Elevated C-reactive protein levels and coronary microvascular dysfunction in patients with coronary artery disease
Fabrizio Tomai1,*,
Flavio Ribichini2,
Anna S. Ghini1,
Valeria Ferrero2,
Giuseppe Andò1,
Corrado Vassanelli2,
Francesco Romeo1,
Filippo Crea3 and
Luigi Chiariello1
1Division of Cardiology and Cardiac Surgery, Università di Roma Tor Vergata, European Hospital, via Portuense 700, 00149 Rome, Italy
2Division of Cardiology, Università del Piemonte Orientale, Novara, Italy
3Institute of Cardiology, Università Cattolica del Sacro Cuore, Rome, Italy
Received 12 January 2005; revised 4 April 2005; accepted 10 May 2005; online publish-ahead-of-print 16 June 2005.
* Corresponding author. Tel: +39 06 65975725; fax: +39 06 65975724. E-mail address: f.tomai{at}tiscali.it
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Abstract
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Aims It is still unknown whether elevated C-reactive protein levels are responsible for coronary microcirculatory dysfunction in patients with coronary artery disease (CAD). This study was aimed at evaluating the association between C-reactive protein levels and endothelium-dependent and endothelium-independent coronary blood flow (CBF) responses in non-culprit arteries of patients with CAD.
Methods and results We studied 28 patients (14 with normal and 14 with elevated C-reactive protein levels, >5 mg/L) with single-vessel disease and otherwise angiographically normal coronary arteries undergoing percutaneous transluminal coronary angioplasty (PTCA). CBF was measured in the non-PTCA vessel using an intracoronary Doppler guide wire and quantitative coronary angiography at baseline, after intracoronary infusion of substance P and of adenosine, and expressed as per cent change from baseline. The increases in CBF during infusion of substance P and of adenosine were lesser in patients with elevated than in those with normal C-reactive protein levels (34±22 vs. 61±34%, P=0.04 and 131±53 vs. 189±89%, P=0.03, respectively). Multivariable analysis identified elevated C-reactive protein level as the only independent predictor of reduced response to substance P (P=0.01) and adenosine (P=0.02).
Conclusion In patients with CAD, evidence of systemic inflammation is independently associated with endothelium-dependent and endothelium-independent coronary microvascular dysfunction, which, in turn, may be critical to precipitate myocardial ischaemia, in particular, in unstable patients.
Key Words: Adenosine Coronary disease Endothelium Inflammation Microcirculation
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Introduction
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A large body of evidence has shown that atherosclerosis is an inflammatory disease. Vascular inflammation contributes to the pathogenesis of atherosclerosis and, later in the disease process, is a major contributor to acute coronary syndromes.1 Several recent investigations have supported the notion that at least one of the potential mechanisms linking inflammation to CAD is vasomotor dysfunction.28 In particular, we recently demonstrated that in patients with stable or unstable angina, elevated C-reactive protein levels were independently associated with enhanced vasoreactivity of the culprit stenosis.4 The association between inflammation and coronary microvascular dysfunction in this setting, however, is still largely unknown. Thus, the aim of this study was to evaluate the effect of inflammation on endothelium-dependent and endothelium-independent coronary microvascular vasomotion in patients with obstructive CAD.
