CLINICAL STUDY: CHRONIC CORONARY ARTERY DISEASE
Plasma homocysteine levels and late outcome after coronary angioplasty
Guido Schnyder, MD ,*,
Yvonne Flammer, MD*,
Marco Roffi, MD ,
Riccardo Pin, MD* and
Otto Martin Hess, MD*
* Division of Cardiology, Swiss Cardiovascular Center Bern, University Hospital, Bern, Switzerland
Department of Cardiovascular Medicine/F25, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
Division of Cardiology, University of California at San Diego Medical Center, University of California, San Diego, California, USA
Manuscript received March 21, 2002;
revised manuscript received June 24, 2002,
accepted July 12, 2002.
* Reprint requests and correspondence: Dr. Guido Schnyder, University of California at San Diego Medical Center, Cardiology Division, 200 West Arbor Drive, San Diego, California, 92103-8784, USA.
g.schnyder{at}lycos.com
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Abstract
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OBJECTIVES: The aim of this study was to evaluate a possible relationship between homocysteine levels on admission and late outcome after successful percutaneous coronary intervention (PCI).
BACKGROUND: Increasing evidence suggests that mild to moderate elevation of total plasma homocysteine is a graded and potentially modifiable risk factor for cardiovascular disease and death that appears to be largely independent of other traditional risk factors.
METHODS: A total of 549 patients were included after successful PCI of at least one coronary stenosis ( 50%). End points were cardiac death, nonfatal myocardial infarction (MI), target lesion revascularization (TLR), and a composite of major adverse cardiac events (MACE). The relationship between homocysteine levels and study endpoints was assessed.
RESULTS: After a median (± SD) follow-up of 58 ± 20 weeks, 6 patients died of cardiac death, 14 were diagnosed with a new MI, and 71 underwent repeat TLR. A graded relationship between homocysteine levels (quartiles) and freedom from MACE was found (p = 0.01). Homocysteine levels (± SD) were associated with cardiac death (14.9 ± 1.7 µmol/l vs. 9.6 ± 4.3 µmol/l, p < 0.005), TLR (10.7 ± 4.4 µmol/l vs. 9.5 ± 4.3 µmol/l, p < 0.05), and overall MACE (11.0 ± 4.4 µmol/l vs. 9.4 ± 4.3 µmol/l, p < 0.005). These findings remained unchanged after adjustment for potential confounders.
CONCLUSIONS: Plasma homocysteine is an independent predictor of mortality, nonfatal MI, TLR, and overall adverse late outcome after successful coronary angioplasty.
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Abbreviations and Acronyms
| | CI | | confidence interval | | HDL | | high-density lipoprotein | | LDL | | low-density lipoprotein | | MACE | | major adverse cardiac events | | MI | | myocardial infarction | | PCI | | percutaneous coronary intervention | | RR | | relative risk | | TLR | | target lesion revascularization |
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Total plasma homocysteine has emerged as an important and potentially modifiable cardiovascular risk factor which correlates with the severity of coronary and carotid artery disease (1–5). Elevated homocysteine levels predict mortality, the occurrence of late cardiac events in patients with established coronary atherosclerosis, and the incidence of cerebrovascular accidents in middle-aged men and elderly patients (6–9). There are also some indications linking homocysteine levels with late lumen loss after percutaneous coronary intervention (PCI) or after carotid endarterectomy (10–13), whereby the exact mechanism is not clear but may be linked to homocysteine-induced myointimal hyperplasia, connective tissue proliferation, and endothelial dysfunction (12–15). However, in the light of some contradictory findings in prospective studies, this possible pathophysiologic mechanism between homocysteine levels and restenosis remains uncertain (16–18). Furthermore, there is growing belief that atherosclerotic disease itself may elevate homocysteine levels and that this emerging cardiovascular risk factor is only a silent bystander and should be considered a marker rather than a true risk factor (19). Encouraged by our previous findings of an association between angiographic restenosis and homocysteine levels, but with clinical end points not reaching statistical significance (11), we now report in an extension study with more than twice as many patients, the effect of homocysteine levels on late clinical outcome after successful PCI, with special regard to the traditional cardiovascular risk factors.
