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Initial serum glucose level and white blood cell predict ventricular arrhythmia after first acute myocardial infarction
American Journal of Emergency Medicine (2010) 28, 418–423
www.elsevier.com/locate/ajem
Original Contribution
Initial serum glucose level and white blood cell predict ventricular arrhythmia after first acute myocardial infarction Jiann-Hwa Chen MD a,b , Chiu-Liang Tseng MD c,d , Shin-Han Tsai MD, PhD a,e , Wen-Ta Chiu MD, PhD a,e,⁎ a
Graduate Institute of Injury Prevention and Control, Taipei Medical University, Taipei, Taiwan Department of Emergency Medicine, Cathay General Hospital, Taipei, Taiwan c Department of Emergency Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan d Chang Gung University College of Medicine, Taoyuan, Taiwan e Department of Neurosurgery, Shuang-Ho Hospital, Taipei, Taiwan b
Received 20 December 2008; revised 24 December 2008; accepted 25 December 2008
Abstract Objective: The aims of this study are to analyze the factors that predispose the occurrence of ventricular arrhythmia (VA) in young patients with a first acute myocardial infarction (AMI) in the emergency department (ED) and to establish predictive implications. Methods: This is a 10-year retrospective cohort study. Patients who were older than 18 years and younger than 45 years with a first attack of AMI were recruited from the ED of 3 university teaching hospitals from January 1, 1998, to December 31, 2007. Results: Five hundred young patients (472 men and 28 women) who met the inclusion criteria were enrolled. Within these patients, the incidence of life-threatening VA with first attack of AMI was 8% (n = 40). They were categorized into 2 groups: VA attack (n = 40) and non-VA attack (n = 460). In univariable analyses, acute anterolateral ST-segment elevation myocardial infarction (65% vs 47.8%; P = .04), elevate white blood cell (WBC) count (16.4 ± 3.4 vs 11.5 ± 3.1 × 103/mm3; P b .01), and initial serum glucose level (202.6 ± 90.9 vs 151.9 ± 64.7 mg/dL; P b .01) were significantly increased in the VA group. Multiple logistic regression model identified WBC count and initial serum glucose level as the significant independent variables in the prediction of VA attack for young patients with first attack of AMI. The receiver operating characteristic area for WBC count and serum glucose level in predicting the risk of VA occurring after AMI was 0.869 and 0.756, respectively. Conclusion: Initial serum glucose level and WBC may be used as valuable predictors for VA attack in young patients with first AMI. © 2010 Elsevier Inc. All rights reserved.
⁎ Corresponding author. Taipei Medical University, Taipei City, Taiwan, R.O.C. Tel.: +886 2 27390217; fax: +886 2 27390387. E-mail address: [email protected] (W.-T. Chiu). 0735-6757/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.ajem.2008.12.036
Initial serum glucose level and white blood cell predict VA
1. Introduction Acute myocardial infarction (AMI) is a critical illness in the emergency department (ED). Patients can die suddenly from ventricular arrhythmia (VA) or cardiogenic shock. Approximately 1.5 million Americans sustain AMI each year, of which 6% to 10% are younger than 45 years [1]. In Chinese, young patients with first attack of AMI account for 10% to 12% of all patients with AMI [2,3]. During AMI attack, younger patients tend to have different clinical presentation compared to older patients, such as, they are more likely to have Q-wave myocardial infarction (MI), less extensive coronary artery disease, good residual left ventricular function, and a better prognosis [2,4]. Ventricular arrhythmia, including ventricular tachycardia and ventricular fibrillation, are life-threatening complications of AMI [5]. The incidence of VA has been reported to be 1.9% to 10.2% in all patients with AMI [5-10]. They are the most frequent causes of death related to AMI because they often occur before monitoring. Early VA occurred in AMI are related to large infarction [11]. The characteristics associated with the occurrence of VA include younger age [5,10-13], smoking [9,10], absence of history of diabetes [10,14], ST elevation MI, and higher Killip class [5]. The risk factors to predict occurrence of VA can optimize the premonitoring management of AMI in ED. Prompt identification of high-risk patients could also have great impact on ED and the modes of interhospital transports for primary angioplasty or intensive care unite admission. There is evidence increase of 6-fold in-hospital mortality related to the occurrence of VA after AMI [5,11,15-17]. Thus, identifying patients with AMI with a high risk of VA attack and further preventing the attack could markedly improve outcomes. The purpose of this study is to assess the incidence of lifethreatening VA and their risk factors in young patients with first AMI based on routinely collected information. We also set out to assess whether currently available risk factors could predict the VA occurrence after AMI in ED.
2. Method This is a 10-year retrospective cohort study focusing on VA occurrence requiring defibrillation for young patients with first attack of AMI. All adult patients (older than 18 years and younger than 45 years) who were admitted to the ED in 3 university teaching hospitals in Taiwan from January 1, 1998, to December 31, 2007, with a diagnosis of AMI were eligible for inclusion. The medical records of all patients with AMI were retrieved according to International Classification of Diseases, Ninth Revision codes 410.xx by admission diagnoses. We assessed the subject's eligibility by admission diagnoses of AMI and excluded the cases that did not fulfill the criteria of AMI diagnosis.
