Edward M. Boyle

Endothelial cell injury in cardiovascular surgery: the systemic inflammatory response.

Many of the components currently used to perform cardiovascular operations lead to systemic insults that result from cardiopulmonary bypass circuit-induced contact activation, circulatory shock, and resuscitation, and a syndrome similar to endotoxemia. Experimental observations have demonstrated that these events have profound effects on activating endothelial cells to recruit neutrophils from the circulation. Once adherent to the endothelium, neutrophils release cytotoxic proteases and oxygen-derived free radicals, which are responsible for much of the end-organ damage seen after cardiovascular operations. Recently the cellular and molecular mechanisms of endothelial cell activation have become increasingly understood. It is conceivable that once the molecular mechanisms of endothelial cell activation are better defined, therapies will be developed allowing the selective or collective inhibition of vascular endothelial activation during the perioperative period.

Endothelial Cell Injury in Cardiovascular Surgery

In the last decade the endothelium has been shown to play a major role in regulating membrane permeability, lipid transport, vasomotor tone, coagulation, inflammation, and vascular wall structure. These critical endothelial cell functions are extremely sensitive to injury in the form of hypoxia, exposure to cytokines, endotoxin, cholesterol, nicotine, surgical manipulation, or hemodynamic shear stress. In response to injury endothelial cells become activated, tipping the balance of endothelial-derived factors to disrupt barrier function, and enhance vasoconstriction, coagulation, leukocyte adhesion, and smooth muscle cell proliferation. Although these responses likely exist as protective mechanisms, if the stimuli are severe the responses may become excessive, resulting in damaged tissue, impaired organ function, and an abnormal fibroproliferative response. Recent discoveries in the field of vascular biology have led to an expanded understanding of many of the complications of cardiovascular operations. Because of the wide impact endothelial cell dysfunction has on patients with cardiovascular disease, issues pertaining to endothelial biology are in the forefront of research that will affect the current and future practice of cardiothoracic surgery.

Inhibition of the Tissue Factor-Thrombin Pathway Limits Infarct Size after Myocardial Ischemia-Reperfusion Injury by Reducing Inflammation

Functional inhibition of tissue factor (TF) has been shown to improve coronary blood flow after myocardial ischemia/reperfusion (I/R) injury. TF initiates the coagulation protease cascade, resulting in the generation of the serine protease thrombin and fibrin deposition. Thrombin can also contribute to an inflammatory response by activating various cell types, including vascular endothelial cells. We used a rabbit coronary ligation model to investigate the role of TF in acute myocardial I/R injury. At-risk areas of myocardium showed increased TF expression in the sarcolemma of cardiomyocytes, which was associated with a low level of extravascular fibrin deposition. Functional inhibition of TF activity with an anti-rabbit TF monoclonal antibody administered either 15 minutes before or 30 minutes after coronary ligation reduced infarct size by 61% (P = 0.004) and 44% (P = 0.014), respectively. Similarly, we found that inhibition of thrombin with hirudin reduced infarct size by 59% (P = 0.014). In contrast, defibrinogenating the rabbits with ancrod had no effect on infarct size, suggesting that fibrin deposition does not significantly contribute to infarct size. Functional inhibition of thrombin reduced chemokine expression and inhibition of either TF or thrombin reduced leukocyte infiltration. We propose that cardiomyocyte TF initiates extravascular thrombin generation, which enhances inflammation and injury during myocardial I/R.

