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To assess the risk of ischaemic stroke associated with total serum homocyst(e)ine (tHcy) concentration.

• Age 50 to 64 years.
• Cardiovascular disease and related outcomes in men.
• No prior history of stroke.

• Prevalent stroke
  
• Unavailable serum tHcy concentration level
  
• Both prevalent stroke and unavailable serum homocysteine levels
  

The Caerphilly study is a community based prospective study of cardiovascular disease and related outcomes in men age 45 to 59 years who were recruited between 1979 and 1983 from the town of Caerphilly South Wales and the adjacent villages.

 All men in the eligible age group were identified from the electoral register (2818) and invited to participate with an 89% recruitment rate. In 1984, 2398 men aged 50 to 64 years participated in phase II of the study.

Serum homocyst(e)ine concentration levels were performed on phase II stored blood samples at a later date.

This analysis is based on 2254 men with no prior history of stroke.

 The phase II follow up collected the following measurements; medical history, smoking history, London School of Hygiene and Tropical Medicine chest pain questionnaire, height, weight and blood pressure measured with a random zero sphygmomanometer and a 12 lead electrocardiogram (ECG).

A detailed food frequency questionnaire was self completed before attending the clinic and used to estimate the mean daily dietary intake of nutrients and vitamins.

Outcome Measure: Stroke

Risk factors for stroke in cases and non-cases were examined using the unpaired t test and z test in the comparison of means and proportions. Total homocyst(e)ine, vitamin B12 and alcohol were not normally distributed and all calculations were done on log transformed data. Associations between serum tHcy concentration and several potential confounding variables were examined using linear regression. Mean values of serum tHcy concentration were compared in cases and non-cases using the unpaired t test.

 

 

• Risk factors for stroke in cases and non-cases were examined.
• Associations between serum tHcy concentration and several potential confounding variables were examined.
• The relation between ischaemic stroke and serum tHcy concentration was examined.Cox proportional hazard modelling was used to perform survival analysis and to adjust for confounders.
• Date of entry was taken as the date the blood was taken for serum total homocyst(e)ine. Participants were censored at date of ischaemic stroke, date of death or date of end of follow up, which was 31 December 1997.
• The risk set was defined using both the dates of entry and age at entry and there was no difference in the results when analysed separately.
• The proportional hazard assumption for the goodness of fit of the Cox regression model was tested over three intervals of time each containing the same number of stroke events.

2254 men, 50-64 years of age recruited between 1984-88 and followed for 10 years.

There is no significant relation between hcy and stroke in this cohort. However, its importance may be greater for premature strokes (<65 years) and in hypertensive men.

The adjusted hazard ratio for stroke when the top 5% of the serum tHcy concentration distribution was compared with the rest was 2.0 (95% CI 0.9 to 4.2) p=0.07.

There was a significant interaction between serum tHcy concentration and age in the fully adjusted Cox proportional hazard model (p=0.003) when both were treated as continuous variables.

The adjusted odds ratio of stroke when comparing the top quintile of the serum tHcy concentration distribution with the rest, stratified by age at stroke, was 2.5 (95% CI 1.0 to 6.2) p = 0.02 in men who were under 65 years of age, as compared with 0.5 (95% CI 0.2 to 1.2) p=0.16 for men aged 65 years or over.

Serum total homocyst(e)ine and potential confounding variables for ischaemic stroke in the non-cases

