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(Circulation. 2000;102:2329.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

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

Hal V. Barron, MD; Christopher P. Cannon, MD; Sabina A. Murphy, MPH; Eugene Braunwald, MD; C. Michael Gibson, MS, MD

From the Cardiovascular Division (H.V.B., S.A.M., C.M.G.), Department of Medicine, University of California San Francisco; Department of Medical Affairs (H.V.B.), Genentech Inc, South San Francisco, Calif; and Department of Medicine, Brigham & Women’s Hospital (C.P.C., E.B.), Boston, Mass.

Correspondence to C. Michael Gibson, MS, MD, Cardiology, University of California San Francisco, 3333 California St, Suite 430, San Francisco, CA 94118.

	Abstract

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Background—Elevation of the white blood cell (WBC) count during acute myocardial infarction (AMI) is associated with adverse outcomes. We examined the relationship between the WBC count and angiographic findings to gain insight into this relationship.

Results and Methods—We evaluated data from 975 patients in the Thrombolysis In Myocardial Infarction (TIMI) 10A and 10B trials. Patients with a closed artery at 60 and 90 minutes had higher a WBC count than patients with an open artery (P=0.02). Likewise, the presence of angiographically apparent thrombus was associated with a higher WBC count (11.5±5.2x10⁹/L, n=290, versus 10.7±3.5x10⁹/L, n=648; P=0.008). In addition, a higher WBC count was associated with poorer TIMI myocardial perfusion grades (4-way P=0.04). Mortality rates were higher in patients with a higher WBC count (0% for WBC count 0 to 5x10⁹/L, 4.9% for WBC count 5 to 10x10⁹/L, 3.8% for WBC count 10 to 15x10⁹/L, 10.4% for WBC count >15x10⁹/L; P=0.03). The development of new congestive heart failure or shock was also associated with a higher WBC count (0% for WBC count 0 to 5x10⁹/L, 5.2% for WBC count 5 to 10x10⁹/L, 6.1% for WBC count 10 to 15x10⁹/L, 17.1% for WBC count >15x10⁹/L; P<0.001), an observation that remained significant in a multivariable model that adjusted for potential confounding variables (odds ratio 1.21, P=0.002).

Conclusions—Elevation in WBC count was associated with reduced epicardial blood flow and myocardial perfusion, thromboresistance (arteries open later and have a greater thrombus burden), and a higher incidence of new congestive heart failure and death. These observations provide a potential explanation for the higher mortality rate observed among AMI patients with elevated WBC counts and helps explain the growing body of literature that links inflammation and cardiovascular disease.

Key Words: myocardial infarction • blood flow • mortality • blood cells • heart failure

	Introduction

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Inflammation has been demonstrated to be an important risk factor for the development of cardiovascular events.^{1 2 3} Patients with elevated white blood cell (WBC) counts have been shown to have a higher risk of developing an acute myocardial infarction (AMI)^{4 5 6 7} and to be at higher risk for adverse events during the acute setting.^{7 8} Although the mechanism responsible for these associations is unknown, several hypotheses have been postulated, including a leukocyte-mediated hypercoagulable state,⁹ leukocyte-mediated no-reflow,¹⁰ and indirect cardiotoxicity mediated through proinflammatory cytokines.¹¹

The goal of the present study was to determine the relationship between the WBC count and coronary blood flow (both epicardial and microvascular) and other angiographic characteristics in the presence of AMI to gain insight into this pathophysiology of the relation between the WBC count and AMI.

