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J Am Coll Cardiol, 2002; 39:241-246
© 2002 by the American College of Cardiology Foundation
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CLINICAL STUDY: MYOCARDIAL INFARCTION

Prognostic significance of peripheral monocytosis after reperfused acute myocardial infarction:a possible role for left ventricular remodeling

Yuichiro Maekawa, MD*, Toshihisa Anzai, MD*,*, Tsutomu Yoshikawa, MD*, Yasushi Asakura, MD*, Toshiyuki Takahashi, MD*, Shiro Ishikawa, MD*, Hideo Mitamura, MD* and Satoshi Ogawa, MD*

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

Manuscript received June 5, 2001; revised manuscript received September 6, 2001, accepted October 23, 2001.

* Reprint requests and correspondence: Dr. Toshihisa Anzai, Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
anzai{at}cpnet.med.keio.ac.jp


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: The aim of this study was to determine the significance of peripheral monocytosis in clinical outcome after reperfused acute myocardial infarction (AMI), especially relating to post-infarct left ventricular (LV) remodeling.

BACKGROUND: Peripheral monocytosis occurs two to three days after AMI, reflecting infiltration of monocytes and macrophages into the necrotic myocardium. However, the prognostic significance of peripheral monocytosis after AMI remains to be determined.

METHODS: A total of 149 patients with first Q-wave AMI were studied. White blood cell (WBC) count, percentage of monocytes and serum C-reactive protein level were measured every 24 h for four days after the onset of AMI. We assessed association between peripheral monocytosis and prognosis including pump failure, LV aneurysm and long-term outcome after AMI.

RESULTS: Patients with pump failure (p < 0.0001) or LV aneurysm (p = 0.005) had higher peak monocyte counts than those without these complications. Predischarge left ventriculography revealed that peak monocyte count was positively correlated with LV end-diastolic volume (p = 0.024) and negatively correlated with ejection fraction (p = 0.023). Multivariate analyses showed that peak monocyte count ≥900/mm3 was an independent determinant of pump failure (relative risk [RR] 9.83, p < 0.0001), LV aneurysm (RR 4.78, p = 0.046) and cardiac events (RR 6.30, p < 0.0001), including readmission for heart failure, recurrent myocardial infarction and cardiac deaths, including sudden deaths.

CONCLUSIONS: Peripheral monocytosis is associated with LV dysfunction and LV aneurysm, suggesting a possible role of monocytes in the development of LV remodeling after reperfused AMI.

Abbreviations and Acronyms
  ACE
  angiotensin-converting enzyme
  AMI
  acute myocardial infarction
  BNP
  brain natriuretic peptide
  CI
  confidence interval
  CK
  creatine kinase
  CRP
  C-reactive protein
  IL-6
  interleukin-6
  LV
  left ventricular
  MCP-1
  monocyte chemoattractant protein-1
  M-CSF
  macrophage-colony stimulating factor
  PTCA
  percutaneous transluminal coronary angioplasty
  RR
  relative risk
  WBC
  white blood cell

Left ventricular (LV) remodeling after acute myocardial infarction (AMI) is the process of infarct expansion followed by progressive LV dilation and is associated with an adverse clinical outcome (1,2). Defective infarct healing, as well as large infarct size and wall stress, is a major determinant of infarct expansion (3). The vulnerable myocardium, which consists of necrotic myocardium and inflammatory cells, is susceptible to wall stress, resulting in infarct expansion. Ventricular aneurysm or subacute cardiac rupture is one of the resultant features of infarct expansion (4,5). We have reported that a marked elevation of serum C-reactive protein (CRP) level is associated with subacute cardiac rupture, LV aneurysm, and an adverse long-term outcome after AMI, suggesting an important role of inflammatory response in infarct expansion and LV remodeling (6). However, the mechanism of the phenomenon has not been fully elucidated. C-reactive protein is produced in the liver by stimulation of monocyte-related cytokines, such as interleukin-1, interleukin-6 (IL-6) and tumor necrosis factor-alpha. Ikeda et al. reported (7) that plasma IL-6 level, which is predominantly secreted from monocytes and macrophages, correlated well with serum CRP level in patients with AMI. These findings suggest that monocytes may be related to the process of infarct healing and LV remodeling.