419 Life-threatening VA was defined as ventricular fibrillation or sustained ventricular tachycardia that required emergent resuscitation. Acute myocardial infarction was defined by the European Society of Cardiology/American College of Cardiology criteria as typical increase and gradual decrease (troponin) or more rapid increase and decrease creatine kinase-MB of biochemical markers of myocardial necrosis and ischemic symptoms (mainly constrictive chest pain lasting more than 30 minutes) or electrocardiogram changes indicative of ischemia (ST-segment elevation or depression on at least 2 derivations) [18]. Patients were excluded either if they did not meet the above criteria or if they had 1 of the following 6 criteria: (1) previous cardiac resuscitation, infectious disease, or signs of cardiac inflammation; (2) severe skeletal muscle damage and/or trauma; (3) a previous episode of AMI; (4) AMI diagnosed at another hospital and referred for further treatment; (5) duration of AMI more than 24 hours; (6) a history of percutaneous coronary intervention or coronary artery bypass grafting. Patients were categorized into 1 of 2 study groups, VA and non-VA attack in the ED stay. Data were collected by a retrospective review of medical records for each patient, including documentation of the clinical history of major cardiac risk factors, such as family history of cardiovascular disease, smoking, hypertension, diabetes mellitus, hyperlipidemia [1], demographic characteristics, initial signs and symptoms on ED presentation, specific location of AMI. Venous blood samples were routinely drawn in the ED. Various laboratory values were also collected from medical records. Hypertension was defined as a history of hypertension more than 2 years that required the initiation of antihypertensive therapy by the primary physician. Diabetes mellitus was defined as when the patient reported a history of diabetes or was receiving treatment with an oral hypoglycemic agent or insulin. Smoking status was recorded as either “never smoked” or “smoker” (current or former smoker). Hyperlipidemia was defined as having a reported history of elevated fasting concentration of total cholesterol or triglycerides or undergoing treatment for hyperlipidemia. A positive family history for cardiovascular disease was defined as evidence of coronary artery disease in either one of parent or sibling before 60 years of age, such as a history of MI, coronary artery bypass surgery, angina pectoris, or pathological exercise tolerance test diagnostic of ischemia. The infarct site of AMI was assessed by at least 2 adjacent ST elevation in precordial leads V2-4 (anterior wall) or leads II, III, aVF (inferior wall). Lateral wall MI was assessed by lead I, aVL, V5, or V6. Non–ST-elevation MI was identified by normal ST segment despite combined myocardial ischemic pain and increased cardiac enzyme activity. Data were presented as mean ± SD or frequency expressed as percentage. Categorical variables were compared between 2 groups using χ2 test or Fisher exact test when appropriate, whereas continuous variables were compared using independent samples t test. The variables
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J.-H. Chen et al.
with univariate comparison P b .1 between 2 groups were eligible for inclusion in a forward selection multiple logistic regression model, which identified the clinical factors in the ED that were independent predictors of VA occurring after first AMI. The receiver operation characteristic (ROC) curves for the statistically independent variables associated with VA attack after first AMI were also drawn. A P value less than .05 was considered statistically significant. A common statistical package (SPSS 14.0 for Windows, SPSS, Inc, Chicago, Ill) was used to perform all statistical tests.
3. Results During the 10-year period of the study, 582 patients were admitted to the ED with AMI, but only 500 patients (472 men and 28 women) were eligible for inclusion in the study. Of the 582 patients, 82 patients were excluded because of previous percutaneous coronary intervention or coronary artery bypass grafting (14 patients), AMI more than 24 hours' duration (11 patients), referral from another hospital (47 patients), or VA occurrence before being admitted to these hospitals (10 patients). This study showed that the incidence of life-threatening VA occurring in young patients with first AMI in ED was 8% (n = 40), and in which the rate of ventricular fibrillation and sustained ventricular tachycardia was 4.8% (n = 24) and Table 1
Table 2 Comparison of clinical signs and symptoms and laboratory tests between the 2 patient groups
Signs and symptoms, n (%) Chest pain Cold sweating Radiation pain Nausea or vomiting Dyspnea Palpitation Laboratory tests on admission WBC × 103 (per mm3) Hb (g/dL) Platelet × 103 (per mm3) Creatine (mg/dL) CPK (IU/L) CPK-MB (IU/L) Troponin I Potassium (mmol/L) Calcium (mg/dL) Glucose (mg/dL) Ejection fraction (%)
VA attack (n= 40)
Non–VA attack P (n = 460)
40 (100) 35 (87.5) 19 (47.5) 11 (27.5) 14 (35) 2 (5)
458 381 242 122 177 21
16.4 ± 3.4 15.2 ± 1.4 248.4 ± 49.5
11.5 ± 3.1 14.9 ± 1.7 252.2 ± 65.3
1.1 234.4 23.6 3.5 3.7 8.5 202.6 49.7
(99.5) (82.8) (52.6) (26.5) (38.5) (4.6)
± 0.4 1.2 ± 1.1 ± 206.5 210.6 ± 188.5 ± 20.5 19.9 ± 17.2 ± 3.8 2.7 ± 3.6 ± 0.6 4.2 ± 2.5 ± 0.5 8.7 ± 0.5 ± 90.9 151.9 ± 64.7 ± 13.2 53.6 ± 13.5
.68 .45 .53 .85 .66 .90 .00 ⁎ .4 .72 .94 .45 .19 .34 .21 .07 .00 ⁎ .08
The P value between 2 groups was evaluated by independent samples t test for continuous variables and by χ2 test or Fisher exact test when appropriate for categorical variables. Hb indicates hemoglobin. ⁎ P b .05 between 2 groups.
Clinical characteristics of the patients VA attack Non–VA attack P (n = 40) (n = 460)
Age Men Cardiovascular risk actors Family history of CAD Smoking Hypertension Diabetes Hyperlipidemia Obesity** Infarct site Non–ST elevation MI Anterolateral Inferoposterior Killip class on admission I II III IV
40.3 ± 3.7 40.2 ± 4.6 38 (95) 434 (94.4)
.92 .86
16 33 8 5 20 2
.87 .80 .12 .51 .13 .11
(40) (82.5) (20) (12.5) (50) (5)
176 368 145 75 284 71
(38.3) (79.8) (31.5) (16.3) (61.7) (15.4)
1 (2.5) 26 (65) 13 (32.5)
48 (10.4) 220 (47.8) 192 (41.7)
.11 .04 ⁎ .25
13 19 3 4
213 164 51 19
.07 .18 .45 .10
(32.5) (47.5) (7.5) (10)
(46.3) (35.7) (11.1) (4.1)
Values are expressed as number (percentage). Family history of CAD defined as the presence of CAD in either one of parent or sibling before 60 years of age. Obesity defined as body mass index ≥30 (calculated as body weight in kilogram divided by height in meters squared). The P value between 2 groups was evaluated by χ2 test or Fisher exact test for categorical variables. CAD indicates coronary artery disease. ⁎ P b .05 between 2 groups.
