Increased Body Temperature After Reperfused Acute Myocardial Infarction Is Associated With Adverse Left Ventricular Remodeling

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1 Journal of Cardiac Failure Vol. 13 No Increased Body Temperature After Reperfused Acute Myocardial Infarction Is Associated With Adverse Left Ventricular Remodeling KOTARO NAITO, MD, TOSHIHISA ANZAI, MD, TSUTOMU YOSHIKAWA, MD, FACC, YUICHIRO MAEKAWA, MD, YASUO SUGANO, MD, TAKASHI KOHNO, MD, KEITARO MAHARA, MD, TERUO OKABE, MD, YASUSHI ASAKURA, MD, AND SATOSHI OGAWA, MD, FACC Tokyo, Japan ABSTRACT Background: Fever is frequently observed in patients with acute myocardial infarction (AMI); however, its prognostic significance remains to be determined. We sought to determine the prognostic significance of increased body temperature (BT) after AMI. Methods and Results: We examined 156 consecutive patients with reperfused first anterior AMI. Axillary BT was serially measured every 6 hours for a week. Patients were divided into quartiles by peak BT from the lowest to highest levels. Peak BT within the first week showed a significant positive correlation with peak C-reactive protein level (P!.1), but not with peak creatine kinase level. There were positive correlations of peak BT with the incidence of pump failure (P 5.22), left ventricular (LV) aneurysm (P 5.29), and readmission for heart failure (P 5.6). Higher peak BT was associated with greater LV end-diastolic volume (P 5.31), greater end-systolic volume (P 5.8), and lower LV ejection fraction (P 5.14) 2 weeks after AMI. Multiple logistic regression analyses revealed that peak BT quartile was an independent predictor of in-hospital cardiac events (odds ratio /quartile, P 5.8). Furthermore, peak BT quartile was a significant predictor of readmission for heart failure by Cox proportional hazard model analysis (P 5.48). Conclusions: Increased BT after AMI was associated with a worse clinical outcome and infarct expansion, suggesting a relationship between systemic inflammatory response and LV remodeling. (J Cardiac Fail 27;13:25e33) Key Words: Acute coronary syndrome, Fever, Inflammation, Immune system. Fever is one of the most frequent clinical signs encountered in human pathologic conditions such as infection, inflammation, and tissue injury. It is known that most patients with acute myocardial infarction (AMI), especially a large AMI, develop fever within 24 to 48 hours of the onset. 1,2 Many previous reports revealed that fever after AMI was associated with elevated serum levels of cardiac enzymes From the Division of Cardiology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan. Manuscript received February 28, 26; revised manuscript received September 14, 26; revised manuscript accepted September 28, 26. Reprint requests: Toshihisa Anzai, MD, Division of Cardiology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo , Japan. Supported in part by Keio University Medical School Facility and an Alumni Grant to Toshihisa Anzai, MD /$ - see front matter Ó 27 Elsevier Inc. All rights reserved. doi:1.116/j.cardfail derived from the myocardium. 3e5 Thus it has been recognized as a nonspecific response to tissue necrosis, rather than a prognostic marker in AMI. Myocardial necrosis induces infiltration of inflammatory cells including neutrophils, monocytes, and macrophages. These cells lead to synthesis of numerous cytokines including interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor-a, and interferon-g, which act as endogenous pyrogens. These cytokines are released into the systemic circulation and transported to the preoptic-anterior hypothalamic area, the brain region where body temperature (BT) is regulated. Prostaglandin E 2 induced by these cytokines plays an essential role in the preoptic-anterior hypothalamic area and the development of fever. An inflammatory reaction after AMI is a prerequisite for healing and scar formation. However, defective infarct healing caused by excessive inflammation, as well as large infarct size and wall stress, is a major determinant of infarct expansion. 6 The vulnerable myocardium, which consists of 25

2 26 Journal of Cardiac Failure Vol. 13 No. 1 February 27 necrotic myocardium and inflammatory cells, is susceptible to wall stress, resulting in infarct expansion. Elevated BT may reflect these inflammatory responses after AMI and may be related to infarct expansion and left ventricular (LV) remodeling. Alternatively, an elevated BT may augment the inflammatory response to myocardial necrosis, because increased temperature is known to activate host immune function. Though BT can be readily measured, the prognostic significance of an elevated BT after AMI remains to be determined. The primary aim of this study was to examine the effect of increased BT on clinical outcome and LV remodeling after a reperfused first anterior AMI. Study Population Methods We studied 321 consecutive patients with first anterior STelevation AMI who were admitted to Keio University Hospital between 1995 July and 24 November. The diagnosis of anterior AMI was made on the basis of chest pain lasting $3 minutes, the presence of new ST-segment elevation in at least 2 adjacent precordial leads, and an increase in the serum creatine kinasemyocardial band (CK-MB) fraction. None of the patients had a previous history of myocardial infarction. Patients who were admitted 