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CARDIOLOGY CASEBOOK |
Simplistic laboratory tests that are initially and routinely ordered by clinicians evaluating diseases are often unappreciated simply because they are routine. Resurrection of the leukocyte count is presented as a prime example of a sensitive measure and a prognostic indicator of acute myocardial infarction (MI) heretofore not given adequate coverage.
QUESTIONS
ANSWERS
1. c. inflammation
Cardiovascular disease is the leading cause of death in the Western world, and the most insidious form is atherosclerosis.1 Although the risk factors for CHD have been identified, they do not explain the basis for the disease. Inflammation is a significant risk factor and key in the development of CV events. The relationship of inflammation to atherosclerosis has been established, that is, monocyte recruitment from peripheral blood into the vessel wall after endothelial injury, accumulation of inflammatory cells in the lipid plaque, neovascularization of adventitia and intima, and subsequent rupture, thrombosis, and vasoconstriction of exposed intimal tissue.1
2. b. the biochemical factors supporting the relationship of inflammation to atherosclerosis
c. the need for sensitive and specific CHD markers that stratify the risks
Efforts are focused on finding a reliable biological marker of inflammation to help stratify those at risk. The stimulus to find a reliable inflammatory marker came from the relationship between inflammation and atherosclerosis. Study of the inflammatory state, vascular consequences, and diagnostic testing has progressed over the years.2 The evaluation of inflammation includes evaluating the leukocyte count, the study of CRP concentrations, cellular adhesion molecules, and markers of plaque stability. The leukocyte count is an independent risk factor for CHD and is a prognostic marker for future CV events. The cost of a leukocyte count is low compared with the cost of assessing other vascular risk markers.
3. d. leukocyte count (WBC)
The leukocyte count has been correlated with CHD since the 1920s. In the past several decades, evidence consistently shows a clear and positive correlation between the leukocyte count and future CV outcomes, even after adjustment for other risk factors.1 The leukocyte count is a stable, standardized, widely available, and inexpensive measure of systemic inflammation and is predictive of CV events and mortality in patients with CHD.3 Elevated WBC count increases the risks of acute MI and post-MI complications, such as reinfarction and arrhythmias.
In the Persantine-Aspirin Re-Infarction Study (PARIS)-1 study, an elevated WBC count was associated with an increased incidence of reinfarction. WBC count is a strong predictor of MI, similar to total cholesterol and blood pressure (BP), and is independent of the patient’s sex and history of smoking.4 The incidence of acute MI in smokers with elevated WBC counts (>9000/µL) is 4 times as high as the incidence in smokers with WBC counts less than 6000/µL.4 Leukocytosis is a manifestation of hematologic stress in addition to being a marker of chronic inflammation. In this context, hematologic stress is considered a nonspecific CV risk factor associated with leukocytosis and increased cate-cholamine levels.4
4. a. the leukocyte count
An elevated leukocyte count following an MI is strongly associated with recurrence of coronary events and increase in mortality.1 In patients with unstable angina (UA), those with the highest leukocyte counts had an 8-fold greater chance of having a major CV event than did those with lower counts.1 When the leukocyte count was correlated with angiographically documented CHD, higher counts were found in patients with disease. Leukocyte counts are higher in acute MI, compared with UA, and higher in transmural MI than in subendocardial infarcts, and are increased in left ventricular failure.1 Leukocyte counts are predictive of mortality at 6 weeks and 1 year. Post-MI mortality was higher when the WBC was greater than 10 000/µL.1
5. e. any of the above
With the impact of established risk factors and the extent of existing atherosclerosis, the relationship of the leukocyte count and CHD risk has not been established. However, the utility of total versus differential leukocyte counts as a risk marker of CHD has been evaluated. Leukocyte subpopulations, cell adhesion molecules and cytokine levels, stratify acute MI risk. The systemic inflammatory response in acute MI may trigger cytokine expression (interleukins) in the circulating leukocytes, resulting in procoagulant activity and thrombosis. Many cell types may be involved in this process and some are independent predictors of CHD. Cell adhesion molecules: circulating ß-integrins (Mac-1) help to catalyze the conversion of factor X to factor Xa, bind fibrinogen, and may play a role in thrombus formation. C-reactive protein: in addition to its use as a CV measure, CRP is proatherogenic and activates procoagulant properties of other cells, such as endothelial cells. CRP triggers the secretion of IL-6 and endothelin-1 and lessens the availability of nitric oxide in endothelial cells.