	Methods

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We pooled data from the Thrombolysis In Myocardial Infarction (TIMI) 10A and 10B trials for this analysis. The TIMI 10A trial was a nonrandomized, open-label, dose-escalation study of 8 ascending doses of Tenectaplase, a mutant of recombinant tissue plasminogen activator (TNK; 5, 7.5, 10, 15, 20, 30, 40, and 50 mg IV over 5 seconds) in 113 patients.¹² TIMI 10B was an 880-patient randomized trial that compared 30, 40 and 50 mg TNK with front-loaded recombinant tissue plasminogen activator (rt-PA).¹³ Angiography was performed at 60, 75, and 90 minutes after thrombolytic administration.^{12 13} Nitroglycerin (IV or SL) was administered every 15 minutes if the systolic blood pressure exceeded 110 mm Hg.^{12 13} The TIMI studies were approved by the institutional review board of each participating center, and the trial was conducted according to the principles of the Declaration of Helsinki. The WBC counts were obtained at baseline enrollment in the trial, before treatment with the study drug, and were analyzed at the clinical site. The baseline and peak creatine kinase (CK) values were available for TIMI 10B and were expressed as the ratio of the value to the upper limit of normal at the clinical site.

Angiographic Analysis Methods
The TIMI flow grade was assessed at the TIMI Angiographic Core Laboratory as previously defined.¹⁴ To determine coronary flow as a continuous quantitative variable, the number of cineframes required for contrast medium to first reach standardized distal coronary landmarks in the infarct-related artery (the TIMI frame count) was measured with a frame counter on a cineviewer. The data presented here were converted to the most common cinefilm speed used in the United States: 30 frames/s.^{15 16 17 18 19} All flow data were assessed by a single observer (C.M.G.). The optimal single-plane projection that identified the stenosis in its greatest severity with minimal foreshortening or overlapping of branches and end-diastolic frames were chosen for quantitative angiographic analysis with a previously described and validated automated edge detection algorithm.¹⁹ The TIMI myocardial perfusion grade was assessed as previously defined.²⁰

Statistical Analysis
All analyses were performed with Stata Version 6.0.²¹ All continuous variable values are reported as mean±SD. ANOVA with a Bonferroni correction for multiple corrections or multiple linear regression was used for the analysis of continuous variables. When appropriate, the ² test or logistic regression was used for the analysis of categorical variables. Multivariate association between WBC count and 30-day congestive heart failure (CHF) was evaluated with logistic regression models. Odds ratios are reported with logistic regression models that adjust for factors that are independently associated with the outcome variable.

	Results

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Baseline Characteristics
The WBC count ranged from 3.5 to 75.7x10⁹/L. The median WBC count was 10.4x10⁹/L, and the interquartile interval was 8.4 to 12.91x10⁹/L (Figure). Smokers had a higher WBC count than nonsmokers (Table 1). Patients with a prior AMI, prior angina, or anterior infarctions and patients previously treated with aspirin and ß-blockers had a significantly lower WBC count. An increased WBC count was associated with an increased baseline platelet count (r=0.22, P<0.001) and an increased hematocrit (r=0.17, P<0.001). There was a trend toward a lower WBC count in patients previously treated with HMG-CoA reductase inhibitors, and only a mild trend was identified for higher WBC count to be associated with higher baseline CK levels (r=0.07, P=0.059). There was no association between the WBC count and prior CHF, time from symptom onset to enrollment, or use of ACE inhibitors on admission. There was no association between prothrombin time, partial thromboplastin time, baseline fibrinogen, or fibrinogen levels 1 hour after thrombolytic administration.

View larger version (13K): [in this window] [in a new window]   Figure 1. Cumulative distribution of baseline WBC count in 975 study patients. Median WBC count was 10.4x109/L, and mean WBC count was 11.0±4.1x109/L. The 25th and 75th percentiles of WBC count were 8.4 and 12.9x109/L, respectively.

View this table: [in this window] [in a new window]   Table 1. Categorical Baseline Characteristics and the WBC Count

Relationship of WBC Count to Clinical Outcomes
The mortality rate was higher in patients with a higher WBC count (P=0.03) (Table 2). When analyzed as a continuous variable, the WBC count also tended to be higher in patients who died within 30 days (P=0.2) (Table 3). The development of new CHF or shock was associated with a higher WBC count (P<0.001) (Tables 2 and 3). The development of a recurrent AMI was not related to the WBC count (Tables 2 and 3). The development of any of the clinical end points (death/recurrent MI/CHF/shock) occurred more frequently in patients with a higher WBC count (P<0.005) (Tables 2 and 3).

