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Clinical Chemistry 46: 385-391, 2000;
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(Clinical Chemistry. 2000;46:385-391.)
© 2000 American Association for Clinical Chemistry, Inc.

Articles

Correlation between Plasma Total Homocysteine and Copper in Patients with Peripheral Vascular Disease

Mohammad A. Mansoor1, Claes Bergmark2, Steve J. Haswell3, Ian F. Savage3, Peter H. Evans4, Rolf K. Berge5, Asbjørn M. Svardal6 and Ole Kristensen1

1 Division of Clinical Chemistry, Central Hospital in Rogaland, 4003 Stavanger, Norway.

2 Department of Surgery, St. Görans Hospital, Stockholm 17176, Sweden.

3 Department of Chemistry, University of Hull, Hull HU6 7RX, United Kingdom.

4 Department of Public Health, University of Glasgow, Glasgow G12 8QQ, United Kingdom.
Departments of
5 Clinical Biochemistry and
6 Pharmacology, University of Bergen, Bergen N-5021, Norway.
a Author for correspondence. Fax 47-51519507; e-mail amansoor{at}online.no


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: Increased concentrations of both plasma total homocysteine and copper are separately associated with cardiovascular disease. Correlations between plasma total homocysteine, trace elements, and vitamins in patients with peripheral vascular disease have not been investigated.

Methods: The concentrations of trace elements in plasma were determined by the multielement analytical technique of total-reflection x-ray fluorescence spectrometry. Plasma total homocysteine was determined by HPLC.

Results: In the univariate and multivariate regression analyses, copper was positively correlated with plasma total homocysteine in all subjects (coefficient ± SE, 0.347 ± 0.113; P = 0.0026 and coefficient ± SE, 0.422 ± 0.108; P = 0.0002, respectively), and in patients with peripheral vascular disease (coefficient ± SE, 0.370 ± 0.150; P = 0.016; and coefficient ± SE, 0.490 ± 0.151; P = 0.0025, respectively). Correlation between copper and plasma total homocysteine was not detected in healthy control subjects. The concentration of calcium in plasma (67.5 vs 80.8 µg/g) was significantly lower in the patients than in the control subjects (P = 0.02). When the patients were divided into groups, the patients with suprainguinal lesions had significantly higher copper concentrations (P = 0.04) and significantly lower selenium and calcium concentrations (P = 0.01 and 0.008, respectively) than the healthy subjects. Patients had higher concentrations of autoantibodies against oxidized LDL and concentrations of thiobarbituric acid-reactive substance than the healthy subjects (P <0.0001 and P = 0.001, respectively). The concentrations of plasma total homocysteine and {alpha}-tocopherol were significantly higher, and the concentrations of vitamin B6 and ß-carotene were lower in the patients than the healthy subjects.

Conclusion: Our findings suggest that the atherogenicity of homocysteine may be related to copper-dependent interactions.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Classic homocystinuria patients have abnormally increased concentrations of plasma total homocysteine (p-tHcy)1 attributable to homozygous deficiency of the enzyme cystathionine ß-synthase. The concentrations of p-tHcy in these patients may reach up to 300 µmol/L; therefore, this condition is called severe hyperhomocysteinemia (1)(2). Severe hyperhomocysteinemia in these patients seems to be associated with increased risk of cardiovascular disease (CVD) and death in an early age attributable to CVD (1). Increased concentrations of copper in plasma are also detected in these patients (3). There are indications that increased concentrations of copper in plasma are also associated with increased risk of coronary artery disease (4)(5).

During recent years, it has also been demonstrated that mildly increased p-tHcy also increases the risk of CVD. It has been estimated that a 5 µmol/L increase in p-tHcy may increase the risk of CVD as much as a 0.5 mmol/L increase in cholesterol (6). The concentrations of homocysteine in plasma increase because of the reduced activity of one of the enzymes (cystathionine ß-synthase), methylenetetrahydrofolate reductase, or methionine synthase or because of deficiencies of the B vitamins, B12, B6, B2, and folate, which function as coenzymes in homocysteine metabolism (7).

A few studies, however, have not shown an association of homocysteine with CVD (8)(9). It has also been shown that patients with a genetic deficiency of methylenetetrahydrofolate reductase (mutation C677T) have increased p-tHcy, and that this mutation may not be associated with CVD (10). Data based on clinical studies also suggest that vitamin B6 and folate deficiencies are independently associated with increased risk of CVD and that vitamin B6 offers protection against CVD (11)(12).