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Methods
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This was a prospective study enrolling 549 consecutive patients having undergone successful PCI of at least one native coronary stenosis (50%). The study population included a subgroup of 205 patients scheduled for six months follow-up angiography with quantitative results published elsewhere (11). Patients were not enrolled if they had recent myocardial infarction (MI) (<2 weeks), significant left main disease, were undergoing PCI of a bypassed native vessel with patent graft, had impaired renal function (serum creatinine >1.8 mg/dl), or were taking multivitamins. Fasting homocysteine levels were measured on admission using a rapid high-performance liquid chromatographic assay (20). Percutaneous coronary intervention was performed according to standard techniques, with success defined as residual diameter stenosis <50% with Thrombolysis in Myocardial Infarction flow grade 3 pattern. Angiographic evaluation was performed using an automated edge-detection system (Philips Integris-BH-3000, Version 2, if online or Philips View-Station-CDM-3500, Version 2, if offline; Philips, Best, The Netherlands) with techniques described elsewhere (11). Patients were recruited between September 1997 and May 1998. Written informed consent was obtained from each patient. This study was approved by the Institutional Review Board of the University Hospital in Bern, Switzerland.
Follow-up and study end points.
Resting electrocardiogram and noninvasive stress test were performed at one-year follow-up, or earlier if symptoms recurred. Adverse events were defined as: 1) death from any cause; 2) cardiac death, defined as sudden, unexplained death, or death related to MI; 3) nonfatal MI, defined as new Q waves (>40 ms; >0.2 mV) in two or more contiguous electrocardiographic leads; 4) ischemia-driven target lesion revascularization (TLR) with angiographic restenosis 50%; and 5) a composite of major adverse cardiac events (MACE) defined as any of the above cardiac events. Patients who had more than one lesion treated by PCI were defined as having TLR if at least one dilated lesion fulfilled revascularization criteria. Finally, patients with more than one event had only the first occurring event computed for overall MACE determination.
Statistical analysis
A sample size of 540 patients (135 patients in each homocysteine quartile) was calculated to detect a 15% absolute difference in MACE rates between the highest and lowest homocysteine quartiles. Assuming a 15% dropout rate, the planned sample size would yield 460 patients with complete follow-up and give the study a statistical power of 0.90 at a significance level of 0.05. Plasma homocysteine levels were not normally distributed (skewness: 1.61) and, therefore, were log-transformed before analysis. Results were shown in natural units. Plasma homocysteine was first considered as a continuous value and then as a categorical variable divided into quartiles to examine the between-quartile relationship with end points. Continuous variables are reported as mean ± SD. Categorical variables are reported as counts (percentages) and compared between groups using a chi-square test. Continuous variables were examined by a two-tailed t test or by the Mann-Whitney U test if not normally distributed. The Spearman rank correlation coefficient was used to estimate the correlation between homocysteine levels and different continuous variables. Baseline characteristics were compared over homocysteine quartiles with a chi-square test or Fisher exact test when appropriate for categorical variables, and a one-way analysis of variance was used for continuous variables. The Bonferroni t test was use for multiple comparisons between continuous variables and homocysteine quartiles. Freedom from MACE was analyzed by means of Kaplan-Meier curves, with differences between homocysteine quartiles assessed with the Mantel-Cox log-rank test. Cox proportional-hazards regression models were used to examine the relationship between plasma homocysteine and the different end points, after adjustment for multiple clinical and angiographic covariates significantly associated with each end point in univariate analysis. A two-sided 5% level of significance was considered significant for all statistical tests. Data were prospectively collected and analyzed using StatView Version 4.5 (SAS Institute, Cary, North Carolina).
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Results
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A total of 549 patients were consecutively included after successful PCI of at least one coronary stenosis (50%), with a total of 732 successfully treated lesions. Of the patients, 45 did not complete full follow-up criteria, 41 refused noninvasive stress testing, and 4 with proven ischemia refused re-angiography. This left a total of 504 patients (91.8%) with complete one-year follow-up. In terms of baseline clinical, laboratory, and angiographic criteria, the 45 patients without complete follow-up did not significantly differ from the remaining population.
