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Homocysteine and Coronary Artery Disease With special Reference to Biochemical Effects Of Vitamin Therapy

Jonasson, Torfi LU (2006) In Lund University Faculty of Medicine Doctoral Dissertation Series 2006:65.
Abstract
An elevated plasma level of homocysteine has been suggested as a risk factor for cardiovascular disease. The objectives of this thesis were to study the influence of renal function on homocysteine levels in patients with coronary artery disease and to explore the association of elevated plasma levels of homocysteine to oxidative stress, inflammation, and endothelial dysfunction. The effects of plasma homocysteine lowering with vitamin supplementation were also studied.



Paper 1. Patients with coronary heart disease were studied, 59 with elevated levels of plasma homocysteine and 34 with low-normal levels. Patients with elevated levels had higher serum concentrations of cystatin C, a marker for glomerular filtration rate,... (More)
An elevated plasma level of homocysteine has been suggested as a risk factor for cardiovascular disease. The objectives of this thesis were to study the influence of renal function on homocysteine levels in patients with coronary artery disease and to explore the association of elevated plasma levels of homocysteine to oxidative stress, inflammation, and endothelial dysfunction. The effects of plasma homocysteine lowering with vitamin supplementation were also studied.



Paper 1. Patients with coronary heart disease were studied, 59 with elevated levels of plasma homocysteine and 34 with low-normal levels. Patients with elevated levels had higher serum concentrations of cystatin C, a marker for glomerular filtration rate, than patients with low-normal levels of homocysteine. However, a large overlap in cystatin C concentrations between these two groups of patients, suggested that subtle renal dysfunction is not a major determinant of high plasma concentrations of homocysteine in patients with coronary artery disease.



Paper 2 . The main findings of this study were that patients with coronary artery disease and high plasma homocysteine had a lowered ratio of reduced to total homocysteine in plasma, which might reflect increased oxidative activity or decreased reducing capacity in plasma. Vitamin therapy normalised the plasma homocysteine concentrations but the redox status remained unchanged.



Paper 3. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, was not increased in patients with coronary artery disease and high plasma concentration of homocysteine. Substantial reduction of homocysteine by vitamin supplementation did not affect the level of plasma ADMA.



Paper 4. Patients with coronary artery disease and high plasma homocysteine levels had elevated levels of isoprostanes, markers of lipid peroxidation. The increase remained unaffected by plasma homocysteine-lowering therapy, suggesting that homocysteine per se does not cause increased lipid peroxidation. Two out of eight inflammatory markers studied were increased in patients with high plasma homocysteine levels compared to patients with low-normal levels, suggesting an association between homocysteinemia and low-grade inflammation.



Paper 5. We investigated 334 consecutive patients with acute coronary syndrome. Plasma homocysteine levels correlated with markers of inflammation (C reactive protein (CRP) and orosomucoid) but not with levels of antibodies against LDL.



In conclusion, increased lipid peroxidation and altered redox status in patients with hyperhomocysteinemia do not appear to be caused by homocysteine itself. Elevated plasma homocysteine does not increase plasma levels of ADMA. Hyperhomocysteinemia is linked to an inflammatory reaction. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Homocystein är en aminosyra som bildas genom nedbrytning av aminosyran metionin, som tillförs kroppen via födan. Förhöjda blodnivåer av homocystein kan orsakas av medfödda enzymrubbningar, brist på vitaminerna folsyra och B12, och vissa sjukdomar, t ex njursvikt. Medfödd enzymbrist kan ge mycket höga blodnivåer av homocystein, vilket bland annat leder till kärlskada och blodproppsbildning. Forskning under de senaste decennierna har också påvisat ett samband mellan måttligt förhöjt homocystein och hjärt- och kärlsjukdom, men det är inte klarlagt om homocystein i sig framkallar sjukdomarna eller om det finns bakomliggande faktorer som både orsakar förhöjda blodnivåer av homocystein och hjärt- och... (More)
Popular Abstract in Swedish

