The extent of coronary microvascular dysfunction might be related, not only to patient characteristics and procedural factors, but also to the inflammatory status. The aim of the present study was to examine a possible association between inflammation, as reflected by the serum C-reactive protein (CRP) levels, and the extent of baseline and post–percutaneous coronary intervention (PCI) coronary microvascular dysfunction in patients with non–ST-segment elevation acute coronary syndrome undergoing PCI. A total of 42 patients undergoing PCI for non–ST-segment elevation acute coronary syndrome were enrolled. Coronary microvascular resistance (MR) was determined in the territory of culprit artery using a Doppler probe- and a pressure sensor-equipped guidewire both before (taking the collateral blood into account) and after PCI. The periprocedural changes in MR were calculated. The CRP levels at admission were correlated with the pre-PCI MR (r = 0.498, p = 0.001), post-PCI MR (r = 0.429, p = 0.005), and periprocedural changes in MR (r = 0.785, p <0.001). On multivariate regression analysis, the only predictor of the pre-PCI (β = 0.531, p = 0.002) and post-PCI (β = 0.471, p = 0.012) MR was the serum CRP concentration. Likewise, the periprocedural changes in MR was predicted by the serum CRP levels (β = 0.677, p = 0.001) and the presence of angiographic thrombus (β = −0.275, p = 0.02). In conclusion, these results have shown that the CRP level is related to increased coronary MR in the territory of the culprit lesion. This suggests that inflammatory processes might play a role in microvascular impairment in patients with non–ST-segment elevation acute coronary syndrome.
Multiple lines of evidence have suggested a pivotal role for inflammation in the pathogenesis of atherosclerosis and acute coronary syndromes. Elevated C-reactive protein (CRP), a sensitive marker of inflammation, has been shown to be associated with greater rates of cardiovascular events and with adverse outcomes after acute coronary syndromes. In addition to being a marker, much evidence has suggested that CRP might be a culprit mediator in epicardial atherothrombosis. In the published data, however, only a few studies have investigated the link between serum CRP levels and coronary epicardial and microvascular endothelial function. In 2 reports, the CRP levels were shown to be associated with impaired coronary vasoreactivity in patients with coronary risk factors but with angiographically normal coronary arteries and in patients with unstable angina. For the relation between serum CRP levels and coronary microvascular function, the data are likewise limited, inconsistent, and derived only from the evaluation of microcirculation subtended by normal coronary arteries. In all these reports, to avoid the confounding effect of the epicardial lesion on microvascular flow, only the microcirculation subtended by the normal coronaries was studied. However, recently, it became clear that reliable evaluation of the coronary microcirculatory status, even in the presence of an epicardial lesion, could be possible by invasive assessment of the microvascular resistance (MR). The aim of the present study was to examine a possible effect of inflammation, as reflected by the serum CRP levels, on the baseline coronary microcirculatory status and on response of the microcirculation to PCI, as assessed by the MR measured invasively in the presence, and after the removal, of the culprit lesion, in patients presenting with non–ST-segment elevation acute coronary syndrome (NSTE-ACS) undergoing PCI.
