Volume 96, Issue 11 , Pages 1484-1490, 1 December 2005
Relation of High-Sensitivity C-Reactive Protein Level With Coronary Vasospastic Angina Pectoris in Patients Without Hemodynamically Significant Coronary Artery Disease
Article Outline
We prospectively investigated the relation of high-sensitivity C-reactive protein (hs-CRP) to coronary vasospasm and no hemodynamically significant coronary artery disease (CAD) in a sample of 428 patients who underwent coronary angiography. These patients were assigned to 1 of 3 groups. The control group consisted of 66 patients who had no coronary vasospasm and no hemodynamically significant CAD. The vasospasm group consisted of 116 patients who had coronary vasospasm and no hemodynamically significant CAD. The acute coronary syndrome (ACS) group consisted of 246 patients who had ACS and hemodynamically significant CAD. Serum hs-CRP was measured immediately before coronary angiography. Patients were followed for subsequent cardiac events and mortality. Median hs-CRP levels in the control, vasospasm, and ACS groups were 1.0, 5.5, and 8.2 mg/L, respectively. The proportion of hs-CRP increased from the lowest to the highest tertile in the control, vasospasm, and ACS groups, respectively. In the control and vasospasm groups, multivariate analysis showed that hs-CRP was independently associated with a diagnosis of coronary vasospastic angina pectoris (odds ratio 68.74, 95% confidence interval 8.03 to 588.71, p <0.001). During a median follow-up period of 26 months (range 0.4 to 48), 27 cardiac deaths occurred in the ACS group, whereas no cardiac death occurred in the control and vasospasm groups. In conclusion, serum hs-CRP level measured immediately before coronary angiography was an independent marker of coronary vasospasm in patients who had no hemodynamically significant CAD.
We designed this study to (1) assess the clinical characteristics of patients who had coronary vasospastic angina pectoris without hemodynamically significant coronary artery disease (CAD); (2) compare the clinical characteristics and prognoses for these patients with those of patients who had atypical chest pain without coronary vasospasm and with those of patients who had acute coronary syndrome (ACS) and hemodynamically significant CAD; and (3) investigate the possible relation between coronary vasospasm and high-sensitivity C-reactive protein (hs-CRP) with respect to the development of inflammatory CAD and early atherosclerosis.
Methods
Study population
We assessed 1,283 consecutive patients who underwent cardiac catheterization due to suspected ischemic heart disease between December 2000 and December 2003. Coronary vasospastic angina pectoris was defined as the presence of (1) chest pain that occurred at rest and was associated with an electrocardiographic finding of ST-segment elevation or depression, (2) chest pain that was relieved by sublingual administration of nitroglycerin, (3) chest pain that was not associated with increased serum cardiac enzymes, and (4) no hemodynamically significant CAD (<50% stenosis in the lumen diameter of major coronary arteries) with positive findings at intracoronary ergonovine provocation testing. Data for the study group were compared with data from (1) patients who did not have hemodynamically significant CAD and no coronary vasospasm by intracoronary ergonovine testing and (2) patients who had hemodynamically significant CAD and ACS. ACS included acute myocardial infarction and unstable angina pectoris. Diagnosis of acute myocardial infarction required a patient’s condition to satisfy ≥2 of the following criteria: (1) chest pain that was suggestive of myocardial ischemia and lasted ≥30 minutes; (2) enzymatic evidence of acute myocardial necrosis (increase in serum creatine kinase levels to ≥2 times the normal value with a >5% increase in creatine kinase-MB isoenzyme); and (3) new electrocardiographic changes, including the development of Q waves and/or ST-T changes, that lasted ≥48 hours. Unstable angina pectoris was defined as angina pectoris with ≥1 of the following 3 features: (1) it occurred at rest (or with minimal exertion) and lasted >20 minutes (if not interrupted by nitroglycerin); (2) it was severe and described as frank pain and was of new onset within the previous month; and (3) it occurred with a crescendo pattern (i.e., more severe, prolonged, or more frequently than previously). Patients who had collagen disease (n = 1), advanced liver disease (n = 3), renal failure (serum creatinine ≥2.5 mg/dl, n = 63), malignancy (n = 10), any infectious disease (n = 2), loss of blood sample (n = 36), stable angina pectoris (n = 536), or coronary stenting follow-up without hemodynamically significant CAD (n = 204) were excluded from the study. The study protocol was approved by the hospital ethics committee, and written informed consent for participation was obtained from all patients.
