Homocysteine content of plasma proteins in ischemic heart disease

doi:10.1016/0021-9150(88)90003-2

Atherosclerosis

Volume 69, Issues 2–3, February 1988, Pages 109-113

https://doi.org/10.1016/0021-9150(88)90003-2 Get rights and content

Abstract

It has been shown previously that accumulation of homocysteine produces atheromatous changes. The present study was done on 26 male survivors of myocardial infarction 2–3 months after the acute phase and 26 healthy males of the same age (30–60 years). The concentrations of homocysteine, its derivatives and other amino acids were determined in acid hydrolyzate of plasma and in deproteinized plasma. The plasma proteins of survivors of myocardial infarction were found to contain a high concentration of homocysteine. The average value was 958 ± 84 μmol/l of plasma, which was about 25 times the quantity found in the control group. Large differences were also found in α-amino adipic acid and cystathionine concentrations. These substances were found in significantly higher concentrations in the plasma of the survivors compared to controls. The high positive correlation between homocysteine and α-amino adipic acid level (r = 0.83; P < 0.001) suggests a common source of these 2 compounds in the analyzed samples. The levels of the other 15 measured amino acids were not significantly different in the 2 groups. The results support the homocysteine theory and suggest a method for more exact diagnosis of atherosclerosis.

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A metabolomic method using reversed-phase liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) was developed to obtain a systematic view of the development and progression of myocardial infarction (MI) and the treatment or protective effect of the Shexiang Baoxin Pill. By combining with partial least squares discriminant analysis (PLS-DA), 30 biomarkers in rat urine and serum were identified. A lot of pathways were regulated. The metabolomic results not only supplied a systematic view of the development and progression of MI but also provided the theoretical basis for the prevention or treatment of MI.
Biomarkers in the early period of acute myocardial infarction in rat serum and protective effects of Shexiang Baoxin Pill using a metabolomic method
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These 11 biomarkers mainly participate in three pathological processes, including inflammation, hypertrophy and oxidative injury, which are all activated as an insult by AMI (Table 6). The increasing level of homocysteine in serum has been shown to be associated with an increased risk for occlusive vascular disease (Olszewski and Szostak, 1988; Chambers and Kooner, 2001). Welch and Losculzo (1998) reported that homocysteine probably leads to oxidative damage of endothelial cells because of the reactive oxygen radicals that are produced during auto-oxidation of homocysteine in plasma.
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A metabolomic approach using reversed-phase liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) was developed.
Fourteen biomarkers in the early period of acute myocardial infarction (AMI) in rat serum were identified. These biomarkers include 5-methylcytosine, cystathionine ketimine, 2-oxoadipic acid, thymidine, epinephrine, homocystine, uric acid, 12(S)-hydroperoxyeicosatetraenoic acid (12s-HPETE), 11-dehydrocorticosterone, 12(S)-hydroxyeicosatetraenoic acid (12s-HETE), deoxycorticosterone, corticosterone, aldosterone and cortisol. Through pathway analysis of these biomarkers, inflammation, hypertrophy and oxidative injury were considered the most relevant pathological changes in early period of AMI.
Identification of AMI biomarkers not only supplied a systematic view of the progression of AMI in the early period but also provided the theoretical basis for the prevention or treatment of AMI. The results demonstrated that SBP pretreatment could offer protective effects for AMI through regulating the pathway of steroid hormone biosynthesis.
Understanding the transition from alternative medicine to mainstream science: The homocysteine theory of heart disease and the crucial role of effective mentoring
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A deficiency of effective ‘mentoring’ may contribute to the relatively low quality of alternative medicine research and to the medical/scientific community’s reluctance to consider even its most promising theories. This hypothesis derives from a case-study of the homocysteine theory of heart disease (HTSD), one of only a few recent theories to have made the transition from ‘alternative’ to ‘mainstream’.
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In plasma the atherogenic thiol homocysteine (Hcy) circulates either free or bound to proteins (Pb-Hcy). The present study sets out to evaluate the lipoprotein-Hcy (LP-Hcy) binding in vivo and the possible influence of different apolipoprotein content in this binding, being lipoprotein oxidation a possible mechanism of Hcy-induced damage.
