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Clinical Chemistry 47: 887-892, 2001;
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(Clinical Chemistry. 2001;47:887-892.)
© 2001 American Association for Clinical Chemistry, Inc.

Articles

Oxidative Stress and Homocysteine in Coronary Artery Disease

Viviana Cavalca1a, Giuliana Cighetti2, Fabrizia Bamonti3, Alessandro Loaldi1,4, Luana Bortone2, Cristina Novembrino3, Michela De Franceschi4, Romualdo Belardinelli5 and Maurizio D. Guazzi1,4

1 Istituto di Cardiologia, Università degli Studi di Milano, via Parea 4, 20138 Milan, Italy.

2 Dipartimento di Chimica Medica e Biochimica, Università degli Studi di Milano, via Saldini 50, 20133 Milan, Italy.

3 Dipartimento di Scienze Mediche, Università degli Studi di Milano, via F. Sforza 35, 20122 Milan, Italy.

4 IRCCS–Centro Cardiologico, Fondazione Monzino, via Parea 4, 20138 Milan, Italy.

5 Dipartimento di Cardiologia e Cardiochirurgia "G.M. Lancisi", via Baccarani 6, 60100 Ancona, Italy.

aAuthor for correspondence. Fax 39-02-58011194; e-mail viviana.cavalca{at}unimi.it.


   Abstract
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 Abstract
Introduction
 Materials and Methods
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 Discussion
 References
 
Background: Oxidative stress is present in cardiovascular diseases (CVDs), and hyperhomocysteinemia, an independent risk factor for these diseases, may play a role by inducing production of oxygen free radicals.

Methods: To evaluate the possible role of homocysteine (Hcy) in inducing oxidative stress in coronary artery disease (CAD), plasma Hcy was measured in 68 consecutive cardiovascular patients, and plasma malondialdehyde (MDA), both free and total (free + bound), was measured in 40 patients with CAD (18 with chronic stable angina and 22 with unstable angina). As controls, we tested 70 healthy volunteers. Hcy was measured by an immunoenzymatic method and MDA, an index of lipid peroxidation, by gas chromatography–mass spectrometry.

Results: Plasma Hcy concentrations were significantly higher in cardiovascular patients than in controls (10.2 vs 8.9 µmol/L; P <0.0002), with no significant difference between values in the stable and unstable angina subgroups. Similarly, total MDA was significantly higher in the CAD group than in the controls (2.6 vs 1.3 µmol/L; P <0.00001), again with no significant difference between stable and unstable angina patients. By contrast, free MDA, which was significantly higher in the CAD patients than the controls (0.4 vs 0.2 µmol/L; P <0.00001), was also significantly higher in the unstable than in the stable angina group (0.5 vs 0.3 µmol/L; P <0.03). However, no correlation was observed among Hcy and free and total MDA.

Conclusions: Our findings show that a moderate increase of Hcy is associated with CVD but that Hcy at the detected values cannot be considered completely responsible for oxidative damage. That lipid peroxidation is involved in CAD is shown by our observation of significantly increased plasma free and total MDA concentrations compared with controls. Moreover, free MDA values discriminated between unstable and chronic stable angina, and could thus represent a new diagnostic tool.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Epidemiologic studies support a positive association between plasma homocysteine (Hcy)1 concentrations and risk for cardiovascular disease (1)(2). Recent data have shown that hyperhomocysteinemia can be detected in 30% and 42% of patients with coronary artery and cerebrovascular diseases, respectively (3), in agreement with the Hcy theory of atherosclerosis proposed by McCully and Wilson (4). The possible atherogenic mechanisms are summarized in Table 1 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Moreover, some investigators have postulated that Hcy might cause atherosclerosis by damaging the endothelium either directly or by altering oxidative status. Although the mechanism for endothelium damage is not completely understood, it has been suggested that hyperhomocysteinemia may promote the production of hydroxyl radicals, known lipid peroxidation initiators, through Hcy autooxidation and thiolactone formation (10)(19)(20).


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  		Table 1. Hyperhomocysteinemia: possible atherogenic mechanisms.