3.2% (n = 16), respectively. Patients' characteristics stratified by the occurrence of VA after AMI are summarized in Table 1. There were no significant differences in age, sex, cardiovascular risk factors, and Killip class on admission between these 2 groups of patients. In contrast, as the infarct sites in AMI, anterolateral wall AMI had significantly higher rate for VA occurrence (65% vs 47.8%; P = .04). In univariable analyses, higher white blood cell (WBC) count (16.4 ± 3.4 vs 11.5 ± 3.1 × 103/mm3; P b .01) and initial serum glucose level (202.6 ± 90.9 vs 151.9 ± 64.7 mg/dL; P b .01) were associated with an increased risk of VA occurrence requiring defibrillation (Table 2). The multiple logistic regression models were performed to analyze the risk of VA occurring after AMI (dependent variable), and the independent variables included in the analysis were anterolateral wall AMI, Killip class I on admission, and the laboratory data such as WBC count, Table 3 Statistically independent variables associated with VA attack in the multiple logistic regression models
WBC Glucose OR indicates odds ratio.
OR (95% CI)
P
1.001 (1.001-1.002) 1.006 (1.001-1.011)
.000 .014
Initial serum glucose level and white blood cell predict VA initial serum glucose level, serum calcium level, and ejection fraction. The result showed that elevate WBC count and initially increased serum glucose level were significant independent predictors of VA occurrence among patients with first AMI in ED (Table 3). As depicted in Fig. 1, the ROC curves of WBC count and initial serum glucose level in predicting VA occurred after AMI were constructed, and the area under the curves were
421 found to be 0.869 (95% confidence interval [CI], 0.8250,913) and 0.756 (95% CI, 0.686-0.826), respectively. The cutoff points of WBC count and initial serum glucose level for predicting VA occurrence after first AMI were 12 150 per mm3 (sensitivity 97.5%, specificity 60.4%) and 162.5 mg/dL (sensitivity 72.5%, specificity 75.6%).
4. Discussion
Fig. 1 The ROC curves of WBC count (A) and initial serum glucose (B) in predicting VAs in patient with a first AMI. The area under the curve (AROC) for WBC and serum glucose level was 0.869 (95% CI, 0.825-0.913) and 0.756 (95% CI, 0.686-0.826), respectively.
This study had clearly demonstrated that the higher the initial serum glucose level and WBC count among the young patients with first AMI attack when initially presenting in ED, the higher risk for occurrence of life-threatening VA. As in the results, they tended to have extensive myocardial damage and increase in-hospital mortality [5,15-17]. To the best of our knowledge, this was the first article in the literature that highlight the predictors of VA occurrence after first AMI among young patients in ED. There were several studies that reported that hyperglycemia of more than 144 mg/dL is observed in at least 50% of patients with AMI [19,20]. Hyperglycemia when initially present in ED, regardless whether the patient is diabetic or not, is an independent predictor for poor cardiac outcome, including congestive heart failure, cardiogenic shock, and death after AMI [21,22]. Hsu et al [23] reported that the initial serum glucose level in ED was an independent predictive factor for both short- and long-term prognoses after first AMI. Our study showed that the initial serum glucose level in ED was an independent predictive factor for VA occurrence after first AMI in young patients. Acute hyperglycemia has been reported to induce oxidative stress, endothelial dysfunction, inflammation, and active coagulation, which lead to AMI in young patients [24]. The mechanisms underlying VA occurrence after AMI may involved the effects of stress hormones [25]. The higher level of the stress, the greater the surge of serum catecholamines secretion, and the higher the serum glucose in respond to the stimulus. Hyperglycemia may be the reflection of the extent of cardiac damage that can induce VA [11]. Previous studies have demonstrated that a high WBC count is associated with a large infarct, impaired left ventricular function, and increase mortality after AMI [26-28]. Rahimi et al [29] reported that WBC count is a predictor of VA occurrence after non–ST-segment elevation MI. Our study also confirmed that the higher WBC count on admission, the more frequent VA occurred after AMI. Leukocytosis is a marker of inflammation and is associated with the inflammatory response at the site of plaque in patients with AMI [30,31]. As part of this inflammatory reaction, cytokines like IL-6, IL-8, and CD40 ligand trigger up-regulation of monocyte tissue factor expression, which may facilitate the extrinsic pathway of the coagulation cascade [32]. Leukocyte aggregated and plugged the vessels with thrombus formations leading to ischemic damage of
422 myocardium, which further enhanced by oxygen-free radical formation and complement activation by the activated leukocytes [33-35]. Acute myocardial infarction frequently results in an increase in sympathetic neural activity, leading to a rapid release of polymorphonuclear leukocyte migrated to the endothelium with an increase in its circulating count [36]. The augmented sympathetic neural activity to the heart may be the primary factor in the generation of VA [37]. Therefore, the extent of polymorphonuclear leukocyte's activity may reflect the extent of the myocardium ischemia. There were some notable limitations in this study. First, the study design was a retrospective nonrandomized study, selection and recall biases tend to be the potential problems. Our study population was also relatively small, with a male predominance. Second, in our study, we had excluded the out-hospital cardiac arrest patient who might have AMI attack. Third, we decided to exclude patients with other than first AMI and those with AMI of more than 24 hours' duration. Therefore, the validity of the study may be limited to first AMI without previous coronary disease in ED populations. Fourth, we did not have detailed medication histories of the study group, which may have influenced the VA occurrence after AMI. Finally, in the absence of a differential WBC at admission, we were unable to determine whether the predictive value of the WBC was result from a specific component (eg, neutrophils).
5. Conclusion This study demonstrated that young ED patients with first AMI who were at risk for VA occurrence were characterized by higher initial serum glucose level, WBC count, and STsegment elevation MI in anterolateral wall. Ventricular arrhythmia occurrence after AMI will increase in-hospital mortality. Thus, identification of high-risk AMI survivors and prevention of VA occurrence could markedly improve outcomes. Our study showed that elevated initial serum glucose level and WBC count, considered along with other clinical data, can assist in life-threatening VA occurrence prediction after AMI.
References [1] Choudhury L, Marsh JD. Myocardial infarction in young patients. Am J Med 1999;107:254-61. [2] Chen JH, Huang HH, Yen DH, et al. Different clinical presentations in Chinese people with acute myocardial infarction in the emergency department. J Chin Med Assoc 2006;69:517-22. [3] Hong MK, Cho SY, Hong BK, et al. Acute myocardial infarction in young adults. Yonsei Med J 1994;35:184-9. [4] Doughty M, Mehta R, Bruckman D, et al. Acute myocardial infarction in the young: the University of Michigan experience. Am Heart J 2002; 143:56-62.