Homocystein är en aminosyra som bildas genom nedbrytning av aminosyran metionin, som tillförs kroppen via födan. Förhöjda blodnivåer av homocystein kan orsakas av medfödda enzymrubbningar, brist på vitaminerna folsyra och B12, och vissa sjukdomar, t ex njursvikt. Medfödd enzymbrist kan ge mycket höga blodnivåer av homocystein, vilket bland annat leder till kärlskada och blodproppsbildning. Forskning under de senaste decennierna har också påvisat ett samband mellan måttligt förhöjt homocystein och hjärt- och kärlsjukdom, men det är inte klarlagt om homocystein i sig framkallar sjukdomarna eller om det finns bakomliggande faktorer som både orsakar förhöjda blodnivåer av homocystein och hjärt- och kärlsjukdom. Ett sätt att undersöka denna frågeställning är att behandla individer med högt homocystein med vitaminer, t ex folsyra B12 och B6, som sänker blodnivåerna av homocystein. Om sänkt homocystein minskar sjukligheten talar detta för att homocystein är en sjukdomsframkallande faktor. Resultaten från flera stora kliniska studier av vitaminbehandlig har varit nedslående: man har inte kunnat påvisa att vitaminbehandling minskar risken att drabbas av hjärt- och kärlsjukdom.



Målsättning:



1. Att undersöka vilken betydelse nedsatt njurfunktion har för uppkomsten av höga blodkoncentrationer av homocystein hos patienter med kranskärlssjukdom.



2. Att undersöka om patienter med kranskärlssjukdom och högt homocystein har förhöjda blodnivåer av markörer för inflammation, oxidativ stress och försämrad kärlfunktion.



3. Att undersöka om denna markörer påverkas av vitaminbehandling.



Resultat



Vi har funnit att nedsatt njurfunktion bara är en delförklaring till högt homocystein hos patienter med kranskärlssjukdom. Vitaminbrister bidrar också.



Två markörer för oxidativ stress, ett lågt förhållande mellan reducerat och oxiderat homocystein och förhöjda nivåer av isoprostaner, kunde påvisas hos patienter med kranskärlssjukdom och högt homocystein. Vitaminbehandling, som nästan halverade blodnivåerna av homocystein, påverkade inte dessa markörer. Resultaten talar för att homocystein i sig inte framkallar oxidativ stress. Det är tänkbart att förhållandet är omvänt, dvs att oxidativ stress höjer blodnivåerna av homocystein . En annan förklaring kan vara att någon bakomliggande faktor orsakar både oxidativ stress och förhöjda homocysteinnivåer. Vi kunde inte påvisa något samband mellan blodnivåerna av homocystein och halten av antikroppar mot oxiderat LDL, ett kemiskt förändrat blodfett, som spelar en väsentlig roll i uppkomsten av åderförkalkning. Våra resultat talar mot att homocystein orsakar oxidation av LDL.



Det finns ett samband mellan höga blodnivåer av homocystein och inflammation, men av våra resultat kan man inte säkert avgöra om vitaminbehandlig minskar inflammationen.



I ett delarbete studerades sambandet mellan homocystein och assymetriskt dimetylarginin (ADMA), som är en kroppsegen hämmare av kväveoxid. Kväveoxid bildas bland annat i kärlväggen och framkallar där kärlvidgnig och motverkar blodproppsbildning och åderförkalkning. Förhöjda blodnivåer av ADMA skulle således kunna motverka de gynnsamma effekterna av kväveoxid och bidra till uppkomsten av hjärt- och kärlsjukdom. Förhöjda blodnivåer av ADMA har påvisats hos patienter med högt blodtryck eller njursjukdom. Vi fann ingen förhöjning av ADMA hos patienter med kranskärlssjukdom och högt homocystein. Vitaminbehandling påverkade inte heller blodnivåerna av ADMA.