View this table: [in this window] [in a new window]   Table 2. Clinical Outcomes and the WBC Count

View this table: [in this window] [in a new window]   Table 3. Clinical Outcomes and the WBC Count

The WBC count and the size of the infarct as measured with the maximum CK level showed a moderate but positive correlation (r=0.13, P<0.001). Because baseline CK elevations could contribute to the peak CK value, the rise in the CK after thrombolytic administration was examined separately and was also found to correlate with the WBC count (r=0.13, P<0.001). When the baseline CK before thrombolytic therapy and the rise in CK after thrombolytic therapy were both included in a multivariate model, the rise in CK after thrombolytic therapy was found to be more strongly associated with the WBC count (t=3.57, P<0.001 versus t=1.88, P=0.06).

In a multivariable model that controlled for TIMI flow grade, TIMI myocardial perfusion grade, anterior MI location, baseline and maximum CK level, baseline hematocrit, platelet count, ß-blocker use, time from symptom onset to treatment, prior MI, age, sex, and smoking status, the WBC count remained independently associated with the development of new CHF and with death (Table 4).

View this table: [in this window] [in a new window]   Table 4. Odds Ratios for 30-d Clinical End Points and WBC Count

Relationship of WBC Count to the Angiographic Data
Patients with a closed infarct-related artery at 90 minutes (TIMI grade 0 or 1 flow) had a higher WBC count than did patients with an open artery (11.7±5.9x10⁹/L, n=186 versus 10.8±3.5x10⁹/L, n=750; P=0.01) (Table 5). Likewise, the WBC count of patients who failed to achieve patency early, by 60 minutes, was higher (11.6±4.1x10⁹/L, n=122 versus 10.7±3.6x10⁹/L, n=430; P=0.02). This association was also observed in a multivariate model that controlled for the duration of symptoms (P=0.016). There was no association between the WBC count and the corrected TIMI frame count (number of frames required for dye to reach a standardized distal landmark), percent diameter stenosis, or minimum lumen diameter. The presence of angiographically apparent thrombus was associated with a higher WBC count (11.5±5.2x10⁹/L, n=290 versus 10.7±3.5x10⁹/L, n=648; P=0.008). There also was an association between higher WBC count and worse myocardial perfusion as assessed with the TIMI myocardial perfusion grading system²² (4-way P=0.04) (Table 5).

View this table: [in this window] [in a new window]   Table 5. Angiographic Variables and the WBC Count

	Discussion

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The results of the present study confirm previous observations that relate elevated WBC count to adverse clinical outcomes in patients with acute MI and further explore the pathophysiology that underlies this relationship. Several new important observations were made. First, an elevation in WBC count was associated with a resistance to thrombolytic therapy as demonstrated by lower rates of coronary patency at both 60 and 90 minutes after the administration of thrombolytic therapy, as well as an increased thrombus burden in patients with a patent infarct-related artery. This was independent of duration of symptoms, which has also been associated with thromboresistance. Second, elevations in WBC count were associated with impaired microvascular perfusion as demonstrated by a reduction in myocardial perfusion grade. Third, elevation in WBC count was a strong predictor of the subsequent development of CHF independent of epicardial or microvascular coronary blood flow.