24 hours or more after the onset were excluded from this study (n 5 54). Patients who did not receive emergent revascularization therapies, including percutaneous coronary intervention (PCI) and thrombolysis, were also excluded (n 5 61). Then, patients with infectious disease, collagen disease, malignant disease, or severe hepatic or renal failure were excluded from this study (n 5 5). No patient received steroid and nonsteroidal anti-inflammatory drugs except aspirin and ticlopidin for post-pci antithrombotic therapy. Finally, 156 patients were included in this study. Informed consent was obtained from all patients. The study protocol was in agreement with the guidelines of the Ethics Committee of our institution. Study Protocol Axillary BT was serially measured every 6 hours from the time of admission for a week. We defined the peak BT as the highest BT value within 7 days. The population was divided into quartiles by peak BT from the lowest to highest levels. We collected the following data: age, sex, coronary risk factors (cigarette smoking, hypertension as defined by the Joint National Committee VII, 7 diabetes mellitus as defined by the World Health Organization study group, 8 hypercholesterolemia defined as a total cholesterol level higher than 22 mg/dl), history of preinfarction angina (defined as $1 episode of typical chest pain within 72 hours before the onset of AMI), arrival time from the onset of AMI, systolic and diastolic blood pressure and heart rate on admission, use of revascularization therapy and cardiovascular medication (aspirin, b-blockers, angiotensin-converting enzyme inhibitors, calcium antagonists, statins) after admission, and in-hospital complications, as previously described. 9 Pump failure was defined as greater than class 2 of Killip s classification 1 or greater than subset II of Forrester s classification. 11 Venous blood samples were obtained on admission, every 6 hours during the first 24 hours after admission, and then every 24 hours for at least 4 days, to determine peak peripheral white blood cell count (WBC), serum CK, and C-reactive protein (CRP) levels. The laboratory data of patients who died before the determination of its peak level or were admitted late were excluded. Serum CRP level was measured by latex photometric immunoassay (LPIA-CRP, Mitsubishi Chemical, Inc., Tokyo, Japan). 12 Serum creatinine level on admission was measured by creatinase-sarcosinoxydase-peroxidase method. Blood samples were taken from patients after they had been resting in the supine position for at least 3 minutes. All patients in this study received emergent revascularization therapy. The number of patients with PCI was 138 and that of patients with thrombolysis was 18. Before PCI, patients received aspirin (162 mg). Intravenous heparin (1, IU) was administered after arterial access was obtained to achieve an activated clotting time of 2e3 seconds. Postprocedural antithrombotic therapy consisted of aspirin (81e1 mg/day) and ticlopidine (1 mg twice daily). Platelet glycoprotein IIb/IIIa inhibitors were not used in this study. For thrombolysis, intravenous administration of recombinant tissue plasminogen activator (alteplase 4, IU/kg intravenous bolus, followed by 36, IU/kg over 6 minutes) was performed. Patients with thrombolytic therapy also received anticoagulation (intravenous administration of heparin 5, IU, subsequently adjusted to maintain an activated partial thromboplastin time of between 5 and 7 seconds) and antithrombotic therapies (aspirin 81e1 mg/day). We performed serial measurements of plasma IL-6 and neurohormones, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), norepinephrine, renin activity, angiotensin II, aldosterone, and endothelin-1, on admission, and then 2 weeks and 6 months after the onset of AMI. Plasma IL-6 level was measured by chemiluminescent enzyme immunoassay (CLEIA, Fujirebio Inc., Tokyo, Japan). Plasma ANP and BNP levels were measured by immunoradiometric assay. Plasma norepinephrine level was measured by high-performance liquid chromatography. Plasma renin activity and aldosterone level were measured using commercially available radioimmunoassay kits. Plasma angiotensin II and endothelin-1 levels were measured by radioimmunoassay using specific antibodies directed against synthetic angiotensin II and endothelin-1, respectively. Echocardiographic Analyses Echocardiography was performed 1 to 14 days after AMI in 131 patients (84%). LV end-diastolic and end-systolic dimensions, fractional shortening, and ejection fraction by Gibson method were obtained by M-mode echocardiography. All echocardiographic studies were interpreted by 2 experienced observers without knowledge of the patients background. Angiographic Analyses Significant stenosis was defined as a narrowing O5% of the reference diameter. Thrombolysis In Myocardial Infarction (TIMI) grade was assessed before and after PCI. Left ventriculography was performed 2 weeks after AMI in 128 patients (82%). LV end-diastolic volume, end-systolic volume, and ejection fraction were measured using the right anterior oblique view of left ventriculograms by the area-length method. The presence of LV aneurysm was assessed according to the criteria described by Meizlish et al. 13 Interpretation of catheterization data was performed jointly by 2 experienced observers without knowledge of the patients history.