Clinical and angiographic characteristics.
The study population had a mean age of 62 years with an overall proportion of women of 20% (Table 1). Patients in the fourth homocysteine quartile were significantly older (64 years) and less likely to be women (14%). The highest proportion of women (27%) was found in the first quartile. The distribution of cardiovascular risk factors was similar throughout all quartiles. The severity of the coronary artery disease (as measured by the number of vessels with at least one significant stenosis [50%]) increased steadily over the quartiles. Furthermore, there were significantly fewer patients with a history of MI in the first quartile. Patients in the first quartile had also significantly lower serum creatinine and higher high-density lipoprotein (HDL) cholesterol levels. The mean (± SD) study homocysteine level was 10.1 ± 4.8 µmol/l, 1.1 µmol/l lower in women than in men (9.2 ± 4.9 µmol/l vs. 10.3 ± 4.6 µmol/l, p < 0.05) and increased 0.3 µmol/l for each additional 10 years of age (rs = 0.11, p < 0.01). Overall, homocysteine levels were significantly correlated with serum creatinine (rs = 0.22, p < 0.0001) and HDL cholesterol (rs = –0.15, p < 0.001). The mean (± SD) homocysteine level was also 1.1 µmol/l higher in patients with previous MI than in those without such a history (10.6 ± 5.0 µmol/l vs. 9.5 ± 4.6 µmol/l, p < 0.01). Finally, angiographic characteristics were comparable among the homocysteine quartiles (Table 2).
Study end points
After a mean (± SD) follow-up of 58 ± 20 weeks, 8 patients (1.6%) had died, 6 of them from cardiac origin (1.2%). All but one death and all six cardiac deaths had homocysteine levels in the fourth quartile (p < 0.05) (Table 3). Patients whose death was of cardiac origin had homocysteine levels 5.3 µmol/l higher than the remaining study population (p < 0.005) (Table 4). During follow-up, 14 patients (2.8%) had presented with a new nonfatal MI, and 11 of these patients had homocysteine levels in the upper two quartiles (p = 0.14) (Table 3). Patients with nonfatal MI had homocysteine levels 1.6 µmol/l higher than the remaining study population (p = 0.18) (Table 4). Over the course of the study, 71 patients (14.1%) had undergone TLR, 8.0% in the lowest and 18.9% in the highest homocysteine quartile (p < 0.05) (Table 3). Those patients had homocysteine levels 1.2 µmol/l higher than the remaining study population (p < 0.05) (Table 4). Finally, there was a graded relationship between homocysteine levels and the incidence of MACE. This composite end point was reached by 75 patients (14.9%), 8.0% in the lowest and 22.0% in the highest homocysteine quartile (p = 0.01) (Table 3). This relationship was also evident in the Kaplan-Meier curves for freedom from MACE at one year, with 92.0% of patients in the first homocysteine quartile free of any cardiac event, 88.6% in the second quartile, 82.2% in the third quartile, and 78.0% in the fourth quartile (Fig. 1), a relative risk (RR) increase between extreme quartiles of 2.8 (95% confidence interval [CI] = 1.34 to 5.67) (Fig. 2). These findings were reproduced in subgroups of patients stratified according to the traditional cardiovascular risk factors (gender, diabetes mellitus, hypertension, hypercholesterolemia, and smoking) (Fig. 2). The strongest RR increase between the first and fourth quartile was found in men, smokers, and hypercholesterolemic patients (RR = 3.00, 95% CI = 1.27 to 7.12; RR = 3.50, 95% CI = 0.73 to 9.62; and RR = 2.45, 95% CI = 1.13 to 5.30, respectively). Interestingly, even though the incidence of MACE was independent of levels of cholesterol, HDL cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (p = 0.93, p = 0.35, p = 0.31, and p = 0.45, respectively), there was a substantial RR increase between the first and the fourth homocysteine quartile in patients with LDL cholesterol in the upper 50th percentile (RR = 5.08, 95% CI = 1.49 to 17.33) as opposed to (RR = 1.32, 95% CI = 0.52 to 3.36) LDL cholesterol levels in the lower 50th percentile.
