Impact of Plaque Rupture and Elevated C-Reactive Protein on Clinical Outcome in Patients with Acute Myocardial Infarction: An In

ABSTRACT: Background. Ruptured plaques are associated with elevated C-reactive protein (CRP) that, in turn, are associated with a poor prognosis in acute myocardial infarction (AMI) patients. Objectives. The purpose of this study was to evaluate the impact of plaque rupture and elevated CRP on major adverse cardiac events (MACE) in patients with AMI treated with coronary stenting. Methods. We used pre-intervention intravascular ultrasound (IVUS) to evaluate infarct-related arteries in 72 AMI patients treated with coronary stenting to study the impact of plaque rupture and CRP levels on MACE. Results. Infarct-related artery plaque rupture was observed in 30 patients (42%), and multiple infarct-related artery plaque ruptures were observed in 10 patients (14%). The CRP level was higher in patients with plaque rupture than in those without plaque rupture (31.3 ± 20.3 vs. 4.2 ± 5.8 mg/l; p < 0.001). Patients with elevated CRP levels had more plaque rupture and more multiple plaque ruptures than the normal CRP group (26/42 [62%] vs. 4/30 [13%]; p < 0.001, and 10/42 [24%] vs. 0/30 [0%]; p = 0.004, respectively). Plaque rupture and ST-segment elevation MI independently predicted CRP elevation (Hazard ratio [HR] = 5.329; p < 0.001 and HR = 3.790; p = 0.032, respectively). At 1-year follow up, MACE occurred in 9 plaque rupture patients (30%), in 5 non-plaque rupture patients (12%) and in 29% of elevated CRP patients versus 7% of normal CRP patients. Patients with elevated CRP plus plaque rupture had more MACE than patients with normal CRP and no plaque rupture (31% vs. 4%; p = 0.010). In the multivariate analysis, an elevated CRP was the only independent predictor of MACE (HR = 6.561; p = 0.012). Conclusions. Plaque rupture and elevated CRP were associated with poor prognosis; however, an elevated CRP was the only independent predictor of 1-year MACE in AMI patients treated with coronary stenting.

J INVASIVE CARDIOL 2008;20:428–435

Key Words: myocardial infarction; plaque; inflammation;
intravascular ultrasound

Autopsy studies have indicated that acute myocardial infarctions (AMI) result from spontaneous plaque rupture or erosion and subsequent thrombosis.1,2 Intravascular ultrasound (IVUS) studies have reported culprit-lesion ruptured plaques in a varying percentage of acute coronary syndrome patients (ACS) with an overall frequency averaging slightly less than 50%.3–5 Plaque ruptures tend to occur at a point where the fibrous cap is thinnest and most heavily infiltrated by macrophages, indicating ongoing inflammation at the site of plaque disruption.6 There is also a strong inflammatory response to the tissue injury that occurs during an AMI, and the degree of the inflammatory response might be an important determinant of the clinical outcome.7 C-reactive protein (CRP) has emerged as a simple tool for detecting systemic inflammation in patients with subsequent coronary events.8,9
Several studies have demonstrated an association between elevated CRP levels and culprit-lesion ruptured plaques in AMI patients.5,10,11 However, few reports have studied the relationship between elevated CRP level and clinical outcome in these patients. Therefore, the purpose of the current study was to evaluate the impact of plaque rupture and CRP levels on subsequent cardiac events in patients with a first AMI treated with coronary stenting. It was our hypothesis that an elevated CRP level and the presence of infarct-related artery ruptured plaque would portend a worse prognosis in patients with a first AMI treated with coronary stenting.

Methods

Patient population. From November 26, 2003 to December 15, 2004, we identified a total of 72 patients with a first AMI who underwent pre-percutaneous coronary intervention (PCI) IVUS within 24 hours from symptom onset, were stented successfully, and underwent post-PCI IVUS imaging. We excluded patients with prior MI, subacute or late stent thrombosis, restenosis after stenting, coronary artery bypass graft failure, patients in whom adequate IVUS images could not be obtained, patients studied with IVUS more than 24 hours after symptom onset, lack of post-PCI IVUS, and patients in whom CRP could not be checked within 24 hours from symptom onset.