In the present study, an elevated WBC count was associated with reduced epicardial patency and greater thrombus formation at the site of the ruptured plaque, suggesting that an elevated WBC count may be a marker of a hypercoagulable or thromboresistant state. Several studies have documented that a systemic inflammatory response occurs in patients with AMI and that plasma from patients with AMI stimulates the expression of interleukin (IL)-1ß and IL-8 in leukocytes.²³ The induction of monocyte procoagulant activity with either IL-6 or IL-8 has been proposed as a possible link between the inflammation and thrombosis in patients with coronary artery disease. Neumann et al²⁴ investigated the effects of both of these cytokines on monocyte tissue factor (TF) expression, because the assembly of TF with factor VIIa initiates the extrinsic pathway of the coagulation cascade. They found that IL-6 and IL-8 caused an increase in TF expression on the surface of monocytes, as well as a time- and dose-dependent increase in procoagulant activity. Furthermore, this increase in procoagulant activity was induced at concentrations found in peripheral blood of patients with AMI.²⁵

In addition to the effects of cytokines on monocyte TF expression, it has been hypothesized that the procoagulant activity of circulating leukocytes could be increased via a second mechanism. Mac-1 (CD11b-CD18), a ß₂-integrin that is involved in leukocyte adhesion, also catalyzes the conversion of factor X to factor Xa and binds fibrinogen.²⁶ Ott et al⁹ demonstrated that there was an increase in procoagulant activity in patients who underwent successful primary angioplasty for AMI and that this increase in procoagulant activity was associated with an increase in Mac-1 expression on circulating leukocytes. Finally, the adherence of activated platelets to polymorphonuclear leukocytes via Mac-1 may also play a role in thrombus formation.²⁷

In addition to the reduced patency and greater thrombus burden seen in patients with an elevated WBC count, these patients had poorer downstream microvascular perfusion as assessed with TIMI perfusion grade.²⁰ It is possible that this impaired myocardial perfusion reflects leukocyte-mediated endothelial dysfunction and microvascular plugging, as described in animal models of ischemia-reperfusion.^{10 22 28 29 30}

Patients with an elevated WBC count were at a significantly increased risk of developing CHF. A critical issue is whether larger MIs before thrombolytic administration cause a higher WBC count or, alternatively, whether higher WBC counts cause larger infarcts after thrombolytic administration. The hypothesis that larger MIs before thrombolytic administration cause higher baseline WBC counts was not well supported; only a nonsignificant trend was identified that related the baseline CK (a surrogate of infarct size on presentation) to the WBC count, and no relationship was identified between the duration of symptoms and the WBC count. Furthermore, anterior infarcts (which were associated with larger infarcts, baseline CKs of 1.4±3.2 times upper limit of normal, n=280, versus 0.85±1.2 times upper limit of normal, n=514) were instead associated with lower baseline WBC counts. In contrast, after the administration of the thrombolytic agent, elevated WBC counts were associated with significantly higher peak CKs. Although the peak CK may reflect some contribution from the baseline CK value, it is notable that there was a stronger relationship between CK rise after thrombolytic administration (peak CK minus baseline CK, P=0.0004) and the WBC count than between the baseline CK before thrombolytic administration (P=0.06) and the WBC count. Even after control for the duration of symptoms, the baseline and peak CKs, epicardial and myocardial blood flows, anterior MI location, aspirin use, ß-blocker use, age, sex, smoking status, the hematocrit, and the platelet count (to control for confounding due to hemoconcentration), the WBC count remained independently associated with the development of new CHF.

Thus, it is possible that other mechanisms may explain the increased risk for CHF experienced by patients with elevations in WBC count. Although the cause of myocyte dysfunction in CHF is probably multifactorial, accumulating evidence suggests that oxidative stress and the release of proinflammatory cytokines may play a role in the development and pathogenesis of CHF.¹¹ Several studies have documented that tumor necrosis factor-, one of the many proinflammatory cytokines produced by leukocytes, is involved in myocyte dysfunction.³⁰ In support of an inflammatory cause for CHF after MI, Solodky et al³¹ demonstrated that the appearance of increased leukocyte adhesiveness/aggregation in the peripheral blood of patients with anterior wall MI was independently associated with increases in left ventricular end-diastolic volume. Furthermore, Anzai et al³² found that an elevation in serum C-reactive protein early after AMI was independently associated with readmission for CHF. Cooper et al³³ assessed the predictive value of an elevated WBC count on mortality in the Studies of Left Ventricular Dysfunction (SOLVD) trial. They found that a WBC count of >7000/mm³ was significantly associated with an increased risk of all-cause mortality, suggesting that an elevated WBC count may reflect a greater likelihood of CHF progression. Most recently, Kyne et al³⁴ examined 185 consecutive patients with AMI and found that an increased neutrophil count was the strongest predictor of the development of CHF after AMI (odds ratio 14.3, 95% CI 5.2 to 39.3; P=0.0001).