Leukocytes have a wide range of biological effects: some are potentially protective whereas others can be damaging. For this reason, identification of specific associations between components of the leukocyte count may be necessary.5 Although leukocyte components, such as neutrophils, are powerful predictors of CHD risk, more reliable differentiation is required.5 Differential cell correlation revealed that moderately elevated eosinophil counts were associated with higher risk of CHD.1
Simultaneous assessment of inflammation-sensitive markers may improve classification; the predictive role of the leukocyte count is independent of the CRP level. As a marker for CHD, the leukocyte count had a higher estimate of risk. The leukocyte count added to risk prediction in all CRP categories, yet the CRP added risk information to only the lowest and highest leukocyte quartiles.2 Plasma D-dimer (hemostatic activation) provides complementary information to CRP concentration.2 The lymphocyte count in heart failure fluctuates. A low lymphocyte count suggests a poor prognosis.1
6. e. any of the above
Leukocytes are involved in the pathogenesis of CV events or serve as a risk marker for other factors that cause disease. Leukocytes influence the development of CHD through various biological mechanisms that involve biomechanical, biochemical, hematologic, or electrical pathways.1,4 The relationship of the leukocyte to CHD includes the following:
Aggregation and pressure-dependent microvascular plugging—leukocytes may influence the development of CHD by affecting blood flow through the microvasculature of the cardiac system. Leukocytes are larger and stiffer than erythrocytes and platelets, and their large spherical morphology is greater than the internal diameters of nutritive capillaries. Capillary transit of leukocytes is difficult, thus microvascular circulation is more susceptible to slowing or even momentary occlusion when granulocyte plugging occurs.
Reperfusion and infarct expansion—in the setting of MI, leukocytosis and granulocyte aggregation following necrotic injury aggravate ischemia and extend and expand the infarct when microvascular movement of nutrients and oxygen to the injured area is slowed or halted. During reperfusion, neutrophils and platelets can plug coronary capillaries and cause no-reflow phenomenon and ventricular arrhythmias. Activation of platelets can increase granulocyte adhesiveness to foreign surfaces, such as ischemic endothelia, and related enzymes make the endothelium more susceptible to attack. Ultimately, abnormal granulocyte aggregation and neutrophil binding lead to further impediment of microvascular flow. The leukocyte count that follows an acute MI may influence the success of reperfusion. The higher the post-MI leukocyte count, the poorer the myocardial reperfusion, the higher the mortality, and the greater the risk of post-MI complications.
Endothelial injury, proteolysis, and oxidation—leukocytes may promote the development of CHD by damaging the coronary artery wall. Stimulated neutrophils or granulocytes promote coronary artery injury. An activated granulocyte arriving at a microvascular site delivers a variety of injuries to the vessel lining. In addition, proteolytic enzymes can lead to detachment of endothelial cells from vessel walls and make the endothelium more adhesive and more susceptible to granulocyte and platelet attacks. The release of chemotactic agents, inflammatory mediators, and superoxide anions occurs during the process and may inflict further damage on the vascular endothelium.
Hypercoagulability—leukocytes induce hypercoagulability following acute MI.1
Body mass index and other risk factors—low-grade systemic inflammation may be present in overweight and obese persons. A higher body mass index is associated with higher serum CRP levels.
7. c. VF
The leukocyte count may be related to cardiac electrical stability. On admission for acute MI, the leukocyte count may be predictive of VF. VF occurred in 3% of patients with normal or modestly elevated WBC count (<15 000/µL) and in 15% with greater elevations (>15 000/µL).4
8. a. true
The leukocyte count is a predictor of heart failure. In the Thrombolysis in Myocardial Infarction (TIMI) 10A and 10B trials, high leukocyte counts were associated with new-onset congestive heart failure or shock following MI. In chronic heart failure, however, a diminished lymphocyte count (<20%) was predictive of a 64% mortality rate.1,4
9. b. leukocytosis
Leukocytosis was an independent predictor of CHD and stroke in postmenopausal women.2,3 The highest leukocyte count (>6700/µL) was associated with a 50% increase in the risk of MI, stroke, total vascular disease, and mortality, and it was independent of other risk factors. In the group of women who did not receive hormone replacement therapy and dietary intervention, there was a 230% increase in the risk of coronary death.2
10. a. true
Review of the CV risks associated with leukocytosis and leukocyte plugging—questions remain regarding the safety of stem cell therapy that incorporates injection of granulocyte colony-stimulating factor or granulocyte macrophage colony-stimulating factor, both of which raise leukocyte counts. These interventions may increase the risk of thrombosis and pose greater problems than the problems that may occur with subendocardial injection-induced arrhythmogenesis.1
Summary
Although leukocyte counts are routinely ordered, discussion of the results is frequently limited. The leukocyte count is an old test, and its relationship to acute MI is not given adequate attention in the literature. Nevertheless, much can be gleaned from the leukocyte count that can aid in evaluating CV events and therapeutic responses.
ACKNOWLEDGMENT
Supported in part by a grant from the Applebaum Foundation, in loving memory of Joseph Applebaum.
Reprint requests: Louis Lemberg, MD, University of Miami Miller School of Medicine, Division of Cardiology (D-39), PO Box 0169690, Miami, FL 33101.
Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med. 2007;356:830–840.
Fitzpatrick AL, Kronmal RA, Gardner JP, et al. Leukocyte telomere length and cardiovascular disease in the cardiovascular health study. Am J Epidemiol. 2007;165:14–21.
Prentice RI, Langer RD, Stefanick ML, et al. Combined analysis of Women’s Health Initiative observational and clinical trial data on post-menopausal hormone treatment and cardiovascular disease. Am J Epidemiol. 2006;163(7):589–599.
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