and Notch III mutations in CADASIL.120,121
However, in the post-genomic era, new techniques
have allowed our group and others, the windows to
view stroke patients' vascular tissue specific
transcriptome expression and proteomics. Inherited
genes, environmental modification of their RNA and
protein expression at the level of the vasculature,
coupled with dynamic lifestyle and pharmacologic
interventions hold much promise for better future
understanding of stroke pathophysiology and
characterization of stroke risk profile at the individual
level.
References
- Hankey GJ : Is homocysteine a causal and treatable risk
factor for vascular diseases of the brain (cognitive
impairment and stroke)? Ann Neurol 2002; 51 : 279-281.
- Feigin VL, Anderson CS, Mhurchu CN et al : Systemic
inflammation, endothelial dysfunction, dietary fatty acids and
micronutrients as risk factors for stroke: a selective review.
Cerebrovasc Dis 2002; 13 : 219-224.
- Werner N, Nickenig G, Laufs U : Pleiotropic effects of HMGCoA
reductase inhibitors. Basic Res Cardiol 2002; 97 :
105-
116.
- Sica DA : ACE inhibitors and stroke: new considerations.
J Clin Hypertens (Greenwich) 2002; 4 : 126-129.
- Gorelick PB : Stroke prevention therapy beyond
antithrombotics: Unifying mechanisms in ischemic stroke
pathogenesis and implications for therapy. Stroke 2002;
33
: 862-875.
- Hassan A, Markus HS : Genetics and ischaemic stroke.
Brain 2000; 123 : 1784-1812.
- Diaz-Arrastia R : Homocysteine and neurologic disease.
Arch Neurol 2000; 57 : 1422-1428.
- Sacco RL, Roberts JK, Jacobs BS : Homocysteine as a risk
factor for ischemic stroke: an epidemiologic story in
evolution. Neuroepidemiology 1998; 17 :
167-173.
- Verhoef P, Hennekens CH, Malinow R et al : A prospective
study of plasma homocysteine and risk of ischemic stroke.
Stroke 1994; 25 : 1924-1930.
- Giles WH, Croft J, Greenlund KJ et al : Total homocysteine
concentration and the likelihood of nonfatal stroke. Results
from the Third National Health and Nutrition Examination
Survey, 1988-1994. Stroke 1998; 29 :
2473-2477.
- Kittner SJ, Giles WH, Macko RF et al : Homocysteine and
risk of cerebral infarction in a biracial population: The Stroke
Prevention in Young Women Study. Stroke 1999;
30 : 1554
-1560.
- Bostom AG, Rosenberg IH, Silbershatz H et al : Non fasting
plasma total homocysteine levels and stroke incidence in
elderly persons: the Framingham Study. Ann Intern Med
1999; 131 : 352-355.
- Vermeer SE, van Dijk EJ, Koudstaal PJ et al :
Homocysteine, silent brain infarcts, and white matter
lesions: The Rotterdam Scan Study. Ann Neurol 2002; 51 :
285-289.
- Farmer JA : Pleiotropic effects of statins. Curr Atheroscler
Rep 2000; 2 : 208-217.
- Delanty N, Vaughan CJ : Vascular effects of statins in
stroke. Stroke 1997; 28 : 2315-2320.
- Rosenson RS, Tangney CC : Antiatherothrombotic
properties of statins: implications for cardiovascular event
reduction. JAMA 1998; 279 :
1643-1650.
- Nappo F, De Rosa N, Marfella R et al : Impairment of
endothelial functions by acute hyperhomocysteinemia and
reversal by antioxidant vitamins. JAMA 1999;
281 : 2113-
2118.
- Kristensen B, Malm J, Nilsson TK et al :
Hyperhomocysteinemia and hypofibrinolysis in young adults
with ischemic stroke. Stroke 1999;
30 : 974-980.
- The VITATOPS (Vitamins to Prevent Stroke) Trial: rationale
and design of an international, large, simple, randomised
trial of homocysteine-lowering multivitamin therapy in
patients with recent transient ischaemic attack or stroke.
Cerebrovasc Dis 2002;
13 : 120-126.
- Gariballa SE : Nutritional factors in stroke. Br J Nutr 2000;
84 : 5-17.
