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(Circulation. 2001;104:1471.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Unstable Angina and Elevated C-Reactive Protein Levels Predict Enhanced Vasoreactivity of the Culprit Lesion

Fabrizio Tomai, MD; Filippo Crea, MD; Achille Gaspardone, MD; Francesco Versaci, MD; Anna S. Ghini, MD; Luigi Chiariello, MD; Pier A. Gioffrè, MD

From the Cattedra di Cardiochirurgia, Università di Roma Tor Vergata, and the Istituto di Cardiologia (F.C.), Università Cattolica del Sacro Cuore, Rome, Italy.

Correspondence to Dr Fabrizio Tomai, Divisione di Cardiochirurgia, Università di Roma Tor Vergata, European Hospital, via Portuense 700, 00149 Rome, Italy. E-mail f.tomai{at}tiscalinet.it

	Abstract

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Background— Because plaque inflammation may modulate coronary vasomotion, the association between systemic levels of C-reactive protein (CRP) and coronary vasoreactivity was assessed in patients with stable or unstable angina.

Methods and Results— In 31 patients with stable angina and 23 patients with unstable angina undergoing coronary angiography, minimal luminal diameter (MLD) of the culprit lesion was measured by quantitative coronary angiography at baseline, during the cold pressor test (CPT), and after intracoronary administration of nitroglycerin (NTG) and expressed as percent change from baseline. MLD of patients with unstable angina exhibited a greater reduction during CPT and a greater increase after NTG than did patients with stable angina (-17±14% versus -5±12%, P=0.0013, and 34±25% versus 8±20%, P<0.001, respectively). According to preprocedural serum levels of CRP, 36 patients had normal (0.5 mg/dL) and 18 patients had elevated CRP levels. MLD of patients with elevated CRP levels exhibited a greater reduction during CPT and a greater increase after NTG than of patients with normal CRP levels (-15±12% versus -7±14%, P=0.037, and 31±23% versus 13±25%, P=0.011, respectively). Both unstable angina and elevated CRP levels resulted in independent predictors of enhanced vasoreactivity at the multivariate analysis.

Conclusions— This study confirms enhanced vasoreactivity of the culprit lesion in patients with unstable angina compared with those with stable angina. More importantly, it demonstrates that inflammatory mechanisms play a key role in modulating the reactivity of coronary atherosclerotic plaques and may partially account for the enhanced vasoreactivity of the unstable plaques.

Key Words: angina • inflammation • vasoconstriction • vasodilation

	Introduction

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Agrowing body of data indicates that plaque inflammation plays a key role in the pathogenesis of unstable acute coronary syndromes because the cytokines secreted by activated inflammatory cells have the potential to activate the endothelium, transforming its antiadhesive and anticoagulant properties into adhesive and procoagulant properties.^1–3 Furthermore, they may reduce matrix synthesis and increase its degradation, thus favoring plaque rupture.^1–3 Indeed, plaque inflammation may be responsible for the increased vasoreactivity of the culprit lesion observed in patients with unstable angina,⁴ as suggested by an increased tissue endothelin-1–like immunoreactivity at the site of the unstable atherosclerotic plaque.⁵ Thus, the aims of this study were to evaluate the vasoreactivity of the culprit lesion in patients with stable and unstable angina and to establish whether an enhanced vasoreactivity of the culprit lesion is associated with systemic evidence of inflammation, as assessed by serum C-reactive protein (CRP), a sensitive marker of the inflammatory response.⁶