The diagnosis of AMI was according to a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction.12 Infarct-related arteries were identified using a combination of electrocardiographic (ECG) findings, left ventricular wall motion abnormalities on left ventricular angiography or echocardiography, and coronary angiographic findings. All 72 infarct lesions were treated with stent implantation: 34 with sirolimus-eluting stents, 28 with paclitaxel-eluting stents and 10 with bare-metal stents.

Hospital records of all the patients were reviewed to obtain information on clinical demographics and medical history. Follow-up information was obtained through review of hospital charts, telephone interviews and the interventional database of the Washington Hospital Center. Patients were included only if follow-up information was available for at least 1 year after the date of the IVUS examination unless an adverse event occurred before 1 year’s time. Major adverse cardiac events (MACE) were defined as death from cardiac causes, reinfarction and repeated intervention or revascularization of the target vessel as a result of ischemia. Reinfarction was defined by the presence of recurrent ischemic symptoms or ECG changes accompanied by a creatine kinase level that was more than twice the upper limit of the normal range or > 50% higher than value during index hospitalization (with an elevated MB isoform level). Revascularization of the target vessel was considered to have been prompted by ischemia if there was evidence of ischemia during functional testing or in the presence of recurrent angina.13

CRP analysis. We measured high-sensitivity CRP in all patients. Venous blood samples were obtained before IVUS study within 24 hours of symptom onset. The blood samples were centrifuged and serum was removed and stored at -80°C until the assay could be performed. CRP was analyzed turbidimetrically with sheep antibodies against human CRP; this has been validated against the Dade-Behring method.14 We defined elevated CRP as ≥ 3 mg/l in accordance with the definition adopted elsewhere.5,15

Quantitative coronary angiographic (QCA) analysis. Quantitative analysis (CAAS II, Pie Medical, The Netherlands) was performed using standard protocols.16 With the outer diameter of the contrast-filled catheter as the calibration standard, the pre- and post-PCI reference diameter and minimal lumen diameter were measured in diastolic frames from orthogonal projections.

IVUS imaging protocol. All IVUS examinations were performed before and after stenting after intracoronary administration of 200 µg of nitroglycerin using a commercially available IVUS system (Boston Scientific Corp./SCIMed, Natick, Massachusetts). The IVUS catheter was advanced distal to the target lesion and imaging was performed retrograde to the aorto-ostial junction at an automatic pullback speed of 0.5 mm/sec.

IVUS analysis. Qualitative analysis was performed according to the American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies.17 A ruptured plaque contained a cavity that communicated with the lumen with an overlying residual fibrous cap fragment. A fragmented and loosely adherent plaque without a distinct cavity and without a fibrous cap fragment was not considered a plaque rupture. Rupture sites separated by a > 5 mm length of artery containing a smooth lumen contour and no cavity were considered to represent different plaque ruptures.18,19 Thrombus was considered as an intraluminal mass having a layered or lobulated appearance, evidence of blood flow (microchannels) within the mass, and speckling or scintillation.20 Hypoechoic plaque was less bright compared with the reference adventitia. Hyperechoic, noncalcific plaque was as bright as or brighter than the reference adventitia without acoustic shadowing. Calcific plaque was hyperechoic with shadowing. A calcified lesion contained > 90° of circumferential lesion calcium.