Study Limitations
There are several important limitations to the present study. First, this analysis was retrospective and as such can only identify associations rather than confirm causality. Second, we did not collect information regarding the WBC count differential, which may have contributed important additional information.

Conclusions
Elevations in WBC count on admission are associated with reduced epicardial and myocardial blood flow, thromboresistance (arteries open later and have a greater thrombus burden), and a higher incidence of new CHF, the development of which is independent of coronary blood flow and other covariates. These relationships may explain the higher mortality rates observed among AMI patients with an elevated WBC count and help to clarify the growing body of evidence that links inflammation and cardiovascular disease.

	Acknowledgments

 
This work was supported in part by a grant from Genentech, Inc (South San Francisco, Calif) and from Boehringer Ingelheim (Germany), the sponsors of TIMI 10A and 10B.

	Footnotes

 
Dr Barron is an employee of Genentech, Inc, the sponsor of TIMI 10A and 10B.

Received March 13, 2000; revision received June 16, 2000; accepted June 16, 2000.

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				H. Ince, M. Petzsch, H. D. Kleine, H. Eckard, T. Rehders, D. Burska, S. Kische, M. Freund, and C. A. Nienaber Prevention of Left Ventricular Remodeling With Granulocyte Colony-Stimulating Factor After Acute Myocardial Infarction: Final 1-year Results of the Front-Integrated Revascularization and Stem Cell Liberation in Evolving Acute Myocardial Infarction by Granulocyte Colony-Stimulating Factor (FIRSTLINE-AMI) Trial Circulation, August 30, 2005; 112(9_suppl): I-73 - I-80. [Abstract] [Full Text] [PDF]

				J E Nunez, E Nunez, V Bertomeu, L Facila, J Sanchis, V Bodi, R Sanjuan, M L Blasco, A Martinez, and A Llacer Prognostic value of baseline white blood cell count in patients with acute myocardial infarction and ST segment elevation Heart, August 1, 2005; 91(8): 1094 - 1095. [Full Text] [PDF]

				B. D. Horne, J. L. Anderson, J. M. John, A. Weaver, T. L. Bair, K. R. Jensen, D. G. Renlund, J. B. Muhlestein, and Intermountain Heart Collaborative (IHC) Study Grou Which White Blood Cell Subtypes Predict Increased Cardiovascular Risk? J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1638 - 1643. [Abstract] [Full Text] [PDF]

				B. S. Coller Leukocytosis and Ischemic Vascular Disease Morbidity and Mortality: Is It Time to Intervene? Arterioscler. Thromb. Vasc. Biol., April 1, 2005; 25(4): 658 - 670. [Abstract] [Full Text] [PDF]

				H.-K. Yip, C.-L. Hang, C.-Y. Fang, Y.-K. Hsieh, C.-H. Yang, W.-C. Hung, and C.-J. Wu Level of High-Sensitivity C-Reactive Protein Is Predictive of 30-Day Outcomes in Patients With Acute Myocardial Infarction Undergoing Primary Coronary Intervention Chest, March 1, 2005; 127(3): 803 - 808. [Abstract] [Full Text] [PDF]

				M. Madjid, I. Awan, J. T. Willerson, and S. W. Casscells Leukocyte count and coronary heart disease: Implications for risk assessment J. Am. Coll. Cardiol., November 16, 2004; 44(10): 1945 - 1956. [Abstract] [Full Text] [PDF]