Methods
Forty-six patients presenting with NSTE-ACS and undergoing PCI for a single culprit lesion in a coronary artery were enrolled in the present study. The diagnosis was determined by new ST-segment depression >0.1 mm, T-wave inversion of 0.4 mm in ≥2 leads, or symptoms consistent with ACS and the presentation of elevated troponin T levels (>0.1 ng/ml). All patients received a 600-mg loading dose of clopidogrel and aspirin (300 mg) at admission and underwent successful bare metal stent implantation. Between admission and PCI, all patients received low-molecular-weight heparin and atorvastatin (40 mg/day). The study was conducted in accordance with the Declaration of Helsinki, and our hospital ethics committee approved the study protocol. All patients provided written informed consent. The patients underwent PCI and invasive evaluation of microvascular function an average of 19.5 ± 4.5 hours after admission. Troponin T values were collected at admission and every 4 hours thereafter. The CRP values were collected immediately before coronary angiography and intervention. After administration of 5,000 U heparin and 0.2 mg intracoronary nitroglycerin, the reference angiographic images were obtained, and intracoronary hemodynamic measurements were performed. For assessment of the epicardial and microvascular hemodynamics, a Doppler probe- and pressure sensor-equipped guidewire (Combo Wire XT, Volcano Therapeutics, Rancho Cordova, California) was advanced across the culprit stenosis. This dual-sensor guidewire has a Doppler crystal at the tip and a pressure sensor 1.5 cm from the tip. The aortic pressure was obtained from the guiding catheter, and the distal coronary pressure and average peak flow velocity (APV) were recorded from the dual-sensor guidewire. All hemodynamic signals were obtained at baseline and during maximum hyperemia induced by a bolus of intracoronary papaverine, 15 mg for the right coronary artery and 20 mg for the left coronary artery. After obtaining the pre-PCI measurements, PCI was performed over the Combo Wire (Volcano Therapeutics). During balloon occlusion (30 seconds), the distal pressure was recorded as the coronary wedge pressure. All hemodynamic measurements were repeated after PCI. The fractional flow reserve was calculated as the ratio of the mean distal to the mean aortic pressure during maximum hyperemia. The coronary flow reserve was calculated as the ratio of hyperemic to baseline APV. A velocity-based index of coronary stenosis resistance during hyperemia was calculated as the mean stenosis pressure gradient (aortic pressure minus distal coronary pressure) divided by the APV. In the presence of an epicardial stenosis (before PCI), MR was calculated by taking the collateral flow, as measurable by the coronary wedge pressure, into consideration. Therefore, the pre-PCI MR was calculated at maximum hyperemia, taking the coronary wedge pressure into account as follows: aortic pressure (1/APV) [(distal coronary pressure − coronary wedge pressure)/(aortic pressure − coronary wedge pressure)]. Because the APV correlated with the inverse of the mean transit time, (1/APV) was substituted for the mean transit time in the original formula, which was proposed by Aarnoudse et al. Because the myocardial flow equals the coronary flow in the absence of epicardial stenosis, the post-PCI MR was calculated during maximum hyperemia simply as the distal coronary pressure divided by the APV. All hemodynamic measurements were recorded on a suitable interface (Combo Map, Volcano Therapeutics) and analyzed off-line. The periprocedural changes (difference between the post-PCI and pre-PCI values) in the hemodynamic parameters were calculated.
Statistical tests were performed with the Statistical Package for the Social Sciences, version 17.0, program (SPSS, Chicago, Illinois). Continuous variables are expressed as the mean ± SD. The hemodynamic measurements performed in each step were compared using the paired sample t test. Pearson’s correlation and linear regression analysis was used, where appropriate. The most appropriate cutoff CRP value for the prediction of future events in patients with unstable angina and non–Q-wave myocardial infarction has previously been proposed as 5 mg/L. The patient population was then divided into the 2 groups according to their pre-PCI CRP values (<5 and >5 mg/L), and the group mean values were compared using the Student t test. The group mean values were also adjusted for the possible confounding factors chosen for each parameters using analysis of covariance (for the pre-PCI MR, the low-density lipoprotein cholesterol level, peak troponin T value, interval from admission to PCI, the presence or absence of diabetes mellitus, hypertension, and angiographic thrombus; for post-PCI MR and post-PCI hyperemic APV, low-density lipoprotein cholesterol level, peak troponin T value, stent length, interval from admission to PCI, the presence or absence of diabetes mellitus, hypertension, angiographic thrombus, and predilation). Multivariate linear regression analysis was also computed to identify the independent predictors of pre- and post-PCI MR and periprocedural changes in MR, controlling for possible confounding factors chosen for each, as described in this paragraph. Receiver operating characteristics curve analysis was also performed to determine the optimal threshold of CRP to predict an increase in MR after PCI. Significance was accepted at p <0.05.