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Methods
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Patient selection
Twenty-eight patients (18 men and 10 women, aged 4278, mean 62) with single-vessel disease (left anterior descending or left circumflex coronary artery) and otherwise angiographically normal coronary arteries undergoing percutaneous transluminal coronary angioplasty (PTCA) were studied. Patients were consecutively enroled in order to have a total of 14 patients with raised C-reactive protein levels (>5 mg/L) and 14 patients with normal C-reactive protein levels (
5 mg/L). Ten additional subjects (five men and five women, aged 4977, mean 67) with normal left ventricular (LV) function and C-reactive protein levels (
5 mg/L) and normal coronary arteries at diagnostic angiography performed for atypical chest pain were consecutively enroled, in the same period of time in which patients were enroled and served as a control group. Exclusion criteria included history of myocardial infarction, uncontrolled hypertension, peripheral vascular disease, ejection fraction <50%, valvular heart disease, and/or significant endocrine, hepatic, renal or inflammatory disease, and surgery or major trauma in the previous month. Patients with raised (>0.1 ng/mL) troponin I levels and those with anginal episodes in the last 12 h before the study were excluded. A total of 72 patients with single-vessel disease undergoing PTCA were screened. Forty of these patients were excluded because of the presence of at least one exclusion criteria; four patients with normal C-reactive protein levels were also excluded because the required sample size of 14 patients had already been reached. Cardiovascular risk factors, including diabetes mellitus (random glucose level of >150 mg/dL or hypoglycaemic treatment), hypertension (blood pressure of >140/90 mmHg or antihypertensive treatment), cigarette smoking, hypercholesterolaemia (>200 mg/dL or cholesterol-lowering medication), and positive family history of premature CAD, were assessed and expressed by the risk factors score (i.e. the total number of risk factors in a given patient) from 0 (no risk factor) to 5, which has been shown to be a potent independent predictor of endothelial dysfunction.9 All patients were receiving medical treatment for at least 24 h prior to study entry. All patients with unstable angina received intravenous nitrates, which, however, were withheld for 1 h prior to the study. All patients gave written informed consent for participation in the study, which was approved by the Institutional Ethics Committees of the two centres involved in the study.
Study protocol
The rationale to perform the study protocol prior to PTCA was to avoid the confounding effects of ischaemiareperfusion and microembolization following the procedure on the coronary blood flow (CBF) responses of the control region. Therefore, after diagnostic coronary angiography (control group) or before PTCA (patients group), a 6F guide catheter was introduced into the left main coronary artery. A 0.014 in. Doppler-tipped intracoronary guide wire (FloWire and FlowMap, Cardiometrics, Mountain View, CA, USA) was advanced through the guide catheter into the proximal segment of the non-culprit coronary artery (left anterior descending for the 15 patients undergoing PTCA of the left circumflex and left circumflex for the 13 patients undergoing PTCA of the left anterior descending) and positioned until an optimal and stable Doppler signal, not in the proximity of a side branch, was obtained. In the control subjects, the Doppler wire was randomly positioned in the proximal segment of the left anterior descending (n=5) or of the left circumflex (n=5) coronary artery. No patient received intracoronary nitrates prior to flow measurements. Drug infusions were administered with a constant-rate infusion pump (Braun-Melsungen). Basal measurements were obtained after 2 min intracoronary sodium chloride (0.9%) infusion (rate 1 mL/min). For the assessment of endothelium-dependent coronary vasodilation, three 2 min intracoronary infusions of substance P (Sigma Chemical Co) were administered at increasing dosages of 20, 40, and 60 pmol/min with infusion rates of 0.51.5 mL/min. Then, after a 2 min intracoronary sodium chloride infusion, adenosine (40 µg, as an intracoronary bolus) was administered for the assessment of endothelium-independent coronary vasodilation. Forty micrograms of adenosine is the dose most frequently utilized as intracoronary bolus to achieve maximal hyperemia.10,11 Heart rate and mean arterial pressure, Doppler measurements, and coronary angiography with non-ionic contrast medium and a power injector were obtained after each infusion. Substance P is an endothelium-dependent vasodilator of epicardial and microvessels, akin to acetylcholine.12 However, it permits an examination of microvascular endothelial function without the simultaneous constriction of epicardial arteries, which can be induced by acetylcholine. Adenosine is an endothelium-independent vasodilator primarily of the microcirculation.13
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),14 at a core laboratory (European Imaging Laboratory, Rome, Italy). The contrast-filled non-tapered catheter tip was used for calibration. This allowed the diameters to be measured as absolute values (in millimetres). Measurements of epicardial coronary diameters were made in the segment 5 mm distal to the tip of the Doppler wire at the end-diastole and were obtained for the angiograms taken at the end of each infusion, maintaining the identical projection for all assessed angiograms. High accuracy and precision for this system have been previously demonstrated.14 The degree of vasoreactivity during each infusion was expressed as per cent change in coronary diameter from the baseline measurement on the angiogram obtained prior to the infusion.
Assessment of CBF
Blood flow velocity was calculated from the Doppler frequency shift of a reflected 15 MHz signal by fast Fourier transformation and displayed in a spectral format. Average peak velocity (APV) was derived automatically by the integrated signal-analysing computer. CBF was determined as
x(coronary artery diameter/2)2x(APV/2).15 CBF responses to substance P and adenosine were expressed as per cent changes from the corresponding baseline values.
