Prognostic Significance of Peripheral Monocytosis After Reperfused Acute Myocardial Infarction: A Possible Role for Left Ventricular Remodeling

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1 Journal of the American College of Cardiology Vol. 39, No. 2, by the American College of Cardiology ISSN /02/$22.00 Published by Elsevier Science Inc. PII S (01) Prognostic Significance of Periheral Monocytosis After Reerfused Acute Myocardial Infarction: A Possible Role for Left Ventricular Remodeling Myocardial Infarction Yuichiro Maekawa, MD, Toshihisa Anzai, MD, Tsutomu Yoshikawa, MD, Yasushi Asakura, MD, Toshiyuki Takahashi, MD, Shiro Ishikawa, MD, Hideo Mitamura, MD, Satoshi Ogawa, MD Tokyo, Jaan OBJECTIVES BACKGROUND METHODS RESULTS CONCLUSIONS The aim of this study was to determine the significance of eriheral monocytosis in clinical outcome after reerfused acute myocardial infarction (AMI), esecially relating to ostinfarct left ventricular (LV) remodeling. Periheral monocytosis occurs two to three days after AMI, reflecting infiltration of monocytes and macrohages into the necrotic myocardium. However, the rognostic significance of eriheral monocytosis after AMI remains to be determined. A total of 149 atients with first Q-wave AMI were studied. White blood cell (WBC) count, ercentage of monocytes and serum C-reactive rotein level were measured every 24 h for four days after the onset of AMI. We assessed association between eriheral monocytosis and rognosis including um failure, LV aneurysm and long-term outcome after AMI. Patients with um failure ( ) or LV aneurysm ( 0.005) had higher eak monocyte counts than those without these comlications. Predischarge left ventriculograhy revealed that eak monocyte count was ositively correlated with LV end-diastolic volume ( 0.024) and negatively correlated with ejection fraction ( 0.023). Multivariate analyses showed that eak monocyte count 900/mm 3 was an indeendent determinant of um failure (relative risk [RR] 9.83, ), LV aneurysm (RR 4.78, 0.046) and cardiac events (RR 6.30, ), including readmission for heart failure, recurrent myocardial infarction and cardiac deaths, including sudden deaths. Periheral monocytosis is associated with LV dysfunction and LV aneurysm, suggesting a ossible role of monocytes in the develoment of LV remodeling after reerfused AMI. (J Am Coll Cardiol 2002;39:241 6) 2002 by the American College of Cardiology Left ventricular (LV) remodeling after acute myocardial infarction (AMI) is the rocess of infarct exansion followed by rogressive 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 exansion (3). The vulnerable myocardium, which consists of necrotic myocardium and inflammatory cells, is suscetible to wall stress, resulting in infarct exansion. Ventricular aneurysm or subacute cardiac ruture is one of the resultant features of infarct exansion (4,5). We See age 247 have reorted that a marked elevation of serum C-reactive rotein (CRP) level is associated with subacute cardiac ruture, LV aneurysm, and an adverse long-term outcome after AMI, suggesting an imortant role of inflammatory resonse in infarct exansion and LV remodeling (6). However, the mechanism of the henomenon has not been fully elucidated. C-reactive rotein is roduced in the liver From the Cardioulmonary Division, Deartment of Medicine, Keio University School of Medicine, Tokyo, Jaan. Manuscrit received June 5, 2001; revised manuscrit received Setember 6, 2001, acceted October 23, by stimulation of monocyte-related cytokines, such as interleukin-1, interleukin-6 (IL-6) and tumor necrosis factor-alha. Ikeda et al. reorted (7) that lasma IL-6 level, which is redominantly secreted from monocytes and macrohages, correlated well with serum CRP level in atients with AMI. These findings suggest that monocytes may be related to the rocess of infarct healing and LV remodeling. After AMI, the resident macrohages in infarcts are activated and marginating monocytes localized close to the endothelium migrate into the necrotic myocardium through interaction with adhesion molecules. The macrohages and monocytes synthesize and secrete humoral factors, including a factor increasing monocytooiesis, IL-6, macrohagecolony