- Email: [email protected]
Neutrophils and altered myocardial function
Editorial
Neutrophils and altered myocardial function Kenneth S. Kilgore, PhD, and Benedict R. Lucchesi, PhD, MD Ann Arbor, Mich
See related article on page 94. Acute transmural myocardial infarction often results from an occlusive intracoronary thrombus. In this setting, the ischemic myocardium in the anatomic region served by the occluded artery undergoes progressive biochemical, functional, and morphologic changes. The macroscopic appearance of the affected myocardium will vary with the age of the infarct. Sustained myocardial ischemia of less than 12 hours’ duration most often does not give rise to grossly observable changes. After 18 to 24 hours, the affected myocardial region will appear anemic, with a gray-brown appearance, in contrast to the bordering normal red-brown myocardium. By the second to fourth day of the ischemic event, the necrotic region becomes sharply defined with hyperemic margins. Microscopic changes also progress in a time-dependent manner. Within the initial 18 hours after the onset of the acute ischemic event, at a time when the infarct is not macroscopically evident, there may be evidence of coagulative necrosis with the presence of muscle cross-striations and relatively normal appearing nuclei. By 24 hours, interstitial edema hemorrhage and a sparse number of infiltrating neutrophils may be observed. The neutrophilic infiltrate becomes more prominent over the next 24 to 48 hours. Subsequently, the local inflammatory response consists predominantly of a neutrophilic infiltrate mixed with macrophages and lymphocytes. Without question, timely restoration of blood flow to the ischemic myocardium (angioplasty, thrombolytic therapy) serves to reduce the extent of irreversible cell injury. However, reperfusion is accompanied by early and accentuated delivery of neutrophils to the previously ischemic myocardium. Reperfused myocardium, therefore, is subjected to the overwhelming influence of an intense inflammatory response, which is in marked contrast to what occurs in the absence of reperfusion, in which the evolution of the local inflammatory response progresses over a prolonged period. Failure of neutrophils to accumulate during reperfusion after 12 minutes of ischemia stands in contrast to the excessive accumulation observed to occur after only 90 minutes From the Department of Pharmacology, University of Michigan Medical School. Reprint requests: Benedict R. Lucchesi, MD, PhD, Department of Pharmacology, University of Michigan Medical School, 1301C Medical Science Research Bldg III, Ann Arbor, MI 48109-0632. E-mail: [email protected] Am Heart J 2000;139:32-4. 0002-8703/2000/$12.00 + 0 4/4/96676
of ischemia. Whether neutrophils cause cell injury during early reperfusion after longer ischemic episodes remains unknown; however, the rapidity of polymorphonuclear neutrophil accumulation in the zones of predicted infarction is consistent with this possibility. Regardless, the presence of these inflammatory cell types poses a number of questions as to their role in mediating cardiac injury. For example, how does the accelerated inflammatory response, aside from leading to enhanced cell death, affect myocardial contractile performance? Is there a need to develop a rational approach to controlling the potential acute, as well as prolonged, detrimental consequences associated with the accelerated inflammatory process that occurs with myocardial reperfusion? What factors, if any, determine the intensity of the inflammatory response? How is the process initiated and eventually terminated? These important questions represent some of the major challenges that have yet to be fully examined. Neutrophils are widely recognized as important mediators of cardiac injury and have been the subject of numerous review articles that for the most part focus on ischemia/reperfusion injury.1-3 However, by no means are the deleterious actions of neutrophils limited solely to reperfusion injury. Neutrophils have been implicated in a number of cardiac disorders including ischemic myocardial injury, congestive heart failure (CHF), transplantation rejection, and so on, which share a common, distinguishing feature characterized by activation of the inflammatory response. In this regard, neutrophils have been mentioned as likely participants in reperfusioninduced arrhythmias, development of the postischemic no-reflow phenomenon, and increases in microvascular permeability and injury. Extensive experimental and clinical literature provides compelling evidence for the involvement of the circulating blood elements as contributors to myocardial injury. Considerable attention has been given to interactions that occur among blood platelets, neutrophils, and the vascular endothelium. There is an increasing awareness that the various blood elements interact in the process of thrombus formation and vascular occlusion. In addition, interactions among these cells can lead to the formation and release of vasoactive substances that have the potential to modulate regional blood flow. It is imperative to consider how resident inflammatory cells within a region of injured myocardial tissue can exert a protracted influence on the coronary vascular bed, as well as having a direct effect on myocardial contractile function, as suggested from experimental studies. Should related events