C-reactive protein levels
Venous blood samples obtained at the time of the study were immediately analysed for C-reactive protein concentration, which was immunologically determined by the immunoturbidimetric method (Roche unimate 3 C-reactive protein). The normal upper reference value for C-reactive protein with this method is up to 5 mg/L.16 For data analysis, all patients were prospectively allocated into two groups according to C-reactive protein levels: Fourteen patients (11 men and three women, mean age 61 years) had normal C-reactive protein levels (
5 mg/L) and 14 patients (seven men and seven women, mean age 63 years) had elevated C-reactive protein levels (>5 mg/L).
Statistical analysis
The primary endpoint of the study was to compare the per cent change of CBF from baseline with the peak dose of substance P in patients with CAD and normal or elevated levels of C-reactive protein. To this aim, we calculated that at least 13 patients per group were needed in order to have an 80% power to detect a difference of 30% points for the per cent increase of CBF in response to substance P between the two groups (
=0.05, two-tailed), by assuming in patients with low C-reactive protein levels, a mean per cent CBF increase of 120% and an SD of the per cent CBF increase of 25%.
Two-way ANOVA with a repeated measure design was used to compare absolute values of mean blood pressure and heart rate and per cent changes from baseline of coronary diameter and CBP with the peak dose of substance P and adenosine between patients and control subjects, and between patients with normal and elevated C-reactive protein levels. F test results were corrected for identity covariance matrix by the GreenhouseGeisser method to take into account the possible within-patient correlations. When significant differences were detected, post hoc pairwise comparisons were made using Scheffè F test. Scheffè F test was also used to compare coronary diameter and CBP during substance P and adenosine infusions with corresponding baseline values. Comparisons of the remaining continuous or discrete variables between groups were performed using a two-tailed, unpaired t-test or a
2 test, respectively. Linear regression analysis was used to assess the association between per cent changes in CBF responses and the peak dose of substance P or adenosine with logarithmically transformed C-reactive protein values. To investigate the independent predictors of endothelium-dependent and endothelium-independent coronary microvascular dysfunction, a multivariable regression analysis was performed in which all variables known to be relevant for the study endpoint (the angina status, log-C-reactive protein levels, cardiovascular risk factor score, location of the Doppler wire, angiotensin-converting enzyme inhibitor therapy, 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.
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Results
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Control subjects vs. patients with CAD
The clinical characteristics of control subjects and patients with CAD are summarized in Table 1. Of note, the risk factors score was significantly higher in patients than in controls (2.5±1.1 vs. 1.5±1.0, P=0.02).
The haemodynamic, angiographic, and CBF results are summarized in Table 2. Heart rate and systemic mean blood pressure at baseline, and during substance P and adenosine administrations, were similar in both groups (Table 2).
At baseline, coronary artery diameters were similar in both groups (3.0±0.5 vs. 2.8±0.6 mm, P=0.32). During substance P and adenosine administrations, coronary artery diameter increased both in control subjects and in patients with CAD (all P-values were <0.05), but changes were similar in both groups (Table 2).
At baseline, CBF was similar in both groups (72±17 vs. 73±31, P=0.86). During substance P and adenosine administrations, CBF increased both in control subjects and in patients with CAD (all P-values were <0.05); however, CBF increases in response to substance P and adenosine were significantly reduced in the latter group (per cent increase from baseline 111±71 vs. 48±31%, P<0.001 and 240±121 vs. 160±78%, P=0.02, respectively) (Table 2).
Patients with CAD: normal vs. elevated C-reactive protein levels
The clinical characteristics of patients with normal or elevated C-reactive protein levels are summarized in Table 3. The only statistically significant difference between the two groups was the higher prevalence of unstable angina (14 vs. 86%, P<0.001) in the latter group.
The haemodynamic, Angiographic, and CBF results are summarized in Table 4. Heart rate and systemic mean blood pressure at baseline, and during substance P and adenosine administrations, were similar in both groups (Table 4).