stimulating factor (M-CSF) and monocyte chemoattractant rotein-1 (MCP-1) (8,9). These monocyte-related cytokines induce eriheral monocytosis and infiltration of monocytes into the necrotic myocardium. A revious reort (10) showed that eriheral monocyte count and monocyterelated cytokines were increased in atients with AMI. However, association between eriheral monocyte count and short- or long-term rognosis has not been examined. If the recruitment of circulating monocytes to the injured myocardium lays an imortant role in the infarct healing rocess, eriheral monocytosis may be related to LV remodeling after AMI. The uroses of this study were to assess rognostic

2 242 Maekawa et al. JACC Vol. 39, No. 2, 2002 Monocytosis After Acute Myocardial Infarction January 16, 2002:241 6 Abbreviations and Acronyms ACE angiotensin-converting enzyme AMI acute myocardial infarction BNP brain natriuretic etide CI confidence interval CK creatine kinase CRP C-reactive rotein IL-6 interleukin-6 LV left ventricular MCP-1 monocyte chemoattractant rotein-1 M-CSF macrohage-colony stimulating factor PTCA ercutaneous transluminal coronary angiolasty RR relative risk WBC white blood cell significance of eriheral monocytosis after reerfused AMI, esecially in relation to ost-infarct LV remodeling. METHODS Study oulation. We examined 189 consecutive atients with first Q-wave AMI treated with rimary ercutaneous transluminal coronary angiolasty (PTCA). All atients were admitted to Keio University Hosital within 24 h between January 1994 and December 1999 and were erformed successful reerfusion (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 reviously described (6). We excluded atients in whom the time elased from onset to admission was greater than 24 h (24 atients) and those who died before determination of the eak monocyte count (six atients). Patients with collagen disease, advanced liver disease, renal failure, malignancy or any infectious disease were also excluded (seven atients). Finally, 149 atients were included in this study. Study rotocol. Total and differential counts of leukocytes were measured by an automated hematology analyzer (Sysmex SE-9000, Toa Medical Electronic, Inc., Kobe, Jaan) on admission and every 24 h for at least four days. Serum samles were stored at 70 C and were later analyzed to determine creatine kinase (CK) and CRP levels. C-reactive rotein levels were measured by latex hotometric immunoassay (6). The following data were obtained: age; gender; history of reinfarction angina; coronary risk factors including cigarette smoking, hyertension, diabetes mellitus and hyercholesterolemia; infarct site; use of stent as reerfusion theray; concomitant medications before and after hositalization including beta-blockers and angiotensin-converting enzyme (ACE) inhibitors and in-hosital comlications as reviously described (11). In-hosital comlications included um failure (a grade of class 2 or greater according to Killi 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-u 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 outatient clinic in atients who survived the AMI. The coronary angiograms and left ventriculograms were analyzed by two indeendent angiograhers without knowledge of the atient s background. Global LV ejection fraction and LV end-diastolic volume were estimated from the right anterior oblique rojection of contrast left ventriculograhy during convalescence. Left ventricular aneurysm was assessed from both the right and left anterior oblique views as reviously described (12). In 20 atients with first anterior AMI among the resent oulation, we measured lasma brain natriuretic etide (BNP) levels seven days after the onset. The study rotocol was in agreement with the guidelines of the ethics committee of our institution. Statistical analyses. Continuous data are exressed as the mean value SD. Comarison between two grous was erformed by using the unaired t test or nonarametric means test for continuous variables and by using the chi-square test for categorical variables. Multile logistic regression analysis was used to assess the effect of various factors on um failure or develoment of LV aneurysm. Twelve variables, including those with values 