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(Chest. 2004;125:384-389.)
© 2004 American College of Chest Physicians

Association Between Serum C-Reactive Protein Elevation and Left Ventricular Thrombus Formation After First Anterior Myocardial Infarction*

Toshihisa Anzai, MD; Tsutomu Yoshikawa, MD; Hidehiro Kaneko, BS; Yuichiro Maekawa, MD; Shiro Iwanaga, MD; Yasushi Asakura, MD and Satoshi Ogawa, MD

* From the Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

Correspondence to: Toshihisa Anzai, MD, Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; e-mail: anzai{at}cpnet.med.keio.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Study objectives: Most left ventricular (LV) thrombi that occur after acute myocardial infarction (AMI) are formed within 2 weeks, when inflammatory cells have infiltrated into the necrotic myocardium. Inflammatory changes on the endocardial surface may induce platelet deposition and fibrin net formation through interaction with proinflammatory cytokines. We sought to determine the significance of the inflammatory response reflected by serum C-reactive protein (CRP) elevation in LV thrombus formation after AMI.

Design: We examined 160 patients with first anterior AMI. Peak serum creatine kinase (CK) and CRP levels were determined by serial measurements. Echocardiography was performed 10 to 14 days after the onset. We assessed the association between the elevation of serum CRP levels and LV thrombus formation after AMI.

Results: LV thrombus was observed in 13 patients (8%). There was no difference in age, sex, coronary risk factors, preinfarction angina, use of revascularization therapy and anticoagulant therapy, platelet count, and fibrinogen level on hospital admission between the two groups. The mean (± SD) peak serum CRP level was markedly increased in patients with LV thrombus compared to those without (18.0 ± 12.6 vs 9.4 ± 8.1 mg/dL; p = 0.001), despite their having similar peak CK levels. Multivariate analysis showed that a peak CRP level of >= 20 mg/dL was an independent predictor of thrombus formation (relative risk, 4.82; p = 0.037) among variables including older age (>= 60 years old), peak CK level (>= 3,000 IU/L), and peak WBC count (>= 12,000 cells/µL).

Conclusion: A greater elevation of serum CRP level was associated with a higher incidence of LV thrombus after AMI, suggesting an important role of the inflammatory response in mural thrombus formation.

Key Words: C-reactive protein • inflammation • mural thrombosis • myocardial infarction • remodeling


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Left ventricular (LV) mural thrombus is one of the major complications of acute myocardial infarction (AMI), especially anterior Q-wave AMI associated with aneurysmal formation.1 Most thrombi are formed within 2 weeks of the occurrence of the AMI. A previous study showed that 83% of thrombi were detected within the first week after AMI, 5% within 2 weeks, and 12% > 2 weeks after AMI.2 A systemic hypercoagulable state and local hemostasis on the surface of the akinetic myocardium could be related to mural thrombus formation during the early phase of AMI.1 However, the precise mechanisms have not been determined.

During the first 2 weeks after a coronary event, WBCs infiltrate into the necrotic myocardium and inflammatory changes occur on the endocardial surface.3 We have reported that serum C-reactive protein (CRP) level is elevated during the acute phase of AMI and its peak level is a useful marker to predict subacute cardiac rupture and 1-year cardiac mortality.4 CRP is produced in the liver on stimulation by monocyte-related cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor-{alpha}.5 These proinflammatory cytokines are secreted predominantly from monocytes and macrophages, which infiltrate into the necrotic myocardium. They are known to induce platelet deposition and fibrin net formation by increasing the expression of tissue factor, fibrinogen, factor VIII, and von Willebrand factor, activating endothelial cells, increasing platelet production, and reducing the levels of inhibitors of hemostasis such as antithrombin and protein S.6 In addition, platelet-activating factor, which is released from infiltrating neutrophils, facilitates platelet aggregation.7 Local hemostasis on the surface of the akinetic myocardium may promote local interactions among proinflammatory cytokines, platelets, and coagulation cascades, leading to mural thrombus formation. We hypothesized that a greater inflammatory response, reflected by serum CRP elevation, is associated with a higher incidence of LV thrombus formation after AMI.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Patients
We examined 173 consecutive patients who had experienced a first anterior AMI. All patients had been admitted to Keio University Hospital within 24 h between February 1995 and July 2001. A diagnosis of AMI was made on the basis of a new ST-segment elevation of >= 2 mm in at least two adjacent precordial leads and either of the following criteria: chest pain lasting > 30 min; or a twofold or greater increase in serum creatine kinase (CK)-MB fraction value.4 We excluded patients who died before determination of the peak CRP level (six patients) and patients with collagen disease, advanced liver disease, renal failure, malignancy, or any infectious disease (seven patients). Finally, 160 patients were included in this study.