Clinical data
Patients’ clinical records were reviewed for cardiac risk factors, including cigarette smoking habits, diabetes mellitus, hypertension, and hypercholesterolemia. History of smoking was assessed by asking patients if they had ever smoked >10 cigarettes a day for ≥1-year period during their lifetime. Diabetes was considered to be present if the patient received dietary treatment, medical therapy, or the 2 therapies combined for such a condition. Systemic hypertension was considered to be present if the patient received medical therapy for such a condition or had a blood pressure >140/90 mm Hg. Hypercholesterolemia was considered to be present if a patient had a serum total cholesterol level >200 mg/dl.
Laboratory analysis
Blood specimens for measurement of hs-CRP were collected in citrate-treated tubes immediately before coronary angiography and after an overnight fast and centrifuged for ≥15 minutes. The plasma component was frozen and sent on dry ice to the core laboratory of our hospital, where samples were stored at −70°C until subsequent measurement. Serum hs-CRP was measured in duplicate by enzyme-linked immunosorbent assay on the basis of purified protein and polyclonal anti-CRP antibodies (IMMULITE hs-CRP, Diagnostic Products Corp., Los Angeles, California). The lower limit of this assay was 0.10 mg/L and coefficients of variation were ≤5% at 0.20 mg/L of CRP.
Cardiac catheterization
Cardiac catheterization was performed as scheduled at the outpatient department or within 36 hours after admission if the patient had been admitted due to chest pain. All antispastic drugs (i.e., calcium channel blockers and/or nitrate) were withdrawn ≥24 hours before cardiac catheterization, except sublingual nitroglycerin, which was withdrawn ≥2 hours before cardiac catheterization. Left ventricular ejection fraction was calculated by using Simpson’s method. Quantitative coronary angiography using an edge-detection algorithm was performed using Judkin’s techniques and a digital angiographic system (Integris BH 3000, Philips, Bast, The Netherlands). An independent cardiologist interpreted all coronary angiograms. A decrease >50% in the lumen diameter of major coronary arteries was considered to represent hemodynamically significant CAD. Only patients who did not have hemodynamically significant CAD subsequently underwent intracoronary ergonovine provocation testing.
Intracoronary ergonovine provocation test
For patients who had no evidence of hemodynamically significant CAD, a provocation test for coronary vasospasm was undertaken in succession with intracoronary ergonovine (Methergin; Novartis, Basel, Switzerland) that was administered in a stepwise dose (1, 5, 10, and 30 μg) as previously described.1 The drug was introduced into the right coronary artery and subsequently into the left coronary artery. A positive finding at intracoronary ergonovine provocation testing for coronary vasospasm was defined as a decrease >70% in the diameter of an arterial lumen with concurrent chest pain and ischemic ST-segment changes during the provocation test. Intracoronary ergonovine administration was stopped in patients who developed coronary vasospasm during testing and 100 μg of intracoronary nitroglycerin (Millisrol, G.Pohl-Boskamp, Hohenlockstedt, Germany) was administered. Focal spasm was defined as discrete transient vessel narrowing >70% that was localized in a major coronary artery, whereas diffuse spasm was diagnosed when segmental vessel narrowing >70% was observed from the proximal to distal segment in the 3 major coronary arteries.
Patient follow-up
Follow-up data were obtained from monthly visits to staff physicians in the outpatient clinic, hospital records, and telephone interviews. Events were defined as death, nonfatal reinfarction, and recurrent angina. Cause of death was further classified as cardiac or noncardiac.