0.10 by univariate analyses, were further assessed by multile logistic regression analysis. Long-term cardiac event-free survival was estimated using Kalan-Meier curves and the log-rank (Mantel-Cox) test to assess the significance of differences according to the resence or absence of eriheral monocytosis. Long-term cardiac events after the onset of AMI were assessed by Cox roortional hazards model. To determine cut-off oints of the eak monocyte count as redictors of um failure, LV aneurysm and long-term cardiac events, receiver oerating characteristic (ROC) analyses were erformed. A value 0.05 was considered statistically significant. All statistical analyses were erformed using Statview 5.0 software (SAS Institute Inc., Cary, North Carolina). RESULTS Patient characteristics. For the entire study oulation, the mean age was years (range 29 to 93). Mean interval from the onset of AMI to arrival at hosital was 5 5 h. The mean monocyte count on admission was /mm 3 and eak monocyte count was /mm 3. The mean time from the onset of AMI to the eak of monocyte count was 2 1 days. Peak monocyte count did not significantly differ according to atient characteristics (Table 1). Relationshi between eak CK and CRP levels and eak monocyte count. Peak monocyte count showed a significant ositive correlation with eak CK and CRP level (r , and r , , resectively), although the correlation between eak monocyte count and

3 JACC Vol. 39, No. 2, 2002 January 16, 2002:241 6 Maekawa et al. Monocytosis After Acute Myocardial Infarction 243 Table 1. Patient Characteristics and Peak Monocyte Counts Peak Monocyte Count (/mm 3 ) Present Absent Age 70 years (55) (94) NS Male gender (127) (22) NS Cigarette smoking (79) (70) NS Hyertension (94) (55) NS Diabetes mellitus (69) (80) NS Hyercholesterolemia (70) (79) NS Anterior infarction (62) (87) NS Preinfarction angina (72) (77) NS ACE inhibitors (114) (35) NS Beta-blockers (91) (58) NS Stent use (77) (72) NS Data are resented as the mean value SD or number of atients. ACE angiotensin-converting enzyme; NS not significant. eak CK level was not close as that between eak monocyte count and eak CRP level. In-hosital comlications and eak monocyte count. Peak monocyte counts were higher in atients with um failure than in those without um failure ( vs /mm 3, ). Patients with the resence of LV aneurysm were associated with higher eak monocyte counts than those with the absence of LV aneurysm ( vs /mm 3, 0.005). Peak monocyte counts were also higher in atients with malignant ventricular arrhythmias than in those without these comlications ( vs /mm 3, 0.032). Coronary angiograhic and left ventriculograhic findings. Primary PTCA was erformed in all atients at a mean of 6 6 h after the onset of AMI. Peak monocyte count was not different between atients with and without multivessel coronary artery disease ( vs /mm 3, 0.97). There was no difference in eak monocyte count between atients with and without stent imlantation ( vs /mm 3, 0.93). Left ventriculograhy was erformed in 105 atients (70%) during convalescence, a mean of days after the onset of AMI. Peak monocyte count was ositively correlated with LV end-diastolic volume ( 0.024) and negatively correlated with LV ejection fraction ( 0.023). Long-term rognosis. Of the 149 atients, 93% (n 138) were followed for more than 12 months. Mean follow-u eriod was (range one to 78) months. Peak monocyte counts were higher in atients who were readmitted for heart failure during the follow-u eriod after AMI than in those without heart failure ( vs /mm 3, ). In atients who suffered cardiac deaths, including sudden deaths, during in-hosital course and the follow-u eriod after AMI, eak monocyte counts were higher than in survivors ( vs /mm 3, 0.048). Peak monocyte counts were higher in atients with cardiac events, including readmission for heart failure, recurrent myocardial infarction and cardiac deaths, including sudden deaths, than in those without these events ( vs /mm 3, ). Determinants of um failure, LV aneurysm and longterm cardiac events. Cut-off oints of eak monocyte count for um failure, LV aneurysm and long-term cardiac events, determined by ROC analysis, were 881/mm 3, 851/ mm 3 and 865/mm 