Sammanfattningsvis har vi inte kunnat styrka teorierna att högt homocystein i sig orsakar oxidativ stress, inflammation eller förhöjda blodnivåer av ADMA. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Associate professor Nilsson-Ehle, Herman, Dept. of Hematology, Medical section 2, Sahlgrenska University Hospital, SE-413 45 Gothenburg
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Klinisk kemi, Clinical chemistry, pyridoxine., oxidative stress, lipid peroxidation, inflammation, homocysteine, endothelial function, folate, F2-isoprostanes, cystatine C, Acut coronary syndrome, cardiovascular disease, asymmetric dimethylarginine, cobalamine
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2006:65
publisher
Department of Cardiology, Clinical sciences, Lund University
defense location
Segerfalksalen, Wallenberg Neurocentrum
defense date
2006-05-26 13:00:00
ISSN
1652-8220
ISBN
91-85481-90-4
language
English
LU publication?
yes
additional info
id
83bd8cf3-d9f8-4da8-81a0-6d1e96631414 (old id 546971)
date added to LUP
2016-04-01 16:38:42
date last changed
2019-05-22 01:48:34
@phdthesis{83bd8cf3-d9f8-4da8-81a0-6d1e96631414,
  abstract     = {An elevated plasma level of homocysteine has been suggested as a risk factor for cardiovascular disease. The objectives of this thesis were to study the influence of renal function on homocysteine levels in patients with coronary artery disease and to explore the association of elevated plasma levels of homocysteine to oxidative stress, inflammation, and endothelial dysfunction. The effects of plasma homocysteine lowering with vitamin supplementation were also studied.<br/><br>
<br/><br>
Paper 1. Patients with coronary heart disease were studied, 59 with elevated levels of plasma homocysteine and 34 with low-normal levels. Patients with elevated levels had higher serum concentrations of cystatin C, a marker for glomerular filtration rate, than patients with low-normal levels of homocysteine. However, a large overlap in cystatin C concentrations between these two groups of patients, suggested that subtle renal dysfunction is not a major determinant of high plasma concentrations of homocysteine in patients with coronary artery disease.<br/><br>
<br/><br>
Paper 2 . The main findings of this study were that patients with coronary artery disease and high plasma homocysteine had a lowered ratio of reduced to total homocysteine in plasma, which might reflect increased oxidative activity or decreased reducing capacity in plasma. Vitamin therapy normalised the plasma homocysteine concentrations but the redox status remained unchanged.<br/><br>
<br/><br>
Paper 3. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, was not increased in patients with coronary artery disease and high plasma concentration of homocysteine. Substantial reduction of homocysteine by vitamin supplementation did not affect the level of plasma ADMA.<br/><br>
<br/><br>
Paper 4. Patients with coronary artery disease and high plasma homocysteine levels had elevated levels of isoprostanes, markers of lipid peroxidation. The increase remained unaffected by plasma homocysteine-lowering therapy, suggesting that homocysteine per se does not cause increased lipid peroxidation. Two out of eight inflammatory markers studied were increased in patients with high plasma homocysteine levels compared to patients with low-normal levels, suggesting an association between homocysteinemia and low-grade inflammation.<br/><br>
<br/><br>
Paper 5. We investigated 334 consecutive patients with acute coronary syndrome. Plasma homocysteine levels correlated with markers of inflammation (C reactive protein (CRP) and orosomucoid) but not with levels of antibodies against LDL.<br/><br>
<br/><br>
In conclusion, increased lipid peroxidation and altered redox status in patients with hyperhomocysteinemia do not appear to be caused by homocysteine itself. Elevated plasma homocysteine does not increase plasma levels of ADMA. Hyperhomocysteinemia is linked to an inflammatory reaction.},
  author       = {Jonasson, Torfi},
  isbn         = {91-85481-90-4},
  issn         = {1652-8220},
  language     = {eng},
  publisher    = {Department of Cardiology, Clinical sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series},
  title        = {Homocysteine and Coronary Artery Disease With special Reference to Biochemical Effects Of Vitamin Therapy},
  volume       = {2006:65},
  year         = {2006},
}