- Hankey GJ, Eikelboom JW : Homocysteine levels in patients
with stroke: clinical relevance and therapeutic implications.
CNS Drugs 2001; 15(6)
: 437-443.
- Christen WG, Ridker PM : Blood levels of homocysteine
and
athero-sclerotic vascular disease. Curr Atheroscler Rep 2000; 2 : 194 -199.
- Eikelboom JW, Lonn E, Genest J et al : Homocysteine and
cardiovascular disease: a critical review of the epidemiologic
evidence. Ann Intern Med 1999; 131 : 363-375.
- Ross R : Atherosclerosis: an inflammatory disease.
N Engl
J Med 1999; 340 : 115-126.
- Rauch U, Osende JI, Fuster V et al : Thrombus formation on
atherosclerotic plaques: pathogenesis and clinical
consequences. Ann Intern Med 2001; 134 :
224-238.
- Kullo IJ, Edwards WD, Schwartz RS : Vulnerable plaque:
pathobiology and clinical implications. Ann Intern Med 1998;
129 : 1050-1060.
- Nieto FJ : Infections and atherosclerosis: new clues from an
old hypothesis? Am J Epidemiol 1998;
148 :
937-948.
- Di Napoli M, Papa F : Inflammation, hemostatic
markers,
and antithrombotic agents in relation to long-term
risk of new
cardiovascular events in first-ever ischemic stroke
patients.
Stroke2002; 33 (7)
: 1763-1771.
- SoRelle R : Inflammation-sensitive proteins:
another
ingredient in stroke? Circulation 2002;
4 : 105(22): e9111.
- Engstrom G, Lind P, Hedblad B et al : Effects
of cholesterol
and inflammation-sensitive plasma proteins on incidence
of
myocardial infarction and stroke in men. Circulation 2002;
105 (22) : 2632-2637.
- Ridker PM : Inflammatory biomarkers, statins, and the risk
of
stroke: cracking a clinical conundrum. Circulation 2002; 105 (22) : 2583-2585.
- Sitzer M, Markus HS, Mendall MA et al : C-reactive protein
and carotid intimal medial thickness in a community
population. J Cardiovasc
Risk 2002; 9 (2) :
97-103.
- Jialal I, Devaraj S : Inflammation and atherosclerosis:
the
value of the high-sensitivity C-reactive protein assay as a
risk marker. Am J Clin
Pathol 2001; 116 Suppl :
S108-115.
- van Exel E, Gussekloo J, de Craen AJ et al : Inflammation
and stroke: the Leiden 85-Plus Study. Stroke 2002;
33 :
1135-1138.
- Castellanos M, Castillo J, Garcia MM :
Inflammationmediated
damage in progressing lacunar infarctions : A
potential therapeutic target. Stroke 2002;
33 (4) : 982-987.
- Takeoka M, Takahashi T : Infectious and inflammatory
disorders of the circulatory system and stroke in childhood.
Curr Opin Neurol 2002; 15(2) :
159-164.
- Macko RF, Ameriso SF, Barndt R et al : Precipitants of
brain
infarction: roles of preceding infection/inflammation and
recent psychologic stress. Stroke 1996;
27 : 1999-2004.
- Grau AJ, Buggle F, Heindl S et al : Recent infection as a
risk
factor for cerebrovascular ischemia. Stroke 1995; 26 :
373-
379.
- Grau AJ, Buggle F, Becher H et al : Recent bacterial and
viral infection is a risk factor for cerebrovascular ischemia:
clinical and biochemical studies. Neurology 1998; 50 :
196 -
203.
- Wu T, Trevisan M, Genco RJ et al : Periodontal disease and
risk of cerebrovascular disease: the First National Health
and Nutrition Examination Survey and its follow-up study.
Arch Intern Med 2000; 160 : 2749-2755.
- Lowe GD : The relationship between infection, inflammation,
and cardiovascular disease: an overview. Ann Periodontol 2001; 6 (1) : 1-8.
- Buhlin K, Gustafsson A, Hakansson J et al : Oral health and
cardiovascular disease in Sweden. J Clin Periodontol 2002;
29(3 ) : 254-259.