J.-H. Chen et al. [5] Henkel DM, Witt BJ, Gersh BJ, et al. Ventricular arrhythmias after acute myocardial infarction: a 20-year community study. Am Heart J 2006;151:806-12. [6] Awadhi AH, Ravindran J, Abraham KA, et al. The prevalence and outcome of ventricular arrhythmias in acute myocardial infarction. Ir J med Sci 1990;159:101-3. [7] Thompson CA, Yarzebski J, Goldberg RJ, et al. Changes over time in the incidence and case-fatality rates of primary ventricular fibrillation complicating acute myocardial infarction. Am Heart J 2000;139: 1014-21. [8] Behar S, Reicher-Reiss H, Shechter M, et al. Frequency and prognostic significance of secondary ventricular fibrillation complicating acute myocardial infarction. Am J Cardiol 1993;71:152-6. [9] Volpi A, Cavalli A, Santoro E, et al. Incidence and prognosis of secondary ventricular fibrillation in acute myocardial infarction. Evidence for a protective effect of thrombolytic therapy. GISSI Investigators. Circulation 1990;82:1279-88. [10] Ruiz-Bailen M, Aguayo D, Ruiz-Navarro S, et al. Ventricular fibrillation in acute myocardial infarction in Spanish patients: results of the ARIAM database. Crit Care Med 2003;31:2144-51. [11] Mont L, Cinca J, Blanch P, et al. Predisposing factors and prognostic value of sustained monomorphic ventricular tachycardia in the early phase of acute myocardial infarction. J Am Coll ardiol 1996;28: 1670-6. [12] Lawrie DM, Higgins MR, Godman MJ, et al. Ventricular fibrillation complicating acute myocardial infarction. Lancet 1968;2:523-8. [13] Lie KI, Wellens HJ, Durrer D. Characteristics and predictability of primary ventricular fibrillation. Eur J Cardiol 1974;1:379-84. [14] Wyman MG, Wyman RM, Cannom DS, et al. Prevention of primary ventricular fibrillation in acute myocardial infarction with prophylactic lidocaine. Am J Cardiol 2004;94:545-51. [15] Volpi A, Maggioni A, Franzosi M, et al. In-hospital prognosis of patients with acute myocardial infarction complicated by primary ventricular fibrillation. N Engl J Med 1987;317:257-61. [16] Behar S, Goldbourt U, Reicher-Reiss H, et al. Prognosis of acute myocardial infarction complicated by primary ventricular fibrillation. Am J Cardiol 1990;66:1208-11. [17] Jensen GV, Trop-Pedersen C, Hildebrandt P, et al. Does in-hospital ventricular fibrillation affect prognosis after myocardial infarction? Eur Heart J 1997;18:890-2. [18] The joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefined: a consensus document of the joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. Eur Heart J 2000;21:1502-13. [19] Stubbs PJ, Laycock J, Aghband-Zadeh J, et al. Circulating stress hormone and insulin concentrations in acute coronary syndromes: identification of insulin resistance on admission. Clin Sci (Lond) 1999; 96:589-95. [20] Capes SE, Hunt D, Malmberg K, et al. Stress hyperglycemia and increased risk of death after acute myocardial infarction in patients with and without diabetes: a systemic overview. Lancet 2000;355: 773-8. [21] Ishihara M, Inoue I, Kawagoe T, et al. Impact of acute hyperglycemia on left ventricular function after reperfusion therapy in patients with a first anterior wall acute myocardial infarction. Am Heart J 2003;146: 674-8. [22] Sewdarsen M, Vythilingum S, Jialal I, et al. Prognostic importance of admission plasma glucose in diabetic and non-diabetic patients with acute myocardial infarction. Q J Med 1989;71:461-6. [23] Hsu CW, Chen HH, Sheu WH, et al. Initial serum glucose level as a prognostic factor in the first acute myocardial infarction. Ann Emerg Med 2007;49:618-26. [24] Ceriello A. Acute hyperglycemia: a “new” risk factor during myocardial infarction. Eur Heart J 2005;150:814-20. [25] Vetter NJ, Strange RC, Adams W, et al. Initial metabolic and hormonal response to acute myocardial infarction. Lancet 1974;1:284-8.
Initial serum glucose level and white blood cell predict VA [26] Barron HV, Cannon CP, Murphy SA, et al. Association between white blood cell count, epicardial blood flow, myocardial perfusion, and clinical outcomes in the setting of acute myocardial infarction. A Thrombolysis In Myocardial Infarction 10 substudy. Circulation 2000; 102:2329-34. [27] Menon V, Lessard D, Yarzebski J, et al. Leukocytosis and adverse hospital outcomes after acute myocardial infarction. Am J Cardiol 2003;92:368-72. [28] Kojima S, Sakamoto T, Ishihara M, et al, on behalf of the JACSS Investigators. The white blood cell count is an independent predictor of non-reflow and mortality following acute myocardial infarction in the coronary intervention era. Ann Med 2004;36:153-60. [29] Rahimi K, Watzlawek S, Thiele H, et al. Incidence, time course, and predictors of early malignant ventricular arrhythmias after non–STsegment elevation myocardial infarction in patients with early invasive treatment. Eur Heart J 2006;27:1706-11. [30] Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999; 340:115-26.
423 [31] Madjid M, Awan I, Willerson JT, et al. Leukocyte count and coronary heart disease. J Am Coll Cardiol 2004;44:1945-56. [32] Marx N, Neumann FJ, Ott I, et al. Induction of cytokine expression in leukocytes in acute myocardial infarction. J Am Coll Cardiol 1997;30: 165-70. [33] Dormandy J, Ernst E, Matrai A, et al. Hemorrheologic changes following acute myocardial infarction. Am Heart J 1982;104: 1364-7. [34] Lucchesi BR, Werns SW, Fantone JC. The role of the neutrophil and free radicals in ischemic myocardial injury. J Mol Cell Cardiol 1989; 21:1241-51. [35] Schmid-Schonbein GW. The damaging potential of leukocyte activation in the microcirculation. Angiology 1993;44:45-56. [36] Hetherington SV, Quie PG. Human polymorphonuclear leukocytes of the bone marrow, circulation, and marginated pool: function and granule protein content. Am J Hematol 1985;20:235-46. [37] Sharma AD, Corr PB. Adrenergic factors in arrhythmogenesis in the ischemic and reperfused myocardium. Eur Heart J 1983;4:79-90.