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Figure 1 Kaplan-Meier curves for freedom from major adverse cardiac events according to homocysteine quartiles. There is a strong dose-response relationship between homocysteine quartiles and the incidence of major adverse cardiac events, with 92.0% of patients in the first homocysteine quartile free of any cardiac event, 88.6% in the second quartile, 82.2% in the third quartile, and 78.0% in the fourth quartile (p < 0.05), a relative risk increase between extreme quartiles of 2.8 (95% confidence interval = 1.34 to 5.67).
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Figure 2 Relative risk of major adverse cardiac events according to homocysteine quartiles among total study population and subgroups of patients stratified according to the traditional cardiovascular risk factors. Squares indicates the relative risk (RR) of major adverse cardiac events for patients in the second, third, and fourth homocysteine quartile compared with patients in the first quartile; size of square is proportional to number of patients; and horizontal line indicates 95% confidence interval (CI); RRs are displayed on logarithmic scale. The strongest RR increase between the first and fourth quartile was found in men, smokers, and hypercholesterolemic patients (RR = 3.00, 95% CI = 1.27 to 7.12; RR = 3.50, 95% CI = 0.73 to 9.62; and RR = 2.45, 95% CI = 1.13 to 5.30, respectively).
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Additional covariates
Besides homocysteine levels, four other factors were univariate risk predictors for MACE: diabetes mellitus treated with oral hypoglycemics, treatment of restenotic lesions, vessel diameter, and post-PCI residual minimal luminal diameter (Table 5). After multivariate Cox regression analysis, only homocysteine levels (multivariate, p = 0.005), diabetes mellitus treated with oral hypoglycemics (multivariate, p = 0.004), and treatment of restenotic lesions (multivariate, p = 0.006) retained statistical significance. The same factors were also significantly associated with the need for TLR (Table 5), with similar results after multivariate analysis (homocysteine levels [multivariate, p = 0.02], diabetes mellitus treated with oral hypoglycemics [multivariate, p = 0.007], and treatment of restenotic lesions [multivariate, p = 0.003]). With regard to nonfatal MI, homocysteine quartiles and the number of diseased coronary arteries per patient were univariate risk predictors (Table 5), but only homocysteine quartiles retained statistical significance after multivariate analysis (multivariate, p = 0.04). Finally, death rates were dependent on homocysteine levels, the number of diseased coronary arteries per patient, and left ventricular ejection fraction (Table 5). After multivariate analysis, only left ventricular ejection fraction (multivariate, p = 0.046) and homocysteine levels (multivariate, p = 0.008) remained independent predictors of cardiac death, while only plasma homocysteine (multivariate, p = 0.009) retained statistical significance for overall death. Similar results were obtained when patients in the two lower homocysteine quartiles were compared with patients in the two higher quartiles.
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Discussion
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Elevated homocysteine levels have been shown to predict mortality, the occurrence of late cardiac events in patients with established coronary atherosclerosis, and the incidence of cerebrovascular accidents (6–9). This study now provides the first prospective evidence that homocysteine levels also predict long-term outcome after PCI. Plasma homocysteine is not only a significant predictor of TLR but also of mortality, nonfatal MI, and overall MACE after successful PCI. Furthermore, this observed association appeared to be independent of other known risk factors for impaired outcome after PCI and could be reproduced in subgroups of patients stratified according to the traditional cardiovascular risk factors, clearly demarcating the effect of elevated homocysteine levels from those very factors.