Statistical analysis
Because the distributions of continuous variables were skewed, data are presented as median (lower interquartile range, upper interquartile range). Differences among the 3 groups were analyzed by the Kruskal-Wallis nonparametric test for continuous variables and chi-square test for noncontinuous variables; differences between groups were analyzed by the Mann-Whitney U statistic test and chi-square test. Stepwise logistic regression was used to identify independent risk factors and to estimate the odds ratio and 95% confidence intervals for coronary vasospastic angina pectoris in patients who did not have hemodynamically significant CAD. All variables with a p value <0.1 were entered into multivariate analysis to analyze their effect on the diagnosis of coronary vasospastic angina pectoris in patients who did not have hemodynamically significant CAD. Covariables that were controlled for possible confounding effects included age (years), male gender (no, yes), body mass index (kilograms per square meter), current smoker (no, yes), diabetes (no, yes), systemic hypertension (no, yes), total cholesterol level (milligrams per deciliter), peripheral white blood cell count (tertiles), peripheral monocyte count (tertiles), hematocrit (percentage), peripheral platelet count (tertiles), hs-CRP (tertiles), and left ventricular ejection fraction (percentage).
Univariate and multivariate analyses were performed using Cox’s proportional hazards regression model, which took into account the timing of events during follow-up. All univariate parameters with a p value <0.1 were entered into the analysis. Odds ratios and 95% confidence intervals were also calculated. Differences in the incidence of cardiac death between groups were evaluated by the Kaplan-Meier method with the log-rank statistic. A p value <0.05 was considered statistically significant. Statistical analyses were performed with SPSS 11.0 for Windows (SPSS, Inc., Chicago, Illinois).
Results
Clinical characteristics
Of the 1,283 patients who underwent cardiac catheterization, 428 consecutive patients were included in the final analysis. Among these patients, 66 had no hemodynamically significant CAD and no coronary vasospasm (control group), 116 had coronary vasospastic angina pectoris without hemodynamically significant CAD (vasospasm group; Figure 1), and 246 had ACS and hemodynamically significant CAD (ACS group). Comparison of the 3 groups showed that patients in the ACS group had significantly higher levels of total cholesterol, peripheral white blood cell count, peripheral monocyte count, peripheral platelet count, and hs-CRP and lower left ventricular ejection fraction. In addition, patients in the ACS group were more likely to be older, to be men and to have a history of smoking, diabetes mellitus, and systemic hypertension than were patients in the other 2 groups. Compared with the control group, patients in the vasospasm group were more likely to be men, to have a history of smoking, and to have higher peripheral white blood cell count, peripheral monocyte count, and hs-CRP level (Table 1).
Figure 1.
(A, C) Baseline coronary angiograms and (B, D) coronary angiograms performed after intracoronary ergonovine testing in a patient who had coronary vasospastic angina and anomalous origin of the left circumflex artery. Diffuse vasoconstriction with 100% diameter decreases in the midportion of the left anterior descending artery (B, arrowhead) and proximal portion of the posterior lateral artery of the right coronary artery (D, arrowhead) were noted on an ergonovine provocation test for coronary vasospasm.