In the present study, we looked for associations between homocysteine and other biochemical factors that seem to be associated with CVD. We determined the concentrations of p-tHcy, trace elements, antioxidants, B vitamins, and a product of lipid peroxidation, thiobarbituric acid-reactive substance (TBARS). TBARS is the measurement of lipid peroxidation in the plasma samples. The plasma samples are heated with thiobarbituric acid at low pH, and the adduct of thiobarbituric acid-lipid peroxide, or TBARS, is separated and determined by HPLC-fluorescence detection.

To evaluate the role of homocysteine and copper in atherogenesis, we explored the relationships between homocysteine and trace elements in plasma from patients with peripheral vascular disease (PVD).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
subjects
Sixty-five patients with PVD and 65 sex- and age-matched healthy control subjects were included in this case-control study. The characteristics of the participants of the present study are described in Table 1 . Angiograms of the patients allowed us to divide the patients into three groups: suprainguinal (n = 28), lesions confined to the segments proximal of the inguinal ligament; infrainguinal (n = 17), lesions confined to only distal to the inguinal ligament; and multilevel (n = 13), lesions located at both locations. The remaining patients had abdominal aortic aneurysms, carotid artery stenosis, and renal artery stenosis. Plasma samples were drawn after surgery and were stored at -80 °C until the samples were analyzed. Details on the study participants have been described previously (13)(14).


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  		Table 1. Characteristics of patients and healthy control subjects participating in the present study.

biochemical methods
Plasma tHcy and related thiols were measured by an HPLC method as described previously (15). The concentrations of serum folate and vitamin B12 were determined by standard laboratory methods. The concentrations of vitamin B6 were measured by an apotyrosine decarboxylase method (16). The concentrations of autoantibodies against oxidized LDL (Ox-LDL) were measured according to methods described elsewhere (17). The concentrations of 16 trace elements were determined by the multielement analytical technique of total-reflection x-ray fluorescence spectrometry. Analyses were performed using a total-reflection x-ray fluorescence Seifert-Link Extra II spectrometer; the spectrometer measures the intensity of the element-characteristics fluorescence x-rays following ultra low-angle primary x-ray irradiation of the plasma sample material with a molybdenum x-ray tube (18). The concentrations of vitamins A, {alpha}-tocopherol, and ß-carotene were determined according to an isocratic HPLC method (19). The concentrations of TBARS were measured as described previously by Yagi (20) and Chiu et al. (21).

Informed consent was obtained from all participants, and the study was approved by the Ethics Committee at Karolinska Sjukhuset, Stockholm, Sweden.

statistical analyses
The Mann–Whitney U-test was applied to evaluate the differences between the groups. Differences with P values <0.05 were considered significant. All P values are two-tailed. Log-converted values of all variables were used in the univariate and multivariate regression analyses. Log-converted p-tHcy was used as a dependent variable, and all other analytes were assigned as independent variables. Significantly correlated variables in the univariate analyses were included in the multivariate regression analysis. The statistical program, StatView for the Macintosh (Abacus Concepts) was used for all calculations.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
trace elements
We measured concentrations of nutritional and toxic elements, namely calcium, iron, zinc, copper, selenium, chloride, iodine, molybdenum, cobalt, nickel, barium, tin, mercury, lead, cadmium, and arsenic, in plasma from patients with PVD and compared them with the corresponding concentrations measured in plasma from the healthy control subjects (Table 2 ). The concentrations of calcium in plasma from the patients were significantly lower than in plasma from the healthy control subjects (P = 0.02; Table 2 ). The patients with suprainguinal types of vascular lesions had significantly higher concentrations of copper and significantly lower concentrations of selenium and calcium (Fig. 1 ).


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  		Table 2. Concentrations of trace elements in plasma from patients with PVD and healthy control subjects.



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  		Figure 1. Box plot representations of trace elements in control healthy subjects and patients with different types and extent of disease.

(A), copper; (B), selenium; (C), calcium. The boxes include observations from the 25th and 75th percentiles. The central horizontal lines in the boxes represent 50th percentiles, and the lines outside the boxes represent 10th and 90th percentiles. C, controls; In, infrainguinal; Mu, multilevel disease; Su, suprainguinal.

p-tHcy, VITAMINS, AUTOANTIBODIES AGAINSTOx-LDL, AND TBARS
The concentrations of p-tHcy, the autoantibodies against Ox-LDL, TBARS, and {alpha}-tocopherol were significantly higher in the patients than the healthy control subjects (Table 3 ). The concentrations of vitamin B6 (pyridoxal-5-phosphate) and ß-carotene were significantly lower in the patients than the healthy control subjects (Table 3 ).