	Methods

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Patients
A total of 54 patients undergoing diagnostic coronary angiography were studied. Thirty-one patients (25 men and 6 women, 48 to 75 years of age, mean age, 62 years) had stable angina defined as angiographically documented coronary artery disease and stable effort angina for 6 months before the study. Twenty-three patients (23 men and 2 women, 37 to 75 years of age, mean age, 60 years) had unstable angina (Braunwald’s class IIIB).⁷ The angiographic inclusion criteria was the presence of a clearly identifiable culprit lesion in the proximal two thirds of a major coronary artery, with an internal diameter reduction of between 50% and 90% (by quantitative cardiovascular software program ACA, Philips, DCI),⁸ without incomplete or retarded flow. Identification of the culprit lesion in patients with unstable angina relied on a consideration of anatomic factors (13 patients had only a single coronary stenosis), the architecture of the lesion (irregular or complex), and the localization of ECG or scintigraphic ischemic changes. In patients with stable angina, the identification of the target lesion relied on a consideration of anatomic factors (22 patients had only a single coronary stenosis), the severity of the lesion (the most severe), and the localization of ECG or scintigraphic ischemic changes. Angiographic exclusion criteria were the presence of a left main stem lesion, ostial lesions, branching of the vessel within the target lesion, or severe 3-vessel disease. Clinical exclusion criteria were Q-wave myocardial infarction within 3 months before the study, uncontrolled hypertension, peripheral vascular disease, significant endocrine, hepatic, renal or inflammatory disease, and surgery or major trauma in the previous month. Because myocardial necrosis may induce an increase in CRP serum levels, patients with troponin I levels >0.1 ng/mL were excluded.⁷

All patients were receiving medical treatment for 24 hours before the study (Tables 1 and 2). All patients with unstable angina received intravenous nitrates. All patients received the morning dose of treatment before diagnostic coronary angiography, which was performed within the following 4 hours. All patients gave written informed consent for participation in the study, which was approved by the institutional ethics committee.

View this table: [in this window] [in a new window]   Table 1.  Baseline Clinical Characteristics of Patients With Stable and Unstable Angina

View this table: [in this window] [in a new window]   Table 2.  Baseline Clinical Characteristics of Patients With Normal and Elevated CRP Levels

Study Protocol
After diagnostic coronary angiography, the optimal view for visualizing the culprit lesion was selected, and this view was maintained throughout the study. In all patients, ioversol (Optiray 320, Mallinckrodt Medical) was used as a contrast agent. After the baseline arteriogram, a cold pressor test (CPT) was performed. The patient placed a hand and forearm in a basin containing a slurry of ice water for 90 seconds, and a second arteriogram was taken at 80 seconds. After 5 minutes, intracoronary nitroglycerin (NTG) (400 µg in 2 mL of saline) was administered as a bolus, and, after 30 seconds, a third arteriogram was taken. Arterial pressure, cardiac rhythm, and the ECG were continuously monitored throughout the study.

Quantitative Coronary Angiography
Quantitative angiographic analysis was made by experienced technicians who were unaware of the study protocol with the use of the automated edge-detection system CMS (Medis Medical Imaging Systems)⁹ in the European Imaging Laboratory (Rome, Italy). The contrast-filled nontapered catheter tip was used for calibration. This allowed the diameters to be measured as absolute values (in millimeters). Minimal luminal diameter (MLD) of the culprit lesion, reference segment diameter (RD), and percent diameter stenosis (DS) were obtained with this analysis system. All measurements were done at end-diastole and were obtained for the angiograms taken at baseline, during the CPT, and after NTG administration. Care was taken to choose identical projections of the target lesion for all assessed angiograms. High accuracy and precision for this system have been previously demonstrated.⁹ Nonetheless, 40 randomly selected measurements were reanalyzed by a blinded observer. Results were reproducible. The mean of the difference between measurements was 0.03±0.2 mm (P=0.24). In particular, interobserver and intraobserver variability for MLD changes during CPT were 0.02±0.1 mm (P=0.27) and 0.01±0.1 mm (P=0.4), respectively.

The degree of vasoreactivity during CPT and after NTG was expressed as absolute values of MLD, RD, and DS and their percent changes from baseline. Maximal vasoreactivity was also assessed as percent change of MLD from values obtained during CPT to those obtained after NTG, with the formula [(MLD NTG-MLD CPT)/MLD CPT]x100.

