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Homocysteine thiolactone contributes to the prognostic value of fibrin clot structure/function in coronary artery disease

cris.virtual.author-orcid#PLACEHOLDER_PARENT_METADATA_VALUE#
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cris.virtual.author-orcid0000-0002-0791-5057
cris.virtual.author-orcid0000-0001-5845-4409
cris.virtualsource.author-orcid#PLACEHOLDER_PARENT_METADATA_VALUE#
cris.virtualsource.author-orcid#PLACEHOLDER_PARENT_METADATA_VALUE#
cris.virtualsource.author-orcid06f046d1-df27-46e5-abe5-17d98aeed726
cris.virtualsource.author-orcid4dde7a12-8c22-4e89-9d57-7c74b050ccc5
dc.abstract.enFibrin clot structure/function contributes to cardiovascular disease. We examined sulfur-containing metabolites as determinants of fibrin clot lysis time (CLT) and maximum absorbance (Absmax) in relation to outcomes in coronary artery disease (CAD) patients. Effects of B-vitamin/folate therapy on CLT and Absmax were studied. Plasma samples were collected from 1,952 CAD patients randomized in a 2 x 2 factorial design to (i) folic acid, vitamins B12, B6; (ii) folic acid, vitamin B12; (iii) vitamin B6; (iv) placebo for 3.8 years in the Western Norway B-Vitamin Intervention Trial. Clot lysis time (CLT) and maximum absorbance (Absmax) were determined using a validated turbidimetric assay. Acute myocardial infarction (AMI) and mortality were assessed during a 7-year follow-up. Data were analyzed using bivariate and multiple regression. Survival free of events was studied using Kaplan Mayer plots. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Baseline urinary homocysteine (uHcy)-thiolactone and plasma cysteine (Cys) were significantly associated with CLT while plasma total Hcy was significantly associated with Absmax, independently of fibrinogen, triglycerides, vitamin E, glomerular filtration rate, body mass index, age, sex plasma creatinine, CRP, HDL-C, ApoA1, and previous diseases. B-vitamins/folate did not affect CLT and Absmax. Kaplan-Meier analysis showed associations of increased baseline CLT and Absmax with worse outcomes. In Cox regression analysis, baseline CLT and Absmax (>cutoff) predicted AMI (CLT: HR 1.58, 95% CI 1.10–2.28; P = 0.013. Absmax: HR 3.22, CI 1.19–8.69; P = 0.021) and mortality (CLT: HR 2.54, 95% CI 1.40–4.63; P = 0.002. Absmax: 2.39, 95% CI 1.17–4.92; P = 0.017). After adjustments for other prognostic biomarkers these associations remained significant. Cys and uHcy-thiolactone, but not tHcy, were significant predictors of AMI in Cox regression models that included CLT. Conclusions uHcy-thiolactone and plasma Cys are novel determinants of CLT, an important predictor of adverse CAD outcomes. CLT and Absmax were not affected by B-vitamin/folate therapy, which could account for the lack of efficacy of such therapy in CAD.