3 Increased Body Temperature After Reperfused Acute MI Naito et al 27 Study End Points and Long-Term Follow-Up The first study end points were occurrence of in-hospital complications including pump failure, malignant ventricular arrhythmias, and cardiac rupture or cardiac death. After discharge, follow-up data were obtained through direct contact at an outpatient clinic of our institute where the patients received monthly check-up or by telephone interview. The occurrence of readmission for heart failure and a major adverse cardiac event (MACE), including in-hospital and out-of-hospital cardiac death, nonfatal myocardial infarction, reintervention, and coronary artery bypass grafting, were the secondary end points of this study. events and long-term clinical outcomes, receiver operating characteristics curve analyses were performed. Regarding the long-term follow-up data, we performed Cox proportional hazard model analyses to assess the effect of variables, including peak BT quartile, on MACE and readmission for heart failure as the outcome events of interest to determine the adjusted hazard of the secondary end point. The assumption of the proportional hazard model was evaluated by examining the log ( log) plots and satisfied. A 2-sided 5% level of significance was considered significant for all statistical tests. All statistical analyses were performed using SPSS 13. for Windows (SPSS Inc., Chicago, IL). Statistical significance was defined as a P value of!.5. Statistical Analyses Continuous data were expressed as the mean value 6 SD and examined by 1-way analysis of variance with post-hoc tests (Bonferroni s multiple comparison test). Categorical variables were reported as frequencies with percentages and compared between groups using chi-squared test (with Yates continuity correction). If 1 of the cell expected counts has value less than 5, we used Fisher s exact test instead of chi-squared test to obtain P values for categorical variables. Using Student s t-test to compare peak BT as a continuous variable between 2 groups with or without each clinical outcome, the necessary number of samples was 63 (calculated for effect size 5.5 C, a 5.5, power 5.9). Then, if the expected correlation coefficient (r) between BT and LV ejection fraction, end-systolic volume, or end-diastolic volume were.3, the necessary number of samples would be 113 (calculated for a 5.5, power 5.9). Therefore, we considered that 156 patients, the total number in this study, were sufficient to analyze the relation between BT and LV remodeling after AMI. Multiple logistic regression analysis was used to assess the effect of various factors on in-hospital complications and cardiac death. Thirteen variables, consisting of those with P values!.1 by univariate analysis, were further assessed by multiple logistic regression analysis. To determine cutoff points of the heart rate on admission and peak CK level as predictors of in-hospital cardiac Patient Characteristics Table 1. Patients Baseline Characteristics Results The study population had a mean age of (range 19 to 88) years with an overall male proportion of 85%. Mean peak BT was C, occurring at hours after the onset of AMI. Patients were divided into quartiles by peak BT as follows; 1st quartile, peak BT #37.2 C; 2nd quartile, 37.3e37.5 C; 3rd quartile, 37.6e37.9 C; 4th quartile, $38. C. The prevalence of cardiovascular risk factors and the presence or absence of preinfarction angina were similar in all quartiles. Mean interval from the onset of AMI to hospital arrival was hours. The percentage of arrival within 6 hours after the onset was similar in each quartile. The patient s number with PCI did not differ among quartiles. Regarding medication after admission, administration rates of aspirin, b-blockers, angiotensin-converting enzyme inhibitors, calcium antagonists, and statins were not significantly different in each quartile. Serum creatinine level and systolic and diastolic blood pressure on admission were not different in each Peak BT Quartile