Endothelial Cell Injury in Cardiovascular Surgery: Ischemia-Reperfusion

Myocardial ischemia and reperfusion is a common occurrence in cardiovascular surgery patients. Acute ischemia results in a spectrum of derangements, which range from transient reversible stunning of the myocardium to severe irreversible abnormalities such as infarction. Many of these abnormalities are accentuated upon reperfusion with oxygenated blood. Recently, the endothelium has been shown to play a key role in the injury suffered after ischemia and reperfusion. When rendered hypoxic and then reoxygenated, endothelial cells become activated to express proinflammatory properties that include the induction of leukocyte-adhesion molecules, procoagulant factors and vasoconstrictive agents that increase vasomotor tone. These changes may contribute to the no-reflow phenomenon by promoting endothelial edema, neutrophil and platelet plugging, microthrombosis, and enhanced vasomotor tone. An increased understanding of the role that hypoxic endothelial cell activation plays in myocardial dysfunction after ischemia/reperfusion may allow therapies to be designed to further attenuate this response.

Endothelial cell injury in cardiovascular surgery : The pathophysiology of vasomotor dysfunction

Impaired vasomotor function has been suggested as playing a role in the pathophysiology of hypertension, diabetes, hypercholesterolemia, and atherosclerosis, all of which are common in cardiovascular surgery patients. In addition to chronic vasomotor dysfunction, alterations in vasomotor tone can result in acute arterial spasm, microcirculatory ischemia, and wide variations in systemic blood pressure. Changes in the health of the vascular endothelium may also impact the late patency of coronary artery bypass grafts, the progression of atherosclerosis in the native coronary circulation, and the long-term success of cardiac transplants. In the resting state the endothelium produces several substances that promote vascular relaxation and inhibition of platelet function, thus assuring the unhindered flow of blood through the capillaries. In response to injury, the endothelium loses some capacity to relax and also releases powerful vasoconstrictive agents. Attempting to understand the contributions that these substances play in the vasomotor dysfunction seen after cardiothoracic surgery is an area of active investigation.

Inhibition Of Interleukin-8 Blocks Myocardial Ischemia-Reperfusion Injury

INTRODUCTION Interleukin-8 is thought to play a role in neutrophil activation and transcapillary migration into the interstitium. Because neutrophils are principal effector cells in acute myocardial ischemia-reperfusion injury, we postulated that the inhibition of interleukin-8 activity with a neutralizing monoclonal antibody directed against rabbit interleukin-8 (ARIL8.2) would attenuate the degree of myocardial injury encountered during reperfusion. METHODS In New Zealand White rabbits, the large branch of the marginal coronary artery supplying most of the left ventricle was occluded for 45 minutes, followed by 2 hours of reperfusion. Fifteen minutes before reperfusion, animals were given an intravenous bolus of either 2 mg/kg of ARIL8.2 or 2 mg/kg anti-glycoprotein-120, an isotype control antibody that does not recognize interleukin-8. At the completion of the 120-minute reperfusion period, infarct size was determined. RESULTS In the area at risk for infarction, 44.3% +/- 4% of the myocardium was infarcted in the anti-glycoprotein-120 group compared with 24.8% +/- 9% in the ARIL8.2 group (p < 0.005). In control animals, edema and diffuse infiltration of neutrophils were observed predominantly in the infarct zone and the surrounding area at risk. Tissue myeloperoxidase determinations did not differ significantly between groups, indicating that the cardioprotective effect of ARIL8.2 was independent of an effect on neutrophil infiltration. CONCLUSIONS A specific monoclonal antibody that neutralizes interleukin-8 significantly reduces the degree of necrosis in a rabbit model of myocardial ischemia-reperfusion injury.

An essential role for NF-κB in the cardioadaptive response to ischemia

Abstract Background . Ischemic preconditioning (IP) is the phenomenon whereby brief episodes of ischemia protect the heart against a subsequent ischemic stress. We hypothesize that activation of the transcription factor NF-κB mediates IP. Methods . Rabbits were randomly allocated to one of three groups: (1) 45 minutes of myocardial ischemia followed by 2 hours of reperfusion (I/R); (2) three cycles of 5-minute ischemia and 5 minutes of reperfusion followed by I/R (IP + I/R); or (3) IP in the presence of ProDTC, a specific NF-κB inhibitor, followed by I/R (IP ProDTC + I/R). Infarct size, indices of regional contractility, and NF-κB activation were determined. Results . In preconditioned rabbits (IP + I/R), infarct size was reduced 83% compared with both I/R alone and IP ProDTC + I/R groups ( p ProDTC + I/R groups ( p ProDTC + I/R groups showed NF-κB activation with I/R that was absent in preconditioned animals. Conclusions . The cytoprotective effects induced by IP require activation of NF-κB.