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  		Table 3. Concentrationsa of p-tHcy, vitamins, Ox-LDL, and TBARS in plasma from patients with PVD and healthy control subjects.

regression analyses
The univariate analyses demonstrated significant positive correlation of log p-tHcy with log plasma copper (coefficient ± SE, 0.347 ± 0.113; P = 0.0026) and total cysteine (coefficient ± SE, 0.822 ± 0.21; P = 0.0002). There was a significant negative correlation of log p-tHcy with serum folate, vitamin B12, vitamin B6, ß-carotene, and arsenic (Table 4 ). Significantly correlated variables obtained in this study were included in a multivariate regression analysis (r = 0.75; P <0.0001 for the model). In this model, p-tHcy in all subjects was positively correlated with copper (coefficient ± SE, 0.422 ± 0.108; P = 0.0002) and total cysteine (coefficient ± SE, 0.664 ± 0.199; P = 0.001) and negatively correlated with serum folate (coefficient ± SE, -0.397 ± 0.070; P <0.0001). When this population material was split into patients and controls, a strong positive correlation between p-tHcy and copper (coefficient ± SE, 0.490 ± 0.151; P = 0.0025) and a strong negative correlation with serum folate (coefficient ± SE, -0.460 ± 0.104; P <0.0001) was detected in the patients. In the healthy control subjects, p-tHcy correlated negatively with folate and positively only with total cysteine (Table 5 ).


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  		Table 4. Univariate linear regression analyses for the relationship between log tHcy (dependent variable) and log vitamins and log trace elements (independent variables).


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  		Table 5. Multivariate regression analysisa for the relationship between log tHcy (dependent variable) and log vitamins and trace elements (independent variables).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The major finding of the present study is the detection of a strong positive correlation between p-tHcy and copper in patients with PVD. A strong correlation between plasma homocysteine and copper may indicate that they have a significant impact on the process of atherogenesis. Because it was demonstrated that an interaction between copper and homocysteine enhanced the inhibitory action of homocysteine on NO-mediated relaxation of isolated aortic rings of rats, it has been suggested that superoxide and hydrogen peroxide generation by copper-catalyzed reactions may have participated in the process (22). Homocysteine in the presence of a transition metal can mediate oxidation of LDL in vitro, and its synergistic effects with copper may be associated with retarded cell growth, probably attributable to oxidative stress (23)(24)(25)(26). Because thiols have an affinity for metal ions such as copper and iron, a steady increase in the concentrations of plasma homocysteine may eventually contribute to increased copper concentrations in patients with PVD (27)(28). It has been observed that copper ions bind to LDL particles and that LDL particles can be thiolated with homocysteine (29)(30)(31). Increased concentrations of homocysteine and copper may participate in the oxidation of LDL, and as a consequence, they may contribute to increased Ox-LDL and TBARS, as detected in the present study. This conclusion is supported by previous investigations, which indicated that free copper ions in contrast to bound copper ions may not function as a catalyst of LDL oxidation in the artery wall and that metal-dependent acceleration of LDL oxidation by macrophages may be augmented by the presence of thiols in the medium (32)(33).

Our results regarding the concentrations of TBARS in patients with PVD are contrary to some published studies (34)(35). Blom et al. (34) detected higher concentrations of TBARS in healthy subjects compared with patients with a deficiency in cystathionine ß-synthase. However, it seems that low concentrations of homocysteine in the presence of copper ions enhance lipid peroxidation of LDL, whereas high concentrations of homocysteine protect LDL against oxidative modification (prooxidant and antioxidant roles) (36). In an animal model, hyperhomocysteinemia attributable to exposure to nitrous oxide (N2O) was associated with induction of tissue lipid peroxidation (37). Increased concentrations of p-tHcy and hyperhomocysteinemia attributable to methionine loading were associated with increased concentrations of malondialdehyde and plasma F2-isoprostane (38)(39). F2-isoprostanes belong to a class of prostaglandin-like compounds that are produced by free radical-mediated lipid peroxidation of arachidonic acid independent of cyclooxygenase (40).

Optimal concentrations of antioxidant vitamins ({alpha}-tocopherol, ß-carotene, and vitamin A), B vitamins (vitamin B6, vitamin B12, and folate), and selenium may be protective against peroxidation of lipids and induction of hyperhomocysteinemia and thus provide a decreased risk of CVD. Deficiency of these elements may be associated with increased oxidation of lipids and development of hyperhomocysteinemia and increased risk of CVD (41)(42)(43)(44)(45). This is probably relevant because the concentrations of plasma vitamin B6 and ß-carotene in all patients, and concentrations of selenium in patients with suprainguinal disease were significantly lower, whereas the concentrations of p-tHcy in all patients and copper in patients with suprainguinal disease were significantly higher than those in healthy control subjects.

