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(Chest. 2004;126:1032-1039.)
© 2004 American College of Chest Physicians

Risk Stratification and Prognostic Implication of Plasma Biomarkers in Nondiabetic Patients With Stable Coronary Artery Disease*

The Role of High-Sensitivity C-Reactive Protein

Hsin-Bang Leu, MD; Chih-Pei Lin, DDS; Wen-Tasi Lin, BS; Tao-Cheng Wu, MD and Jaw-Wen Chen, MD

* From the Division of Cardiology, Department of Medicine (Drs. Leu, Wu, and Chen), and Department of Pathology (Dr. Lin and Ms. Lin), Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

Correspondence to: Jaw-Wen Chen, MD, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, 201, Sec. 2, Shih-Pai Rd, Taipei, Taiwan, ROC; e-mail: jwchen{at}vghtpe.gov.tw


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To evaluate the implication of plasma biomarkers to future cardiovascular events in nondiabetic patients with stable coronary artery disease (CAD).

Designs and settings: Prospective, follow-up study at a tertiary referral center.

Patients and measurement: Serial plasma biomarkers including high-sensitivity C-reactive protein (hsCRP), homocysteine, soluble adhesion molecules, von Willebrand factor, and lipid profiles were determined before coronary angiograms in a series of nondiabetic CAD patients with stable angina. Among them, 75 consecutive patients who received coronary revascularization (48 coronary interventions and 27 coronary bypass surgeries) later and another 75 age- and gender-matched patients who preferred medical treatment were both enrolled. In patients of each group, major cardiovascular events including cardiac death, nonfatal myocardial infarction, new or repeated coronary revascularization, and hospitalization for unstable angina, stroke, or peripheral artery disease were prospectively followed up for at least 6 months.

Results: Patients were followed up to 40 months (median, 18 months). The incidences of major cardiovascular events were similar between the two groups. For patients with medical treatment, plasma levels of hsCRP, homocysteine, low-density lipoprotein, and the ratio of total cholesterol (TC) to high-density lipoprotein cholesterol (HDL-C) were significantly higher in those with cardiovascular events than those without. However, only hsCRP > 0.1 mg/dL (relative risk [RR], 2.78; 95% confidence interval [CI], 1.21 to 6.41; p = 0.016) and TC/HDL-C ratio > 4.8 (RR, 2.42; 95% CI, 1.04 to 5.65; p = 0.041) were independent predictors by multivariable analysis. For patients with revascularization, basal plasma hsCRP levels were higher in those with cardiovascular events than those without (p = 0.04). However, no biochemical markers could predict future major cardiovascular events in these patients.

Conclusions: In nondiabetic patients with CAD, basal plasma hsCRP levels were increased with future cardiovascular events regardless of different treatment strategies. Both plasma hsCRP level and TC/HDL-C ratio independently predict future cardiovascular events, confirming the role of plasma biomarkers in clinical risk stratification especially in patients with medical treatment.

Key Words: cholesterol • coronary artery disease • C-reactive protein • high-density lipoprotein cholesterol • homocysteine


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
There is increasing evidence that inflammation may play an important role in the pathogenesis of atherosclerosis and its complication.1 Circulating inflammation markers and lipid profiles may be correlated with the disease activity and parallel the transition from stable lesions to vulnerable plaque. Recently, some novel plasma biomarkers such as high-sensitivity C-reactive protein (hsCRP), a sensitive marker of vascular inflammation, and homocysteine, a nonspecific risk factor of endothelial dysfunction, are used to assess the severity of atherosclerosis and to identify high-risk patients with coronary artery disease (CAD) for appropriate therapies.23 The association of an elevated plasma hsCRP level with future cardiovascular events has been shown in patients with unstable angina4 and previous myocardial infarction,5 in patients undergoing coronary angioplasty,6 and even in clinically healthy men.7

It is suggested, however, that homocysteine may eliminate the oxide bioavailability of nitric oxide and promoted endothelium to be "proatherogenic" by releasing proinflammatory cytokines.8 Though conflicting results were observed in some prospective studies,91011 homocysteine was suggested to predict recurrent vascular events, especially among individuals with preexisting cardiovascular disease.12 Further, circulating soluble adhesion molecules and von Willebrand factor (vWF), a marker of endothelial injury, were also reported to be associated with future adverse events in patients with CAD.13 Conventional cardiovascular risk factors such as diabetes mellitus, hypercholesterolemia, and smoking may contribute to inflammatory process in atherosclerosis.1 They may be also related to the elevated biochemical markers in patients with adverse events.1415