- Rutherford JD : Chlamydia pneumoniae and
atherosclerosis. Curr Atheroscle r Rep 2000; 2 : 218-225.
- Wimmer LJ, Sandmann-Strupp R, Saikku P et al :
Association of chlamydial infection with cerebrovascular
disease. Stroke 1996; 27 : 2207-2210.
- Cook PJ, Honeybourne D, Lip GYH et al : Chlamydia
pneumoniae antibody titers are significantly associated with
acute stroke and transient cerebral ischemia. The West
Birmingham Stroke Project. Stroke 1998; 29 : 404-410.
- Glader CA, Stegmayr B, Boman J et al : Chlamydia
pneumoniae antibodies and high lipoprotein (a) levels do not
predict ischemic cerebral infarctions: results from a nested
case-control study in Northern Sweden. Stroke 1999; 30 :
2013-2018.
- Elkind MSV, Lin I-F, Grayston JT et al : Chlamydia
pneumoniae and the risk of first ischemic stroke: the
Northern Manhattan Stroke Study. Stroke 2000; 31 : 1521-
1525.
- Fagerberg B, Gnarpe J, Gnarpe H et al : Chlamydia
pneumoniae but not cytomegalovirus antibodies are
associated with future risk of stroke and cardiovascular
disease: a prospective study in middle-aged to elderly men
with treated hypertension. Stroke 1999; 30 : 299-305.
- Markus HS, Sitzer M, Carrington D et al : Chlamydia
pneumoniae infection and early asymptomatic carotid
atherosclerosis. Circulation 1999; 100 : 832-837.
- Gibbs RGJ, Sian M, Mitchell AWM et al : Chlamydia
pneumoniae does not influence atherosclerotic plaque
behavior in patients with established carotid artery stenosis.
Stroke 2000; 31 : 2930-2935.
- Schmidt C, Hulthe J, Wikstrand J et al : Chlamydia
pneumoniae seropositivity is associated with carotid artery
intima-media thickness.Stroke 2000; 31 : 1520-1531.
- LaBiche R, Koziol D, Quinn TC et al : Presence of
Chlamydia pneumoniae in human symptomatic and
asymptomatic carotid atherosclerotic plaque. Stroke 2001;
32 : 855-860.
- Yamashita K, Ouchi K, Shirai M et al : Distribution of
Chlamydia pneumoniae infection in the atherosclerotic
carotid artery. Stroke 1998; 29 : 773-778.
- Ngeh J, Anand V, Gupta S : Chlamydia pneumoniae and
atherosclerosis - what we know and what we don't. Clin
Microbiol Infect 2002; 8(1) : 2-13.
- Nieto FJ, Adam E, Sorlie P et al : Cohort study of
cytomegalovirus infection as a risk factor for carotid intimalmedial
thickening, a measure of subclinical atherosclerosis.
Circulation 1996; 94 : 922-927.
- Markus HS, Mendall MA : Helicobacter pylori infection: a risk
factor for ischemic cerebrovascular disease and carotid
atheroma. J Neurol Neurosurg Psychiatry 1998; 64 : 104 -
107.
- Markus HS, Risley P, Mendall MA et al : Helicobacter pylori
infection, the cytotoxin gene A strain, and carotid artery
intima-media thickness. J Cardiovasc Risk 2002; 9 (1) : 1-6.
- Ameriso SF, Fridman EA, Leiguarda RC et al : Detection of
Helicobacter pylori in human carotid atherosclerotic
plaques. Stroke 2001; 32 : 385-391.
- Endres M, Lavfs U, Huang Z et al : Stroke protection by 3-
hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors
mediated by endothelial nitric oxide synthase. Proc Natl
Acad Sci USA 1998; 95 : 8880 -8885.
- Vaughan CJ, Delanty N : Neuroprotective properties of
statins in cerebral ischemia and stroke. Stroke 1999; 30 :
1969-1973.
- Amin-Hanjani S, Stagliano NE, Yamada M et al : Mevastatin,
an HMG-CoA reductase inhibitor, reduces stroke damage
and upregulates endothelial nitric oxide synthase in mice.
Stroke 2001; 32 : 980-986.