Among the compounds with terminal carbonyl groups that result from lipid peroxidation (21)(22)(23), malondialdehyde (MDA), which is widely used as an index of oxidative damage (22)(24), has received particular attention in pharmacological studies for its ability to interact with lipoproteins. These modified lipoproteins are taken up by macrophages, which are transformed into foam cells that contribute to atherosclerotic plaque development (25) and progression of atherogenesis (26).

In biological matrices, MDA exists as both the free form and bound to nucleophilic (SH or NH2) groups of enzymes, amino acids, proteins, and nucleic acids (22). Only low amounts of free MDA are present in biological samples; thus, the more abundant total (free + bound) MDA usually is determined from its reaction with thiobarbituric acid (27). However, in our opinion, the course of a disease could be better monitored by measuring both free and total MDA, the former being an index of both recent and potential damage and the latter of old damage. Thus, in the present study, we used a highly sensitive and specific method, based on gas chromatography–mass spectrometry, that measures both MDA forms (28).

Because a relationship may be hypothesized between Hcy and MDA, the aim of this study was to investigate the relationship between homocysteinemia and oxidative stress in patients with coronary artery disease (CAD) by evaluating free and total MDA concentrations as indexes of oxidative stress.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Sixty-eight consecutive patients (49 men and 19 women; mean age, 56.4 ± 3.4 years) with CAD were studied. The patient group included 22 with unstable angina (group B of the Braunwald classification) and 18 with stable effort angina (no changes in the pattern of angina for at least 2 months before the study and stable ischemic response to a repeated stress test). Twenty-four-hour Holter monitoring was carried out on the patients with stable angina to exclude those with spontaneous ischemic episodes. The 28 remaining patients had heterogeneous ischemic symptoms impossible to classify with certainty as stable or unstable angina, or had an episode of acute myocardial infarction more than 2 months previously.

Patient exclusion criteria were acute or chronic inflammatory disease, immunological disease, diabetes mellitus, metabolic diseases, history or presence of neoplastic disease, age over 70 years, heart failure, recent major surgical procedure, administration of drugs influencing plasma Hcy concentrations, and established deficiency of vitamin B12 or folate (29).

A control group of 70 subjects (50 men and 20 women; mean age, 54.3 ± 3.1 years) was recruited from a large population of healthy volunteer blood donors or former donors, all participating in a health survey program. The patients and controls were well matched not only for age and sex but also for smoking habit (36% of CAD patients and 38% of controls were smokers) and alcohol consumption (reported by 15% of CAD patients and 20% of controls) habits. The last two variables were considered because they are involved in the clinical instability of CAD (30) and in peroxidative stress (31), respectively. All patients and controls signed consent forms, and the procedures followed were approved by our institution’s responsible committee.

Peripheral blood samples were collected on ice from fasting subjects into evacuated tubes containing EDTA as anticoagulant. Plasma was separated within 30 min in a refrigerated centrifuge at 4 °C and stored at -80 °C until analysis.

The plasma Hcy concentration was measured in all 68 patients, and MDA was measured in the 40 angina patients.

hcy assay
Plasma Hcy was measured by a fluorescence polarization immunoassay (Homocysteine; Abbott) on an automated analyzer (IMx system; Abbott). Optimal procedures in blood sample collection and handling were followed to prevent the passage of Hcy from red cells to plasma and thus ensure reliable measurements. The cutoff separating normal from abnormally increased plasma concentrations in our laboratory is 11.6 µmol/L, which is in agreement with the literature; hyperhomocysteinemia was classified as mild (11.7–16 µmol/L), moderate (16.1–30 µmol/L), intermediate (30.1–100 µmol/L), and severe (>100 µmol/L), as reported (32)(33)(34).

mda assay
Free and total (free + bound) plasma MDA was determined using selected-ion monitoring gas chromatography–mass spectrometry in the electron impact mode as recently reported by Cighetti et al. (28). Synthesized MDA-d2, used as internal standard, was added to the plasma samples before manipulation for analysis. For free MDA determination, 0.2 mL of plasma was diluted with 0.4 mol/L citric buffer (pH 4.0) added to 0.5 mmol/L butylated hydroxytoluene (5 nmol), 0.25 nmol of MDA-d2 was then added, and the sample derivatized with 1 µmol of phenylhydrazine for 30 min at room temperature (final volume, 0.5 mL). The stable derivative (phenylpyrazole) was extracted with hexane and measured by gas chromatography–mass spectrometry. The butylated hydroxytoluene was added to the samples as an antioxidant.