American Heart Journal Volume 139, Number 1, Part 1
be operative in human clinical states of disease, the circulating elements of the blood may serve as targets in the development of therapeutic interventions to regulate myocardial blood flow and to prevent or reverse abnormalities in contractile function. Experimental models of acute ischemic myocardial injury indicate that the inflammatory response, after termination of the ischemic event, contributes to acute as well as progressive development of tissue damage. Thus it is essential to consider the role of resident inflammatory cells that have entered the affected region upon reperfusion and reach a peak number in a matter of hours, as opposed to a relatively long delay in establishing an inflammatory response in the absence of reperfusion. In the former case, access of the inflammatory cells to the reperfused area occurs when many of the myocytes in the reperfused area are either normal or reversibly injured. In contrast, in the absence of reperfusion, the slow but progressive invasion of the injured region by circulating blood elements occurs at a time when most if not all of the myocytes in the affected region have undergone irreversible injury. It is important to recognize that ischemia of limited duration (<50 minutes) does not result in a significant degree of tissue injury when compared with that which develops after 60 to 90 minutes of ischemia. There is a disproportionate increase in the extent of tissue damage relative to the small increase in the duration of the total ischemic insult. One possible explanation for this difference may reside in the observation that reperfusion is an effective stimulus for activation of the complement system, which, along with the anaphylatoxins (C3a and C5a) and assembly of the membrane attack complex, serves to extend tissue injury by accentuating the local inflammatory response and by direct cytolytic attack at the cell membrane. Recent experimental data demonstrate that reperfusion induces the local expression of complement proteins, which most likely originate from endothelial cells and myocytes.4 Furthermore, studies on human heart muscle obtained at autopsy show evidence for expression of mRNAs and proteins for all of the components of the classic complement pathway with continuing activation of the complement cascade extending into the healing phase.5 These studies suggest that the myocardium is capable of expressing factors (anaphylatoxins) that recruit neutrophils to the site of injury for extended periods of time, thereby presenting the possibility that neutrophils may not only be involved in acute injury but also in long-term tissue damage and/or modulation of tissue function. This presents an intriguing question: What is (are) the precise role(s) of the neutrophil in mediating both the early and late stages of myocardial injury? This question assumes greater significance when one considers the study by Kyne et al7 reported in this issue of the Journal. The investigators present data indi-
Kilgore and Lucchesi 33
cating a relation between neutrophilia at the time of admission and the development of CHF in patients who have survived an acute myocardial infarction. Detrimental effects of neutrophil activation and accumulation in the reperfused heart, for the most part, have focused on the acute events after reperfusion (4 to 24 hours of reperfusion), whereas the effects of resident inflammatory cells and their continued activation remain to be elucidated. Therefore, what are the longterm consequences of neutrophil activation on the myocardium in terms of function, tissue viability, and vascular reactivity? Effects of “resident” neutrophils were investigated by Mickelson et al,6 who demonstrated that inflammatory cells within the region of reperfused myocardium, when stimulated by exogenous mediators (ie, plateletactivating factor), promoted significant impairment of cardiac function hours after the initial reperfusion. The observed changes coincided with thromboxane peak release at 1 minute and leukotriene peak release at 2 minutes. Longer post–ischemic reperfusion time was associated with increasingly greater changes in the recorded functional parameters. After 6 hours of reperfusion, the functional changes and the formation of thromboxane and leukotrienes, in response to the administration of platelet activating factor, reached a significant level compared with baseline values and values obtained with hearts from sham-operated animals. Experimental data demonstrate that vasoactive mediators derived from resident inflammatory cells could contribute to compromising coronary artery blood flow and the development of myocardial contractile dysfunction that occurs long after the index ischemic event has been terminated by reperfusion. The work of Kyne et al7 has extended the time frame of neutrophil-mediated