C-Reactive Protein Levels
Venous blood samples obtained on hospital admission were immediately analyzed for CRP concentration, which was immunologically determined by the immunoturbidimetric method (Roche Unimate 3 CRP). The normal upper reference value for CRP with this method is up to 0.5 mg/dL.¹⁰ For data analysis, all patients were prospectively allocated into 2 groups, according to preprocedural CRP levels: 36 patients (29 men, mean age, 62 years) had normal CRP levels (0.5 mg/dL) and 18 patients (17 men, mean age, 61 years) had elevated CRP levels (>0.5 mg/dL).

Statistical Analysis
Differences in MLD, RD, and DS after CPT or NTG were examined by repeated-measures ANOVA followed by post hoc Scheffè F tests. Percent changes from baseline of MLD, RD, and DS after CPT or NTG between patients with stable and unstable angina and those with normal and elevated CRP levels were examined by 2-tailed, unpaired t test. Comparisons of the remaining continuous or discrete variables between groups were performed with a 2-tailed, unpaired t test or a ² test, respectively. Linear regression analysis was used to compare percent changes in maximal vasoreactivity of MLD with logarithmically transformed CRP values. To investigate the independent predictors of enhanced vasoreactivity of the culprit lesion, a logistic regression analysis was performed in which location of the culprit lesion and its morphology, extent of coronary artery disease and the presence of unstable angina, elevated CRP levels, hypertension, hypercholesterolemia, diabetes, smoking, and statin therapy were entered as independent variables. Data are expressed as mean±SD, unless otherwise indicated. Values of P<0.05 were considered significant.

	Results

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The clinical characteristics of the patients are summarized in Tables 1 and 2.

Hemodynamic Results
Baseline systemic mean blood pressure was similar in patients with stable and unstable angina (112±16 versus 108±14 mm Hg, P=0.297). During CPT and after NTG, blood pressure was similar in both groups (127±20 versus 123±15 mm Hg, P=0.449, and 100±14 versus 98±13 mm Hg, P=0.491, respectively) and significantly changed in both groups compared with baseline values (P<0.001). Baseline heart rate was similar in patients with stable and unstable angina (73±14 versus 72±15 bpm, P=0.86). During CPT and after NTG, heart rate was similar in both groups (78±15 versus 78±17 bpm, P=0.90, and 79±15 versus 77±14 bpm, P=0.55, respectively) and significantly changed in both groups compared with baseline values (P<0.05).

Angiographic Results: Stable Versus Unstable Angina
At baseline, MLD of the culprit lesion and RD were similar in patients with stable or unstable angina (Table 3). During CPT, MLD of the culprit lesion diminished both in patients with stable angina (P=0.06) and patients with unstable angina (P<0.001); however, the MLD was smaller in the latter group (absolute reduction from baseline, 0.04±0.13 versus 0.15±0.13 mm; percent reduction from baseline, 5±12% versus 17±14%, P=0.0013) (Figure 1 and Table 3). After NTG, MLD of the culprit lesion dilated both in patients with stable angina (P=0.034) and in patients with unstable angina (P<0.001); however, the MLD was greater in the latter group (absolute increase from baseline, 0.08±0.20 versus 0.28±0.21 mm; percent increase from baseline, 8±20% versus 34±25%, P<0.001) (Figure 1 and Table 3).

View this table: [in this window] [in a new window]   Table 3.  Angiographic Results: Stable Versus Unstable Angina

View larger version (20K): [in this window] [in a new window]   Figure 1. Percent changes from baseline of MLD (left) and of RD (right) in patients with stable (open bars) and unstable (hatched bars) angina during CPT and after intracoronary injection of NTG. Data are presented as mean±SEM.

During CPT and after NTG, RD diminished or increased both in patients with stable angina (P<0.001) and in patients with unstable (P<0.001) angina, but it was similar in both groups (Figure 1 and Table 3).

During CPT and after NTG, DS had changes similar to those observed for MLD (Table 3).