www.elsevier.com/locate/ajem
Original Contribution
Initial serum glucose level and white blood cell predict ventricular arrhythmia after first acute myocardial infarction Jiann-Hwa Chen MD a,b , Chiu-Liang Tseng MD c,d , Shin-Han Tsai MD, PhD a,e , Wen-Ta Chiu MD, PhD a,e,⁎ a
Graduate Institute of Injury Prevention and Control, Taipei Medical University, Taipei, Taiwan Department of Emergency Medicine, Cathay General Hospital, Taipei, Taiwan c Department of Emergency Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan d Chang Gung University College of Medicine, Taoyuan, Taiwan e Department of Neurosurgery, Shuang-Ho Hospital, Taipei, Taiwan b
Received 20 December 2008; revised 24 December 2008; accepted 25 December 2008
Abstract Objective: The aims of this study are to analyze the factors that predispose the occurrence of ventricular arrhythmia (VA) in young patients with a first acute myocardial infarction (AMI) in the emergency department (ED) and to establish predictive implications. Methods: This is a 10-year retrospective cohort study. Patients who were older than 18 years and younger than 45 years with a first attack of AMI were recruited from the ED of 3 university teaching hospitals from January 1, 1998, to December 31, 2007. Results: Five hundred young patients (472 men and 28 women) who met the inclusion criteria were enrolled. Within these patients, the incidence of life-threatening VA with first attack of AMI was 8% (n = 40). They were categorized into 2 groups: VA attack (n = 40) and non-VA attack (n = 460). In univariable analyses, acute anterolateral ST-segment elevation myocardial infarction (65% vs 47.8%; P = .04), elevate white blood cell (WBC) count (16.4 ± 3.4 vs 11.5 ± 3.1 × 103/mm3; P b .01), and initial serum glucose level (202.6 ± 90.9 vs 151.9 ± 64.7 mg/dL; P b .01) were significantly increased in the VA group. Multiple logistic regression model identified WBC count and initial serum glucose level as the significant independent variables in the prediction of VA attack for young patients with first attack of AMI. The receiver operating characteristic area for WBC count and serum glucose level in predicting the risk of VA occurring after AMI was 0.869 and 0.756, respectively. Conclusion: Initial serum glucose level and WBC may be used as valuable predictors for VA attack in young patients with first AMI. © 2010 Elsevier Inc. All rights reserved.
⁎ Corresponding author. Taipei Medical University, Taipei City, Taiwan, R.O.C. Tel.: +886 2 27390217; fax: +886 2 27390387. E-mail address: [email protected] (W.-T. Chiu). 0735-6757/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.ajem.2008.12.036
Initial serum glucose level and white blood cell predict VA
1. Introduction Acute myocardial infarction (AMI) is a critical illness in the emergency department (ED). Patients can die suddenly from ventricular arrhythmia (VA) or cardiogenic shock. Approximately 1.5 million Americans sustain AMI each year, of which 6% to 10% are younger than 45 years [1]. In Chinese, young patients with first attack of AMI account for 10% to 12% of all patients with AMI [2,3]. During AMI attack, younger patients tend to have different clinical presentation compared to older patients, such as, they are more likely to have Q-wave myocardial infarction (MI), less extensive coronary artery disease, good residual left ventricular function, and a better prognosis [2,4]. Ventricular arrhythmia, including ventricular tachycardia and ventricular fibrillation, are life-threatening complications of AMI [5]. The incidence of VA has been reported to be 1.9% to 10.2% in all patients with AMI [5-10]. They are the most frequent causes of death related to AMI because they often occur before monitoring. Early VA occurred in AMI are related to large infarction [11]. The characteristics associated with the occurrence of VA include younger age [5,10-13], smoking [9,10], absence of history of diabetes [10,14], ST elevation MI, and higher Killip class [5]. The risk factors to predict occurrence of VA can optimize the premonitoring management of AMI in ED. Prompt identification of high-risk patients could also have great impact on ED and the modes of interhospital transports for primary angioplasty or intensive care unite admission. There is evidence increase of 6-fold in-hospital mortality related to the occurrence of VA after AMI [5,11,15-17]. Thus, identifying patients with AMI with a high risk of VA attack and further preventing the attack could markedly improve outcomes. The purpose of this study is to assess the incidence of lifethreatening VA and their risk factors in young patients with first AMI based on routinely collected information. We also set out to assess whether currently available risk factors could predict the VA occurrence after AMI in ED.
2. Method This is a 10-year retrospective cohort study focusing on VA occurrence requiring defibrillation for young patients with first attack of AMI. All adult patients (older than 18 years and younger than 45 years) who were admitted to the ED in 3 university teaching hospitals in Taiwan from January 1, 1998, to December 31, 2007, with a diagnosis of AMI were eligible for inclusion. The medical records of all patients with AMI were retrieved according to International Classification of Diseases, Ninth Revision codes 410.xx by admission diagnoses. We assessed the subject's eligibility by admission diagnoses of AMI and excluded the cases that did not fulfill the criteria of AMI diagnosis.