Overall (n 5 156) 1st #37.2 C (n 5 41) 2nd 37.3e5 C (n 5 42) 3rd 37.6e9 C (n 5 38) 4th $38. C (n 5 35) P Value Age, years Male sex, n (%) 133 (85) 35 (85) 35 (83) 33 (87) 3 (86).98 Smoking, n (%) 95 (61) 24 (59) 27 (64) 25 (66) 19 (54).72 Hypertension, n (%) 72 (46) 18 (44) 18 (43) 2 (53) 16 (46).82 Diabetes mellitus, n (%) 52 (33) 11 (27) 18 (43) 13 (34) 1 (29).41 Hypercholesterolemia, n (%) 66 (42) 15 (37) 19 (45) 16 (42) 16 (46).83 Preinfarction angina, n (%) 92 (59) 26 (63) 27 (64) 21 (55) 18 (51).6 Arrival time from onset!6 hours, n (%) 121 (78) 3 (73) 33 (79) 32 (84) 26 (74).65 Medication after admission Aspirin, n (%) 139 (89) 37 (9) 39 (93) 35 (92) 28 (8).26 b-blocker, n (%) 115 (74) 32 (78) 28 (67) 29 (76) 26 (74).66 ACE inhibitor, n (%) 91 (58) 22 (54) 27 (64) 22 (58) 2 (57).8 Calcium antagonist, n (%) 29 (19) 8 (2) 7 (17) 1 (26) 4 (11).42 Statin, n (%) 49 (31) 13 (32) 16 (38) 1 (26) 1 (29).69 Serum creatinine, mg/dl Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm Continuous variables are presented as mean 6 SD. These were examined by 1-way analysis of variance. Categorical variables were compared among groups using chi-squared test and presented as number (percentage). BT, body temperature; ACE, angiotensin-converting enzyme; BP, blood pressure; bpm, beats per minute.

4 28 Journal of Cardiac Failure Vol. 13 No. 1 February 27 quartile. However, the peak BT quartile showed a significant positive correlation with heart rate on admission (Table 1). Relationship between Peak CK, WBC and CRP Levels, and Peak BT Peak CK level of the 1st to 4th quartile of peak BT was , , , and IU/L, respectively (P 5.51, Fig. 1A). In patients with TIMI 3 reperfusion, peak CK level were also similar in each BT quartile ( , , , and IU/L, respectively, P 5.79). Peak WBC count was 12, , 12,6 6 42, 12,6 6 32, and 13,4 6 4 /mm 3, respectively. A Peak CK (IU/L) B Peak CRP (mg/dl) P =.51 P <.1 * Fig. 1. Peak creatine kinase (CK) level and C-reactive protein (CRP) level, and peak body temperature (BT). The 1st quartile, peak BT #37.2 C; the 2nd quartile, peak BT e37.5 C; the 3rd quartile, peak BT e37.9 C; and the 4th quartile, peak BT $ 38. C. did not significantly correlate with peak CK level (P 5.51) (A). However, higher peak BT quartile was associated with significantly higher peak CRP level (P!.1) (B). Significant difference * P!.1 vs. 1st quartile, y P!.1 vs. 2nd quartile, and z P!.1 vs. 3rd quartile by post-hoc tests (Bonferroni s multiple comparison test). did not significantly correlate with peak WBC count (P 5.49). However, higher peak BT quartile was associated with significantly higher peak CRP level (P!.1, Fig. 1B). When peak BT was assessed as a continuous variable, it was positively correlated with peak CRP level (r 5.55, P!.1). Echocardiographic Findings LV end-diastolic dimension of the 1st to 4th quartile of peak BT was , , 5 6 6, and mm, respectively. LV end-diastolic dimension tended to be higher in patients with higher peak BT (P 5.74). Similarly, LV end-systolic dimension of the 1st to 4th quartile of peak BT was , , , and mm, respectively. LV end-systolic dimension did not correlated with peak BT quartile (P 5.16, respectively). Ejection fraction by Gibson method and fractional shortening did not significantly correlate with peak BT. Angiographic Findings Table 2 revealed the relationship between angiographic findings and peak BT. The proportion of patients with a #6 lesion (proximal to the first septal branch) as a culprit lesion (from the 1st to 4th quartile, the incidence was 44%, 62%, 5%, and 6%, respectively, P 5.21) and with multivessel disease (1st to 4th quartile, 22%, 26%, 26%, and 4%, respectively, P 5.43) were not significantly different in all quartiles. In patients who underwent emergent coronary angiography, the rate of spontaneous reperfusion (initial TIMI flow grade $2) was similar in all quartiles (1st to 4th quartile, 39%, 29%, 21%, and 26%, respectively, P 5.52). The incidence of no-reflow phenomenon after reperfusion therapy (post TIMI