injury, focusing on events 4 days after myocardial infarction. Additionally, in lieu of infarct size as the primary indicator of tissue injury, the authors examined the role of neutrophils in mediating the early development of CHF after acute myocardial infarction. When peripheral total leukocyte counts and percentage of neutrophils were determined, it was found upon hospital admission that the presence of neutrophilia correlated with early onset of CHF. Thus the association of high circulating leukocyte levels may have predictive value for the subsequent development of CHF. Furthermore, the possibility exists that neutrophils are involved, directly in the pathophysiology of CHF through their ability to respond, and continue to be recruited in response to prolonged, low-grade activation of the tissue-associated complement cascade.4,5 Evidence in the literature regarding the pathophysiologic role of neutrophils, coupled with that presented in the current study by Kyne et al, suggests that neutrophils serve a role in the pathogenesis of heart failure. Admittedly, much remains to be done to establish firm
American Heart Journal January 2000
34 Kilgore and Lucchesi
support for the concept. It should be emphasized, however, as the authors of this study note, neutrophils may not contribute directly to the extension of tissue injury but may represent a “proxy” or surrogate indicator of other mediators of inflammation that are directly involved in the process. This raises an important question as to whether circulating leukocytes may be of value as a predictive indicator for the subsequent development of CHF. Many epidemiologic studies have examined the correlation between total leukocyte counts and the development of cardiac dysfunction and/or tissue injury. The circulating leukocyte count has been shown to correlate with the magnitude of coronary artery disease8 and is considered to be a risk factor for the subsequent development of ischemic heart disease.9,10 Findings presented by Kyne et al have extended these earlier observations to the setting of CHF, although the predictive value of this observation has yet to be established with certainty. The implication that neutrophils may mediate altered cardiac function and tissue survival is an important one in that it provides a potential therapeutic approach by which to arrest or delay the development of cardiac decompensation. Experimental therapeutic interventions that prevent or reduce neutrophil infiltration or reactivity have resulted in beneficial effects in terms of reducing the extent of tissue injury. Basic research investigations with animal models of ischemia/reperfusion injury suggest a number of potential sites at which therapeutic interventions may be of benefit. Therapies designed to inhibit the detrimental activities of neutrophils is a rapidly expanding arena with a considerable number of therapeutic approaches currently under investigation.11 Recent developments have focused attention on modulating activation of the complement system, inhibiting the generation of lipid-derived mediators, preventing adhesion of neutrophils to endothelial cells and cardiac myocytes, and controlling the secretory processes by which neutrophils release their cytotoxic constituents (eg, proteolytic enzymes and reactive oxygen metabolites).12 Thus efforts are devoted toward understanding the interactions among the mediators, adhesion pathways, and secretory processes that are intensified by the act of reperfusion and result in myocardial damage above and beyond that attributable to the ischemic insult itself. However, despite extensive knowledge concerning the role of the neutrophil in the jeopardized myocardium and the presence of pharmacologic inhibitors of neutrophil actions, only limited clinical data are currently available. A reason for this disparity may be that although a number of potential therapies exist, the complexity of cardiac pathophysiology has thus far limited the analysis of antineutrophil therapies
in the clinical setting. Although some clinical studies with antineutrophil strategies have been conducted, to date, these approaches have met with limited success, thereby doing little to resolve the issue. In aggregate, it is important to recognize that there is no definitive answer to the question as to the role of the neutrophil in mediating both acute and protracted injury to the reperfused myocardium. Regardless of whether neutrophils have a direct role or merely a proxy relation, the importance of this cell type as a predictive indicator for the subsequent development of cardiac decompensation should not be ignored. How to tie in the increased presence of neutrophilia with the development of heart failure or other types of cardiac injury remains an important question that represents a major challenge in the field of cardiac research. With this in mind, efforts in this arena should be directed at understanding not only the acute effects of neutrophil infiltration but also on the interactions of resident inflammatory cells and newly recruited neutrophils. Data presented by Kyne et al should be given serious consideration.