Study Protocol
Total and differential counts of WBCs were measured by an automated hematology analyzer (Sysmex SE-9000; Toa Medical Electronic Inc; Kobe, Japan) on hospital admission and every 24 h thereafter for at least 4 days. Serum samples were stored at -70°C and later were analyzed to determine CK and CRP levels. The CRP level was measured by latex photometric immunoassay.4 Peak serum CK and CRP levels were determined by serial measurements (every 4 h and every 24 h, respectively). The plasma fibrinogen level and platelet count were measured on hospital admission. The following data were obtained as previously described8 : age; sex; history of preinfarction angina; coronary risk factors, including cigarette smoking, hypertension, diabetes mellitus, and hypercholesterolemia; use of thrombolysis or percutaneous transluminal coronary angioplasty (PTCA) as reperfusion therapy; concomitant use of medications before and after hospitalization, including aspirin, anticoagulant therapy using heparin, ß-blockers, and angiotensin-converting enzyme inhibitors; and in-hospital complications. Heparin was used in all patients for at least the initial 24 h after the occurrence of the AMI under monitoring of activated prothrombin time (control range, 45 to 60 s). According to the American College of Cardiology/American Hospital Association guidelines,9 warfarin was subsequently administered if an LV aneurysm was present on echocardiography and there was no contraindication for anticoagulant therapy. Preinfarction angina was defined as previously described.8 In-hospital complications included pump failure (a grade of class 2 or greater according to the Killip classification, or subset II or greater according to the Forrester classification), recurrent myocardial infarction, malignant ventricular arrhythmia (ie, sustained ventricular tachycardia or ventricular fibrillation under ECG monitoring), and cardiac death. Follow-up data, including hospital readmission for heart failure, recurrent myocardial infarction, and cardiac deaths including sudden deaths, were obtained through direct contact at an outpatient clinic from patients who survived the AMI.

Transthoracic echocardiography was performed at a mean duration of 12 days after the AMI (Sonos 5500; Phillips; Amsterdam, the Netherlands). LV end-diastolic and end-systolic dimensions, and thickness of the interventricular septum (IVS) and posterior wall (PW) were measured. LV mural thrombus was diagnosed by the presence of a discrete echodense mass with well-defined borders that was present in an asynergic region that was seen in two views, and was present throughout both systole and diastole.10 The coronary angiograms and left ventriculograms were analyzed by two independent angiographers without knowledge of the patient’s background. Global LV ejection fraction and LV end-diastolic volume were estimated from the right anterior oblique projection of contrast left ventriculography during convalescence. The study protocol was in agreement with the guidelines of the ethics committee of our institution.

Statistical Analysis
Continuous data are expressed as the mean ± SD. Comparison between two groups was performed using the unpaired t test or nonparametric means test (Mann-Whiteney U test) for continuous variables, and using the Fisher exact test for categoric variables. Multiple logistic regression analysis was used to assess the effect of various factors on mural thrombus formation. A p value of < 0.05 was considered to be statistically significant. All statistical analyses were performed using a statistical software package (Statview 5.0; SAS Institute; Cary, NC).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Patient Characteristics
For the entire study population, the mean age was 64 ± 13 years (range, 19 to 93 years). The mean time interval from the onset of AMI to arrival at the hospital was 5 ± 5 h. LV mural thrombus was observed in 13 patients (8%). Patient characteristics did not differ between patients with and without LV thrombus according to age, sex, coronary risk factors, preinfarction angina, use of emergent revascularization therapy (ie, thrombolysis or PTCA), or use of antiplatelet agents or cardiovascular drugs before and after hospitalization (Table 1 ).


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  		Table 1.. Patient Characteristics and LV Thrombus*

 
In-Hospital Complications and LV Thrombus
Malignant ventricular arrhythmia and in-hospital cardiac death tended to be more commonly observed in patients with LV thrombus compared with those without LV thrombus (Table 2 ). Systemic embolic complications were not observed in this study population.


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  		Table 2.. In-Hospital Complications and LV Thrombus*

 
Serum CK Level, Inflammatory Response, and LV Thrombus
Table 3 shows the relationship between the presence or absence of LV thrombus and the results of blood tests, including peak CK levels, peak CRP levels, peak WBC counts, fibrinogen levels, and platelet counts. Peak CK level was not significantly different between patients with and without LV thrombus. The mean time from the onset of AMI to the peak CK level was also comparable between the two groups (17 ± 6 and 17 ± 7 h, respectively; difference not significant). In contrast, peak CRP level in patients with LV thrombus was higher than that in those without LV thrombus. The time from the onset to peak CRP was similar in patients with and without LV thrombus (3 ± 1 vs 3 ± 1 days, respectively; difference not significant). Peak WBC count was not significantly different between patients with and without LV thrombus. The differential count showed that peak neutrophil and monocyte counts also tended to be higher, but not significantly, in patients with LV thrombus than in those without LV thrombus. Plasma fibrinogen level and platelet count were comparable between patients with and without LV thrombus.