419 Life-threatening VA was defined as ventricular fibrillation or sustained ventricular tachycardia that required emergent resuscitation. Acute myocardial infarction was defined by the European Society of Cardiology/American College of Cardiology criteria as typical increase and gradual decrease (troponin) or more rapid increase and decrease creatine kinase-MB of biochemical markers of myocardial necrosis and ischemic symptoms (mainly constrictive chest pain lasting more than 30 minutes) or electrocardiogram changes indicative of ischemia (ST-segment elevation or depression on at least 2 derivations) [18]. Patients were excluded either if they did not meet the above criteria or if they had 1 of the following 6 criteria: (1) previous cardiac resuscitation, infectious disease, or signs of cardiac inflammation; (2) severe skeletal muscle damage and/or trauma; (3) a previous episode of AMI; (4) AMI diagnosed at another hospital and referred for further treatment; (5) duration of AMI more than 24 hours; (6) a history of percutaneous coronary intervention or coronary artery bypass grafting. Patients were categorized into 1 of 2 study groups, VA and non-VA attack in the ED stay. Data were collected by a retrospective review of medical records for each patient, including documentation of the clinical history of major cardiac risk factors, such as family history of cardiovascular disease, smoking, hypertension, diabetes mellitus, hyperlipidemia [1], demographic characteristics, initial signs and symptoms on ED presentation, specific location of AMI. Venous blood samples were routinely drawn in the ED. Various laboratory values were also collected from medical records. Hypertension was defined as a history of hypertension more than 2 years that required the initiation of antihypertensive therapy by the primary physician. Diabetes mellitus was defined as when the patient reported a history of diabetes or was receiving treatment with an oral hypoglycemic agent or insulin. Smoking status was recorded as either “never smoked” or “smoker” (current or former smoker). Hyperlipidemia was defined as having a reported history of elevated fasting concentration of total cholesterol or triglycerides or undergoing treatment for hyperlipidemia. A positive family history for cardiovascular disease was defined as evidence of coronary artery disease in either one of parent or sibling before 60 years of age, such as a history of MI, coronary artery bypass surgery, angina pectoris, or pathological exercise tolerance test diagnostic of ischemia. The infarct site of AMI was assessed by at least 2 adjacent ST elevation in precordial leads V2-4 (anterior wall) or leads II, III, aVF (inferior wall). Lateral wall MI was assessed by lead I, aVL, V5, or V6. Non–ST-elevation MI was identified by normal ST segment despite combined myocardial ischemic pain and increased cardiac enzyme activity. Data were presented as mean ± SD or frequency expressed as percentage. Categorical variables were compared between 2 groups using χ2 test or Fisher exact test when appropriate, whereas continuous variables were compared using independent samples t test. The variables
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with univariate comparison P b .1 between 2 groups were eligible for inclusion in a forward selection multiple logistic regression model, which identified the clinical factors in the ED that were independent predictors of VA occurring after first AMI. The receiver operation characteristic (ROC) curves for the statistically independent variables associated with VA attack after first AMI were also drawn. A P value less than .05 was considered statistically significant. A common statistical package (SPSS 14.0 for Windows, SPSS, Inc, Chicago, Ill) was used to perform all statistical tests.
3. Results During the 10-year period of the study, 582 patients were admitted to the ED with AMI, but only 500 patients (472 men and 28 women) were eligible for inclusion in the study. Of the 582 patients, 82 patients were excluded because of previous percutaneous coronary intervention or coronary artery bypass grafting (14 patients), AMI more than 24 hours' duration (11 patients), referral from another hospital (47 patients), or VA occurrence before being admitted to these hospitals (10 patients). This study showed that the incidence of life-threatening VA occurring in young patients with first AMI in ED was 8% (n = 40), and in which the rate of ventricular fibrillation and sustained ventricular tachycardia was 4.8% (n = 24) and Table 1
Table 2 Comparison of clinical signs and symptoms and laboratory tests between the 2 patient groups
Signs and symptoms, n (%) Chest pain Cold sweating Radiation pain Nausea or vomiting Dyspnea Palpitation Laboratory tests on admission WBC × 103 (per mm3) Hb (g/dL) Platelet × 103 (per mm3) Creatine (mg/dL) CPK (IU/L) CPK-MB (IU/L) Troponin I Potassium (mmol/L) Calcium (mg/dL) Glucose (mg/dL) Ejection fraction (%)
VA attack (n= 40)
Non–VA attack P (n = 460)
40 (100) 35 (87.5) 19 (47.5) 11 (27.5) 14 (35) 2 (5)
458 381 242 122 177 21
16.4 ± 3.4 15.2 ± 1.4 248.4 ± 49.5
11.5 ± 3.1 14.9 ± 1.7 252.2 ± 65.3
1.1 234.4 23.6 3.5 3.7 8.5 202.6 49.7
(99.5) (82.8) (52.6) (26.5) (38.5) (4.6)
± 0.4 1.2 ± 1.1 ± 206.5 210.6 ± 188.5 ± 20.5 19.9 ± 17.2 ± 3.8 2.7 ± 3.6 ± 0.6 4.2 ± 2.5 ± 0.5 8.7 ± 0.5 ± 90.9 151.9 ± 64.7 ± 13.2 53.6 ± 13.5
.68 .45 .53 .85 .66 .90 .00 ⁎ .4 .72 .94 .45 .19 .34 .21 .07 .00 ⁎ .08
The P value between 2 groups was evaluated by independent samples t test for continuous variables and by χ2 test or Fisher exact test when appropriate for categorical variables. Hb indicates hemoglobin. ⁎ P b .05 between 2 groups.
Clinical characteristics of the patients VA attack Non–VA attack P (n = 40) (n = 460)
Age Men Cardiovascular risk actors Family history of CAD Smoking Hypertension Diabetes Hyperlipidemia Obesity** Infarct site Non–ST elevation MI Anterolateral Inferoposterior Killip class on admission I II III IV
40.3 ± 3.7 40.2 ± 4.6 38 (95) 434 (94.4)
.92 .86
16 33 8 5 20 2
.87 .80 .12 .51 .13 .11
(40) (82.5) (20) (12.5) (50) (5)
176 368 145 75 284 71
(38.3) (79.8) (31.5) (16.3) (61.7) (15.4)
1 (2.5) 26 (65) 13 (32.5)
48 (10.4) 220 (47.8) 192 (41.7)
.11 .04 ⁎ .25
13 19 3 4
213 164 51 19
.07 .18 .45 .10
(32.5) (47.5) (7.5) (10)
(46.3) (35.7) (11.1) (4.1)
Values are expressed as number (percentage). Family history of CAD defined as the presence of CAD in either one of parent or sibling before 60 years of age. Obesity defined as body mass index ≥30 (calculated as body weight in kilogram divided by height in meters squared). The P value between 2 groups was evaluated by χ2 test or Fisher exact test for categorical variables. CAD indicates coronary artery disease. ⁎ P b .05 between 2 groups.