3, resectively. Therefore, we used 900/ mm 3 as a cut-off oint for the analyses in clinical usefulness. The cut-off oint for um failure, LV aneurysm and long-term cardiac events yielded sensitivities of 70%, 60% and 75% and secificities of 80%, 73% and 81%, resectively. Predictive factors for um failure and LV aneurysm. Univariate significant redictors of um failure were older age ( 70 years), eak white blood cell (WBC) count 12,000/mm 3, eak monocyte count 900/mm 3, eak CK level 3,000 IU/l and use of beta-blockers after hositalization. Those of LV aneurysm were anterior infarction, eak monocyte count 900/mm 3 and eak CK level 3,000 IU/l (Table 2). Multile logistic regression analysis showed that eak monocyte count 900/mm 3 was an indeendent redictor of um failure (relative risk [RR] 9.83, 95% confidence interval [CI] 3.29 to 29.40, ), whereas eak WBC count 12,000/mm 3 and eak CK level 3,000 IU/l were not (Table 3). In the same analysis, eak monocyte count 900/mm 3 was also an indeendent redictor of LV aneurysm (RR 4.78, 95% CI Table 2. Univariate Predictors of Pum Failure and LV Aneurysm Patients With Pum Failure (%) Patients With LV Aneurysm (%) Age 70 years (n 55) 29 (53) (23) Male gender (n 127) 46 (36) (17) Cigarette smoking (n 79) 27 (34) (18) Diabetes mellitus (n 69) 25 (36) (20) Hyercholesterolemia (n 70) 21 (30) (16) Anterior infarction (n 62) 23 (37) (31) Peak WBC count 12,000/mm 3 (n 77) 35 (45) (21) Peak monocyte count 900/mm 3 (n 43) 27 (63) (40) Peak CK level 3,000 IU/l (n 50) 28 (56) (35) ACE inhibitors (n 114) 35 (31) (20) Beta-blockers (n 91) 27 (30) (19) Stent use (n 77) 23 (30) (18) ACE angiotensin-converting enzyme; CK creatine kinase; LV left ventricular; WBC white blood cell.

4 244 Maekawa et al. JACC Vol. 39, No. 2, 2002 Monocytosis After Acute Myocardial Infarction January 16, 2002:241 6 Table 3. Multile Logistic Regression Analysis for Pum Failure Relative Risk 95% CI Age 70 years Peak WBC count 12,000 /mm Peak monocyte count 900 /mm Peak CK level 3,000 IU/l Beta blockers CI confidence interval; CK creatine kinase; WBC white blood cell to 22.19, 0.046) as well as anterior infarction and eak CK level 3,000 IU/l (Table 4). Long-term cardiac event-free survival and redictive factor of cardiac events. Kalan-Meier curves and the log-rank test revealed that the eak monocyte count 900/ mm 3 was associated with a higher incidence of cardiac events during the follow-u eriod (Fig. 1). Cox roortional hazards analysis revealed that eak monocyte count 900/mm 3 was the sole indeendent redictor of the cardiac events among the variables (Table 5). Substudy for lasma BNP levels. Plasma BNP levels seven days after the onset of anterior AMI were higher in atients with eak monocyte count 900/mm 3 than those with eak monocyte count 900/mm 3 ( vs g/ml, ), although eak CK levels were not significantly different between the two grous (3,850 2,933 vs. 2,777 2,531 IU/l, ). DISCUSSION This study showed that the eak monocyte count had a significant ositive correlation with LV end-diastolic volume obtained from redischarge left ventriculograhy. Patients with um failure or LV aneurysm had higher eak monocyte counts than those without these comlications. Multivariate analyses showed that a eak monocyte count 900/mm 3 was an indeendent determinant of um failure, LV aneurysm and long-term cardiac events, suggesting a ossible role of monocytes in the develoment of LV remodeling after reerfused AMI. Role of leukocytes in infarct healing. An association between leukocytosis and the rognosis of atients with AMI has been demonstrated by several investigators (13 16). These studies examined large numbers of atients and showed the relationshi between initial WBC counts and Table 4. Multile Logistic Regression Analysis for LV Aneurysm Relative Risk 95% CI Peak monocyte count 900 /mm Peak CK level 3,000 IU/l Anterior infarction CI confidence interval; CK creatine kinase; LV left ventricular. Figure 1. Kalan-Meier curves and log-rank test revealed that a higher eak monocyte count was associated with lower cardiac event-free survival during the follow-u eriod after acute myocardial infarction. Cardiac events were defined as readmission for heart failure, recurrent myocardial