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  		Table 3.. Serum CK Level, Inflammatory Response, and LV Thrombus*

 
Echocardiographic Findings
Echocardiography was performed at a mean of 12 days after the onset of AMI. LV end-diastolic and end-systolic dimensions did not differ between patients with and without LV thrombus. Fractional shortening was also comparable between the two groups. The thickness of the IVS, and the ratio between IVS and PW thickness were less in patients with LV thrombus than in those without (Table 4 ).


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  		Table 4.. Echocardiographic Findings and LV Thrombus*

 
Coronary Angiographic and Left Ventriculographic Findings
Coronary angiography was performed in 135 patients (84%). The prevalence of multivessel coronary artery disease (22% vs 30%, respectively; difference not significant) and the absence of collateral circulation (80% vs 66%, respectively; difference not significant) were not different between patients with and without LV thrombus. Left ventriculography was performed in 90 patients (56%) at a mean of 13 days after occurrence of the AMI. LV end-diastolic volume index (80 ± 18 vs 78 ± 17 mL/m2, respectively; difference not significant) and ejection fraction (45 ± 6% vs 54 ± 12%, respectively; difference not significant) were comparable between patients with and without LV thrombus.

Follow-up Data
Of the 160 patients, 96 (60%) were observed for > 12 months. The mean follow-up period was 33 ± 21 months (range, 1 to 78 months). Embolic complication was not observed in any of the patients with or without LV thrombus. The occurrence of ischemic cardiac events, including recurrent myocardial infarction (0% vs 1%, respectively; difference not significant), hospital readmission for unstable angina (17% vs 17%, respectively; difference not significant), PTCA (17% vs 11%, respectively; difference not significant), and coronary artery bypass grafting (17% vs 4%, respectively; difference not significant), was similarly observed in patients with and without LV thrombus. The incidence of hospital readmission for heart failure (0% vs 8%, respectively; difference not significant) and the 1-year cardiac mortality rate (0% vs 1%, respectively; difference not significant) were also comparable between the two groups.

Determinants of LV Thrombus
The cutoff point of peak CRP level as a predictor of LV thrombus was determined to be 20 mg/dL by receiver operating characteristic analysis. Multiple logistic regression analysis using variables such as age, peak CK level, peak WBC count, and peak CRP level showed that a peak CRP level of >= 20 mg/dL was an independent predictor of LV thrombus (relative risk, 4.82; p = 0.037), whereas variables such as age of >= 60 years, peak WBC count of >= 12,000 cells/µL, and peak CK level of >= 3,000 IU/L were not independent predictors of LV thrombus (Table 5 ).


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  		Table 5.. Multiple Logistic Regression Analysis for LV Thrombus*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
This study showed that a higher serum peak CRP level was associated with LV mural thrombus formation after the occurrence of a first anterior AMI. Multivariate analyses showed that a peak CRP level of >= 20 mg/dL was an independent determinant of mural thrombus formation among variables including older age, higher peak WBC count, and higher peak CK level, suggesting a possible role for the inflammatory response in mural thrombus formation after AMI.

Incidence of LV Thrombus
LV thrombus is a well-recognized complication of AMI. Its overall incidence at postmortem was reported to be 30 to 40%.10 11 In survivors of AMI, the incidence of LV thrombus was estimated at 20 to 30% by two-dimensional echocardiography, in which the sensitivity for the diagnosis of LV thrombus was in the range of 75 to 95% and the specificity was in the range of 88 to 100%.10 12 However, most of the studies yielding those data were performed before the era of reperfusion therapy. Previous pooled data13 showed that the prevalence of LV thrombus in patients who had experienced an anterior AMI and had been treated with thrombolytic therapy was 14% (338 of 2,442 patients), compared with a prevalence of 24% (247 of 1,022 patients) among patients not treated with thrombolytic therapy. Anticoagulant therapy is also known to prevent LV thrombus formation in patients with AMI. On the basis of a meta-analysis,14 there was a 68% reduction in the risk of developing an LV thrombus after the use of anticoagulant therapy. In the present study, revascularization therapy was more commonly performed than in the previous studies, and all patients received anticoagulant therapy with continuous infusion of heparin during at least the initial 24 h. These treatments may have contributed to the relatively low incidence of LV thrombus and the absence of embolic complications during follow-up in this study.