flow grade #2) was not different in each quartile (1st to 4th quartile, 15%, 26%, 16%, and 29%, respectively, P 5.42). Figure 2 presents the relationship between left ventriculographic findings and peak BT. Left ventriculography 2 weeks after AMI revealed that higher peak BT was associated with greater LV end-diastolic volume (P 5.31), greater end-systolic volume (P 5.8), and lower LV ejection fraction (P 5.14). The incidence of LV aneurysm increased markedly with increasing quartile of peak BT; from the 1st to 4th quartile, the incidence was 2%, 37%, 48%, and 56%, respectively (P 5.29). In-Hospital Complications and Cardiac Death In-hospital cardiac events are shown in Table 3. Nine patients died during hospitalization. Regarding the cause of in-hospital cardiac death, 5 patients died of pump failure, 2 patients died of malignant ventricular arrhythmias, and 2 patients died of cardiac rupture. Both Killip s classification (P 5.6) and Forrester s classification (P 5.1) showed a significantly positive correlation with peak BT quartile. The number of patients with pump failure was 14 (34%), 18 (43%), 19 (5%), and 24 (69%), the 1st to 4th quartile of peak BT, respectively. The incidence of

5 Increased Body Temperature After Reperfused Acute MI Naito et al 29 Table 2. Angiographic Findings and Peak BT Peak BT Quartile Overall (n 5 156) 1st #37.2 C (n 5 41) 2nd 37.3e5 C (n 5 42) 3rd 37.6e9 C (n 5 38) 4th $38. C (n 5 35) P Value Culprit lesion 5 #6, n (%) 84 (54) 18 (44) 26 (62) 19 (5) 21 (6).21 Multivessel disease, n (%) 44 (28) 9 (22) 11 (26) 1 (26) 14 (4).43 Initial TIMI $2, n (%) 45 (29) 16 (39) 12 (29) 8 (21) 9 (26).52 Post TIMI #2, n (%) 33 (21) 6 (15) 11 (26) 6 (16) 1 (29).42 All data are categorical variables presented as number (percentage). These were compared among groups using chi-squared test. BT, body temperature; TIMI, thrombolysis in myocardial infarction. pump failure increased markedly with increasing quartile of peak BT (P 5.22). Similarly, the number of patients with malignant ventricular arrhythmias was 2 (5%), 5 (12%), 6 (16%), and 9 (26%), respectively. The incidence of malignant ventricular arrhythmias tended to be higher in higher peak BT quartiles (P 5.7). Patients with cardiac rupture were observed in the 3rd quartile (1 patient) and 4th quartile (1 patient). The correlation between the incidence of cardiac rupture and peak BT was not significant (P 5.36). The number of patients with cardiac death was 1 (2%), 2 (5%), 2 (5%), and 4 (11%), respectively. A higher incidence of cardiac death was observed in patients with increasing quartiles of peak BT, although the correlation between the incidence of cardiac death and peak BT quartile was not significant (P 5.45). Overall in-hospital cardiac events, including pump failure, malignant ventricular arrhythmias, cardiac rupture, and cardiac death, were more commonly observed in patients with higher peak BT quartile (15 [37%], 2 [48%], 2 [53%], and 27 [77%], respectively, P 5.4, Table 3). Long-Term Cardiac Events Patients were followed for a mean of (range 1 to 36) months. Patients who readmitted for heart failure were observed in the 3rd quartile (1 patient) and 4th quartile (4 patients). The incidence of readmission for heart failure was higher in higher peak BT quartile (P 5.6, Table 3). There was no patient with out-of-hospital cardiac death during the observation period of this study. The incidence of MACE, including in-hospital and out-of-hospital cardiac death, nonfatal myocardial infarction, reintervention, and coronary artery bypass grafting, in the 1st to 4th quartile of peak BT was 1 (24%), 9 (21%), 7 (18%), and 11 (31%), respectively. The correlation between the incidence of MACE and peak BT quartile was not significant (P 5.36, Table 3). Determinants of Short- and Long-Term Clinical Outcomes Cutoff points of heart rate on admission and peak CK level for in-hospital cardiac events, determined by receiver operating characteristics curve analysis were 8 bpm and 3 IU/L, respectively. In univariate