Angiographic Results: Normal Versus Elevated CRP Levels
At baseline, MLD of the culprit lesion and RD were similar in patients with normal or elevated CRP levels (Table 4). During CPT, MLD of the culprit lesion diminished both in patients with normal (P=0.007) and patients with elevated CRP levels (P<0.001); however, the MLD was smaller in the latter group (absolute reduction from baseline, 0.06±0.13 versus 0.15±0.14 mm; percent reduction from baseline, 7±14% versus 15±12%, P=0.037) (Figure 2 and Table 4). After NTG, MLD of the culprit lesion dilated both in patients with normal (P=0.006) and patients with elevated CRP levels (P<0.001); however, the MLD was greater in the latter group (absolute increase from baseline, 0.1±0.21 versus 0.3±0.20 mm; percent increase from baseline, 13±25% versus 31±23%, P=0.011) (Figure 2 and Table 4). Percent change in maximal vasoreactivity of MLD was significantly correlated with log-CRP values (r=0.48, P<0.001) (Figure 3). Of note, it was greater in patients with unstable angina and elevated CRP levels than in those with unstable angina and normal CRP levels (80±36% versus 47±36%, P=0.04) as well as in patients with stable angina and elevated CRP levels than in those with stable angina and normal CRP levels (19±22% versus 12±20%, P=0.47).

View this table: [in this window] [in a new window]   Table 4.  Angiographic Results: Normal Versus Elevated CRP Levels

View larger version (20K): [in this window] [in a new window]   Figure 2. Percent changes from baseline of MLD (left) and of RD (right) in patients with normal (open bars) and elevated (hatched bars) CRP serum levels during CPT and after intracoronary injection of NTG. Data are presented as mean±SEM.

View larger version (18K): [in this window] [in a new window]   Figure 3. Relation between percent changes in maximal vasoreactivity of MLD (Maximal % in MLD) and logarithmically transformed CRP levels (Log-CRP).

During CPT and after NTG, RD diminished or increased both in patients with normal (P<0.001) or elevated (P<0.001) CRP levels, but it was similar in both groups (Figure 2 and Table 4).

During CPT and after NTG, DS had changes similar to those observed for MLD (Table 4).

Independent Predictors of Enhanced Vasoreactivity
Predictors of the enhanced vasoreactivity are illustrated in Table 5. Unstable angina (P=0.006), elevated CRP serum level (P=0.021), and hypercholesterolemia (P=0.023) were the only statistically significant independent predictors of enhanced vasoreactivity.

View this table: [in this window] [in a new window]   Table 5.  Multivariate Analysis

	Discussion

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This study shows that (1) patients with unstable angina, compared with those with chronic stable angina, exhibit a greater vasoreactivity of the culprit lesion; (2) elevated CRP levels are associated with an enhanced vasoreactivity of the culprit lesion; (3) the reference segment of a coronary artery is unaffected by this enhanced vasoreactivity; and (4) unstable angina, elevated CRP levels, and hypercholesterolemia are independent predictors of enhanced vasoreactivity of the culprit lesion. A limitation of our study was that antianginal medications were not discontinued for ethical reasons; thus, these drugs could have interfered with the vasoconstriction induced by CPT and the vasodilation induced by NTG. However, it is likely that if antianginal medications had been weaned, both vasoconstriction induced by CPT and vasodilation induced by NTG would have resulted in even greater effects. Another limitation of our study was that an analysis of the mean vasomotor response over a certain period of time would have been preferable. However, peak MLD changes during CPT were detected at 80 seconds as previously reported,^4,11 whereas those during NTG were analyzed at 30 seconds because at this time a significant reduction of systemic blood pressure could be detected in all patients. Another limitation was that CRP was measured on admission and coronary angiography was performed up to 48 hours later. Yet, the median time from the admission to coronary angiography was similar between patients with stable or unstable angina and in those with normal or elevated CRP levels.