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Table 4 Haemodynamic, angiographic, and CBF results in patients with normal and elevated C-reactive protein levels
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At baseline, coronary artery diameters were similar in both groups (2.8±0.7 vs. 2.8±0.6 mm, P=0.99). During substance P and adenosine administrations, coronary artery diameter increased both in patients with normal (P=0.004 and P=0.009, respectively) and in patients with elevated (P<0.001 and P=0.09, respectively) C-reactive protein levels, but changes were similar in both groups (Table 4).
At baseline, CBF was similar in both groups (75±37 vs. 72±24, P=0.84). During substance P and adenosine administrations, CBF increased both in patients with normal and in patients with elevated C-reactive protein levels (all P values were <0.001); however, CBF increases in response to the peak dose of substance P and adenosine were significantly reduced in the latter group (per cent increase from baseline 61±34 vs. 34±22%, P=0.04 and 189±89 vs. 131±53%, P=0.03, respectively) (Table 4, Figures 1 and 2). Of note, per cent change in CBF responses to the peak dose of substance P or to adenosine were inversely correlated with log-C-reactive protein values (r=0.49, P=0.008 and r=0.48, P=0.01, respectively) (Figures 3 and 4).

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Figure 1 Per cent changes from baseline of CBF in response to substance P infusion. The increase in CBF in response to substance P infusion was attenuated in patients with elevated C-reactive protein levels (solid circles) compared with that in patients with normal C-reactive protein levels (open circles). Data are presented as mean±SEM.
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Figure 2 Per cent changes from baseline of CBF in response to adenosine infusion. The increase in CBF in response to adenosine infusion was attenuated in patients with elevated C-reactive protein levels (solid circles) compared with that in patients with normal C-reactive protein levels (open circles). Data are presented as mean±SEM.
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Figure 3 Relation between per cent changes from baseline of CBF in response to the peak dose of substance P and logarithmically transformed C-reactive protein levels (log-C-reactive protein).
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Figure 4 Relation between per cent changes from baseline of CBF in response to adenosine and logarithmically transformed C-reactive protein levels (log-C-reactive protein).
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On univariate analysis, C-reactive protein levels and unstable angina were associated with both endothelium-dependent (P=0.009 and P=0.06, respectively) and endothelium-independent (P=0.007 and P=0.04, respectively) coronary microvascular dysfunction. However, at the multivariable analysis, C-reactive protein level remained the only independent predictor of both endothelium-dependent (P=0.01) and endothelium-independent (P=0.02) coronary microvascular dysfunction (Tables 5 and 6).
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Discussion
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This study confirms that patients with CAD exhibit coronary microvascular dysfunction.11,1719 In particular, it is in agreement with previous investigations showing a reduced vasodilator response to dipyridamole and to oxygen consumption in control regions of patients with single-vessel disease, thus suggesting the presence of a diffuse vasodilator abnormality of coronary resistance vessels in these patients, at least partially independent of epicardial stenoses.20,21 More importantly, our study demonstrates for the first time that among patients with obstructive atherosclerosis and a similar risk factor profile, evidence of systemic inflammation is associated with a further impairment of both endothelium-dependent and endothelium-independent coronary microvascular vasomotion, which, in turn, may be critical to precipitate myocardial ischaemia, in particular in unstable patients.
We recently found that elevated C-reactive protein levels are independently associated with enhanced vasoreactivity of the culprit lesion in patients with stable or unstable angina, thus suggesting that inflammatory mechanisms play an important role in modulating the reactivity of coronary atherosclerotic plaques.4 The present study was aimed at assessing the role of inflammation in coronary microcirculatory dysfunction, known to modulate the severity of myocardial ischaemia both in patients with stable22 and in patients with unstable angina.23 To avoid the confounding effects of epicardial stenoses on coronary flow reserve, CBF responses to endothelium-dependent and endothelium-independent stimuli were assessed in the non-culprit vessel of patients with single-vessel disease. As endothelium-dependent stimulus, we utilized substance P that allows the assessment of microvascular endothelial function in the absence of the confounding effect of direct constriction of vascular smooth muscle cells, as it is the case with the endothelium-dependent stimulus of acetylcholine.12 We found that elevated C-reactive protein levels are associated with a striking reduction of coronary microvascular response to substance P. Accordingly, C-reactive protein levels were inversely correlated with per cent change in CBF responses to substance P. More importantly, C-reactive protein was the only independent predictor of coronary microvascular endothelial dysfunction. Thus, the impairment associated with elevated C-reactive protein levels is additive to that conferred by risk factors. Furthermore, at the multivariable analysis, an elevated C-reactive protein level, but not unstable angina, resulted in an independent predictor of a blunted coronary microvascular endothelial function, thus suggesting that the latter is not secondary to unstable angina per se. Our findings are in keeping and expand those previously obtained by Fichtlscherer et al.,3,24 who found that elevated C-reactive protein levels are independent predictors of endothelial dysfunction and of impaired nitric oxide bioavailability in the systemic circulation of patients with CAD, and those by Teragawa et al.6 and Schindler et al.,8 who found that elevated C-reactive protein levels are associated with coronary microvascular dysfunction in patients without CAD. Taken together, all these findings support the notion that the impairment of coronary endothelial function is at least one of the potential mechanisms linking inflammation to atherosclerosis progression and to acute coronary syndromes.