References 1. Winn RK, Ramamoorthy C, Vedder NB, et al. Leukocyte-endothelial cell interactions in ischemia-reperfusion injury. Ann N Y Acad Sci 1997;832:311-21. 2. Korthuis RJ, Anderson DC, Granger DN. Role of neutrophil-endothelial cell adhesion in inflammatory disorders. J Crit Care 1994;9:47-71. 3. Virkhaus R, Lucchesi BR, Simpson PJ, et al. The role of adhesion molecules in cardiovascular pharmacology: meeting review. J Pharmacol Exp Ther 1995;273:569-75. 4. Yasojima K, Kilgore KS, Washington RA, et al. Complement gene expression by rabbit heart upregulation by ischemia and reperfusion. Circ Res 1998;82:1224-30. 5. Yasojima K, Schwab C, McGeer EG, et al. Human heart generates complement proteins that are upregulated and activated after myocardial infarction. Circ Res 1998:83:860-9. 6. Mickelson JK, Simpson PJ, Lucchesi BR. Myocardial dysfunction and coronary vasoconstriction induced by platelet-activating factor in the post-infarcted rabbit isolated heart. J Mol Cell Cardiol 1988; 20:547-61. 7. Kyne L, Hausdorff JM, Knight E, et al. Neutrophils and congestive heart failure after acute myocardial infarction. Am Heart J 2000; 139:94-100. 8. Kostis JB, Turkevitch D, Shard J. Association between leukocyte count and the presence and extent of coronary atherosclerosis as determined by coronary arteriography. Am J Cardiol 1984;53:997-9. 9. Gillum RF, Ingram DD, Makuc DM. White blood cell count, coronary heart disease and death: the NHANES I epidemiologic followup study. Am Heart J 1993;125:855-63. 10. Endrud K, Grimm RH. The white blood cell count and risk for coronary heart disease. Am Heart J 1992;124:207-13. 11. Cavanagh SP, Gough MJ, Homer-Vanniasinkam S. The role of the neutrophil in ischaemia-reperfusion injury: potential therapeutic interventions. Cardiovasc Surg 1998;6:112-8. 12. Hansen PR. Role of neutrophils in myocardial ischemia and reperfusion. Circulation 1995;91:1872-85.
Neutrophils and altered myocardial function Kenneth S. Kilgore, PhD, and Benedict R. Lucchesi, PhD, MD Ann Arbor, Mich
See related article on page 94. Acute transmural myocardial infarction often results from an occlusive intracoronary thrombus. In this setting, the ischemic myocardium in the anatomic region served by the occluded artery undergoes progressive biochemical, functional, and morphologic changes. The macroscopic appearance of the affected myocardium will vary with the age of the infarct. Sustained myocardial ischemia of less than 12 hours’ duration most often does not give rise to grossly observable changes. After 18 to 24 hours, the affected myocardial region will appear anemic, with a gray-brown appearance, in contrast to the bordering normal red-brown myocardium. By the second to fourth day of the ischemic event, the necrotic region becomes sharply defined with hyperemic margins. Microscopic changes also progress in a time-dependent manner. Within the initial 18 hours after the onset of the acute ischemic event, at a time when the infarct is not macroscopically evident, there may be evidence of coagulative necrosis with the presence of muscle cross-striations and relatively normal appearing nuclei. By 24 hours, interstitial edema hemorrhage and a sparse number of infiltrating neutrophils may be observed. The neutrophilic infiltrate becomes more prominent over the next 24 to 48 hours. Subsequently, the local inflammatory response consists predominantly of a neutrophilic infiltrate mixed with macrophages and lymphocytes. Without question, timely restoration of blood flow to the ischemic myocardium (angioplasty, thrombolytic therapy) serves to reduce the extent of irreversible cell injury. However, reperfusion is accompanied by early and accentuated delivery of neutrophils to the previously ischemic myocardium. Reperfused myocardium, therefore, is subjected to the overwhelming influence of an intense inflammatory response, which is in marked contrast to what occurs in the absence of reperfusion, in which the evolution of the local inflammatory response progresses over a prolonged period. Failure of neutrophils to accumulate during reperfusion after 12 minutes of ischemia stands in contrast to the excessive accumulation observed to occur after only 90 minutes From the Department of Pharmacology, University of Michigan Medical School. Reprint requests: Benedict R. Lucchesi, MD, PhD, Department of Pharmacology, University of Michigan Medical School, 1301C Medical Science Research Bldg III, Ann Arbor, MI 48109-0632. E-mail: [email protected] Am Heart J 2000;139:32-4. 0002-8703/2000/$12.00 + 0 4/4/96676