Using planimetry software (TapeMeasure, INDEC Systems, Inc., Mountain View, California), we measured the external elastic membrane (EEM) and lumen cross-sectional area (CSA), and final stent CSA. Plaque plus media (P&M) CSA was calculated as EEM CSA minus lumen CSA. The lesion was the site with the smallest lumen CSA; if there were multiple image slices with the same minimum lumen CSA, then the image slice with the largest EEM and P&M was measured. Coronary artery remodeling was assessed by comparing the lesion site to the reference EEM CSA. The remodeling index was the lesion site EEM CSA divided by the average of the proximal and distal reference EEM CSA. Positive remodeling was defined as a remodeling index > 1.05, intermediate remodeling as a remodeling index between 0.95 and 1.05, and negative remodeling as a remodeling index < 0.95.21

Statistical analysis. Statistical analysis was performed using SAS, version 9.1 (SAS Institute, Cary, North Carolina). Continuous variables were presented as the mean value ± 1 standard deviation; comparisons were conducted by the Student’s t-test or the nonparametric Wilcoxon test if the normality assumption was violated. Discrete variables are presented as percentages and relative frequencies; comparisons were conducted by the chi-square test or Fisher’s exact test, as appropriate. Logistic regression analysis was used to identify the independent predictors of MACE. Survival curves were constructed by the Kaplan-Meier method, and differences in survival were assessed using the log-rank test. A p-value < 0.05 was considered statistically significant.

Results

Plaque rupture vs. no plaque rupture. Infarct-related artery plaque rupture was observed in 30 patients (42%), and multiple infarct-related artery plaque ruptures were observed in 10 patients (14%). Clinical, angiographic, and IVUS findings according to the presence/absence of plaque rupture are summarized in Table 1. More patients with plaque rupture had a history of diabetes mellitus. The baseline CRP level was significantly higher and the baseline left ventricular ejection fraction was significantly lower in patients with plaque rupture compared with patients without plaque rupture. Post-PCI QCA minimal lumen diameters were similar in patients with/without plaque rupture. IVUS reference EEM, lumen and P&M CSA were significantly larger, and IVUS lesion site EEM and P&M CSA were significantly larger in the plaque rupture group. Intracoronary thrombus, hypoechoic plaque and positive remodeling were more frequently observed in the plaque rupture group.

Elevated vs. normal CRP. CRP elevation was observed in 42 patients (58%). Clinical, angiographic, and IVUS findings according to presence or absence of elevated CRP levels are summarized in Table 2. Patients with elevated CRP presented more frequently with ST-segment elevation MI and a history of smoking. Creatine-kinase MB and troponin-1 levels tended to be higher in the elevated CRP group compared with the normal CRP group. Plaque rupture and multiple plaque ruptures were observed more frequently and plaque cavity CSA was significantly larger in the elevated CRP group than in the normal CRP group. Hypoechoic plaque was observed more frequently in the elevated CRP group than in the normal CRP group.

Multiple logistic regression analysis was performed to determine independent predictors of CRP elevation. The following variables were tested (all with p < 0.2 in univariate analysis): age, clinical presentation, smoking, creatine kinase-MB level, troponin-1 level, multivessel disease, plaque rupture, multiple plaque rupture, plaque cavity CSA, thrombus, hypoechoic plaque and positive remodeling. Plaque rupture and ST-segment elevation MI were the independent predictors of CRP elevation (Hazard ratio [HR] = 5.329; 95% CI 3.885–8.421; p < 0.001 and HR = 3.790; 95% CI 1.195–5.760; p = 0.032, respectively).

MACE

Follow-up data were available in all patients. At 1-year follow up, MACE occurred in 9 patients (30%) in the plaque rupture group and in 5 patients (12%) in the non-plaque rupture group, and in 12 patients (29%) in the elevated CRP group and 2 patients (7%) in the normal CRP group. In the plaque rupture group, there were 4 cardiac deaths, 3 patients had target vessel revascularization, and 2 patients had reinfarction. In the non-plaque rupture group, there were 2 cardiac deaths, 3 patients had target vessel revascularization, and no patients had reinfarction. When patients were divided into 4 groups according to the baseline CRP levels and presence/absence of plaque rupture, events were more common and event-free survival was worse in patients with an elevated CRP level and an infarct-related artery plaque rupture than in patients with normal CRP without plaque rupture (Table 3, Figure 1).