3.2% (n = 16), respectively. Patients' characteristics stratified by the occurrence of VA after AMI are summarized in Table 1. There were no significant differences in age, sex, cardiovascular risk factors, and Killip class on admission between these 2 groups of patients. In contrast, as the infarct sites in AMI, anterolateral wall AMI had significantly higher rate for VA occurrence (65% vs 47.8%; P = .04). In univariable analyses, higher white blood cell (WBC) count (16.4 ± 3.4 vs 11.5 ± 3.1 × 103/mm3; P b .01) and initial serum glucose level (202.6 ± 90.9 vs 151.9 ± 64.7 mg/dL; P b .01) were associated with an increased risk of VA occurrence requiring defibrillation (Table 2). The multiple logistic regression models were performed to analyze the risk of VA occurring after AMI (dependent variable), and the independent variables included in the analysis were anterolateral wall AMI, Killip class I on admission, and the laboratory data such as WBC count, Table 3 Statistically independent variables associated with VA attack in the multiple logistic regression models
WBC Glucose OR indicates odds ratio.
OR (95% CI)
P
1.001 (1.001-1.002) 1.006 (1.001-1.011)
.000 .014
Initial serum glucose level and white blood cell predict VA initial serum glucose level, serum calcium level, and ejection fraction. The result showed that elevate WBC count and initially increased serum glucose level were significant independent predictors of VA occurrence among patients with first AMI in ED (Table 3). As depicted in Fig. 1, the ROC curves of WBC count and initial serum glucose level in predicting VA occurred after AMI were constructed, and the area under the curves were
421 found to be 0.869 (95% confidence interval [CI], 0.8250,913) and 0.756 (95% CI, 0.686-0.826), respectively. The cutoff points of WBC count and initial serum glucose level for predicting VA occurrence after first AMI were 12 150 per mm3 (sensitivity 97.5%, specificity 60.4%) and 162.5 mg/dL (sensitivity 72.5%, specificity 75.6%).
4. Discussion
Fig. 1 The ROC curves of WBC count (A) and initial serum glucose (B) in predicting VAs in patient with a first AMI. The area under the curve (AROC) for WBC and serum glucose level was 0.869 (95% CI, 0.825-0.913) and 0.756 (95% CI, 0.686-0.826), respectively.
This study had clearly demonstrated that the higher the initial serum glucose level and WBC count among the young patients with first AMI attack when initially presenting in ED, the higher risk for occurrence of life-threatening VA. As in the results, they tended to have extensive myocardial damage and increase in-hospital mortality [5,15-17]. To the best of our knowledge, this was the first article in the literature that highlight the predictors of VA occurrence after first AMI among young patients in ED. There were several studies that reported that hyperglycemia of more than 144 mg/dL is observed in at least 50% of patients with AMI [19,20]. Hyperglycemia when initially present in ED, regardless whether the patient is diabetic or not, is an independent predictor for poor cardiac outcome, including congestive heart failure, cardiogenic shock, and death after AMI [21,22]. Hsu et al [23] reported that the initial serum glucose level in ED was an independent predictive factor for both short- and long-term prognoses after first AMI. Our study showed that the initial serum glucose level in ED was an independent predictive factor for VA occurrence after first AMI in young patients. Acute hyperglycemia has been reported to induce oxidative stress, endothelial dysfunction, inflammation, and active coagulation, which lead to AMI in young patients [24]. The mechanisms underlying VA occurrence after AMI may involved the effects of stress hormones [25]. The higher level of the stress, the greater the surge of serum catecholamines secretion, and the higher the serum glucose in respond to the stimulus. Hyperglycemia may be the reflection of the extent of cardiac damage that can induce VA [11]. Previous studies have demonstrated that a high WBC count is associated with a large infarct, impaired left ventricular function, and increase mortality after AMI [26-28]. Rahimi et al [29] reported that WBC count is a predictor of VA occurrence after non–ST-segment elevation MI. Our study also confirmed that the higher WBC count on admission, the more frequent VA occurred after AMI. Leukocytosis is a marker of inflammation and is associated with the inflammatory response at the site of plaque in patients with AMI [30,31]. As part of this inflammatory reaction, cytokines like IL-6, IL-8, and CD40 ligand trigger up-regulation of monocyte tissue factor expression, which may facilitate the extrinsic pathway of the coagulation cascade [32]. Leukocyte aggregated and plugged the vessels with thrombus formations leading to ischemic damage of
422 myocardium, which further enhanced by oxygen-free radical formation and complement activation by the activated leukocytes [33-35]. Acute myocardial infarction frequently results in an increase in sympathetic neural activity, leading to a rapid release of polymorphonuclear leukocyte migrated to the endothelium with an increase in its circulating count [36]. The augmented sympathetic neural activity to the heart may be the primary factor in the generation of VA [37]. Therefore, the extent of polymorphonuclear leukocyte's activity may reflect the extent of the myocardium ischemia. There were some notable limitations in this study. First, the study design was a retrospective nonrandomized study, selection and recall biases tend to be the potential problems. Our study population was also relatively small, with a male predominance. Second, in our study, we had excluded the out-hospital cardiac arrest patient who might have AMI attack. Third, we decided to exclude patients with other than first AMI and those with AMI of more than 24 hours' duration. Therefore, the validity of the study may be limited to first AMI without previous coronary disease in ED populations. Fourth, we did not have detailed medication histories of the study group, which may have influenced the VA occurrence after AMI. Finally, in the absence of a differential WBC at admission, we were unable to determine whether the predictive value of the WBC was result from a specific component (eg, neutrophils).
5. Conclusion This study demonstrated that young ED patients with first AMI who were at risk for VA occurrence were characterized by higher initial serum glucose level, WBC count, and STsegment elevation MI in anterolateral wall. Ventricular arrhythmia occurrence after AMI will increase in-hospital mortality. Thus, identification of high-risk AMI survivors and prevention of VA occurrence could markedly improve outcomes. Our study showed that elevated initial serum glucose level and WBC count, considered along with other clinical data, can assist in life-threatening VA occurrence prediction after AMI.
References [1] Choudhury L, Marsh JD. Myocardial infarction in young patients. Am J Med 1999;107:254-61. [2] Chen JH, Huang HH, Yen DH, et al. Different clinical presentations in Chinese people with acute myocardial infarction in the emergency department. J Chin Med Assoc 2006;69:517-22. [3] Hong MK, Cho SY, Hong BK, et al. Acute myocardial infarction in young adults. Yonsei Med J 1994;35:184-9. [4] Doughty M, Mehta R, Bruckman D, et al. Acute myocardial infarction in the young: the University of Michigan experience. Am Heart J 2002; 143:56-62.
