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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

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.

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