It is worth noting that in our study, elevated C-reactive protein levels were associated also with a blunted coronary microvascular response to adenosine, an endothelium-independent stimulus. In particular, C-reactive protein levels were inversely correlated with per cent change in CBF responses to adenosine and, more importantly, C-reactive protein was the only independent predictor of endothelium-independent coronary microvascular dysfunction. Accordingly, C-reactive protein has recently been shown to upregulate angiotensin type 1 receptors in vascular smooth muscle cells.25 Furthermore, the long-term outcome of patients with CAD can be predicted not only by an impaired endothelial coronary vasoreactivity, but also by an endothelium-independent dysfunction.26
The present study failed to find any significant difference in epicardial vasomotor function in patients with elevated and in patients with normal C-reactive protein levels. These findings confirm those obtained in a previous study in patients with stable and unstable angina, in which we found that elevated C-reactive protein levels are associated with an enhanced vasoreactivity of the culprit lesion but not of the uninvolved epicardial coronary segment.4 Interestingly, an association between C-reactive protein levels and endothelial dysfunction has been observed is some studies but not in others.6,8 Taken together, these findings indicate that inflammation alters vasomotion at the site of coronary atherosclerotic plaques and in coronary microcirculation, whereas its effect on vasomotor function of angiographically normal epicardial coronary segments is still controversial.
Recent investigations showing a widespread inflammation involving distal coronary vessels in patients with acute coronary syndromes2730 are in keeping with our findings of a widespread coronary microvascular dysfunction in patients with CAD and evidence of systemic inflammation.
Study limitations
A first limitation of this study is that controls were subjects with cardiovascular risk factors and atypical chest pain, normal LV function, normal C-reactive protein levels, and normal coronary arteries at angiography. Although this is not an ideal control population, it represents, however, the best approximate to normals among patients undergoing invasive testing for chest pain. Another limitation of our study was lack of discontinuation of antianginal medications prior to the study, because of ethical reasons. Some medications could have affected CBF responses to substance P and adenosine. However, medical therapy was similar in patients with elevated and in patients with normal C-reactive protein levels, and therefore it is unlikely that this may have influenced the observed results. Another limitation of our study is that some drugs, in particular statins,31 might have reduced C-reactive protein levels. This could have led, however, to an underestimation of the detrimental effects of C-reactive protein on coronary microvascular dysfunction. Another potential limitation is that elevated C-reactive protein levels might be secondary to myocardial ischaemia or parcellar necrosis. However, this is unlikely to be the case in our study, because patients with anginal episodes in the last 12 h before the study and those with raised troponin I levels were excluded. Furthermore, a previous study in patients with vasospastic angina failed to find raised levels of C-reactive protein in the presence of frequent daily ischaemic episodes.32 Finally, previous experimental in vitro investigations suggest that adenosine-induced vasodilation is partially due to the endothelial function.33 However, a clinical study13 has convincingly shown that adenosine-induced vasodilation is not affected by L-NG monomethyl arginine, a selective nitric oxide inhibitor, at least at a dose of adenosine similar to that used in our study.
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Conclusions
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In patients with CAD, evidence of systemic inflammation is independently associated with endothelium-dependent and endothelium-independent coronary microvascular dysfunction, which, in turn, may be critical to precipitate myocardial ischaemia, in particular in unstable patients. The identification of a causeeffect relationship between C-reactive protein and coronary microcirculation should be addressed in further studies.
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