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Homocysteine in cardiovascular disease with special reference to longitudinal changes
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Abnormalities in homocysteine metabolism have been suggested as risk factors for stroke and myocardial infarction. In retrospective studies, elevated levels of total plasma homocysteine (tHcy) and/or methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism have indicated an increase in risk. However, the fewer prospective studies have not been as conclusive. To further explore this, tHcy was studied in four prospective settings.

The first was a prospective nested case-referent cohort within the Västerbotten Intervention Program (VIP) and WHO MONICA project on 312 ischemic and 60 haemorrhagic first-ever strokes. The aim was to study tHcy and its main genetic determinant MTHFR. Risk for haemorrhagic stroke increased exponentially through tHcy quartiles, independent of hypertension and BMI, and increased for MTHFR 677 CT and TT. MTHFR 1298A>C appeared to be protective. In multivariate models, after adjustment for tHcy, BMI and hypertension, both tHcy and MTHFR remained as independent predictors for hemorrhagic stroke. Neither tHcy, nor the two MTHFR polymorphisms were significant predictors for ischemic strokes.

The second was a prospective long-term follow-up study within the VIP and MONICA cohorts to determine whether a first-ever myocardial infarction (AMI) causes increased levels of tHcy. Fifty cases developing AMI after the first screening participated in a second screening (mean follow-up 8.5 years) with 56 matched referents. Increase in tHcy did not differ between cases and referents. tHcy was related to AMI at follow-up, but not at baseline and no longer significant after adjusting for creatinine and albumin.

The third was a method study to determine if cystatin C, creatinine, albumin and other lipoprotein risk markers of cardiovascular disease could be analysed in Stabilyte™ plasma stored at -80°C. It was found to be suitable for all analyses tested and using this tube would simplify sampling for epidemiological studies.

The fourth study was a prospective longitudinal long-term study of 735 subjects (340 men and 395 women, age 25-64 at first screening), participating in two MONICA screenings nine years apart, who donated blood in Stabilyte™ tubes to study change over time in tHcy and its determinants. We confirmed the age dependency in a cross sectional setting. In contrast, if followed longitudinally over time, no change in tHcy or in the prevalence of hyperhomocysteinemia was found. Cystatin C and creatinine increased, and albumin decreased. In multivariate models baseline levels of albumin, creatinine, cystatin C, and to some extent hs-CRP, were predictors of tHcy at follow-up but gender differences were seen. Age was not a major determinant of change in tHcy over nine years.

In conclusion, tHcy and MTHFR are risk factors for first-ever haemorrhagic, but not ischemic stroke in a prospective setting. A first myocardial infarction does not cause an increase in tHcy. No long-term changes were seen in tHcy over a nine-year period in neither men, nor in women.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap , 2005. , 72 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 969
Keyword [en]
Medical sciences, homocysteine, methylenetetrahydrofolate reductase (MTHFR), first-ever stroke, first-ever myocardial infarction, longitudinal, prospective, risk factor
Keyword [sv]
National Category
Medical and Health Sciences
Research subject
Clinical Chemistry
URN: urn:nbn:se:umu:diva-529ISBN: 91-7305-887-4OAI: diva2:143721
Public defence
2005-05-27, Betula, 6M, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Available from: 2005-05-04 Created: 2005-05-04 Last updated: 2012-01-26Bibliographically approved
List of papers
1. Elevated plasma homocysteine: cause or consequence of myocardial infarction?
Open this publication in new window or tab >>Elevated plasma homocysteine: cause or consequence of myocardial infarction?
Show others...
2004 (English)In: Journal of Internal Medicine, ISSN 0954-6820, Vol. 256, no 6, 491-498 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: To determine whether a first myocardial infarction leads to increased plasma homocysteine concentrations and whether the association between homocysteine and myocardial infarction was greater at follow-up compared with baseline. DESIGN: A population-based, prospective, nested case-referent study. SETTING: Screening took place at the nearest health survey centre in northern Sweden. SUBJECTS: Of more than 36,000 persons screened, 78 developed a first myocardial infarction (average 18 months after sampling). Fifty of these had participated in a follow-up health survey (average 8(1/2) years between surveys) and were sex- and age-matched with 56 referents. MAIN OUTCOME MEASURES: Comparison of plasma homocysteine levels in case and referent subjects before and after development of a first myocardial infarction. RESULTS: No statistically significant difference was found between cases and referents regarding homocysteine at baseline or follow-up. Plasma homocysteine and plasma creatinine increased significantly, and plasma albumin decreased significantly over time. Conditional univariate logistic regression indicated that high homocysteine at follow-up but not baseline was associated with first myocardial infarction (OR 2.49; 95% CI: 1.03-6.02), but the relation disappeared in multivariate analyses including plasma creatinine and plasma albumin. High plasma creatinine remained associated with first myocardial infarction at both baseline (OR 2.94; 95% CI: 1.05-8.21) and follow-up (OR 3.38; 95% CI: 1.21-9.48). CONCLUSION: In this study, first myocardial infarction did not cause increased plasma homocysteine concentration.

Case-Control Studies, Creatinine/blood, Female, Homocysteine/*blood, Humans, Male, Middle Aged, Myocardial Infarction/*blood, Prospective Studies, Risk Factors, Serum Albumin/analysis, Smoking/adverse effects
urn:nbn:se:umu:diva-12981 (URN)10.1111/j.1365-2796.2004.01415.x (DOI)15554950 (PubMedID)
Available from: 2007-11-23 Created: 2007-11-23 Last updated: 2015-04-29Bibliographically approved
2. Analysis of cystatin C, creatinine, albumin, lipids and lipoprotein concentrations in serum and acidified citrate plasma (Stabilyte) tubes compared.
Open this publication in new window or tab >>Analysis of cystatin C, creatinine, albumin, lipids and lipoprotein concentrations in serum and acidified citrate plasma (Stabilyte) tubes compared.
2004 (English)In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, Vol. 42, no 8, 978-981 p.Article in journal (Other academic) Published
Albumins/*analysis, Blood Specimen Collection/methods/standards, Citric Acid/*chemistry, Creatinine/*blood, Cystatins/*blood, Humans, Hydrogen-Ion Concentration, Lipids/*blood, Lipoproteins/*blood, Plasma/chemistry, Regression Analysis, Reproducibility of Results, Serum/chemistry
urn:nbn:se:umu:diva-15191 (URN)10.1515/CCLM.2004.160 (DOI)15387454 (PubMedID)
Available from: 2007-09-13 Created: 2007-09-13 Last updated: 2009-11-16Bibliographically approved
3. Longitudinal changes in homocysteine and its determinants over a nine year period
Open this publication in new window or tab >>Longitudinal changes in homocysteine and its determinants over a nine year period
Manuscript (Other academic)
urn:nbn:se:umu:diva-4568 (URN)
Available from: 2005-05-04 Created: 2005-05-04 Last updated: 2010-01-13Bibliographically approved

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