logistic regression analysis of the relations to overall in-hospital cardiac events, including pump failure, malignant ventricular arrhythmias, cardiac rupture, and cardiac death, the variables with P values!.1 were peak BT quartile, older age ($7 years), absence of preinfarction angina, heart rate on admission $8 beats/min, and peak CK $3 IU/L. Similarly, those related to LV aneurysm were peak BT quartile, older age ($7 years), absence of preinfarction angina, and peak CK $3 IU/L. The final multiple logistic regression analysis using these variables showed that higher peak BT was an independent determinant of in-hospital cardiac events (odds ratio /quartile, P 5.8, Table 4), and LV aneurysm (odds ratio /quartile, P 5.1, Table 5) among these variables. In univariate logistic regression analysis of the relations to readmission for heart failure, the variables with P values!.1 were BT quartile and older age ($7 years). The final Cox proportional hazard analysis using these variables showed that higher peak BT quartile was an independent determinant of readmission for heart failure among these variables (hazard ratio /quartile, P 5.48, Table 6). was not a significant predictor of MACE, including in-hospital and out-of-hospital cardiac death, nonfatal myocardial infarction, reintervention, and coronary artery bypass grafting, by Cox proportional hazard analysis. Plasma IL-6 and Neurohormones Plasma IL-6 level on admission (1st to 4th quartile: , , , and pg/ml, respectively, P 5.12), BNP level 6 months after AMI (1st to 4th quartile: , , , and pg/ml, respectively, P 5.82), and ANP level 6 months after AMI (1st to 4th quartile: , , , and pg/ml, respectively, P 5.52) tended to be higher in patients with higher peak BT quartile. Higher peak BT quartile was associated with higher plasma IL-6 level 6 months after AMI (1st to 4th quartile: , , , and pg/ml, respectively, P 5.2) and higher BNP level 2 weeks after AMI (1st to 4th quartile: , , , and pg/ml, respectively, P 5.13). Other plasma neurohormones, including norepinephrine, renin activity, angiotensin II, aldosterone, and endothelin-1, were not

6 3 Journal of Cardiac Failure Vol. 13 No. 1 February 27 A 12 1 P =.31 * significantly different in each quartile of peak BT during the observation period. Discussion LVEDV (ml/m 2 ) In this study, we assessed the prognostic significance of increased BT in patients with reperfused first anterior AMI. Patients with higher peak BT had a worse clinical outcome and adverse LV remodeling, in association with higher peak serum CRP level, compared with those without. Increased BT was an independent predictor of in-hospital cardiac events after AMI. Furthermore, increased BT was associated with higher plasma BNP level during convalescence and development of LV aneurysm and late-phase heart failure, suggesting a relationship between systemic inflammatory response and LV remodeling. B 8 P =.8 Significance of Elevated BT after AMI LVESV (ml/m 2 ) C * P =.14 Body temperature often begins to rise within 4 to 8 hours after the onset of AMI, and usually resolves by the 4th or 5th day after infarction. 1,2 Increased BT could be an epiphenomenon of the inflammatory response after myocardial necrosis. However, there are several lines of evidence showing augmentative effects of increased BT on immune function. 14e16 Previous reports revealed that a marked increase in serum CRP level 12,17 and increased peripheral monocyte count, 18 but not peak CK level, are associated with a worse clinical outcome and infarct expansion, suggesting an adverse effect of an enhanced inflammatory response in LV remodeling. Although elevated BT is a natural consequence of the healing process, it could be related to inappropriate activation of the inflammatory system, resulting in exaggerated LV remodeling. Possible Effects of Increased BT on Infarct Size and Repair Process LVEF ( ) * Fig. 2. Left ventriculographic findings 2 weeks after acute myocardial infarction and peak body temperature (BT). The 1st quartile, peak BT # 37.2 C; the 2nd quartile, peak BT e37.5 C; the 3rd quartile, peak BT e37.9 C; and the 4th quartile, peak BT $ 38. C. Elevated peak BT was associated with greater left ventricular end-diastolic volume Because temperature has a strong influence on oxygen consumption, elevated BT increases oxygen demand and may affect infarct size. Moderate cooling by 3 Cto5 C during myocardial ischemia has been shown to markedly reduce infarct size in animal models. 