- Jonnson N, Asplund K : Does pretreatment with statins
improve clinical outcome after stroke? A pilot case-referent
study. Stroke 2001; 32 : 1112-1115.
- Farmer JA : Pleiotropic effects of statins. Curr Atheroscler
Rep 2000; 2 : 208-217.
- Delanty N, Vaughan CJ : Vascular effects of statins in
stroke. Stroke 1997; 28 : 2315-2320.
- Rosenson RS, Tangney CC : Antiatherothrombotic
properties of statins: implications for cardiovascular event
reduction. JAMA 1998; 279 : 1643-1650.
- Rosenson RS, Lowe GDO : Effects of lipids and lipoproteins
on thrombosis and rheology. Atherosclerosis 1998; 140 :
271-280.
- Scandanavian Simvastatin Survival Study Group.
Randomized trial of cholesterol lowering in 4444 patients
with coronary heart disease: the Scandanavian Simvastatin
Survival Study . Lancet 1994; 344 : 1383-1389.
- Sacks FM, Pfeffer MA, Moye LA et al. The effect of
pravastatin on coronary events after myocardial infarction in
patients with average cholesterol levels: Cholesterol and
Recurrent Events Trial investigators. N Engl J Med 1996;
335 : 1001-1009.
- White HD, Simes RJ, Anderson NE et al : Pravastatin
therapy and the risk of stroke. N Engl J Med 2000; 343 : 317-
326.
- Byington RP, Davis BR, Plehn JF et al : Reduction of stroke
events with pravastatin: The Prospective Pravastatin
Pooling (PPP) Project. Circulation 2001; 103 : 387-392.
- Herbert PR, Gaziano JM, Chan KS et al : Cholesterol
lowering with statin agents, risk of stroke, and total mortality:
an overview of randomized trials. JAMA 1997; 278 : 313-
321.
- Blauw GJ, Lagaay AM, Smelt AHM et al : Stroke, statins,
and cholesterol: a meta-analysis of randomized, placebocontrolled,
double blind trials with HMG- CoA reductase
inhibitors. Stroke 1997; 28 : 946-950.
Vascular Biology and Stroke
Neurology India, 50, (Suppl. 1) December 2002
- Crouse JR III, Byington RP, Hoen HM et al : Reductase
inhibitor monotherapy and stroke prevention. Arch Intern
Med 1997; 157 : 1305-1310.
- Bucker HC, Griffith LE, Guyatt GH : Effect of HMG CoA
reductase inhibitors on stroke : A meta-analysis of
randomized controlled trials. Ann Intern Med 1998; 128 :
89
-95.
- Crouse JR III, Byington RP, Furberg CD : HMG-CoA
reductase inhibitor therapy and stroke risk reduction: an
analysis of clinical trial data. Atherosclerosis 1998; 138 : 11-
24.
- Ross SD, Allen IE, Connelly JE et al : Clinical outcomes in
statin treatment trials: a meta-analysis. Arch Intern Med 1999; 159 : 1793-1802.
- Goldberg AC : Clinical implications of statin event trials. Curr
Atheroscler Rep 2002; 4(5) : 337-342.
- Blake GJ, Ridker PM, Kuntz KM : Projected life-expectancy
gains with statin therapy for individuals with elevated Creactive
protein levels. J Am Coll Cardiol 2002; 40(1) : 49-
55.
- Teo KK, Burton JR : Who Should Receive HMG CoA
Reductase Inhibitors? Drugs 2002; 62(12) : 1707-1715.
- MRC/BHF Heart Protection Study of cholesterol lowering
with simvastatin in 20,536 high-risk individuals: a
randomised placebo-controlled trial. Lancet 2002; 6;
360(9326) : 7-22.
- MacMahon S, Peto R, Cutler JA et al : Blood pressure,
stroke, and coronary heart disease, I: effects of prolonged
differences in blood pressure: evidence from nine
prospective observational studies corrected for the
regression dilution bias. Lancet 1990; 335 : 765-774.
- Collins R, Peto R, MacMahon S et al : Blood pressure,
stroke and coronary heart disease, II: Short-term reductions
in blood pressure: overview of randomised drug trials in their
epidemiological context. Lancet 1990; 335 : 827-838.