Endothelial cell injury in cardiovascular surgery: atherosclerosis.

Most of the indications for cardiovascular operation and many of its complications are in large part due to advanced atherosclerosis. The pathogenesis of atherosclerosis involves inflammatory infiltration of the vessel wall, cellular proliferation, fibrous plaque formation, and ultimately plaque rupture and occlusive thrombosis. Many of these events are linked, at least initially, to chronic injury of the vascular endothelium. Endothelial cell injury from hypertension, diabetes mellitus, hyperlipidemia, fluctuating shear stress, smoking, or transplant rejection disrupts normal endothelial cell function. This results in the loss of the constitutive protective mechanisms and an increase in inflammatory, procoagulant, vasoactive, and fibroproliferative responses to injury. These changes promote vasospasm, intimal proliferation, and thrombus formation, all of which play a significant role in the initiation, progression, and clinical manifestations of atherosclerosis. Understanding the role of the chronically injured endothelium and its interactions with circulating immune cells and the underlying smooth muscle cells may lead to novel therapeutic interventions for the prevention and treatment of atherosclerosis.

Penetrating cardiac injuries: a population-based study.

BACKGROUND Wide variances exist in reports of survival rates after penetrating cardiac injuries because most are hospital-based reports and thus are affected by the local trauma system. The objective of this study was to report population-based, as well as hospital-based, survival rates after penetrating cardiac injury. METHODS Retrospective cohort analysis was performed during a 7-year period of 20,181 consecutive trauma admissions to a regional Level I trauma center and 6,492 medical examiners reports. A meta-analysis was performed comparing survival rates with available population-based reports. RESULTS There were 212 penetrating cardiac injuries identified, for an incidence of approximately 1 per 100,000 man years and 1 per 210 admissions. The overall survival rate was 19.3% (41 of 212) for the population studied, with survival rates of 9.7% (12 of 123) for gunshot wounds and 32.6% (29 of 89) for stab wounds. Ninety-six of the 212 patients were transported to the trauma center for treatment, resulting in an overall hospital survival rate of 42.7% (41 of 96), with a hospital survival rate of 29.3% (12 of 41) for gunshot wounds and 52.7% (29 of 55) for stab wounds. CONCLUSION Review of population-based studies indicates that there has been only a minor improvement in the survival rates for the treatment of penetrating cardiac injuries.

Endothelial cell injury in cardiovascular surgery: The procoagulant response

The vascular endothelium plays a critical role in the regulation of coagulation through the constitutive expression and release of anticoagulants and the inducible expression of procoagulant substances. Cardiopulmonary bypass dysregulates this process by activating endothelial cells, initially promoting bleeding and then thrombosis. Endothelial cell activation in response to circulating inflammatory mediators leads to the initiation of coagulation when tissue factor is expressed throughout the intravascular space. This results in the widespread consumption of coagulation factors. Additionally, there is a cardiopulmonary bypass-related qualitative platelet defect that is exacerbated by thrombocytopenia as platelets are consumed from the circulation by clot and adherence to the cardiopulmonary bypass circuit. Finally, cardiopulmonary bypass results in the endothelial release of plasminogen activators, which lead to an increase in systemic fibrinolysis. The diffuse generation of thrombin, driven by the inducible intravascular expression of tissue factor, plays a major role in all of these processes. Efforts to understand the critical role of the endothelium in coagulation may lead to novel therapies to prevent bleeding or thrombosis in cardiovascular surgery patients.