dc.affiliationWydział Rolnictwa, Ogrodnictwa i Bioinżynierii
dc.affiliation.instituteKatedra Biochemii i Biotechnologii
dc.contributor.authorSikora, Marta
dc.contributor.authorSkrzydlewski, Paweł
dc.contributor.authorPerła-Kaján, Joanna
dc.contributor.authorJakubowski, Hieronim
dc.date.access2025-08-27
dc.date.accessioned2025-08-27T07:15:26Z
dc.date.available2025-08-27T07:15:26Z
dc.date.copyright2022-12-27
dc.date.issued2022
dc.description.abstract<jats:p>Fibrin clot structure/function contributes to cardiovascular disease. We examined sulfur-containing metabolites as determinants of fibrin clot lysis time (CLT) and maximum absorbance (Abs<jats:sub>max</jats:sub>) in relation to outcomes in coronary artery disease (CAD) patients. Effects of B-vitamin/folate therapy on CLT and Abs<jats:sub>max</jats:sub> were studied. Plasma samples were collected from 1,952 CAD patients randomized in a 2 x 2 factorial design to (<jats:italic>i</jats:italic>) folic acid, vitamins B<jats:sub>12</jats:sub>, B<jats:sub>6</jats:sub>; (<jats:italic>ii</jats:italic>) folic acid, vitamin B<jats:sub>12</jats:sub>; (<jats:italic>iii</jats:italic>) vitamin B<jats:sub>6</jats:sub>; (<jats:italic>iv</jats:italic>) placebo for 3.8 years in the Western Norway B-Vitamin Intervention Trial. Clot lysis time (CLT) and maximum absorbance (Abs<jats:sub>max</jats:sub>) were determined using a validated turbidimetric assay. Acute myocardial infarction (AMI) and mortality were assessed during a 7-year follow-up. Data were analyzed using bivariate and multiple regression. Survival free of events was studied using Kaplan Mayer plots. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Baseline urinary homocysteine (uHcy)-thiolactone and plasma cysteine (Cys) were significantly associated with CLT while plasma total Hcy was significantly associated with Abs<jats:sub>max</jats:sub>, independently of fibrinogen, triglycerides, vitamin E, glomerular filtration rate, body mass index, age, sex plasma creatinine, CRP, HDL-C, ApoA1, and previous diseases. B-vitamins/folate did not affect CLT and Abs<jats:sub>max</jats:sub>. Kaplan-Meier analysis showed associations of increased baseline CLT and Abs<jats:sub>max</jats:sub> with worse outcomes. In Cox regression analysis, baseline CLT and Abs<jats:sub>max</jats:sub> (&gt;cutoff) predicted AMI (CLT: HR 1.58, 95% CI 1.10–2.28; <jats:italic>P</jats:italic> = 0.013. Abs<jats:sub>max</jats:sub>: HR 3.22, CI 1.19–8.69; <jats:italic>P</jats:italic> = 0.021) and mortality (CLT: HR 2.54, 95% CI 1.40–4.63; <jats:italic>P</jats:italic> = 0.002. Abs<jats:sub>max</jats:sub>: 2.39, 95% CI 1.17–4.92; <jats:italic>P</jats:italic> = 0.017). After adjustments for other prognostic biomarkers these associations remained significant. Cys and uHcy-thiolactone, but not tHcy, were significant predictors of AMI in Cox regression models that included CLT. <jats:bold>Conclusions</jats:bold> uHcy-thiolactone and plasma Cys are novel determinants of CLT, an important predictor of adverse CAD outcomes. CLT and Abs<jats:sub>max</jats:sub> were not affected by B-vitamin/folate therapy, which could account for the lack of efficacy of such therapy in CAD.</jats:p> <jats:p><jats:bold>Trial registration:</jats:bold> URL: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://clinicaltrials.gov" xlink:type="simple">http://clinicaltrials.gov</jats:ext-link>. Identifier: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT00354081" xlink:type="simple">NCT00354081</jats:ext-link>.</jats:p>
dc.description.accesstimeat_publication
dc.description.bibliographyil., bibliogr.
dc.description.financepublication_nocost
dc.description.financecost0,00
dc.description.if3,7
dc.description.number10
dc.description.points100
dc.description.versionfinal_published
dc.description.volume17
dc.identifier.doi10.1371/journal.pone.0275956
dc.identifier.issn1932-6203
dc.identifier.urihttps://sciencerep.up.poznan.pl/handle/item/4404
dc.identifier.weblinkhttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0275956
dc.languageen
dc.relation.ispartofPLoS ONE
dc.relation.pagese0275956
dc.rightsCC-BY
dc.sciencecloudnosend
dc.share.typeOPEN_JOURNAL
dc.titleHomocysteine thiolactone contributes to the prognostic value of fibrin clot structure/function in coronary artery disease
dc.typeJournalArticle
dspace.entity.typePublication
oaire.citation.issue10
oaire.citation.volume17