Linear regression	Β coefficient*	95% CI	p Value
Age (per 5 years)	0.04	0.021 to 0.05	<0.01
Systolic BP (per 10 mm Hg)	0.006	0.006 to 0.012	0.03
Diastolic BP (per 10 mm Hg)	−0.0002	−0.01 to 0.01	0.97
†Alcohol (per SD in ml/day)	−0.04	−0.05 to −0.03	<0.01
Body mass index (per SD in kg/m2)	−0.1	−0.14 to −0.07	<0.01
Creatinine (per SD in μmol/l)	0.06	0.04 to 0.07	<0.01
Total cholesterol (per SD in mmol/l)	−0.0006	−0.01 to 0.01	0.93
HDL cholesterol (per SD in mmol/l)	−0.02	−0.03 to −0.007	<0.01
†Triglycerides (per SD in mmol/l)	−0.01	−0.02 to 0.02	0.1
Folate (per SD in μg/day)	−0.05	−0.06 to −0.04	<0.01
†B12 (per SD in μg/day)	−0.04	−0.05 to −0.03	<0.01
B6 (per SD in mg/day)	−0.02	−0.04 to −0. 01	<0.01
	‡Mean serum tHcy (μm/l)	SD
Never smoked Ex smoker Current smoker	11.3 11.5 12.1	1.3 1.3 1.4	p=<0.01
Hypertensive Normotensive	12.1 11.6	1.3 1.3	p=0.01
Manual social class Non-manual social class	11.8 11.5	1.4 1.3	p=0.09
Diabetic Not diabetic	10.7 11.7	1.3 1.3	p=0.01
ECG ischaemia Normal ECG	11.8 11.7	1.3 1.3	p=0.5

*Change in homocysteine (natural log) per unit change in risk factor. †Natural log transformed ‡Geometric mean.

 

107 men (4.7%) developed stroke There was no significant difference in mean serum t-hcy levels between stroke cases (12.2 m mol/L, 95% CI, 11.6-13.1) and non-cases (11.7 m mol/L, 95% CI, 11.5-11.9) (P=0.14). The adjusted odds ratio comparing the top quintile of t-hcy with the rest was 2.5 (95% CI, 1.0-6.2) for strokes in those <65 years and 0.5 (95% CI, 0.2-1.3) >65 years (P for interaction =0.02). The adjusted hazard ratio for a standard deviation increase in t-hcy was 0.8 (95% CI, 0.6-1.2 for normotensive men and 1.3 (95% CI, 1.1-1.7) for hypertensive men. (P for interaction=0.01).

Hazard ratio of stroke comparing each quintile of serum total homocyst(e)ine concentration with the first

 

Quintile of tHcy	n	Cases	Mean tHcy	Rate /1000 person years	Age adjusted hazard ratio (95% CI) (n=2112)	Hazard ratio adjusted* (95% CI) (n=2112)
1	455	21	8. 2	4.4	1.0	1.0
2	454	21	10.0	4.5	1.2 (0.6 to 2.2)	1.3 (0.7 to 2.4)
3	444	23	11.4	5.0	1.3  (0.7 to 2.4)	1.3 (0.7 to 2.4)
4	453	14	13.2	3.0	0.8 (0.4 to 1.6)	0.8 (0.4 to 1.6)
5	448	28	19.0

• The authors found a greater risk of ischaemic stroke associated with tHcy in hypertensive men. Overall, there is no significant relation between homocyst(e)ine and ischaemic stroke in this cohort.
• Our study supports the hypothesis that any true effect is weak or non-existent and may be only important in certain subgroups. Future randomised controlled trials of folic acid supplementation may provide more robust evidence as to whether interventions that lower tHcy can prevent atherosclerosis and future risk of stroke.
• In view of our results, such trials would either require very large numbers of participants or recruit subjects at high risk. However, its aetiological importance may be greater for premature ischaemic strokes (<65 years) and in hypertensive men.

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The data provided in this study is very interesting and helpful. Once again it is observed the relationship of stroke and hypertension. It is necessary to conduct further studies to see the effect of homocysteine and stroke relationship in different population and also necessary for intervention trials. This study is not a representative sample. The data reflects only for men. A comparison study with and without stroke is also necessary to make further conclusions. This paper will open a new avenue of research to focus on stroke and its relationship with homocysteine. Future studies should focus on vitamin B12 and folic acid in relation to inflammatory markers and homocysteine in stroke .