19e21 However, most patients acquired a maximum BT 2 to 3 days after AMI, when the infarct size is already determined. Therefore, the elevated BT in this study might reflect postinfarction inflammatory response, but not cause greater infarct size. Elevation of systemic BT is known to activate gene expression relating to extracellular matrix degradation. A previous report showed that expression of cellular matrix = (LVEDV, P 5.31) (A), greater end-systolic volume (LVESV, P 5.8) (B), and lower left ventricular ejection fraction (LVEF, P 5.14) (C). Significant difference *P!.1 vs. 1st quartile, and yp!.1 vs. 2nd quartile by post-hoc tests (Bonferroni s multiple comparison test).

7 Increased Body Temperature After Reperfused Acute MI Naito et al 31 Table 3. Short- and Long-Term Cardiac Events and Peak BT Peak BT Quartile Overall (n 5 156) 1st #37.2 C (n 5 41) 2nd 37.3e5 C (n 5 42) 3rd 37.6e9 C (n 5 38) 4th $38. C (n 5 35) P Value In-hospital cardiac events Pump failure, n (%) 75 (48) 14 (34) 18 (43) 19 (5) 24 (69)*,y.22 VT/VF, n (%) 22 (14) 2 (5) 5 (12) 6 (16) 9 (26).7 Cardiac rupture, n (%) 2 (1) () () 1 (3) 1 (3).36 Cardiac death, n (%) 9 (6) 1 (2) 2 (5) 2 (5) 4 (11).45 Overall, n (%) 82 (53) 15 (37) 2 (48) 2 (53) 27 (77)*,y,z.4 Long-term cardiac events Readmission for heart 5 (3) () () 1 (3) 4 (11)*,y.6 failure, n (%) MACE, n (%) 37 (24) 1 (24) 9 (21) 7 (18) 11 (31).36 All data are categorical variables presented as number (percentage). These were compared among groups using chi-squared test. *P!.5 vs. 1st quartile. y P!.5 vs. 2nd quartile. z P!.5 vs. 3rd quartile. BT, body temperature; VT/VF, sustained ventricular tachycardia and/or ventricular fibrillation; MACE, major adverse cardiac event. MACE included in-hospital and out-of-hospital cardiac death, nonfatal myocardial infarction, reintervention, and coronary artery bypass grafting. metalloproteinase-3 was enhanced during the early phase after heat shock. 22 Myocardial matrix metalloproteinases regulate the breakdown and accumulation of myocardial extracellular matrix and play a major role in postinfarction LV remodeling. It is possible that increased BT might affect LV remodeling through activation of myocardial matrix metalloproteinases. Proinflammatory Cytokines and LV Remodeling IL-6 is a major proinflammatory cytokine released predominantly from monocytes and macrophages. Several reports have shown that the increase of plasma IL-6 level after AMI was caused by spillover from cardiac tissue 23,24 and was related to a worse clinical outcome, including cardiac death and cardiogenic shock. 25 We previously reported that a persistent elevation of plasma IL-6 level was associated with a greater increase in LV volume after AMI. 26 Therefore, elevated BT might reflect increased spillover of proinflammatory cytokines from the infarcted heart, which is related to exaggerated LV remodeling. Variable Table 4. Predictors of In-Hospital Cardiac Events n Univariate P Value Multiple Logistic Regression Analysis Odds Ratio 95% CI P Value Peak BT/quartile e2.3.8 Age $7 years e Absence of preinfarction 64! e8.7.3 angina Heart rate on admission e $8 bpm Peak CK $3 IU/L e In-hospital cardiac events included pump failure, malignant ventricular arrhythmias, cardiac rupture, and cardiac death. CI, confidence interval; BT, body temperature; CK, creatine kinase. Alternatively, proinflammatory cytokines including IL-6 have the potential to depress cardiac function when expressed at a sufficiently high concentration. 