- Gueyffier F, Boissel J-P, Boutie F et al : Effect of
antihypertensive treatment in patients having already
suffered from stroke: gathering the evidence. The INDANA
(Individual Data Analysis of Antihypertensive intervention
trials) Project Collaborators. Stroke 1997; 28 : 2557-2562.
- Rodgers A, Neal B, MacMahon S : The effects of blood
pressure lowering in cerebrovascular disease. Neurol Rev
Int 1997; 2 (1) : 12-15.
- Hankey GJ, Warlow CP : Treatment and secondary
prevention of stroke: evidence, costs, and effects on
individuals and populations. Lancet 1999; 354 : 1457-1463.
- Makino Y, Kawano Y, Minami J et al : Risk of stroke in
relation to level of blood pressure and other risk factors in
treated hypertensive patients. Stroke 2000; 31 : 48-52.
- Kaplan RC : Treatment of hypertension to prevent stroke:
translating evidence into clinical practice. J Clin Hypertens 2001; 3 (3) : 153-156.
- Klungel OH, Heckbert SR, Longstreth WT Jr et al :
Antihypertensive drug therapies and the risk of ischemic
stroke. Arch Intern Med 2001; 161 : 37-43.
- Prisant LM, Moser M : Hypertension in the elderly: can we
improve the results? Arch Neurol 2000; 160 : 283-289.
- Hillen T, Dundas R, Lawrence E et al : Antithrombotic and
antihypertensive management 3 months after ischemic
stroke: a prospective study in an inner city population.
Stroke 2000; 31 : 469-475.
- Kernan WN, Visioli CM, Brass LM et al : Blood pressure
exceeding national guidelines among women after stroke.
Stroke 2000; 31 : 415-419.
- Aceon (perindopril erbumine) Drug Information. 9605 2E
Rev 7/99. Marietta, Georgia: Solvay Pharmaceuticals, Inc.;
1999.
- Rossi GP, Rossi A, Sacchetto A et al : Hypertensive
cerebrovascular disease and the renin-angiotensin system.
Stroke 1995; 26 : 1700-1706.
- Farmer JA, Torre-Amione G : The renin angiotensin system
as a risk factor for coronary artery disease. Curr Atheroscler
Rep 2001; 3 : 117-124.
- Cohn JN : ACE inhibition and vascular remodeling of
resistance vessels: vascular compliance and cardiovascular
implications. Heart Disease 2000; 2 : S2-S6.
- Schwartz Kopff B, Brehm M et al : Repair of coronary
arterioles after treatment with perindopril in hypertensive
heart disease. Hypertension 2000; 36 : 220-225.
- Sihm I, Schroeder AP, Aalkjaer C et al : Normalization of
structural cardiovascular changes during antihypertensive
treatment with a regimen based on the ACE-inhibitor
perindopril. Blood Pressure 1995; 4 : 241-248.
- Thybo NK, Stephens N, Cooper A et al : Effect of
antihypertensive treatment on small arteries of patients with
previously untreated essential hypertension. Hypertension 1995; 25(part I) : 474-481.
- Giannattasio C, Achilli F, Failla M et al : Radial , carotid and
aortic distensibility in congestive heart failure: effects of
high-dose angiotensin-converting enzyme inhibitor or lowdose
association with angiotensin type 1 receptor blockade. J Am Coll Cardiol 2002; 39 (8) : 1275-1282.
- Contri MB, Taparelli F, Miselli M et al : Dose-dependent
prevention of fibrosis in aorta of salt-loaded stroke-prone
spontaneously hypertensive rats by combined delapril and
indapamide treatment. J Cardiovasc Pharmacol 2002; 40 (3) : 388-398.
- The Heart Outcome Prevention Evaluation Study
Investigators. Effects of an angiotensin-converting enzyme
inhibitor, ramipril, on cardiovascular events in high-risk
patients. N Engl J Med 2000; 342 : 145-153.
- Francis GS : ACE inhibition in cardiovascular disease. N
Engl J Med 2001; 342 : 201-202.