In 34 healthy subjects we assayed fasting plasma lipoprotein and correspondent apolipoprotein (apo A-I, apo A-II, apo C-II, apo C-III, apo B, apo(a) and apo E content, and Hcy bound to different plasma protein fractions; moreover ten subjects underwent an oral methionine load in order to evaluate possible “dynamic” modifications of Pb-Hcy and LP-Hcy after induction of hyperhomocysteinemia. Pb-Hcy (mean values 9.22±1.7 μmol/L) represented about 78% of total plasma Hcy (mean values 11.8±1.8 μmol/L). Pb-Hcy distribution between the different fractions was as follows (μmol/L): VLDL = 0.25 ± 0.08 (2.7 %); LDL=0.88±0.22 (9.5 %); HDL=1.40±0.36 (15.2%); fractions with density greater than 1.21 g/mL (Lipoprotein-Free Protein Fraction, LPDS) =6.7±1.2 (72.6 %). Hcy/protein ratios (nmol/mg of protein) in each protein fraction were: VLDL=0.32±0.19, LDL=0.43±0.37, HDL=0.26±0.18, LPDS<0.1, thus suggesting a higher binding capacity for Hcy by VLDL and LDL. These data were confirmed by the higher increase in Hcy content in LDL and VLDL (76 and 90%, respectively vs 36% and 3.1% for HDL and LPDS fractions) after hyperhomocysteinemia. Lp-Hcy binding significantly correlated with the apo B content of VLDL and LDL and Apo A-I content of HDL.
An important fraction of plasma Hcy circulates bound to LP (about 27% of Pb-Hcy); VLDL and LDL show the highest binding capacity for Hcy, probably due to their content in Apo B, a possible high capacity binding site for Hcy.
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In our recent report, it remained unclear whether or not triglyceride-rich lipoprotein remnants (RLP) were associated with the risk of sudden coronary death in younger cases without coronary atherosclerosis that were detected in about 10% of all sudden coronary death cases in Japan. These cases were categorized as ‘origin unknown, but suspected to be due to coronary spasm’, the so called ‘pokkuri disease’ in Japan. The present study population consisted of 108 sudden death cases without coronary atherosclerosis [(pokkuri disease n=57) and non-cardiac sudden death (control n=51)] aged 20–69 years from Kanagawa prefecture in Japan. All individuals had died suddenly and unexpectedly, most had no significant history of medical conditions including cardiac symptoms and had not taken medications prior to death according to their medical records. All the autopsies were performed within 12 h after death. Plasma total cholesterol (TC), triglycerides (TG), phospholipids, RLP-C and RLP-TG, VLDL-C, LDL-C, HDL-C, apolipoproteins A-I, A-II, B, C-II, C-III, E, Lp (a) and homocysteine were measured in postmortem plasma samples. The TG-rich lipoprotein remnants measured as RLP-C and RLP-TG were significantly higher in pokkuri disease compared with controls both in fasting and postprandial states (P<0.05 and P<0.001), indicating that RLP-C and RLP-TG were the most significant risk factor in pokkuri disease among the parameters tested in this study. In conclusion the TG level in RLP (RLP-TG) appeared to be strongly associated with the risk of sudden death in the absence of coronary atherosclerosis (pokkuri disease).
Vitamin intake: A possible determinant of plasma homocyst(e)ine among middle-aged adults
1997, Annals of Epidemiology
PURPOSE: Many epidemiologic studies have identified elevated plasma homocyst(e)ine as a risk factor for atherosclerosis and thromboembolic diseases. To examine the relationship between vitamin intakes and plasma homocyst(e)ine, we analyzed dietary intake data from a case-control study of 322 middleaged individuals with atherosclerosis in the carotid artery and 318 control subjects without evidence of this disease.
METHODS: All of these individuals were selected from a probability sample of 15,800 men and women who participated in the Atherosclerosis Risk in Communities (ARIC) Study.
RESULTS: Plasma homocyst(e)ine was inversely associated with intakes of folate, vitamin B6, and vitamin B12 (controls only for this vitamin)—the three key vitamins in homocyst(e)ine metabolism. Among nonusers of vitamin supplement products, on average each tertile increase in intake of these vitamins was associated with 0.4 to 0.7 μmol/L decrease in plasma homocyst(e)ine. An inverse association of plasma homocyst(e)ine was also found with thiamin, riboflavin, calcium, phosphorus, and iron. Methionine and protein intake did not show any significant association with plasma homocyst(e)ine.
CONCLUSIONS: In almost all analyses, cases and controls showed similar associations between dietary variables and plasma homocyst(e)ine. Plasma homocyst(e)ine among users of vitamin supplement products was 1.5 μmol/L lower than that among nonusers. Further studies to examine possible causal relationships among vitamin intake, plasma homocyst(e)ine, and cardiovascular disease are needed.

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Research paperHomocysteine content of plasma proteins in ischemic heart disease

Abstract

Metabolism

Pathological findings in homocysteinuria

J. Clin. Pathol.

Homocysteine-induced arteriosclerosis. Role of endothelial cell injury and platelet response to its genesis

J. Clin. Invest.

Morphologic studies in a patient with homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency

Pediatr. Res.

Vascular pathology of homocysteinemia. Implications for the pathogenesis of arteriosclerosis

Am. J. Pathol.

Homocysteine theory of arteriosclerosis. Development and current status

Growth promotion by homocysteic acid

Science

Research paper
Homocysteine content of plasma proteins in ischemic heart disease