infarction and cardiac deaths, including sudden deaths rognosis after AMI. Kyne et al. (17) reorted that a higher neutrohil ercentage count ( 65%) on admission was an indeendent redictor of um 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 resonse by one-oint measurements of WBC count, because neutrohil count on admission could be influenced by time from onset to arrival. Although neutrohils are the first leukocytes to be found in damaged tissue, they are removed from myocardial tissue after hagocytosing the debris. Therefore, neutrohils do not aear to have a role in the subsequent events of infarct healing. Monocytes and macrohages are other leukocytes involved in infarct healing. As monocytes migrate from caillaries into the extravascular sace, they are transformed into macrohages. At two to three days, macrohages begin to outnumber neutrohils and lay a major role in tissue reair (18,19). Macrohages hagocytose necrotic tissue and se- Table 5. Univariate and Multivariate Cox Proortional Hazards Analysis for Cardiac Events Univariate Relative Risk Multivariate Analysis 95% CI Age 70 years Cigarette smoking Anterior infarction Peak WBC count ,000 /mm 3 Peak monocyte count /mm 3 Peak CK level ,000 IU/l ACE inhibitors Beta-blockers Cardiac events included readmission for heart failure, recurrent myocardial infarction and cardiac deaths including sudden deaths. ACE angiotensin-converting enzyme; CI confidence interval; CK creatine kinase; WBC white blood cell.

5 JACC Vol. 39, No. 2, 2002 January 16, 2002:241 6 Maekawa et al. Monocytosis After Acute Myocardial Infarction 245 crete several cytokines, which stimulate fibroblast roliferation, collagen roduction and other healing rocess. These monocyte-related cytokines romote eriheral monocytosis and infiltration of eriheral monocytes into the necrotic myocardium in a ositive feedback manner. Although the acute hase of inflammation is a necessary resonse for the healing rocess, ersistent and excessive activation could be deleterious to the host. Relationshi between monocytes and LV remodeling after AMI. In the resent study, eak monocyte count was not closely correlated with eak CK level. Meisel et al. (20) showed that eak monocyte count had a significant correlation with eak CK level (r 0.39, 0.001), reresenting the extent of myocardial necrosis. However, in their study, there was no recise information regarding the use of revascularization theray. In addition, the average time to eak CK level in their study was greater (33 14 h) than that in our resent study (18 12 h). It is ossible that the washout effect of CK from reerfused myocardium may be in art resonsible for the weak correlation in the resent study. Alternatively, the inflammatory resonse may vary among atients with AMI and may be one of the factors that affect LV remodeling after AMI. In fact, multivariate analyses revealed that a eak monocyte count 900/mm 3 was an indeendent redictor of um failure and LV aneurysm among variables including eak CK levels 3,000 IU/l. Plasma BNP is a clinically useful marker to redict late-hase LV function after AMI. Its level seven days after AMI is known to be correlated with increase in LV end-diastolic volume, imlicating the extent of ost-infarct LV remodeling (21). We showed the significant relationshi between eak monocyte counts and lasma BNP levels seven days after the onset of anterior AMI. It is ossible that eriheral monocytosis is related to infarct healing and thereby reflects LV remodeling. Study limitations. First, we did not erform functional analysis of eriheral 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 resent study to show that the increased eriheral monocytes infiltrate into the necrotic myocardium and contribute to the infarct healing rocess, although revious athologic study showed that eriheral monocytosis recedes increase in number of monocytes and macrohages in the infarct tissue (18). Third, we could not recisely evaluate the effect of ACE inhibitors or beta-blockers on eriheral monocytosis, because the dose and the time from onset to initial administration of these drugs were variable among the atients. Conclusions. 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