For measurement of total MDA, 0.2-mL plasma samples, prepared and analyzed as described for free MDA, were hydrolyzed in the presence of 1 mol/L NaOH at 60 °C for 60 min before the derivatization step. Pure MDA, crystallized as the sodium salt (35), and MDA-d2 were used for calibration curves.

statistical analysis
Data were analyzed using a SPSS program licensed to Prof. Liverani, Istituto di Igiene e Medicina Preventiva, Università degli Studi di Milano. The Wilcoxon test was used for statistical analysis of nonparametric values; ANOVA and the Dubin-Watson test were used for regression analysis. Differences were considered significant at P <0.05. All results are reported as median values.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Plasma Hcy concentrations were significantly higher in our cardiovascular patients than in controls (10.2 vs 8.9 µmol/L; P <0.0002; Fig. 1A ). According to our cutoff, 22 patients (33%) and 10 controls (15%) had hyperhomocysteinemia.



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  		Figure 1. Distribution of plasma Hcy (A) and of total (B) and free (C) MDA in patients with cardiovascular disease (CVD) and controls. #, P <0.001.

As shown in Fig. 1BUp , total plasma MDA was twice as high in cardiovascular patients as in the controls (2.6 vs 1.3 µmol/L; P <0.00001). All of the patients but only 12 controls (17%) had a total MDA value over the cutoff used in our laboratory (1.64 µmol/L). The same twofold increase was observed in plasma free MDA concentrations (0.4 and 0.2 µmol/L in the patients and controls, respectively; P <0.00001) as shown in Fig. 1CUp . At our cutoff (0.35 µmol/L), 37 patients (55%) and 12 controls (17%) had increased free MDA.

The tested variables in the subgroups with stable and unstable angina are compared in Fig. 2 . Plasma Hcy and total MDA concentrations did not differ significantly between the two subgroups. Both subgroups included the same proportion of patients (33%) with hyperhomocysteinemia (median Hcy, 10.2 and 10.4 µmol/L in the stable and unstable angina patients, respectively). The significant difference in Hcy compared with the controls was maintained (P <0.02 and P <0.03 for stable and unstable angina patients, respectively).



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  		Figure 2. Plasma Hcy and total and free MDA concentrations (in µmol/L) in patients with stable ({square}) and unstable () angina. #, P <0.01.

Similarly, total MDA did not differ in the stable and unstable angina subgroups (2.4 and 2.7 µmol/L, respectively), whereas free MDA was significantly higher (0.3 vs 0.5 µmol/L; P <0.03). MDA concentrations above our cutoff were observed in 16 of 22 (72%) patients with unstable angina compared with 5 of 18 (30%) of those with stable angina. In both subgroups, total and free MDA concentrations were significantly higher than in the controls.

Regression analysis revealed no correlation among Hcy and total and free MDA plasma concentrations regardless of the way the variables were considered (r = 0.004, confirmed by a Dubin-Watson test value of 1.932).


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Various authors have proposed that hyperhomocysteinemia and lipid peroxidation play a role in the genesis of atherosclerosis and heart disease (1)(2)(3)(4). It has also been suggested that high Hcy concentrations, via the formation of thiolactone, may be responsible for the production of oxygen free radicals and a consequent increase in lipid peroxidation (10)(19)(20). The present study was therefore performed to evaluate the possible role of Hcy in the production of oxygen free radicals in CAD patients with stable and unstable angina, using MDA concentrations as an index of oxidative status. Moreover, simultaneous measurement of total and free MDA allowed us to distinguish between old and recent damage.