As previously reported,⁴ our study confirms that the unstable plaque is hyperreactive to the constrictor stimulus of the CPT. This latter is known to evoke a systemic neurohumoral response, but the evidence that uninvolved coronary segments exhibited similar responses in patients with stable and unstable angina supports the concept that the enhanced vasoreactivity is a local plaque-related phenomenon. For the assessment of endothelium-dependent vasodilation, a pharmacological challenge such as acetylcholine might have provided a more powerful effect than that provided by the relatively mild provocative stimulus of the CPT. However, coronary vasomotion of large epicardial arteries in response to CPT has been previously shown to mirror the effects of the endothelium-dependent vasodilator acetylcholine.¹¹

The intracoronary administration of a high dose of NTG caused a significant increase of the MLD of the culprit lesion, compared with baseline, both in patients with stable angina and patients with unstable angina. However, the increase of MLD was greater in patients with unstable angina than in those with stable angina, thus indicating an increased resting tone at the site of the unstable plaque. Of note, all unstable patients but not stable patients were receiving intravenous NTG at the time of the study, thus suggesting that the systemic administration of currently available vasodilators that dilate vascular smooth muscle nonspecifically are unlikely to produce an adequate and persistent dilation of the unstable lesion. In a previous elegant study, carried out by Bogaty et al⁴ in patients with stable angina and patients with unstable angina, the intracoronary administration of isosorbide dinitrate caused a similar luminal diameter increase of the stable and unstable plaques. This discrepancy might be due to the utilization of an inadequate dose of nitrates in the study of Bogaty et al; indeed, in that study, the intracoronary administration of 2 mg of isosorbide dinitrate did not affect systemic blood pressure, whereas in our study the intracoronary administration of 400 µg of NTG resulted in a significant reduction of systemic blood pressure.

In our study, unstable angina was the strongest independent predictor of enhanced vasoreactivity of the culprit lesion. This confirms the findings of previous studies suggesting that the smooth muscle hyper reactivity frequently observed in unstable coronary plaque may predispose to or be a marker for the recurrence of acute ischemia at this site.^4,12

The mechanisms responsible for the increased vasoreactivity of the unstable atherosclerotic plaque are multiple and still poorly understood. Vasoconstrictors released by endothelial cells and macrophages activated by inflammatory mediators may play a key role.^2,3 This hypothesis is supported by an in vitro study from Zeiher et al,⁵ who found increased endothelin-1–like immunoreactivity in unstable than in stable coronary plaques obtained by directional coronary atherectomy. Of note, endothelin-1, a potent vasoconstrictor peptide, is produced not only by endothelial cells but also by macrophages¹³ and polymorphonuclear leukocytes¹⁴ activated by inflammatory mediators. Accordingly, the results of the present study demonstrate that in patients with unstable angina, elevated CRP levels are independently associated with enhanced vasoreactivity of the culprit lesion. Indeed, unstable patients with elevated CRP levels exhibited both a greater dilation of the culprit lesion after NTG and a greater constriction of the culprit lesion during CPT, thus suggesting in these patients both an enhanced resting tone of the culprit lesion and an alteration of endothelium-dependent vasodilation. Interestingly, in patients with stable angina also, CRP levels were independently associated with enhanced vasoreactivity of the culprit lesion. These findings are in keeping with the results of several previous investigations showing an independent prognostic relevance of CRP for the risk of coronary artery disease not only in patients with stable and unstable angina but also in apparently healthy men.¹⁵

A recent study by Fichtlscherer et al¹⁶ found that elevated CRP levels are independent predictors of endothelial dysfunction in patients with coronary artery disease. In particular, patients with elevated CRP levels, compared with those with normal CRP levels, exhibited a reduced forearm vasodilator response to acetylcholine. These findings have been recently confirmed by Hingorani et al,¹⁷ who showed that a mild inflammatory reaction induced by Salmonella typhi vaccine impairs forearm endothelium-dependent vasodilation.

Besides unstable angina and elevated CRP levels, in our study hypercholesterolemia also independently predicted enhanced vasoreactivity of the culprit lesion. This is not surprising because the vascular activity of endogenous endothelin-1 is enhanced in hypercholesterolemic patients.¹⁸

	Acknowledgments

 
We are grateful to Teresa Palumbo, RN, Giuseppe Ciccaglione, RT, and Alessandro Pesaola, RN, for their invaluable technical assistance.

Received May 15, 2001; accepted July 20, 2001.

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