of ischemia. Whether neutrophils cause cell injury during early reperfusion after longer ischemic episodes remains unknown; however, the rapidity of polymorphonuclear neutrophil accumulation in the zones of predicted infarction is consistent with this possibility. Regardless, the presence of these inflammatory cell types poses a number of questions as to their role in mediating cardiac injury. For example, how does the accelerated inflammatory response, aside from leading to enhanced cell death, affect myocardial contractile performance? Is there a need to develop a rational approach to controlling the potential acute, as well as prolonged, detrimental consequences associated with the accelerated inflammatory process that occurs with myocardial reperfusion? What factors, if any, determine the intensity of the inflammatory response? How is the process initiated and eventually terminated? These important questions represent some of the major challenges that have yet to be fully examined. Neutrophils are widely recognized as important mediators of cardiac injury and have been the subject of numerous review articles that for the most part focus on ischemia/reperfusion injury.1-3 However, by no means are the deleterious actions of neutrophils limited solely to reperfusion injury. Neutrophils have been implicated in a number of cardiac disorders including ischemic myocardial injury, congestive heart failure (CHF), transplantation rejection, and so on, which share a common, distinguishing feature characterized by activation of the inflammatory response. In this regard, neutrophils have been mentioned as likely participants in reperfusioninduced arrhythmias, development of the postischemic no-reflow phenomenon, and increases in microvascular permeability and injury. Extensive experimental and clinical literature provides compelling evidence for the involvement of the circulating blood elements as contributors to myocardial injury. Considerable attention has been given to interactions that occur among blood platelets, neutrophils, and the vascular endothelium. There is an increasing awareness that the various blood elements interact in the process of thrombus formation and vascular occlusion. In addition, interactions among these cells can lead to the formation and release of vasoactive substances that have the potential to modulate regional blood flow. It is imperative to consider how resident inflammatory cells within a region of injured myocardial tissue can exert a protracted influence on the coronary vascular bed, as well as having a direct effect on myocardial contractile function, as suggested from experimental studies. Should related events
American Heart Journal Volume 139, Number 1, Part 1
be operative in human clinical states of disease, the circulating elements of the blood may serve as targets in the development of therapeutic interventions to regulate myocardial blood flow and to prevent or reverse abnormalities in contractile function. Experimental models of acute ischemic myocardial injury indicate that the inflammatory response, after termination of the ischemic event, contributes to acute as well as progressive development of tissue damage. Thus it is essential to consider the role of resident inflammatory cells that have entered the affected region upon reperfusion and reach a peak number in a matter of hours, as opposed to a relatively long delay in establishing an inflammatory response in the absence of reperfusion. In the former case, access of the inflammatory cells to the reperfused area occurs when many of the myocytes in the reperfused area are either normal or reversibly injured. In contrast, in the absence of reperfusion, the slow but progressive invasion of the injured region by circulating blood elements occurs at a time when most if not all of the myocytes in the affected region have undergone irreversible injury. It is important to recognize that ischemia of limited duration (<50 minutes) does not result in a significant degree of tissue injury when compared with that which develops after 60 to 90 minutes of ischemia. There is a disproportionate increase in the extent of tissue damage relative to the small increase in the duration of the total ischemic insult. One possible explanation for this difference may reside in the observation that reperfusion is an effective stimulus for activation of the complement system, which, along with the anaphylatoxins (C3a and C5a) and assembly of the membrane attack complex, serves to extend tissue injury by accentuating the local inflammatory response and by direct cytolytic attack at the cell membrane. Recent experimental data demonstrate that reperfusion induces the local expression of complement proteins, which most likely originate from endothelial cells and myocytes.4 Furthermore, studies on human heart muscle obtained at autopsy show evidence for expression of mRNAs and proteins for all of the components of the classic complement pathway with continuing activation of the complement cascade extending into the healing phase.5 These studies suggest that the myocardium is capable of expressing factors (anaphylatoxins) that recruit neutrophils to the site of injury for extended periods of time, thereby presenting the possibility that neutrophils may not only be involved in acute injury but also in long-term tissue damage and/or modulation of tissue function. This presents an intriguing question: What is (are) the precise role(s) of the neutrophil in mediating both the early and late stages of myocardial injury? This question assumes greater significance when one considers the study by Kyne et al7 reported in this issue of the Journal. The investigators present data indi-