J.-H. Chen et al. [5] Henkel DM, Witt BJ, Gersh BJ, et al. Ventricular arrhythmias after acute myocardial infarction: a 20-year community study. Am Heart J 2006;151:806-12. [6] Awadhi AH, Ravindran J, Abraham KA, et al. The prevalence and outcome of ventricular arrhythmias in acute myocardial infarction. Ir J med Sci 1990;159:101-3. [7] Thompson CA, Yarzebski J, Goldberg RJ, et al. Changes over time in the incidence and case-fatality rates of primary ventricular fibrillation complicating acute myocardial infarction. Am Heart J 2000;139: 1014-21. [8] Behar S, Reicher-Reiss H, Shechter M, et al. Frequency and prognostic significance of secondary ventricular fibrillation complicating acute myocardial infarction. Am J Cardiol 1993;71:152-6. [9] Volpi A, Cavalli A, Santoro E, et al. Incidence and prognosis of secondary ventricular fibrillation in acute myocardial infarction. Evidence for a protective effect of thrombolytic therapy. GISSI Investigators. Circulation 1990;82:1279-88. [10] Ruiz-Bailen M, Aguayo D, Ruiz-Navarro S, et al. Ventricular fibrillation in acute myocardial infarction in Spanish patients: results of the ARIAM database. Crit Care Med 2003;31:2144-51. [11] Mont L, Cinca J, Blanch P, et al. Predisposing factors and prognostic value of sustained monomorphic ventricular tachycardia in the early phase of acute myocardial infarction. J Am Coll ardiol 1996;28: 1670-6. [12] Lawrie DM, Higgins MR, Godman MJ, et al. Ventricular fibrillation complicating acute myocardial infarction. Lancet 1968;2:523-8. [13] Lie KI, Wellens HJ, Durrer D. Characteristics and predictability of primary ventricular fibrillation. Eur J Cardiol 1974;1:379-84. [14] Wyman MG, Wyman RM, Cannom DS, et al. Prevention of primary ventricular fibrillation in acute myocardial infarction with prophylactic lidocaine. Am J Cardiol 2004;94:545-51. [15] Volpi A, Maggioni A, Franzosi M, et al. In-hospital prognosis of patients with acute myocardial infarction complicated by primary ventricular fibrillation. N Engl J Med 1987;317:257-61. [16] Behar S, Goldbourt U, Reicher-Reiss H, et al. Prognosis of acute myocardial infarction complicated by primary ventricular fibrillation. Am J Cardiol 1990;66:1208-11. [17] Jensen GV, Trop-Pedersen C, Hildebrandt P, et al. Does in-hospital ventricular fibrillation affect prognosis after myocardial infarction? Eur Heart J 1997;18:890-2. [18] The joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefined: a consensus document of the joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. Eur Heart J 2000;21:1502-13. [19] Stubbs PJ, Laycock J, Aghband-Zadeh J, et al. Circulating stress hormone and insulin concentrations in acute coronary syndromes: identification of insulin resistance on admission. Clin Sci (Lond) 1999; 96:589-95. [20] Capes SE, Hunt D, Malmberg K, et al. Stress hyperglycemia and increased risk of death after acute myocardial infarction in patients with and without diabetes: a systemic overview. Lancet 2000;355: 773-8. [21] Ishihara M, Inoue I, Kawagoe T, et al. Impact of acute hyperglycemia on left ventricular function after reperfusion therapy in patients with a first anterior wall acute myocardial infarction. Am Heart J 2003;146: 674-8. [22] Sewdarsen M, Vythilingum S, Jialal I, et al. Prognostic importance of admission plasma glucose in diabetic and non-diabetic patients with acute myocardial infarction. Q J Med 1989;71:461-6. [23] Hsu CW, Chen HH, Sheu WH, et al. Initial serum glucose level as a prognostic factor in the first acute myocardial infarction. Ann Emerg Med 2007;49:618-26. [24] Ceriello A. Acute hyperglycemia: a “new” risk factor during myocardial infarction. Eur Heart J 2005;150:814-20. [25] Vetter NJ, Strange RC, Adams W, et al. Initial metabolic and hormonal response to acute myocardial infarction. Lancet 1974;1:284-8.
Initial serum glucose level and white blood cell predict VA [26] Barron HV, Cannon CP, Murphy SA, et al. Association between white blood cell count, epicardial blood flow, myocardial perfusion, and clinical outcomes in the setting of acute myocardial infarction. A Thrombolysis In Myocardial Infarction 10 substudy. Circulation 2000; 102:2329-34. [27] Menon V, Lessard D, Yarzebski J, et al. Leukocytosis and adverse hospital outcomes after acute myocardial infarction. Am J Cardiol 2003;92:368-72. [28] Kojima S, Sakamoto T, Ishihara M, et al, on behalf of the JACSS Investigators. The white blood cell count is an independent predictor of non-reflow and mortality following acute myocardial infarction in the coronary intervention era. Ann Med 2004;36:153-60. [29] Rahimi K, Watzlawek S, Thiele H, et al. Incidence, time course, and predictors of early malignant ventricular arrhythmias after non–STsegment elevation myocardial infarction in patients with early invasive treatment. Eur Heart J 2006;27:1706-11. [30] Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999; 340:115-26.
423 [31] Madjid M, Awan I, Willerson JT, et al. Leukocyte count and coronary heart disease. J Am Coll Cardiol 2004;44:1945-56. [32] Marx N, Neumann FJ, Ott I, et al. Induction of cytokine expression in leukocytes in acute myocardial infarction. J Am Coll Cardiol 1997;30: 165-70. [33] Dormandy J, Ernst E, Matrai A, et al. Hemorrheologic changes following acute myocardial infarction. Am Heart J 1982;104: 1364-7. [34] Lucchesi BR, Werns SW, Fantone JC. The role of the neutrophil and free radicals in ischemic myocardial injury. J Mol Cell Cardiol 1989; 21:1241-51. [35] Schmid-Schonbein GW. The damaging potential of leukocyte activation in the microcirculation. Angiology 1993;44:45-56. [36] Hetherington SV, Quie PG. Human polymorphonuclear leukocytes of the bone marrow, circulation, and marginated pool: function and granule protein content. Am J Hematol 1985;20:235-46. [37] Sharma AD, Corr PB. Adrenergic factors in arrhythmogenesis in the ischemic and reperfused myocardium. Eur Heart J 1983;4:79-90.