Factors Responsible for LV Thrombus
Several previous studies13 have reported increased LV thrombus formation with anterior infarct location, larger infarct size or dyskinetic zone, and worse LV function. However, cases of large anterior Q-wave AMI with apical aneurysm are not always complicated by LV thrombus. Other than local hemostasis caused by akinesia or aneurysm formation, there are several factors that may be responsible for LV thrombus formation, such as endocardial injury with local exposure or release of thrombogenic substances, systemic inflammatory response and relative hypercoagulable state after AMI. In the present study, the peak CK level did not differ between patients with and without LV thrombus. Furthermore, echocardiographic data showed that LV dimension and LV function, as assessed by fractional shortening, were comparable between patients with and without LV thrombus. Left ventriculography during convalescence revealed that LV volume and ejection fraction were also comparable between the two groups. These findings suggest that large infarct size and LV dysfunction are not the sole mechanism of LV thrombus formation.

Inflammatory Response and Thrombosis
The LV mural thrombus that is formed in the early phase of AMI is composed of fibrin, RBCs, and platelets, which differs from the structure of a well-organized thrombus observed in patients with congestive heart failure.15 In a patient with an AMI, inflammatory changes on the endocardial surface after myocardial necrosis coexist with thrombus formation. We previously reported16 a case of AMI with LV thrombus in which the thrombus rapidly grew in association with massive infiltration of WBCs beneath the endocardial surface. It is possible that local inflammation on the endocardial surface may be related to the development of LV thrombus.

Inflammation and thrombosis appear to be closely related in several clinical settings. Several studies17 18 have shown that elevation of the serum CRP level could predict future cardiovascular events by reflecting inflammation of the coronary arterial wall. These findings have suggested that inflammation in the atherosclerotic plaque may play an important role in the occurrence of plaque rupture and atherothrombosis. A previous study19 showed that peak serum IL-6 level positively correlated well with peak serum CRP level in patients with AMI. IL-6 is known to increase tissue factor expression on cultured monocytes,20 and tissue factor has a major role in thrombus formation by promoting thrombin generation through direct activation of factor X by the tissue factor-factor VIIa complex.21 In addition, the effect of IL-6 on tissue factor also may be mediated indirectly through CRP. CRP at the concentrations found during inflammation has been shown to increase tissue factor procoagulant activity 75-fold in studies using monocyte cultures.22 Previously, Lagrand et al23 reported that CRP deposition was observed in the infarcted myocardium, colocalizing with complement deposition, whereas such deposition was not observed in patients with sepsis whose serum CRP levels were similarly elevated. They postulated the flip-flop phenomenon of the infarcted myocardial membrane in which lysophosphatidylcholine is exposed to phospholipase A2 enzymes, and thereby generates phosphatidylcholine, a ligand of CRP, on the myocardial surface.24 In such a manner, CRP may be selectively captured by the infarcted myocardium from the bloodstream, and may activate the complement system and coagulation cascades. Therefore, the elevation of the serum CRP level may not be an epiphenomenon, but may directly contribute to local inflammation and thrombus formation.

Interaction Between LV Remodeling and Thrombus Formation
Although LV thrombus causes a worse clinical outcome, such as thromboembolism, the effect of LV thrombus on postinfarct LV remodeling has not been determined. If a thrombus firmly attached to the infarcted endocardium partially restores the full thickness, wall stress will decrease according to the Laplace law (wall stress = pressure x radius/[2 x wall thickness]) and may attenuate infarct expansion. Nihoyannopoulos et al25 reported that early mortality and morbidity were lower in patients with LV thrombus than in those without it. In the present study, the LV dimensions and systolic function during convalescence were comparable between patients with and without LV thrombus, although wall thinning was more prominent in patients with LV thrombus than in those without. In this regard, mural thrombus may have some effect to prevent infarct expansion by offering mechanical support to the infarcted myocardium.

Clinical Implications
Although two-dimensional echocardiography is widely available and is a reasonably accurate technique with which to detect LV thrombus, the early prediction of LV thrombus by other clinical variables could be helpful to treat LV thrombosis as early as possible and to prevent subsequent thromboembolism. Based on the present data, a marked elevation of the serum CRP level could suggest a high risk for LV thrombus formation. Anticoagulant therapy that is continued until the convalescent phase would be recommended in such patients to prevent LV thrombus.

Study Limitations
First, because the sample size was limited, the statistical power might not be strong enough for any negative data to be conclusive. To confirm the prognostic significance of serum CRP level in LV thrombus formation, a large prospective clinical trial will be needed. Second, echocardiographic findings during the chronic phase of AMI were not assessed in the present study. Follow-up echocardiographic data will be required to reveal the effect of LV thrombus on postinfarct LV remodeling.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
A greater elevation of the serum CRP level, but not of the CK level, was associated with a higher incidence of LV thrombus formation after AMI, suggesting an important role for the inflammatory response in mural thrombus formation.


   Footnotes
 
Abbreviations: AMI = acute myocardial infarction; CRP = C-reactive protein; IL = interleukin; IVS = interventricular septum; LV = left ventricular; PTCA = percutaneous transluminal coronary angioplasty; PW = posterior wall

Received for publication February 3, 2003. Accepted for publication July 1, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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