27 It is possible that excessive production of proinflammatory cytokines in patients with increased BT might depress myocardial function and accelerate LV remodeling after AMI. Neurohormones and BT Several neurohormones contribute to cardiac failure, which is associated with induction of proinflammatory mediators. Murray et al showed that chronic b-adrenergic stimulation with L-isoproterenol led to increased myocardial gene expression and protein synthesis of tumor necrosis factor-a, IL-1b, and IL Furthermore, in rat cardiac fibroblasts, norepinephrine stimulation resulted in a 5-fold increase in IL-6 mrna level, and carvedilol almost completely prevented the norepinephrine-induced synthesis of IL-6 mrna. 29 The renin-angiotensin-aldosterone system is another neurohormonal system influencing the inflammatory response. 3 A recent study revealed that aldosterone directly induces cyclooxygenase-2 expression and indirectly participates in IL-6 expression in cardiomyocytes. 31 These Variable Table 5. Predictors of LV Aneurysm n Univariate P Value Multiple Logistic Regression Analysis Odds Ratio 95% CI P Value Peak BT/quartile e2.6.1 Age $7 years e Absence of preinfarction e angina Peak CK $3 IU/L 82! e LV, left ventricular; CI, confidence interval; BT, body temperature; CK, creatine kinase.

8 32 Journal of Cardiac Failure Vol. 13 No. 1 February 27 Table 6. Predictors of Readmission for Heart Failure findings suggest that systemic neurohumoral activation might augment the inflammatory response, and influence BT. However, use of b-blockers or angiotensin-converting enzyme inhibitors was not associated with significant change in peak BT. Plasma levels of neurohormones, including norepinephrine, renin activity, angiotensin II, and aldosterone, did not correlate with peak BT in this limited study population. Clinical Implications Body temperature is a practical and easily measurable parameter in the clinical setting. Though it is difficult, as for what we assert only by this study, if risk stratification for LV remodeling could be simply done by measuring BT during the early phase of AMI, it would be clinically useful. Study Limitations Univariate Analysis Cox Proportional Hazard Analysis First, the present findings did not prove a direct effect of increased BT on LV remodeling. Increased BT could be an epiphenomenon rather than the cause of LV remodeling. The mechanisms of the adverse effect of elevated BT on LV remodeling will need to be clarified in further basic and clinical investigations. Second, we did not assess circadian changes in BT, although we measured BT every 6 hours. It is possible that the timing of the onset may influence the peak BT. Third, the degree of the inflammatory response could be influenced by infarct size. Although our data showed that peak CK did not significantly correlate with peak BT, estimation of infarct size by peak CK is not always accurate, especially in cases with successful revascularization therapy. In addition, the statistical power might not be strong enough for any negative data to be conclusive because of the limited sample size. Therefore, we could not exclude the possibility that increased BT might reflect greater infarct size, thereby related to worse LV function. Fourth, the analysis of the data regarding left ventriculography might contain selection bias, because only 82% of all patients underwent left ventriculography in the present study. Conclusion Multivariate Analysis Variable P Value Hazard Ratio 95% CI P Value Peak BT/quartile e Age $7 years e CI, confidence interval; BT, body temperature. Higher BT after AMI was associated with a worse clinical outcome and infarct expansion, suggesting a relationship between systemic inflammatory response and postinfarction LV remodeling. References 1. Antman E, Braunwald E. ST-elevation myocardial infarction: pathology, pathophysiology, and clinical features. In: Zipes DP, Libby P, Bonow R, Braun ER, editors. Heart disease. 7th edition. Philadelphia: W.B. Saunders; 24. p. 1141e Lofmark R, Nordlander R, Orinius E. 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