Table 1. Baseline characteristics
| Variable | No Hemodynamically Significant CAD | Hemodynamically Significant CAD and ACS | p Value | |
|---|---|---|---|---|
| Without Vasospasm | With Vasospasm | |||
| (n = 66) | (n = 116) | (n = 246) | ||
| Age (yrs) | 56 (49,66) | 60(50,70) | 65(56,72)†‡ | 0.001 |
| Men | 32(48%) | 81(70%)⁎ | 187(76%)† | <0.001 |
| Body mass index (kg/m2) | 25(22,28) | 26(24,28) | 25(22,27)† | 0.024 |
| Smoker | 13(20%) | 52(45%)⁎ | 133(54%)† | <0.001 |
| Diabetes mellitus | 9(14%) | 29(25%) | 110(45%)†‡ | <0.001 |
| Systemic hypertension | 22(33%) | 53(46%) | 141(57%)† | 0.001 |
| Total cholesterol (mg/dl) | 206(185,244) | 205(185,235) | 220(188,251)‡ | 0.055 |
| Peripheral white blood cell count(/mm3) | 6,200(5,300,7,000) | 7,300(5,800,8,375)⁎ | 8,750(6,615,10,800)†‡ | <0.001 |
| <6,500(3,300–6,400) | 44(67%) | 42(36%)⁎ | 57(23%)†‡ | <0.001 |
| 6,500–8,900 | 18(27%) | 51(44%)⁎ | 72(29%)‡ | |
| >8,900(9,000–19,700) | 4(6%) | 23(20%) | 117(48%)†‡ | |
| Peripheral monocyte count(/mm3) | 345(275,404) | 479(386,593)⁎ | 507(364,661)† | <0.001 |
| <388(0–387) | 44(67%) | 29(25%)⁎ | 69(28%)† | <0.001 |
| 388–546 | 20(30%) | 50(43%) | 73(30%) | |
| >546(547–1,970) | 2(3%) | 37(32%)⁎ | 104(42%)† | |
| Hematocrit(%) | 40(37,43) | 41(38,43) | 40(36,43) | 0.213 |
| Peripheral platelet count(×103/mm3) | 205(189,244) | 207(177,266) | 235(183,269) | 0.118 |
| <192(69–191) | 22(33%) | 46(40%) | 76(31%) | 0.159 |
| 192–244 | 28(42%) | 33(28%) | 81(33%) | |
| >244(245–1,110) | 16(24%) | 37(32%) | 89(36%) | |
| hs-CRP (mg/L) | 1.0(0.5,2.0) | 5.5(3.3,10.0)⁎ | 8.2(3.4,20.2)†‡ | <0.001 |
| <3.14(0.10–3.10) | 61(92%) | 27(23%)⁎ | 55(22%)† | <0.001 |
| 3.14–9.51 | 5(8%) | 58(50%)⁎ | 80(32%)†‡ | |
| >9.51(9.69–181) | 0 | 31(27%)⁎ | 111(46%)†‡ | |
| Left ventricular ejection fraction(%) | 70(62,76) | 66(60,73) | 56(40,65)†‡ | <0.001 |
| Spasm characteristic | ||||
| Focal spasm | 48(41%) | |||
| Diffuse spasm | 68(59%) | |||
⁎ p <0.05 between patients who did not have vasospasm and patients who did. |
† p <0.05 between patients who did not have vasospasm and patients who had ACS. |
‡ p <0.05 between patients who had vasospasm and patients who had ACS. |
Laboratory test
Median hs-CRP levels in the control, vasospasm, and ACS groups were 1.0, 5.5, and 8.2 mg/L, respectively, which suggests that an inflammatory process was present in patients in the vasospasm group (Figure 2). We divided all data from the 428 patients on peripheral white blood cell count, peripheral monocyte count, peripheral platelet count, and hs-CRP level into tertiles and compared the proportion of these tertiles across the 3 groups. The proportion of hs-CRP increased continuously from the lowest tertile to the highest tertile in the control, vasospasm, and ACS groups, suggesting that inflammation in the vasospasm group was intermediate between those of the control and ACS groups.
Figure 2.
Median serum levels (horizontal lines) of hs-CRP in the control group (squares), vasospasm group (circles), and ACS group (diamonds).
Analysis of variables associated with coronary vasospasm in the vasospasm and control groups in patients who did not have hemodynamically significant CAD
Based on their significance in the univariate analysis (Table 2), 6 variables (male gender, history of smoking, diabetes mellitus, peripheral white blood cell count, peripheral monocyte count, and hs-CRP) were entered into multivariate analysis. Multivariate analysis showed that hs-CRP was independently associated with a diagnosis of coronary vasospastic angina pectoris (Table 3).