- Mann JFE, Gerstein HC, Pogue J et al : for the HOPE
Investigators. Renal insufficiency as a predictor of
cardiovascular outcomes and the impact of ramipril: The
HOPE randomized trial. Ann Intern Med 2001; 134 : 629 -
636.
- PROGRESS Collaborative Group. Randomised trial of a
perindopril-based blood-pressure-lowering regimen among
6105 individuals with previous stroke or transient ischaemic
attack. Lancet 2001; 358 : 1033-1041.
- Basile J : Analysis of recent papers in hypertension: Stroke
incidence reduced in high-risk patients with the ACE
inhibitor ramipril. J Clin Hypertens (Greenwich) 2002; 4 (4) :
298-299.
- Thavarajah S, Mansoor GA : Are Clinical Endpoint Benefits
of Angiotensin converting Enzyme Inhibitors Independent of
their Blood Pressure Effects? Curr Hypertens Rep 2002;
4(4) : 290-297.
- Gustavsen GP : ACE inhibitors prevent stroke in high-risk
patients, independent of blood pressure-lowering effect.
J Fam Pract 2002; 51(7) : 595.
- Markus HS, Ali N, Swaminathan R et al : A common
polymorphism in the methylenetetrahydrofolate reductase
gene, homocysteine, and ischemic cerebrovascular
disease. Stroke 1997; 28 : 1739-1743.
- Bova I, Chapman J, Sylantiev C et al : The A677V
methylenetetrahydrofolate reductase gene polymorphism
and carotid atherosclerosis. Stroke 1999; 30 : 2180-2182.
- Kelly PJ, Rosand J, Kistler JP : Homocysteine, MTHFR
677C->T polymorphism, and risk of ischemic stroke:
Results of a meta-analysis. Neurology 2002; 59 (4) : 529-
536.
- Kario K, Kanai N, Saito K et al : Ischemic stroke and the
gene for angiotensin-converting enzyme in Japanese
hypertensives. Circulation 1996; 93 : 1630-1633.
- Markus HS, Barley J, Lunt R et al. Angiotensin-converting
enzyme gene deletion polymorphism: a new risk factor for
lacunar stroke but not carotid atheroma. Stroke 1995; 26 :
1329-1333.
- Catto A, Carter AM, Barrett JH et al : Angiotensin-converting
enzyme insertion / deletion poly-morphism and
cerebrovascular disease. Stroke 1996; 27 : 435-440.
- Sethi AA, Tybjaerg-Hansen A, Moes Gronholdt M-L et al :
Angiotensin mutations and risk of ischemic heart disease,
myocardial infarction, and ischemic cerebrovascular
disease: six case-control studies from the Copenhagen City
Heart Study. Ann Intern Med 2001; 134 : 941-954.
- Schmidt H, Fazekas F, Kostner GM et al : Angiotensinogen
gene promoter haplotype and macroangiopathy-related
cerebral damage: results of the Austrian Stroke Prevention
Study. Stroke 2001; 32 : 405-412.
- Sierra C, Coca A, Gomez-Angelats E et al : Reninangiotensin
system genetic polymorphisms and cerebral
white matter lesions in essential hypertension. Hypertension 2002; 39 : 343-347.
- Carr FJ, McBride MW, Carswell HV et al : Genetic aspects
of stroke: human and experimental studies. J Cereb Blood
Flow Metab 2002; 22(7) : 767-773.
- Luthra K, Prasad K, Kumar P et al : Apolipoprotein E gene
polymorphism in cerebrovascular disease: a case-control
study. Clin Genet 2002; 62(1) : 39-44.
- Gerdes VE, ten Cate H, de Groot E et al : Arterial wall
thickness and the risk of recurrent ischemic events in
carriers of the prothrombin G20210A mutation with clinical
manifestations of atherosclerosis. Atherosclerosis 2002; 163(1) : 135-140.
- Kalimo H, Ruchoux MM, Viitanen M et al : CADASIL: a
common form of hereditary arteriopathy causing brain
infarcts and dementia. Brain Pathol 2002; 12(3) : 371-384.
- Joutel A, Corpechot C, Ducros A et al : Notch3 mutations in
CADASIL, a hereditary adult-onset condition causing stroke
and dementia. Nature 1996; 24; 383(660 ) : 707-710.
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