Chapter 1. Introduction and literature review
1.4 Homocysteine as a risk factor for vascular diseases
Hemodynamic status of slow flow and low shear stress related vascular remodeling is one of the pathogenesis of atherosclerosis 26-28. Hemodynamic data obtained by
ultrasonography include blood flow velocity, flow resistance and flow volume 29, 30. Hcy has been reported to be higher in those with slow coronary artery flow than in those with normal flow velocity 31. Hcy is an important factor for atherosclerosis in the large cerebral arteries 32. In 1,041 Framingham residents who had Hcy measurement and carotid sonography. The adjusted odds ratio (OR) for stenosis ≥ 25% was 2.0 (95%
confidence interval, CI, 1.4-2.9) for subjects with Hcy levels in the highest compared to the lowest quartile 32. In the Atherosclerosis Risk in Communities (ARIC) Study,
subjects with thickened intima-medial carotid walls (≥ 90th percentile) were more likely to have elevated Hcy levels compared to those without thickened walls (<70th percentile)
33. Hcy may possibly slow the blood flow velocity, and further induce atherosclerosis with reducing the brain flow volume. However, the reports investigating the relationship between serum Hcy and the cerebral hemodynamic status were limited.
1.4.2 Homocysteine, microangiopathy and cerebral white matter lesions (WML) Sclerosis of small cerebral arteries and arterioles is responsible for the diffuse
periventricular white matter abnormalities and the central lacunar lesions evidenced in computed or magnetic resonance tomography 34. The severity of cerebral white matter
lesions (WML) increases with age and the presence of arterial hypertension 35-37.
Although the clinical significance of these lesions remains to be fully understood, WML have been associated with dementia, depression, stroke and mortality 38-41. Patients with Alzheimer’s disease (AD), vascular dementia, and depression have more severe WML than control 38, 39.
It is well known that hyperhomocysteinemia is an independent risk factor for vascular disease. The pathophysiologic mechanism by which Hcy induces angiopathy remains unclear, although various hypotheses have been proposed 42-44. A prospective study performed in Japanese showed significant association between Hcy and risk of lacunar infarcts 45. This finding indicated that Hcy may be related to small vessel disease. Silent brain lacunar infarcts and WML are thought have a small vessel disease origin and are frequently seen in neurologically asymptomatic elderly people 35, 36, 46 and are common among persons with cognitive impairment and dementia 38, 39. Studies have determined the association between Hcy and vascular lesions as well as Hcy and
dementia 2, 47-51. In view of aforementioned report, we propose a hypothesis that Hcy may induce the risk of cerebral arteriole angiopathy and further induce WML and lacunar infarcts; and then further cause cognitive impairment. A population-based study from Rotterdam demonstrated that Hcy is associated with cerebral WML 52. However, studies about the association between Hcy and WML are limited among Asia
population.
1.4.3 The association between total serum homocysteine and clinical vascular events
Epidemiological studies, using cross-sectional, case-control, and cohort designs, have examined the association between Hcy and cerebrovascular disease. Many case-control
and cohort studies have identified a strong, independent and dose-related association between moderately elevated Hcy and atherosclerotic vascular disease, including stroke
1. Brattstrom et al., first reported a case-control study in 1984 that moderate
hyperhomocysteinemia was a possible risk factor for atherosclerotic cerebrovascular diseases 53. These investigators measured non-protein-bounded Hcy following methionine loading in 19 patients with TIA or minor stroke. Sixteen of these patients had Doppler or angiographic evidence of internal carotid artery stenosis or occlusion. In 1992 Brattstrom et al., in a large series of stroke patients, found that plasma Hcy
concentrations were not only elevated in carotid artery disease and lacunar stroke but also in hemorrhagic and embolic stroke 47. Coull and colleagues found similar
elevations of Hcy in patients with acute stroke and TIA. Plasma Hcy concentration was moderately but significantly higher in patients than in control (P<0.0001)48. In a
meta-analysis employing 27 studies relating Hcy to arteriosclerotic vascular in relation to the effects of folic acid on lowering Hcy concentration, Boushey et al., determined the effects of Hcy on the risk of three categories of vascular disease (coronary,
cerebrovascular and peripheral artery diseases)54. Elevations of Hcy were considered an independent graded risk factor for arteriosclerotic vascular disease: a 5 µmole/L Hcy increment elevates risk by as much as a cholesterol increase of 0.5 mmole/L (20 mg/dL).
The OR for cerebrovascular disease is 1.5 (95% CI, 1.3 to 1.9) 54.
However, not all reports have been consistent. Several prospective cohort studies have failed to demonstrate a positive association between Hcy and stroke 55, 56. A Finnish study failed to show a significant association between hyperhomocysteinemia and stroke 55. The relation of serum total Hcy with incidence of atherosclerotic disease was investigated among 7424 men and women aged 40-64 years free of atherosclerotic disease at baseline in 1977. During the 9-year follow-up, 134 male ad 131 female cases
with either myocardial infarction or stroke were identified. The mean serum Hcy concentration of male cases and controls was 9.99 µmole/L and 9.24 µmole/L at baseline and that of female cases and controls was 9.58 µmole/L and 9.24 µmole/L respectively. There was also no significant association between Hcy and atherosclerotic disease, myocardial infarction or stroke in logistic regression analyses. The odds ratios varied from 1.00 to 1.26 for Hcy. The results of this prospective population-based study do not support the hypotheses that serum Hcy is a risk factors for atherosclerotic disease.
Furthermore, two large randomized placebo-controlled trials of Hcy-lowering therapy, Vitamins to Prevent Stroke Study (VITATOPS) for patients with patients with a recent transient ischemic attack or stroke, as well as the Vitamins to Prevent Stroke (VISP) study for patients with a first ever non-disabling stroke, failed to show the clinical benefit on stroke prevention 57, 58.
1.5 The points favor or not favor on a causal relationship between Hcy