Kilgore and Lucchesi 33
cating a relation between neutrophilia at the time of admission and the development of CHF in patients who have survived an acute myocardial infarction. Detrimental effects of neutrophil activation and accumulation in the reperfused heart, for the most part, have focused on the acute events after reperfusion (4 to 24 hours of reperfusion), whereas the effects of resident inflammatory cells and their continued activation remain to be elucidated. Therefore, what are the longterm consequences of neutrophil activation on the myocardium in terms of function, tissue viability, and vascular reactivity? Effects of “resident” neutrophils were investigated by Mickelson et al,6 who demonstrated that inflammatory cells within the region of reperfused myocardium, when stimulated by exogenous mediators (ie, plateletactivating factor), promoted significant impairment of cardiac function hours after the initial reperfusion. The observed changes coincided with thromboxane peak release at 1 minute and leukotriene peak release at 2 minutes. Longer post–ischemic reperfusion time was associated with increasingly greater changes in the recorded functional parameters. After 6 hours of reperfusion, the functional changes and the formation of thromboxane and leukotrienes, in response to the administration of platelet activating factor, reached a significant level compared with baseline values and values obtained with hearts from sham-operated animals. Experimental data demonstrate that vasoactive mediators derived from resident inflammatory cells could contribute to compromising coronary artery blood flow and the development of myocardial contractile dysfunction that occurs long after the index ischemic event has been terminated by reperfusion. The work of Kyne et al7 has extended the time frame of neutrophil-mediated injury, focusing on events 4 days after myocardial infarction. Additionally, in lieu of infarct size as the primary indicator of tissue injury, the authors examined the role of neutrophils in mediating the early development of CHF after acute myocardial infarction. When peripheral total leukocyte counts and percentage of neutrophils were determined, it was found upon hospital admission that the presence of neutrophilia correlated with early onset of CHF. Thus the association of high circulating leukocyte levels may have predictive value for the subsequent development of CHF. Furthermore, the possibility exists that neutrophils are involved, directly in the pathophysiology of CHF through their ability to respond, and continue to be recruited in response to prolonged, low-grade activation of the tissue-associated complement cascade.4,5 Evidence in the literature regarding the pathophysiologic role of neutrophils, coupled with that presented in the current study by Kyne et al, suggests that neutrophils serve a role in the pathogenesis of heart failure. Admittedly, much remains to be done to establish firm
American Heart Journal January 2000
34 Kilgore and Lucchesi
support for the concept. It should be emphasized, however, as the authors of this study note, neutrophils may not contribute directly to the extension of tissue injury but may represent a “proxy” or surrogate indicator of other mediators of inflammation that are directly involved in the process. This raises an important question as to whether circulating leukocytes may be of value as a predictive indicator for the subsequent development of CHF. Many epidemiologic studies have examined the correlation between total leukocyte counts and the development of cardiac dysfunction and/or tissue injury. The circulating leukocyte count has been shown to correlate with the magnitude of coronary artery disease8 and is considered to be a risk factor for the subsequent development of ischemic heart disease.9,10 Findings presented by Kyne et al have extended these earlier observations to the setting of CHF, although the predictive value of this observation has yet to be established with certainty. The implication that neutrophils may mediate altered cardiac function and tissue survival is an