There was no significant difference in the type of implanted stent comparing patients with events versus patients without subsequent events: sirolimus-eluting stent 6/14 (43%) vs. 28/58 (48%); paclitaxel-eluting stent 5/14 (36%) vs. 23/58 (40%); and bare-metal stent 3/14 (21%) vs. 7/58 (12%), (p = 0.661 overall). Patients with subsequent cardiac events were more often diabetic with higher baseline CRP levels than patients without cardiac events (Table 4). IVUS reference EEM, lumen, and P&M CSA were significantly larger, and IVUS lesion site EEM and P&M CSA were significantly larger, and multiple plaque ruptures were observed more frequently in patients with subsequent cardiac events compared with patients without cardiac events (Table 5). Post-PCI QCA minimal lumen diameter and IVUS stent CSA were similar in patients with/without events.

Multiple logistic regression analysis was performed to determine independent predictors of 1-year MACE. The following variables were tested (all with p < 0.2 in univariate analysis): gender, clinical presentation, diabetes mellitus, smoking, CRP level, multivessel disease, stent diameter, post-PCI QCA minimal lumen diameter, reference EEM, lumen and P&M CSA, lesion site EEM, lumen and P&M CSA, lesion length, plaque rupture, multiple plaque rupture, thrombus and hypoechoic plaque. An elevated CRP was the only independent predictor of 1-year MACE (HR = 6.561; 95% CI 2.014–9.748; p = 0.012).

Discussion

The results in the present study showed that the CRP level was significantly higher in AMI patients with IVUS-detectable plaque rupture than in patients without plaque rupture and plaque ruptures (including multiple plaque ruptures) were observed more frequently in AMI patients with elevated CRP than in patients with a normal CRP, and MACE occurred more frequently in patients with an elevated CRP and IVUS-evident plaque rupture than in patients with a normal CRP and no evidence of plaque rupture  (31% vs. 4%), but an elevated CRP was the only independent predictor of MACE.

In the present study, plaque rupture was observed in 53% of ST-segment elevation MI patients and in 33% of non-ST-segment elevation MI patients, and plaque rupture was strongly associated with CRP elevation. Plaques that are prone to rupture are reported to have the following pathologic features:22–24 1) positive remodeling; 2) thin fibrous cap; 3) large lipid/necrotic core; 4) abundant intraplaque vasovasorum; and 5) macrophage infiltration of the thin fibrous cap.

Several studies have demonstrated that patients with culprit lesion plaque rupture showed higher CRP levels in AMI patients.5,10,11 Sano et al5 reported that in the setting of AMI, significantly more plaque ruptures were observed in patients with elevated CRP levels than in patients with a normal CRP and that only the presence of a ruptured plaque correlated with an elevated serum CRP level. Hong et al10 reported a 3-vessel IVUS study and showed that culprit lesion plaque rupture, secondary remote plaque rupture and multiple plaque ruptures were all more common in AMI patients than in stable angina patients and that the only independent clinical predictor of plaque rupture in AMI patients was an elevated CRP level. Tanaka et al11 reported that AMI patients with culprit lesion plaque ruptures presented with higher CRP levels, as compared with AMI patients without plaque rupture; the number of plaque ruptures correlated with CRP levels at 1 month from onset.

In the present study, 1-year MACE occurred in 30% of patients with plaque rupture versus 12% of patients without plaque rupture, and in 29% of patients with an elevated CRP versus 7% of patients with a normal CRP. And, in the present study, the observed CRP values in patients with plaque rupture and in patients with events were very high compared with patients without plaque rupture and in patients without events. An elevated CRP level is associated with a significantly increased risk of future fatal or nonfatal ischemic complications in patients with either ST-segment elevation AMI25–27 or non-ST-segment elevation ACS.28–30 Burke et al31 reported that CRP may correlate with the number of thin-capped fibroatheromas (i.e., vulnerable plaques) in patients who had a sudden death associated with severe coronary artery disease. Suleiman et al32 reported that, compared with patients in the first CRP quartile, the adjusted hazard ratios for death progressively increased with higher quartiles of CRP (second quartile 1.4 [95% CI 0.6–2.9]; third quartile 2.3 [95% CI 1.2–4.6]; fourth quartile 3.0 [95% CI 1.5–5.7]; for trend; p = 0.0002). They concluded that CRP was a marker of long-term mortality in patients with AMI.