Although several plasma biomarkers are suggested to be associated with future cardiovascular events in patients with cardiovascular disease, little is known about the implication of these biomarkers to risk stratification in patients with stable CAD, the majority of patients in clinical practice. The aim of this study was then to investigate the impact of serial plasma biomarkers including hsCRP, homocysteine, soluble adhesion molecules, vWF, and lipid profiles to future cardiovascular events in a group of patients with stable CAD. Since different treatment might differentially modify the effect of plasma biomarkers and probably the clinical course during follow-up period, patients were investigated separately according to their treatment strategies: medical treatment or revascularization.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
A total of 227 consecutive nondiabetic patients with symptomatic CAD proved by coronary artery angiography (CAG) were initially evaluated between March 1999 and June 2001. All of the patients had a history of angina pectoris and/or chest pain with an abnormal ECG findings suggesting myocardial ischemia either at rest or during exercise, or both. In each patient, CAD was confirmed in at least one lesion with > 50% stenosis in luminal diameter on CAG according to the American College of Cardiology/American Heart Association lesion classification. Exclusion criteria were uncontrolled hypertension (BP > 160/90 mm Hg), documented diabetes mellitus, chronic liver disease, renal insufficiency, chronic systemic inflammation status, acute infection, acute myocardial infarction, or recent coronary intervention. In each patient, the treatment strategy was determined within 1 week after CAG. Patients were encouraged to receive coronary revascularization first if indicated. After a detailed discussion with the physician in charge, the patients chose to receive standard medical therapy for CAD or coronary revascularization, either percutaneous intervention (PCI) or coronary artery bypass grafting (CABG). All patients received coronary revascularization or medical treatment within 2 weeks after CAD was confirmed by CAG in the same hospital. If their clinical conditions could not be stabilized within 2 weeks after starting medical treatment or revascularization, the treatment was defined as "incomplete" and the patients were considered "unstable" and then excluded. Standard medical treatment was maintained in every patient including those undergoing coronary revascularization. Medication was adjusted if clinically indicated.

Thus, there were two separated groups of patients with different treatment strategies: medical treatment or coronary revascularization initially received for CAD. Firstly, 75 consecutive patients with initially stable conditions after successful revascularization (48 with PCI and 27 with CABG) were enrolled. They were then matched with another 75 patients receiving medical treatment according to age, gender, history, cardiovascular risk factors, and disease entities. The study protocol was approved by a hospital review board, and informed consent was obtained from each patient.

Blood Sampling
After overnight fasting, 20 mL of blood were collected from peripheral vessels just before CAG in each patient. The blood samples were either analyzed immediately for lipid profiles or stored in a – 20°C refrigerator until analysis for other biomarkers. Patients were excluded if they had received any drugs with antioxidant activity, vitamins, or food additives within 4 weeks before blood sampling.

Measurement of Lipid Profiles and Serum Biomarkers
The lipid profiles including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglyceride, and other biochemical parameters were measured using a Hitachi 7600–310 autoanalyzer (Hitachi; Tokyo, Japan). The low-density lipoprotein cholesterol (LDL-C) concentration was calculated using the Friedewald equation: LDL-C = TC – (HDL-C + triglyceride/5).16 The level of plasma homocysteine was determined by enzyme-linked immonosorbent assay (ELISA) method using a homocysteine enzyme immunoassay (Axis; Oslo, Norway). Plasma levels of hsCRP were determined by the ELISA method using an in vitro diagnostic assay (Dade Behring; Marburg, Germany). Human soluble cell intracellular adhesion molecule-1 (sICAM-1) and human soluble vascular cell adhesion molecule-1 (sVCAM-1) were determined by the ELISA method using the BioSource Cytoscreen sICAM-1 and sVCAM-1 kits (BioSource; Camarillo, CA), respectively. IMUBIND vWF ELISA kits (American Diagnostics; Stamford, CT) were used to determined the level of vWF. The procedures were carried out according to the instructions of the manufacturers.