important one in that it provides a potential therapeutic approach by which to arrest or delay the development of cardiac decompensation. Experimental therapeutic interventions that prevent or reduce neutrophil infiltration or reactivity have resulted in beneficial effects in terms of reducing the extent of tissue injury. Basic research investigations with animal models of ischemia/reperfusion injury suggest a number of potential sites at which therapeutic interventions may be of benefit. Therapies designed to inhibit the detrimental activities of neutrophils is a rapidly expanding arena with a considerable number of therapeutic approaches currently under investigation.11 Recent developments have focused attention on modulating activation of the complement system, inhibiting the generation of lipid-derived mediators, preventing adhesion of neutrophils to endothelial cells and cardiac myocytes, and controlling the secretory processes by which neutrophils release their cytotoxic constituents (eg, proteolytic enzymes and reactive oxygen metabolites).12 Thus efforts are devoted toward understanding the interactions among the mediators, adhesion pathways, and secretory processes that are intensified by the act of reperfusion and result in myocardial damage above and beyond that attributable to the ischemic insult itself. However, despite extensive knowledge concerning the role of the neutrophil in the jeopardized myocardium and the presence of pharmacologic inhibitors of neutrophil actions, only limited clinical data are currently available. A reason for this disparity may be that although a number of potential therapies exist, the complexity of cardiac pathophysiology has thus far limited the analysis of antineutrophil therapies
in the clinical setting. Although some clinical studies with antineutrophil strategies have been conducted, to date, these approaches have met with limited success, thereby doing little to resolve the issue. In aggregate, it is important to recognize that there is no definitive answer to the question as to the role of the neutrophil in mediating both acute and protracted injury to the reperfused myocardium. Regardless of whether neutrophils have a direct role or merely a proxy relation, the importance of this cell type as a predictive indicator for the subsequent development of cardiac decompensation should not be ignored. How to tie in the increased presence of neutrophilia with the development of heart failure or other types of cardiac injury remains an important question that represents a major challenge in the field of cardiac research. With this in mind, efforts in this arena should be directed at understanding not only the acute effects of neutrophil infiltration but also on the interactions of resident inflammatory cells and newly recruited neutrophils. Data presented by Kyne et al should be given serious consideration.
References 1. Winn RK, Ramamoorthy C, Vedder NB, et al. Leukocyte-endothelial cell interactions in ischemia-reperfusion injury. Ann N Y Acad Sci 1997;832:311-21. 2. Korthuis RJ, Anderson DC, Granger DN. Role of neutrophil-endothelial cell adhesion in inflammatory disorders. J Crit Care 1994;9:47-71. 3. Virkhaus R, Lucchesi BR, Simpson PJ, et al. The role of adhesion molecules in cardiovascular pharmacology: meeting review. J Pharmacol Exp Ther 1995;273:569-75. 4. Yasojima K, Kilgore KS, Washington RA, et al. Complement gene expression by rabbit heart upregulation by ischemia and reperfusion. Circ Res 1998;82:1224-30. 5. Yasojima K, Schwab C, McGeer EG, et al. Human heart generates complement proteins that are upregulated and activated after myocardial infarction. Circ Res 1998:83:860-9. 6. Mickelson JK, Simpson PJ, Lucchesi BR. Myocardial dysfunction and coronary vasoconstriction induced by platelet-activating factor in the post-infarcted rabbit isolated heart. J Mol Cell Cardiol 1988; 20:547-61. 7. Kyne L, Hausdorff JM, Knight E, et al. Neutrophils and congestive heart failure after acute myocardial infarction. Am Heart J 2000; 139:94-100. 8. Kostis JB, Turkevitch D, Shard J. Association between leukocyte count and the presence and extent of coronary atherosclerosis as determined by coronary arteriography. Am J Cardiol 1984;53:997-9. 9. Gillum RF, Ingram DD, Makuc DM. White blood cell count, coronary heart disease and death: the NHANES I epidemiologic followup study. Am Heart J 1993;125:855-63. 10. Endrud K, Grimm RH. The white blood cell count and risk for coronary heart disease. Am Heart J 1992;124:207-13. 11. Cavanagh SP, Gough MJ, Homer-Vanniasinkam S. The role of the neutrophil in ischaemia-reperfusion injury: potential therapeutic interventions. Cardiovasc Surg 1998;6:112-8. 12. Hansen PR. Role of neutrophils in myocardial ischemia and reperfusion. Circulation 1995;91:1872-85.