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

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

Young Joon Hong, MD, *Gary S. Mintz, MD, Sang Wook Kim, MD, Teruo Okabe, MD, Anh B. Bui, MD,
Augusto D. Pichard, MD, Lowell F. Satler, MD, Ron Waksman, MD, Neil J. Weissman, MD

Author Affiliations:
From the Cardiovascular Research Institute/Medstar Research Institute, Washington Hospital Center, Washington, D.C., and the *Cardiovascular Research Foundation, New York, New York.
Disclosure: Dr. Mintz has received speaker honoraria and Fellowship support from Boston Scientific Corp.; he also has stock ownership in Volcano Corp., and is a consultant to and research grant recipient from the same.
Manuscript submitted March 7, 2008, provisional acceptance given April 18, 2008, manuscript accepted June 11, 2008.
Address for correspondence: Neil J. Weissman, MD, 100 Irving Street, N.W., Suite EB-5123, Washington, D.C. 20010.  E-mail: [email protected]

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.


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