Clinical Follow-up for Cardiovascular Events
The patients with initially stable conditions under treatment were prospectively followed up regularly in 2- to 4-week intervals for at least 6 months in the same cardiology clinics in a single hospital. For each patient, the occurrence of major cardiovascular events including cardiovascular death, nonfatal acute myocardial infarction, need for revascularization procedures, hospitalization for refractory or unstable angina, and hospitalization for other causes including stroke, transient ischemic attack, or peripheral arterial occlusive disorder were recorded. Myocardial infarction was confirmed if ischemic symptoms present with elevated serum cardiac enzyme levels and/or characteristic ECG changes. The coronary revascularization procedures with either PCI or CABG were confirmed by record review. The procedure-related events were also recorded. Stroke was defined if there was a new neurologic deficit lasting for at least 24 h with definite image evidence of cerebrovascular accident either by MRI or by CT. In all patients, the original medication was basically maintained until the development of adverse effects or cardiovascular events, if there were any.

Statistical Analysis
Data were expressed as mean (SD) if normally distributed, or as median (range) otherwise. The numerical variables and frequencies between groups were compared by Student t test, {chi}2 tests, and/or Mann-Whitney U test as appropriate. In order to evaluate the prediction ability of biochemical parameters on further cardiovascular events, receiver operating characteristics curves were constructed at the most discriminating cutoff point values. However, a serum level of LDL-C > 160 mg/dL or total cholesterol > 200 mg/dL was used as cutoff values for lipid profiles according to Adult Treatment Panel III guidelines.17 Univariate and multivariate Cox proportional hazards regression analyses were used to determine the independent predictors of end point in each group.18 The Kaplan-Meier method with log-rank test was performed to assess the difference of time course event-free survival between these groups; p < 0.05 was considered statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patient Characteristics
Table 1 shows the baseline characteristics of 75 patients receiving revascularization (48 patients with PCI and 27 patients with CABG) and another 75 patients receiving medical treatment. No significant differences were observed in age, gender, CAD risk factors, lipid profile, current medication, and the severity of CAD between the two groups. In addition, there were no significant differences between patients receiving CABG or those receiving PCI, except for multivessel disease (81.4% vs 48%, p = 0.04) and higher serum LDL-C levels (127 ± 26.2 mg/dL vs 111.6 ± 30 mg/dL, p = 0.03) in the former than in the latter group.


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  		Table 1.. Basic Characteristics of Patients Receiving Different Therapeutic Strategies*

 
Clinical Cardiovascular Events During Follow-up
Patients were observed up to 40 months (median, 18 months). All patients received aspirin, or ticlopidine if they could not tolerate or were allergic to aspirin. Other medications including antihypertensive agents and statin were not significantly different from those before the study. During the follow-up period, only 4% of patients receiving medical treatment and 4% of patients receiving coronary revascularization changed some of their original medication due to adverse drug effects. Among them, statins were stopped due to elevated liver enzyme in one patient, nitrate was discontinued due to severe headache in two patients, and angiotensin-converting enzyme (ACE) inhibitors were shifted to angiotensin I receptor blockers due to persistent cough in another three patients. As shown in Table 2 , the incidence of cardiac death, need for revascularization, and unstable angina were similar between medical treatment and revascularization groups. Although statistically insignificant, patients receiving medical treatment tended to have more future cardiovascular events (44% vs 34.6%, p = 0.21) and cardiac mortality (8% vs 1.3%, p = 0.12) than those receiving revascularization.


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  		Table 2.. Occurrence of Major Cardiovascular Events During Follow-up Period in Patients Receiving Medical Treatment or Revascularization*

 
Baseline Characteristics in Patients With and Without Cardiovascular Events During Follow-up
Table 3 shows the comparisons between patients with and without future adverse events in each group. In the revascularization group, patients with future adverse events had more severe CAD (p = 0.05) and higher plasma hsCRP values (p = 0.04) as compared to those without revascularization.


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  		Table 3.. Baseline Characteristics and Baseline Serum Biomarkers in Patients With or Without Clinical Events Related to Different Therapeutic Strategies*

 
In patients receiving medical treatment, baseline plasma levels of hsCRP (p = 0.02), homocysteine (p = 0.01), LDL-C (p = 0.03), and TC/HDL-C ratio (p = 0.005) were significantly higher in those with future cardiovascular events than in those without future cardiovascular events.