The finding of the present study, namely that the patients had lower concentrations of plasma vitamin B6, may have at least two pathogenic effects. Deficiency of vitamin B6 is associated with both hyperhomocysteinemia and defective cross-linking of collagen and elastin (7)(46).

A negative correlation between homocysteine and folate, vitamin B6, and vitamin B12 may be expected because these vitamins function as coenzymes in the metabolism of homocysteine. Although copper does not seem to be involved in the metabolism of homocysteine, its correlation to homocysteine seems to be as strong as that of homocysteine to folate. No correlation between total cysteine and copper was detected. These observations suggest a possible significant role of copper and homocysteine, but not cysteine, in the process of atherogenesis.

The increases in the concentrations of the trace elements copper and iron in patients with CVD have been shown in several studies (5)(47)(48)(49)(50)(51). Copper and iron may participate in the Fenton reaction for the production of free radicals, but the roles of other trace elements in Fenton chemistry remain to be investigated. Therefore, the cause-effect association of these trace elements with CVD requires more investigation. There are also indications that the concentrations of some trace elements change with time in patients with, for example, myocardial infarctions (52). Cigarette smoking may also contribute in creating an imbalance in the concentrations of some plasma trace elements (53). The number of smokers was higher in the patient group than the healthy group (Table 1Up ).

In conclusion, the present study is a systematic investigation of factors associated with increased concentrations of p-tHcy, the correlation of homocysteine with copper and the products of peroxidation that may be produced by the homocysteine-copper interaction, and a deficiency of antioxidants, a decreased biochemical protection for vital components in plasma or increased risk for CVD. We therefore suggest that the atherogenicity of homocysteine may be related to copper-dependent interactions. More studies are required to investigate the combined pathophysiological mechanisms of homocysteine and copper pathogenicity. We propose that reduction of plasma homocysteine and copper with both B vitamins and metal chelators may usefully be evaluated in patients with CVD.


   Acknowledgments
 
We thank Dr. A. Demos for measuring TBARS, {alpha}-tocopherol, ß-carotene, and vitamin A in our plasma samples.


   Footnotes
 
1 Nonstandard abbreviations: p-tHcy, plasma total homocysteine; CVD, cardiovascular disease; TBARS, thiobarbituric acid-reactive substance; PVD, peripheral vascular disease; and Ox-LDL, oxidized LDL.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Interactive Effects of Homocysteine and Copper on Angiogenesis in Porcine Isolated Saphenous Vein
Ann. Thorac. Surg., July 1, 2007; 84(1): 43 - 49.
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C. Koksal, M. Ercan, A. K. Bozkurt, T. Cortelekoglu, and D. Konukoglu
Abdominal Aortic Aneurysm or Aortic Occlusive Disease: Role of Trace Element Imbalance
Angiology, April 1, 2007; 58(2): 191 - 195.
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G. J. Brewer
Iron and Copper Toxicity in Diseases of Aging, Particularly Atherosclerosis and Alzheimer's Disease
Experimental Biology and Medicine, February 1, 2007; 232(2): 323 - 335.
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C. Brasselet, R. Garnotel, A. Lafont, S. Perotin, F. Vitry, E. Durand, L. Ducher, J. Elaerts, D. Metz, and P. Gillery
Prepercutaneous Coronary Intervention Plasma Homocysteine Concentration Is a Useful Predictor of Angioplasty-Induced Myocardial Damage
Clin. Chem., December 1, 2005; 51(12): 2374 - 2377.
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S. Gonzalez, J. M. Huerta, J. Alvarez-Uria, S. Fernandez, A. M. Patterson, and C. Lasheras
Serum Selenium Is Associated with Plasma Homocysteine Concentrations in Elderly Humans
J. Nutr., July 1, 2004; 134(7): 1736 - 1740.
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J. Y. Jeremy, N. Shukla, G. D. Angelini, A. Day, I. Y.P. Wan, S. P. Talpahewa, and R. Ascione
Sustained increases of plasma homocysteine, copper, and serum ceruloplasmin after coronary artery bypass grafting
Ann. Thorac. Surg., November 1, 2002; 74(5): 1553 - 1557.
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V. A. Ploplis, I. Cornelissen, M. J. Sandoval-Cooper, L. Weeks, F. A. Noria, and F. J. Castellino
Remodeling of the Vessel Wall after Copper-Induced Injury Is Highly Attenuated in Mice with a Total Deficiency of Plasminogen Activator Inhibitor-1
Am. J. Pathol., January 1, 2001; 158(1): 107 - 117.
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Mohammad Mansoor
Clinical Chemistry Online, 29 May 2001 [Full text]
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