After AMI, the resident macrophages in infarcts are activated and marginating monocytes localized close to the endothelium migrate into the necrotic myocardium through interaction with adhesion molecules. The macrophages and monocytes synthesize and secrete humoral factors, including a factor increasing monocytopoiesis, IL-6, macrophage-colony stimulating factor (M-CSF) and monocyte chemoattractant protein-1 (MCP-1) (8,9). These monocyte-related cytokines induce peripheral monocytosis and infiltration of monocytes into the necrotic myocardium. A previous report (10) showed that peripheral monocyte count and monocyte-related cytokines were increased in patients with AMI. However, association between peripheral monocyte count and short- or long-term prognosis has not been examined. If the recruitment of circulating monocytes to the injured myocardium plays an important role in the infarct healing process, peripheral monocytosis may be related to LV remodeling after AMI. The purposes of this study were to assess prognostic significance of peripheral monocytosis after reperfused AMI, especially in relation to post-infarct LV remodeling.


   Methods
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Results
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Study population.   We examined 189 consecutive patients with first Q-wave AMI treated with primary percutaneous transluminal coronary angioplasty (PTCA). All patients were admitted to Keio University Hospital within 24 h between January 1994 and December 1999 and were performed successful reperfusion (final Thrombolysis in Myocardial Infarction flow grade 3 in the infarct-related coronary artery without any residual stenosis). A diagnosis of Q-wave AMI was made as previously described (6). We excluded patients in whom the time elapsed from onset to admission was greater than 24 h (24 patients) and those who died before determination of the peak monocyte count (six patients). Patients with collagen disease, advanced liver disease, renal failure, malignancy or any infectious disease were also excluded (seven patients). Finally, 149 patients were included in this study.

Study protocol.   Total and differential counts of leukocytes were measured by an automated hematology analyzer (Sysmex SE-9000, Toa Medical Electronic, Inc., Kobe, Japan) on admission and every 24 h for at least four days. Serum samples were stored at –70°C and were later analyzed to determine creatine kinase (CK) and CRP levels. C-reactive protein levels were measured by latex photometric immunoassay (6). The following data were obtained: age; gender; history of preinfarction angina; coronary risk factors including cigarette smoking, hypertension, diabetes mellitus and hypercholesterolemia; infarct site; use of stent as reperfusion therapy; concomitant medications before and after hospitalization including beta-blockers and angiotensin-converting enzyme (ACE) inhibitors and in-hospital complications as previously described (11). In-hospital complications included pump failure (a grade of class 2 or greater according to Killip’s classification or subset II or greater according to Forrester’s classification), recurrent myocardial infarction, malignant ventricular arrhythmia (sustained ventricular tachycardia or ventricular fibrillation) and cardiac death. Follow-up data, including the history of readmission for heart failure, recurrent myocardial infarction and cardiac deaths, including sudden deaths, were obtained through direct contact at an outpatient clinic in patients who survived the AMI. 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. Left ventricular aneurysm was assessed from both the right and left anterior oblique views as previously described (12). In 20 patients with first anterior AMI among the present population, we measured plasma brain natriuretic peptide (BNP) levels seven days after the onset. The study protocol was in agreement with the guidelines of the ethics committee of our institution.

Statistical analyses.   Continuous data are expressed as the mean value ± SD. Comparison between two groups was performed by using the unpaired t test or nonparametric means test for continuous variables and by using the chi-square test for categorical variables. Multiple logistic regression analysis was used to assess the effect of various factors on pump failure or development of LV aneurysm. Twelve variables, including those with p values <0.10 by univariate analyses, were further assessed by multiple logistic regression analysis. Long-term cardiac event-free survival was estimated using Kaplan-Meier curves and the log-rank (Mantel-Cox) test to assess the significance of differences according to the presence or absence of peripheral monocytosis. Long-term cardiac events after the onset of AMI were assessed by Cox proportional hazards model. To determine cut-off points of the peak monocyte count as predictors of pump failure, LV aneurysm and long-term cardiac events, receiver operating characteristic (ROC) analyses were performed. A p value <0.05 was considered statistically significant. All statistical analyses were performed using Statview 5.0 software (SAS Institute Inc., Cary, North Carolina).


   Results
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Discussion
 References
 
Patient characteristics.   For the entire study population, the mean age was 64 ± 12 years (range 29 to 93). Mean interval from the onset of AMI to arrival at hospital was 5 ± 5 h. The mean monocyte count on admission was 456 ± 289/mm3 and peak monocyte count was 711 ± 292/mm3. The mean time from the onset of AMI to the peak of monocyte count was 2 ± 1 days. Peak monocyte count did not significantly differ according to patient characteristics (Table 1).


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  		Table 1 Patient Characteristics and Peak Monocyte Counts

 
Relationship between peak CK and CRP levels and peak monocyte count.   Peak monocyte count showed a significant positive correlation with peak CK and CRP level (r2 = 0.076, p = 0.0008 and r2 = 0.28, p < 0.0001, respectively), although the correlation between peak monocyte count and peak CK level was not close as that between peak monocyte count and peak CRP level.