				M. Frossard, I. Fuchs, J. M. Leitner, K. Hsieh, M. Vlcek, H. Losert, H. Domanovits, W. Schreiber, A. N. Laggner, and B. Jilma Platelet Function Predicts Myocardial Damage in Patients With Acute Myocardial Infarction Circulation, September 14, 2004; 110(11): 1392 - 1397. [Abstract] [Full Text] [PDF]

				M. Panteghini Role and importance of biochemical markers in clinical cardiology Eur. Heart J., July 2, 2004; 25(14): 1187 - 1196. [Abstract] [Full Text] [PDF]

				C. D. Garlichs, S. Eskafi, I. Cicha, A. Schmeisser, B. Walzog, D. Raaz, C. Stumpf, A. Yilmaz, J. Bremer, J. Ludwig, et al. Delay of neutrophil apoptosis in acute coronary syndromes J. Leukoc. Biol., May 1, 2004; 75(5): 828 - 835. [Abstract] [Full Text] [PDF]

				H S Gurm, D L Bhatt, A M Lincoff, J E Tcheng, D J Kereiakes, N S Kleiman, G Jia, and E J Topol Impact of preprocedural white blood cell count on long term mortality after percutaneous coronary intervention: insights from the EPIC, EPILOG, and EPISTENT trials Heart, October 1, 2003; 89(10): 1200 - 1204. [Abstract] [Full Text] [PDF]

				C. M. O'Connor, M. W. Dunne, M. A. Pfeffer, J. B. Muhlestein, L. Yao, S. Gupta, R. J. Benner, M. R. Fisher, and T. D. Cook Azithromycin for the Secondary Prevention of Coronary Heart Disease Events: The WIZARD Study: A Randomized Controlled Trial JAMA, September 17, 2003; 290(11): 1459 - 1466. [Abstract] [Full Text] [PDF]

				K. W. Mahaffey, C. B. Granger, J. C. Nicolau, W. Ruzyllo, W. D. Weaver, P. Theroux, J. S. Hochman, T. G. Filloon, C. F. Mojcik, T. G. Todaro, et al. Effect of Pexelizumab, an Anti-C5 Complement Antibody, as Adjunctive Therapy to Fibrinolysis in Acute Myocardial Infarction: The COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) Trial Circulation, September 9, 2003; 108(10): 1176 - 1183. [Abstract] [Full Text] [PDF]

				J. S. Forrester, M. J. Price, and R. R. Makkar Stem Cell Repair of Infarcted Myocardium: An Overview for Clinicians Circulation, September 2, 2003; 108(9): 1139 - 1145. [Full Text] [PDF]

				L. J. Dacey, J. DeSimone, J. H. Braxton, B. J. Leavitt, S. J. Lahey, J. D. Klemperer, B. M. Westbrook, E. M. Olmstead, and G. T. O'Connor Preoperative white blood cell count and mortality and morbidity after coronary artery bypass grafting Ann. Thorac. Surg., September 1, 2003; 76(3): 760 - 764. [Abstract] [Full Text] [PDF]

				H. Nakamura, S. Umemoto, G. Naik, G. Moe, S. Takata, P. Liu, and M. Matsuzaki Induction of left ventricular remodeling and dysfunction in the recipient heart after donor heart myocardial infarction: new insights into the pathologic role of tumor necrosis factor-alpha from a novel heterotopic transplant-coronary ligation rat model J. Am. Coll. Cardiol., July 2, 2003; 42(1): 173 - 181. [Abstract] [Full Text] [PDF]

				A. Dibra, J. Mehilli, M. Schwaiger, H. Schuhlen, H. Bollwein, S. Braun, J. Neverve, A. Schomig, and A. Kastrati Predictive value of basal C-reactive protein levels for myocardial salvage in patients with acute myocardial infarction is dependent on the type of reperfusion treatment Eur. Heart J., June 2, 2003; 24(12): 1128 - 1133. [Abstract] [Full Text] [PDF]