Predictors for Future Cardiovascular Events in Patients With Different Treatment Strategies
There was no significant association between plasma biomarkers and the time course of future cardiovascular events in patients receiving revascularization procedures. However, in the medical treatment group, plasma levels of homocysteine and hsCRP, and TC/HDL-C ratio had reasonable accuracy for adverse events by receiver operating characteristics curve analysis. The optimal cutoff point points of hsCRP and homocysteine were 0.1 mg/dL and 12 mg/dL, respectively. Patients with LDL-C levels > 160 mg/dL or TC/HDL-C ratios > 4.8 were also at higher risk for adverse events. Table 4 shows the predictors of future adverse events in patients receiving medical treatment. In univariate Cox analysis, a baseline serum level of hsCRP > 0.1 mg/dL (p = 0.002), homocysteine > 12 mg/dL (p = 0.017), LDL-C > 160 mg/dL (p = 0.019), TC/HDL-C ratio > 4.8 (p = 0.019), and the severity of CAD, especially triple-vessel disease (p = 0.02), were associated with increased risk of future cardiovascular events. However, by multivariate Cox proportional hazards analysis after adjusting age, gender, smoking status, history of hypertension, previous revascularization procedures, biochemical markers, and the severity of CAD, only hsCRP > 0.1 mg/dL (relative risk [RR], 2.78; 95% confidence interval [CI], 1.21 to 6.41; p = 0.016) and TC/HDL-C > 4.8 (RR, 2.42; 95% CI, 1.04 to 5.65; p = 0.041) were independent predictors of future cardiovascular events in patients receiving medical treatment.


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  		Table 4.. Predictors of Future Clinical Cardiovascular Events in Patients Receiving Medical Treatment

 
To demonstrate the relationship between the time course of future adverse cardiovascular events and plasma levels of hsCRP or TC/HDL-C ratio, Kaplan-Meier analysis was done for the patients with different values of hsCRP or TC/HDL-C ratio (Fig 1 ). Patients with baseline plasma hsCRP levels > 0.1 mg/dL (p = 0.0008) or TC/HDL-C ratios > 4.8 (p = 0.0154) had significantly more future cardiovascular events than those with lower hsCRP levels or TC/HDL-C ratios. Furthermore, for plasma hsCRP level or TC/HDL-C ratio, the significant difference in future cardiovascular events could be shown within the first 12 months of follow-up,



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  		Figure 1.. Kaplan-Meier estimation of survival free of cardiovascular events for serum levels of hsCRP (top, A) and TC/HDL-C ratio (bottom, B) in patients receiving medical treatment. The event-free survival rate was significant higher in patients with serum hsCRP levels ≤ 0.1 mg/dL (p = 0.008 by log-rank test) and TC/HDL ratios ≤ 4.8 (p = 0.0154 by log-rank test).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
It has been shown that the plasma hsCRP level and the TC/HDL-C ratio are the two strongest predictors of future cardiovascular events in either healthy men or women.192021 In the present study, patients with baseline plasma hsCRP levels > 0.1 mg/dL or TC/HDL-C ratios > 4.8 were associated with an increased risk for future cardiovascular events, especially in those receiving medical treatment. Furthermore, the significant difference in event rates of these markers could be shown early within the first 12 months of follow-up. Accordingly, patients with stable CAD and increased plasma hsCRP levels or TC/HDL-C ratios may benefit more from early aggressive treatment such as statin therapy to reduce vascular inflammation, as well as further normalize the lipid profile, even though they do not have diabetes mellitus.22

For patients receiving coronary revascularization, however, baseline plasma hsCRP levels were also increased in those with future adverse events. However, by further analysis, no plasma biomarkers including hsCRP could predict future events in this group of patients. One of the possibilities is the variant effect of the revascularization procedures (PCI or CABG) that might modify the predictive value of these plasma biomarkers, especially while the sample size is relatively small. In fact, despite elevated baseline plasma C-reactive protein (CRP) levels associated with increased future risk after PCI23 or CABG,24 a lack of significant association between baseline CRP and restenosis after PCI was also observed.2526 It was further demonstrated that the predictive values of a plasma hsCRP level could be modified by different forms of reperfusion therapy for patients with acute myocardial infarction.27 It has been shown that PCI itself could induce vascular inflammatory response with a subsequent elevated plasma CRP level in the peak at 48 to 72 h.28 Such inflammation correlated well with the magnitude of neointimal hyperplasia after stenting.29 Besides, while being suggested as a marker of inflammation, plasma CRP could also directly contribute to the thrombus formation and its stability.30 Accordingly, the induction of vascular inflammation during PCI or CABG might attenuate the predictive values of baseline plasma biomarkers in the development of future cardiovascular events.