The pathogenesis of homocysteine-induced vascular injury and its possible role with regard to the adverse outcome after PCI are not clearly understood. Nevertheless, increasing evidence suggests that the primary mechanism may be oxidative-endothelial injury and dysfunction (15,21). Homocysteine is rapidly auto-oxidized when added to plasma, forming potent reactive oxygen species, including superoxide and hydrogen peroxide (22). Auto-oxidation of homocysteine not only increases the generation of hydrogen peroxide but also decreases its degradation by impairing intracellular endothelial antioxidant enzymes, thus rendering nitric oxide more susceptible to oxidative inactivation (23). Furthermore, homocysteine auto-oxidation has been shown to promote lipid peroxidation (24), which enhances platelet-derived growth factor gene expression and receptor formation in vascular smooth muscle cell (25). Finally, elevated homocysteine levels may enhance vascular constrictive remodeling by inactivating peroxisome proliferator-activated receptors in endothelial cells and smooth muscle cells (26). All this ultimately increases smooth muscle cells proliferation and chemoattraction (27). Therefore, homocysteine-induced endothelial dysfunction, lipid peroxidation, and inactivation of peroxisome proliferator-activated receptors may promote smooth muscle cell proliferation, extracellular matrix formation, and ultimately increase the need for repeat TLR and overall MACE after PCI. Our findings of a substantial increase in RR of composite end points between extreme homocysteine quartiles in patients with higher LDL cholesterol levels and of only a modest increase with lower LDL cholesterol levels support this possible mechanism. Furthermore, homocysteine levels have been inversely associated with the development of collateral coronary circulation (28) and have been shown to alter the physiologic endothelial antithrombotic phenotype through interaction with coagulation factor V (29), protein C (30), tissue plasminogen (31), and tissue factor activity (32), which may trigger acute or late thromboses. This is supported by our findings of an increased rate of nonfatal MI and a higher mortality among patients with homocysteine levels in the highest quartile.
A critical question is whether the association of homocysteine levels with the outcome after PCI is causative. In the present study, plasma homocysteine was significantly correlated with age, serum creatinine, and HDL cholesterol, as well as significantly associated with gender and previous MI. Furthermore, the treatment of restenotic lesions, as well as lesions in diabetics treated with oral hypoglycemics were significantly associated with a worse outcome after PCI. Adjustment for all these factors did not weaken the predictive power of plasma homocysteine, suggesting an independent association with the outcome after PCI. Angiographic criteria such as larger vessel size and smaller minimal luminal diameter, as well as the use of stents and glycoprotein IIb/IIIa inhibitors have been shown to improve outcome after coronary angioplasty (33–35). Nevertheless, these angiographic characteristics and treatment modalities were similar in all study subgroups and are, therefore, unlikely to have affected our results.
Potential other limitations merit consideration. Having included some patients with a history of MI within the last six months may have increased homocysteine levels on admission (36). Even though this inclusion may have influenced absolute homocysteine levels, this should not have affected our final results, given that blood samples were drawn in a similar fashion for all study patients and rates of recent (<6 months) MI were comparable for all study subgroups.
Overall, this study’s findings seem compelling, but do they withstand the growing belief that atherosclerotic disease itself may elevate homocysteine levels, and that this emerging cardiovascular risk factor is only a silent bystander and should be considered a marker rather than a true cardiovascular risk factor (19)? In our study, the association between homocysteine levels and the outcome after PCI was independent of the traditional cardiovascular risk factors. Furthermore, the differences between the mechanism of restenosis (recoil, remodeling, and excessive neointimal hyperplasia) and the development of atherosclerotic lesions are highlighted by the lack of correlation of the traditional risk factors such as hypertension, smoking, and hypercholesterolemia with the incidence of restenosis. Only diabetes and elevated homocysteine levels influence restenosis, but most importantly, independently from one another. Concerns that elevated homocysteine levels are just a marker rather than a risk factor, therefore, are unwarranted with regard to restenosis. This independent relationship is further emphasized by similar findings after carotid endarterectomy (12,13) and, most importantly, by the recently published benefit of homocysteine-lowering therapy on angiographic restenosis (37).
In conclusion, with the exception of diabetes mellitus and technical procedural considerations, elevated plasma homocysteine seems to be the only known modifiable risk factor influencing late outcome after successful coronary angioplasty.
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Acknowledgments
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We thank the patients and their physicians for participation in this study. We are grateful for the cooperation of the Coronary Catheterization Laboratory staff and the nursing staff of the Swiss Cardiovascular Center in Bern.
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Footnotes
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David Faxon, MD was the guest editor for this paper.
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Abstract
Methods