In-hospital complications and peak monocyte count.   Peak monocyte counts were higher in patients with pump failure than in those without pump failure (941 ± 348 vs. 605 ± 196/mm3, p < 0.0001). Patients with the presence of LV aneurysm were associated with higher peak monocyte counts than those with the absence of LV aneurysm (861 ± 402 vs. 682 ± 256/mm3, p = 0.005). Peak monocyte counts were also higher in patients with malignant ventricular arrhythmias than in those without these complications (788 ± 334 vs. 677 ± 265/mm3, p = 0.032).

Coronary angiographic and left ventriculographic findings.   Primary PTCA was performed in all patients at a mean of 6 ± 6 h after the onset of AMI. Peak monocyte count was not different between patients with and without multivessel coronary artery disease (706 ± 281 vs. 704 ± 292/mm3, p = 0.97). There was no difference in peak monocyte count between patients with and without stent implantation (714 ± 303 vs. 698 ± 263/mm3, p = 0.93). Left ventriculography was performed in 105 patients (70%) during convalescence, a mean of 18 ± 10 days after the onset of AMI. Peak monocyte count was positively correlated with LV end-diastolic volume (p = 0.024) and negatively correlated with LV ejection fraction (p = 0.023).

Long-term prognosis.   Of the 149 patients, 93% (n = 138) were followed for more than 12 months. Mean follow-up period was 33 ± 21 (range one to 78) months. Peak monocyte counts were higher in patients who were readmitted for heart failure during the follow-up period after AMI than in those without heart failure (900 ± 420 vs. 671 ± 250/mm3, p = 0.0036). In patients who suffered cardiac deaths, including sudden deaths, during in-hospital course and the follow-up period after AMI, peak monocyte counts were higher than in survivors (904 ± 210 vs. 696 ± 284/mm3, p = 0.048). Peak monocyte counts were higher in patients with cardiac events, including readmission for heart failure, recurrent myocardial infarction and cardiac deaths, including sudden deaths, than in those without these events (881 ± 445 vs. 656 ± 239/mm3, p = 0.0074).

Determinants of pump failure, LV aneurysm and long-term cardiac events.   Cut-off points of peak monocyte count for pump failure, LV aneurysm and long-term cardiac events, determined by ROC analysis, were 881/mm3, 851/mm3 and 865/mm3, respectively. Therefore, we used 900/mm3 as a cut-off point for the analyses in clinical usefulness. The cut-off point for pump failure, LV aneurysm and long-term cardiac events yielded sensitivities of 70%, 60% and 75% and specificities of 80%, 73% and 81%, respectively.

Predictive factors for pump failure and LV aneurysm.   Univariate significant predictors of pump failure were older age (≥70 years), peak white blood cell (WBC) count ≥12,000/mm3, peak monocyte count ≥900/mm3, peak CK level ≥3,000 IU/l and use of beta-blockers after hospitalization. Those of LV aneurysm were anterior infarction, peak monocyte count ≥900/mm3 and peak CK level ≥3,000 IU/l (Table 2). Multiple logistic regression analysis showed that peak monocyte count ≥900/mm3 was an independent predictor of pump failure (relative risk [RR] 9.83, 95% confidence interval [CI] 3.29 to 29.40, p < 0.0001), whereas peak WBC count ≥12,000/mm3 and peak CK level ≥3,000 IU/l were not (Table 3). In the same analysis, peak monocyte count ≥900/mm3 was also an independent predictor of LV aneurysm (RR 4.78, 95% CI 1.03 to 22.19, p = 0.046) as well as anterior infarction and peak CK level ≥3,000 IU/l (Table 4).


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  		Table 2 Univariate Predictors of Pump Failure and LV Aneurysm

 

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  		Table 3 Multiple Logistic Regression Analysis for Pump Failure

 

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  		Table 4 Multiple Logistic Regression Analysis for LV Aneurysm

 
Long-term cardiac event-free survival and predictive factor of cardiac events.   Kaplan-Meier curves and the log-rank test revealed that the peak monocyte count ≥900/mm3 was associated with a higher incidence of cardiac events during the follow-up period (Fig. 1). Cox proportional hazards analysis revealed that peak monocyte count ≥900/mm3 was the sole independent predictor of the cardiac events among the variables (Table 5).



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  		Figure 1 Kaplan-Meier curves and log-rank test revealed that a higher peak monocyte count was associated with lower cardiac event-free survival during the follow-up period after acute myocardial infarction. Cardiac events were defined as readmission for heart failure, recurrent myocardial infarction and cardiac deaths, including sudden deaths. p < 0.0001.