Goldstein et al33 reported that the presence of multiple complex plaques was associated with a poor prognosis compared with single complex plaques in AMI patients; there was an increased incidence of recurrent ACS (19% vs. 3%), repeated angioplasty (32% vs. 12%) and coronary artery bypass graft surgery (35% vs. 11%). Tanaka et al11 reported that the presence of multiple plaque ruptures was associated with an increased incidence of recurrent ACS (36% vs. 0% vs. 0%) and repeated intervention (36% vs. 20% vs. 4%) compared with single plaque ruptures or no plaque ruptures during the mean follow-up period of 23 months after an AMI.

Suleiman et al32 reported that CRP is a marker of long-term development of heart failure and mortality in patients with AMI. Foussas et al34 reported that the plasma CRP values on admission were related to a significantly increased risk of the 30-day death and 14-day incidence of death, MI and recurrent ischemia in 1,846 patients with an ACS. As noted above, in the study by Tanaka et al,11 CRP levels had a positive correlation with the number of plaque ruptures in patients with a first AMI; and patients with multiple plaque ruptures had a worse poor prognosis; multiple plaque ruptures may reflect a more generalized inflammatory response throughout the coronary tree, one that is ongoing even after the acute event. In the present study, the only independent predictor of MACE was an elevated CRP, not multiple plaque ruptures. The reason that multiple plaque ruptures was not a predictor of MACE in the present study is unclear. Of note: 1) we did not perform 3-vessel IVUS; therefore, we may have underestimated the frequency and minimized the predictive impact of multiple plaque ruptures. An elevated CRP may have been a marker of undetected multiple plaque ruptures in the current study; 2) Most of our patients were treated with statins (67/72, 93%) and clopidogrel (71/72, 99%). Statins are associated with stabilization of coronary plaques.35,36 Rioufol et al37 reported that spontaneous coronary atheromatous plaque rupture detected on the first ACS healed without significant plaque modification in 50% of patients after 2 years of medical therapy with a statin and an antiplatelet agent (clopidogrel and aspirin for ≥ 9 months).

The postprocedural minimum stent CSA is known to be a strong predictor of in-stent restenosis after bare-metal stent38,39 and drug-eluting stent implantation.40–43 Fujii et al44 reported that patients with ruptured plaque had higher composite rates of late events (target lesion revascularization/MI/cardiac deaths) than controls (25% vs. 9%) after successful coronary stenting. However, final stent CSA was not a predictor of subsequent events in the present study. There are two possible explanations: 1) These patients all had good final stent CSAs; 2) In this specific patient population, the atherosclerotic environment (recurrent plaque instability) may be more important than the procedural result in a single culprit lesion.

Study limitations. First, the study population was relatively small. Second, IVUS imaging was performed at the discretion of the individual operators leading to potential selection bias. Third, this analysis was retrospective and is subject to limitations inherent in this type of clinical investigation. Fourth, we did not perform 3-vessel IVUS. Therefore, we did not assess the frequency of non-infarct-related artery plaque ruptures, and we did not demonstrate the relationship between multivessel plaque ruptures and clinical events. Fifth, because the CRP level was not measured serially after AMI, it cannot be ascertained whether the CRP elevations are the result or the cause of the plaque rupture. Sixth, we did not perform serial IVUS follow up and follow-up CRP measurements, thus, we did not demonstrate the relationship between changes in atherosclerosis imaging markers such as change in plaque burden and arterial remodeling, changes in CRP level and clinical outcome. Therefore, further study examining this relationship is needed.

Conclusions
Plaque rupture was associated with systemic inflammation indicated by an elevated CRP in patients with an AMI. Plaque rupture and an elevated CRP are markers for poor outcome in patients with AMI treated with stenting, suggesting that these patients need more aggressive medical therapy as well as more careful clinical follow up.