Results
Patients in whom reliable and stabile intracoronary Doppler signals could be obtained during the procedure (n = 42) constituted the final study population. The baseline clinical and angiographic characteristics are listed in Table 1 .
| Characteristic | Value |
|---|---|
| All patients (n) | 42 |
| Men | 28 (67) |
| Age (yrs) | 55.9 ± 10.6 |
| Diabetes mellitus | 11 (26) |
| Hypertension | 25 (59) |
| Dyslipidemia | 18 (43) |
| Previous smoker | 28 (67) |
| Pre-PCI troponin T (ng/ml) | 0.61 ± 0.88 |
| Ejection fraction (%) by echocardiography | 57.2 ± 8.1 |
| Admission CRP (mg/L) | 8.8 ± 8.2 |
| Culprit coronary artery | |
| Left anterior descending | 22 (52) |
| Diagonal | 3 (7) |
| Intermediate | 2 (5) |
| Circumflex | 10 (24) |
| Right | 5 (12) |
| Multivessel coronary disease | 14 (33) |
| Visually estimated stenosis (%) | 75 ± 16 |
| Angiographic thrombus | 8 (19) |
| Predilation | 25 (60) |
| Stent length (mm) | 18.9 ± 5.8 |
After PCI, the epicardial hemodynamics improved, but the microvascular perfusion remained impaired, as evidenced by a significant increase in the post-PCI MR (from 1.9 ± 0.62 to 2.21 ± 0.53 mm Hg/cm/s, p = 0.005; Table 2 ). The average coronary wedge pressure was 29.6 ± 10.2 mm Hg (range 13 to 41).
| Before PCI | After PCI | Difference | 95% CI | p Value | |
|---|---|---|---|---|---|
| Average peak velocity (cm/s) | |||||
| Baseline | 21.5 ± 10.2 | 35.2 ± 14.4 | 13.7 | −16.2 to −7.4 | <0.001 |
| Hyperemic | 28.1 ± 12.4 | 50.2 ± 18.5 | 22 | −25.5 to −14.1 | <0.001 |
| Distal pressure (mm Hg) | |||||
| Baseline | 80.2 ± 25.5 | 109.3 ± 12 | 29.1 | −32.5 to −18.9 | <0.001 |
| Hyperemic | 62.2 ± 17.3 | 97 ± 13 | 34.9 | −34.6 to −24.7 | <0.001 |
| Fractional flow reserve | 0.65 ± 0.2 | 0.93 ± 0.1 | 0.28 | −0.3 to −0.2 | <0.001 |
| Stenosis resistance hyperemic (mm Hg/cm/s) | 1.5 ± 1.1 | 0.11 ± 0.1 | −1.45 | 1.1 to 2.1 | <0.001 |
| Coronary flow reserve | 1.3 ± 0.4 | 1.7 ± 0.4 | 0.37 | −0.5 to −0.2 | 0.001 |
| Microvascular resistance (mm Hg/cm/s) | 1.9 ± 0.6 | 2.2 ± 0.5 | 0.33 | −0.4 to −0.1 | 0.005 |
The CRP levels correlated with the pre-PCI (r = 0.498, p = 0.001; Figure 1 ) and post-PCI (r = 0.429, p = 0.005) MR and post-PCI hyperemic APV (r = −0.492, p = 0.001). Multivariate regression analyses, which included the possible confounding variables chosen for the baseline and post-PCI MR, revealed that the sole predictor of the pre-PCI (β = 0.531, p = 0.002) and post-PCI MR (β = 0.471, p = 0.012) was the serum CRP concentration.
A robust correlation was found between the preprocedural CRP values and the periprocedural change in MR (absolute change, r = 0.785, p <0.001, Figure 2 ; and percentage of change, r = 0.58, p = 0.001). Multivariate regression analysis revealed that CRP (β = 0.677, p = 0.001) followed by the presence of angiographic thrombus (β = −0.275, p = 0.02) were the only 2 parameters that predicted the periprocedural change in MR.
Receiver operating characteristic curve analysis showed that the best cutoff value of CRP for the prediction of an increase in MR after PCI was 6.7 mg/L, with a sensitivity of 83.3% and specificity of 75% (area under the curve 0.810, 95% confidence interval 0.674 to 0.947; Figure 3 ).