 

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  		Table 5 Univariate and Multivariate Cox Proportional Hazards Analysis for Cardiac Events

 
Substudy for plasma BNP levels.   Plasma BNP levels seven days after the onset of anterior AMI were higher in patients with peak monocyte count ≥900/mm3 than those with peak monocyte count <900/mm3 (301.7 ± 70.9 vs. 123.4 ± 91.6 pg/ml, p = 0.0048), although peak CK levels were not significantly different between the two groups (3,850 ± 2,933 vs. 2,777 ± 2,531 IU/l, p = 0.1522).


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
This study showed that the peak monocyte count had a significant positive correlation with LV end-diastolic volume obtained from predischarge left ventriculography. Patients with pump failure or LV aneurysm had higher peak monocyte counts than those without these complications. Multivariate analyses showed that a peak monocyte count ≥900/mm3 was an independent determinant of pump failure, LV aneurysm and long-term cardiac events, suggesting a possible role of monocytes in the development of LV remodeling after reperfused AMI.

Role of leukocytes in infarct healing.   An association between leukocytosis and the prognosis of patients with AMI has been demonstrated by several investigators (13–16). These studies examined large numbers of patients and showed the relationship between initial WBC counts and prognosis after AMI. Kyne et al. (17) reported that a higher neutrophil percentage count (>65%) on admission was an independent predictor of pump failure. However, the WBC and differential counts were not serially measured in these studies. It might be difficult to assess exactly the extent of inflammatory response by one-point measurements of WBC count, because neutrophil count on admission could be influenced by time from onset to arrival. Although neutrophils are the first leukocytes to be found in damaged tissue, they are removed from myocardial tissue after phagocytosing the debris. Therefore, neutrophils do not appear to have a role in the subsequent events of infarct healing. Monocytes and macrophages are other leukocytes involved in infarct healing. As monocytes migrate from capillaries into the extravascular space, they are transformed into macrophages. At two to three days, macrophages begin to outnumber neutrophils and play a major role in tissue repair (18,19). Macrophages phagocytose necrotic tissue and secrete several cytokines, which stimulate fibroblast proliferation, collagen production and other healing process. These monocyte-related cytokines promote peripheral monocytosis and infiltration of peripheral monocytes into the necrotic myocardium in a positive feedback manner. Although the acute phase of inflammation is a necessary response for the healing process, persistent and excessive activation could be deleterious to the host.

Relationship between monocytes and LV remodeling after AMI.   In the present study, peak monocyte count was not closely correlated with peak CK level. Meisel et al. (20) showed that peak monocyte count had a significant correlation with peak CK level (r = 0.39, p < 0.001), representing the extent of myocardial necrosis. However, in their study, there was no precise information regarding the use of revascularization therapy. In addition, the average time to peak CK level in their study was greater (33 ± 14 h) than that in our present study (18 ± 12 h). It is possible that the washout effect of CK from reperfused myocardium may be in part responsible for the weak correlation in the present study. Alternatively, the inflammatory response may vary among patients with AMI and may be one of the factors that affect LV remodeling after AMI. In fact, multivariate analyses revealed that a peak monocyte count ≥900/mm3 was an independent predictor of pump failure and LV aneurysm among variables including peak CK levels ≥3,000 IU/l.

Plasma BNP is a clinically useful marker to predict late-phase LV function after AMI. Its level seven days after AMI is known to be correlated with increase in LV end-diastolic volume, implicating the extent of post-infarct LV remodeling (21). We showed the significant relationship between peak monocyte counts and plasma BNP levels seven days after the onset of anterior AMI. It is possible that peripheral monocytosis is related to infarct healing and thereby reflects LV remodeling.

Study limitations.   First, we did not perform functional analysis of peripheral monocytes. Measurements of monocyte-related cytokines, such as IL-6, M-CSF and MCP-1, will be needed to assess the monocyte activation following AMI. Second, there is no direct evidence in the present study to show that the increased peripheral monocytes infiltrate into the necrotic myocardium and contribute to the infarct healing process, although previous pathologic study showed that peripheral monocytosis precedes increase in number of monocytes and macrophages in the infarct tissue (18). Third, we could not precisely evaluate the effect of ACE inhibitors or beta-blockers on peripheral monocytosis, because the dose and the time from onset to initial administration of these drugs were variable among the patients.

Conclusions.   The present study demonstrated that peripheral monocytosis is associated with pump failure, LV aneurysm and long-term outcome after reperfused AMI, suggesting a possible role of monocytes in the development of post-infarct LV remodeling. Further detailed studies are required to determine whether these findings would be identified in large clinical trials.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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