Table 2. Univariate analysis of the relation between clinical characteristics and coronary vasospastic angina pectoris in patients without hemodynamically significant coronary artery disease
| Odds Ratio | 95% Confidence Interval | p Value | |
|---|---|---|---|
| Age | 1.02 | 0.99–1.04 | 0.161 |
| Men | 2.46 | 1.32–4.59 | 0.005 |
| Body mass index | 1.02 | 0.95–1.10 | 0.583 |
| Smoking history | 3.31 | 1.63–6.73 | 0.001 |
| Diabetes mellitus | 2.11 | 0.93–4.79 | 0.074 |
| Systemic hypertension | 1.68 | 0.90–3.16 | 0.105 |
| Total cholesterol | 1.00 | 0.99–1.01 | 0.697 |
| Peripheral white blood cell count (>8,900/mm3) | 6.02 | 1.92–18.89 | 0.002 |
| Peripheral monocyte count (>546 mm3) | 28.07 | 6.28–125.56 | <0.001 |
| Hematocrit | 1.03 | 0.96–1.11 | 0.387 |
| Peripheral platelet count (>244 × 103/mm3) | 1.11 | 0.51–2.40 | 0.799 |
| hs-CRP (>9.51 mg/L) | 68.89 | 8.94–531.11 | <0.001 |
| Left ventricular ejection fraction | 1.00 | 0.97–1.02 | 0.773 |
Table 3. Multivariate analysis of variables associated with coronary vasospastic angina pectoris in patients without hemodynamically significant coronary artery disease
| Odds Ratio | 95% Confidence Interval | p Value | |
|---|---|---|---|
| Men | 3.29 | 1.16–9.34 | 0.025 |
| Peripheral monocyte count (>546 mm3) | 15.00 | 2.03–110.85 | 0.008 |
| hs-CRP (>9.51 mg/L) | 68.74 | 8.03–588.71 | <0.001 |
Clinical follow-up
During a median follow-up of 26 months (range 0.4 to 48), patients in the ACS group had a significantly (p <0.0001) lower survival rate than did patients in the control and vasospasm groups (Figure 3). Twenty-seven cardiac deaths occurred in the ACS group, whereas no cardiac death occurred in the control and vasospasm groups. Independent predictors of cardiovascular mortality during follow-up were impaired left ventricular ejection fraction (odds ratio 0.95, 95% confidence interval = 0.92 to 0.97, p <0.001) and advanced age (odds ratio 1.06, 95% confidence interval = 1.01 to 1.11, p = 0.014). Nonfatal reinfarction was noted in only 1 patient in the ACS group. Recurrent angina was significantly (p <0.001) more frequent in the ACS group (17%) than in the vasospasm group (8%) and the control group (0%), but no specific predictor could be identified.
Figure 3.
Kaplan-Meier estimates of freedom from cardiac death during follow-up.
Medications prescribed during follow-up
Compared with the vasospasm group, the ACS group had higher rates of prescription for medications including β blockers, angiotensin-converting enzyme inhibitors, antiplatelet agents, cholesterol-lowering agents, diuretics, and α/β blockers, whereas calcium antagonists were more commonly prescribed for patients in the vasospasm group (Table 4).
Table 4. Medications prescribed during follow-up
| No Hemodynamically Significant CAD | Hemodynamically Significant CAD and ACS | p Value | ||
|---|---|---|---|---|
| Without Vasospasm | With Vasospasm | |||
| (n = 66) | (n = 116) | (n = 246) | ||
| β Blockers | 9(14%) | 4(3%)⁎ | 49(20%)‡ | <0.001 |
| Angiotensin-converting enzyme inhibitors | 10(15%) | 4(3%)⁎ | 62(25%)‡ | <0.001 |
| Antiplatelet agents | 16(24%) | 32(28%) | 220(89%)†‡ | <0.001 |
| Calcium antagonists | 34(52%) | 95(82%)⁎ | 102(41%)‡ | <0.001 |
| Cholesterol-lowering agents | 9(14%) | 22(19%) | 106(43%)† | <0.001 |
| Nitrates | 12(18%) | 40(35%)⁎ | 93(38%)† | 0.011 |
| Diuretics | 17(26%) | 28(24%) | 96(39%)†‡ | 0.008 |
| Angiotensin-II receptor blockers | 8(12%) | 13(11%) | 47(19%) | 0.105 |
| α Blockers | 0(0%) | 3(3%) | 1(0.4%) | |
| α/β Blockers | 3(5%) | 2(2%) | 50(20%)†‡ | <0.001 |
⁎ p <0.05 between patients who did not have vasospasm and patients who did. |
† p <0.05 between patients who did not have vasospasm and patients who had ACS. |
‡ p <0.05 between patients who had vasospasm and patients who had ACS. |
Discussion
This study has 2 potentially important findings. First, hs-CRP was high in patients who had coronary vasospastic angina pectoris and did not have hemodynamically significant CAD. Second, the hs-CRP level in patients who had coronary vasospastic angina pectoris without hemodynamically significant CAD was between those of patients who did not have hemodynamically significant CAD and no vasospasm and patients who had ACS and hemodynamically significant CAD.