Although there do exist previous studies52326 that demonstrate the usefulness of CRP in immediate-term risk stratification, the present study is the first, to our knowledge, to simultaneously investigate the association of plasma biomarkers with long-term prognosis in patients with stable CAD with either medical treatment or revascularization therapy. The presence of significant predictive value of these plasma biomarkers in the long-term prognosis of patients receiving medical treatment but not in those receiving revascularization still need to be confirmed.

Similar to the results of Veterans Affairs High-Density Lipoprotein Intervention Trial,31 baseline lipid profiles were relatively normal, and less than half of the patients with CAD may have hypercholesterolemia in the present study.32 Therefore, only 12% of our patients receiving medical treatment or revascularization received statins. Recently, statins were shown to reduce future cardiovascular events in patients with increased plasma CRP levels,3334 regardless to their plasma lipid profiles.3536 Measurement of hsCRP could then help targeting statin therapy to high-risk patients receiving either medical treatment or revascularization.3637Furthermore, the reduction of CRP after statin therapy was significantly correlated with the severity and progression of atherosclerosis.38 Accordingly, baseline plasma hsCRP levels and TC/HDL-C ratios could be useful to identify a subset of patients who might theoretically benefit from a more aggressive medical treatment including statins.

The present study has some limitations. First, considering the study design and clinical reality, we preferred to match the patients rather than to randomize them. Thereafter, they were similar in age, gender, history, coronary risk factors, and disease entities. The plasma biomarkers and lipid profiles were also similar between the groups. Second, the sample size was not sufficiency large to allow detailed statistical analysis of all competing prognostic risk factors. However, most of the risk factors considered to contribute to prognosis were taken into account with multiple regression analysis. Further studies with larger sample size are needed before these results may be applied clinically as a screening tool for identifying a high-risk subset. Third, the cutoff points of either serum CRP level or TC/HDL-C ratio were not generally applied. Unlike the primary prevention study,2039 in which the cutoff points of hsCRP levels and TC/HDL-C ratios were relatively constant, the cutoff values of plasma hsCRP levels varied from 0.3 mg/dL in patients with unstable angina,40 to 20 mg/dL in patients with acute myocardial infarction.4142 Disease severity, timing of CRP evaluation, and associated risk factors were believed to affect the power of predictive value.

In conclusion, the baseline plasma hsCRP level is increased in nondiabetic patients with stable CAD with future cardiovascular events independent of different treatment strategies. Further, baseline plasma hsCRP levels and TC/HDL-C ratios could independently predict future cardiovascular events, especially in patients receiving medical treatment. Although waiting for further confirmation, our findings did provide a noninvasive but reliable tool to identify a subset of patients with stable CAD at relatively high risk, in whom an aggressive medical treatment such as statin therapy should be early indicated.


   Footnotes
 
Abbreviations: ACE = angiotensin-converting enzyme; CABG = coronary artery bypass grafting; CAD = coronary artery disease; CAG = coronary artery angiography; CI = confidence interval; CRP = C-reactive protein; ELISA = enzyme-linked immunosorbent assay; HDL-C = high-density lipoprotein cholesterol; hsCRP = high-sensitivity C-reactive protein; LDL-C = low-density lipoprotein cholesterol; PCI = percutaneous coronary intervention; RR = relative risk; sICAM-1 = soluble cell intracellular adhesion molecule-1; sVCAM-1 = soluble vascular cell adhesion molecule-1; TC = total cholesterol; vWF = von Willebrand factor

This study was supported by Taipei Veterans Hospital grants VGH 91-042, 92-245, 93-013.

Received for publication December 30, 2003. Accepted for publication May 7, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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