Our study showed significantly higher plasma Hcy concentrations in our cardiovascular patient population as a whole and in the stable and unstable angina subgroups considered separately than in the controls, and confirmed the presence of mild hyperhomocysteinemia in 33% of the patients, as reported by other authors (3). Our patients had adequate serum folate, vitamin B12, and B6 status (data not shown), and factors that could justify the borderline Hcy values, such as renal dysfunction (36) and drugs (e.g., corticosteroids, cyclosporine), were absent. However, Hcy concentration alone did not discriminate between acute and chronic disease.

The involvement of lipid peroxidation in CAD was confirmed by the significantly higher plasma concentrations of total and free MDA observed in our CAD patients compared with the controls. In agreement with Mendis et al. (37), we found that total MDA, although higher in the unstable and stable angina subgroups than in the controls, did not differentiate between the acute and chronic forms of the disease. However, Kostner et al. (38) reported high MDA values in CAD and unstable angina patients without differences between stable angina patients and controls. Pucheu et al. (39) also observed no difference between stable angina patients and controls; moreover, they noted an increase in MDA in patients with acute myocardial infarction only after thrombolysis. In our opinion, the reported discrepancies in both results and absolute values could be related to the different methodologies used. Furthermore, none of the cited authors differentiated between total and free MDA. In fact, because the methods commonly used for plasma MDA measurements are based on the reaction with thiobarbituric acid, which requires a high temperature and strong acid conditions for derivatization (22)(27), they measure only total MDA, or free MDA only after adequate protein precipitation.

In our study, both free and total MDA were determined simultaneously by a recently reported gas chromatographic–mass spectrophotometric method (28), which is based on isotopic dilution and thus avoids the need for correction for efficiency of derivatization and extraction recovery. Moreover, the weak acid conditions in the derivatization step minimize lipid peroxidation, artifact formation, and the release of MDA. The high concentrations of both total and free MDA in all patients indicated increased membrane lipid peroxidation and potential further oxidative damage. Moreover, free MDA was significantly higher in the unstable angina group than in the stable angina group. Our findings support the possibility of recent oxidative stress in unstable angina, in agreement with the increased MDA-modified LDL found in such patients by Holvoet et al. (40) that is associated with the enhanced inflammation that characterizes this disease. Thus, free MDA could be a useful index to discriminate between unstable and chronic stable angina. Clinical studies are being performed to clarify the relationship between free MDA and the clinical characteristics of unstable angina.

Regarding the relationship between Hcy and MDA, some authors have reported increased oxidative stress after methionine loading (41) and in rabbits after methionine-enriched diet for 6 or 9 months (42). However, our results agree with those of Hanratty et al. (43), who found no change in the Hcy concentration and the reaction with thiobarbituric acid in healthy volunteers after the first administration of methionine or after 1 month of treatment (250 mg four times daily). Methionine administration (0.1 g/kg) for 1 week led to a moderate hyperhomocysteinemia that did not impair oxidative status. In our study, no correlation was found between Hcy and MDA concentrations. This could be because hyperhomocysteinemia was classified as mild in 52% of the cases and moderate in 37%. Thus, it appears that the correlation between Hcy and MDA occurs only at high Hcy concentrations, as reported by Ventura et al. (41), who observed a mean Hcy concentration of 54.3 µmol/L after methionine loading. To confirm this hypothesis, studies are in progress on the relationship between Hcy and MDA in hyperhomocysteinemic patients with various diseases.

In conclusion, our findings show that CAD is associated not only with mild or moderate hyperhomocysteinemia but also with increased MDA concentrations. The lack of correlation between Hcy and MDA in CAD indicates that Hcy is not entirely responsible for the oxidative damage in this disease. An original observation deriving from this study is that free, rather than total MDA constitutes a more adequate index to follow the lipid peroxidation pattern in patients with CAD. Moreover, increased plasma concentrations of free MDA could be useful in clinical practice to monitor progression of the disease and to optimize medical therapy.


   Acknowledgments
 
This study was in part supported by MPI 60% Grant 12-1-5124085-20. We thank Prof. A. Liverani for statistical assistance, Loredana Boccotti for technical assistance in preparing and storing samples, and Alix Green for linguistic consultation.


   Footnotes
 
1 Nonstandard abbreviations: Hcy, homocysteine; MDA, malondialdehyde; and CAD, coronary artery disease.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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