Our results indicate that an inflammatory process exists in spastic coronary arteries. Patients who had no evident narrowing on angiogram had diffuse intimal thickening on intracoronary ultrasound scans,2 suggesting that a spastic coronary artery is not a normal coronary artery. Previous studies that used histologic evaluation of coronary plaques or coronary arteries in patients who had variant angina have reported evidence of intimal injury, such as neointimal hyperplasia with infiltration by inflammatory cells.3, 4, 5 These findings indicate that early inflammatory changes might be involved in initiating atherosclerotic lesion formation in a spastic coronary artery and, as suggested by other investigators, in its progression.3, 6, 7 Consistent with these studies, the present study demonstrated a high level of hs-CRP in patients who had coronary vasospastic angina pectoris, which suggests that inflammatory changes occur in spastic coronary arteries.
Kugiyama et al8 suggested that localized deficiency of coronary nitric oxide production is responsible for coronary spasm in patients who have vasospastic angina pectoris. Nakayama et al9 also found an increased prevalence of the T−786→C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene in Japanese patients who had coronary vasospasm. These findings suggest that deficient endothelial nitric oxide production may predispose certain patients to a higher basal tone and coronary vasospasm with provocation testing because of unopposed constrictor effects. Therefore, endothelial dysfunction may play an important role in coronary vasospasm. It has been suggested that dysfunction of endothelial cells is likely the earliest event in the process of lesion formation.10, 11 Long-term inflammation results in endothelial dysfunction and facilitates interactions among modified lipoproteins, monocyte-derived macrophages, T cells, and normal cellular elements of the arterial wall, thus inciting early and late atherosclerotic processes. In addition, atherosclerosis has been noted to impair endothelial vasodilator function in the coronary circulation.12 Our recent study also suggested that peripheral monocyte count is increased in patients who have coronary vasospastic angina pectoris and do not have hemodynamically significant CAD, implying that endothelial dysfunction with atherosclerotic changes is also present.13 Further, in the present study, the level of low-grade inflammation noted in patients who had coronary vasospastic angina pectoris and did not have hemodynamically significant CAD was between those in patients who had neither hemodynamically significant CAD nor vasospasm and patients who had ACS and hemodynamically significant CAD. As a result, it is reasonable to speculate that coronary vasospasm is an early inflammatory condition of a coronary artery because of the presence of endothelial dysfunction with resulting diffuse intimal thickening and impaired nitric oxide production.
Terashima et al14 found that CRP levels were within a normal range in 20 patients who had variant angina; this finding is in conflict with our results for 116 patients who had coronary vasospastic angina pectoris. Terashima et al performed blood sampling a few days before coronary angiography; however, blood sampling in this study was performed immediately before coronary angiography. In addition, their patients had no chest pain at rest within 48 hours preceding coronary angiography, which differs from our study population who may have had chest pain at rest within 36 hours before coronary angiography. Differences in study population, timing of blood sampling, and occurrence of angina before angiography likely account for the different results in this study and those of Terashima et al.
Limitation
We did not have complete data of low-density and high-density lipoproteins to better characterize the observed increase in cholesterol because this is also associated with hs-CRP levels.
References
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- . Diffuse intimal thickening of coronary arteries in patients with coronary spastic angina . J Am Coll Cardiol . 2000;36:432–437
- . Histological evaluation of coronary plaque in patients with variant angina (relationship between vasospasm and neointimal hyperplasia in primary coronary lesions) . J Am Coll Cardiol . 1999;33:198–205
- . Sudden death in Prinzmetal’s angina with coronary spasm documented by angiography. Analysis of three necropsy patients . Am J Cardiol . 1982;50:203–210
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- . T−786→C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm . Circulation . 1999;99:2864–2870
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PII: S0002-9149(05)01432-3
doi:10.1016/j.amjcard.2005.07.055
© 2005 Elsevier Inc. All rights reserved.
Volume 96, Issue 11 , Pages 1484-1490, 1 December 2005
