Endothelial and myocardial injury during ischemia and reperfusion: Pathogenesis and therapeutic implications

AbstractEarly reperfusion remains the most effective way of limiting myocardial necrosis and improving ventricular function in experimental models and human patients. However, the introduction of oxygen and cellular elements, especially the neutrophil, into the ischemic zone may initiate a deleterious cascade of events that limits myocardial salvage after reperfusion. Although the pathogenesis of reperfusion injury remains controversial, recent studies have suggested that the endothelium may play a critical role.Endothelial cells maintain flow in the microcirculation by secreting a number of vasodilatory compounds and substances that prevent plugging of capillaries by inhibiting neutrophil adherence and platelet aggregation. Reperfusion of ischemic myocardium accelerates structural and functional changes in endothelial cells, resulting in a progressive decrease in microcirculatory flow (“no reflow” phenomenon). Numerous studies suggest that activated neutrophils mediate vascular damage by releasing reactive oxygen species and potent proteolytic enzymes. The administration of therapeutic agents that limit endothelial disruption and neutrophil plugging has shown promising results in limiting myocardial reperfusion injury in experimental models

923-3 Fluosol Reduces Myocardial Reperfusion Injury by Prolonged Suppression of Neutrophils by its Detergent Component (RheothRx) and not by Enhancing O2Delivery

Fluosol, a complex mixture of O2carrying perfluorocarbons (PFCs) emulsified by the detergent pluronic F-68 and a variety of lipids, significantly reduces myocardial reperfusion injury (RI) in animals and humans as shown in some initial clinical trials. Potential mechanisms for Fluosol include enhanced O2delivery to the reperfused tissue and modulation of various neutrophil (PMNs) functions. Recent studies in dogs and man demonstrate the same beneficial effect for treatment of Rl with the detergent component alone, RheothRx, which is currently undergoing clinical trials. We have shown that the effect of Fluosol on PMNs is related to this detergent. However, prolonged infusion (48 hrs) of detergent is required to reduce Rl to the same extent as Fluosol given over only 1 hr. Possible mechanisms for the beneficial effects of Fluosol (O2delivery vs effects on PMNs) were investigated in a model of regional ischemia utilizing rabbits undergoing 30mins of circumflex occlusion and 48 hrs of reperfusion. Infarct size (area of necrosis, AN) was determined histologically and expressed as percent of risk region (area at risk, AR). Animals received Fluosol (30cc/kg) with or without O2or saline over the first 60mins of reperfusion. AR was similar in all groups. (Mean±SEM of AN/AR (%), n=11 for all groups). The treatment with Fluosol with or without O2(44±3 and 40;±3, respectively) was significantly (p<0.05) reduced compared to control (63±4). Another group received F-I08, a larger size pluronic detergent found to be 2.5-fold more potent in suppressing PMN function in vitrocompared to F-68, during the first 3 hrs of reperfusion. This treatment did not alter the infarct size (63±5). RheothRx was found to form 4 nm micelles in solution whereas Fluosol formed particles approximately 100 times larger. Similar sized particles were formed by substituting the perfluorocarbons with mineral oil. The in vitroactivity of this pluronic/mineral oil micelle on PMN function was similar to Fluosol. Infusion of these larger oil micelles was tolerated by rabbits and used in further infarct studies.ConclusionsThese studies suggest that (1) reduction of RI by Fluosol is not due to enhanced O2delivery by the PFCs to reperfused myocardium and (2) since the Fluosol emulsion markedly reduces the clearance of the detergent F-68 (t½: Fluosol ≅ 8 hrs vs RheothRx ≅ 1.5 hrs). prolonged PMN suppression rather than potency of suppression is the mechanism whereby Fluosol ameliorates RI. Fluosol's clinical efficacy may be enhanced by prolonging its infusion to ensure an adequate blood level to suppress PMN function beyond the time of reperfusion injury. RheothRx's clinical usefulness may be facilitated by decreasing its renal clearance by delivering larger micelles of the detergent in order to produce prolonged PMN suppression with a shorter infusion time

Novel Guidewire Design and Coating for Continuous Delivery of Adenosine During Interventional Procedures.

Background: The no-reflow phenomenon compromises percutaneous coronary intervention outcomes. There is an unmet need for a device that prevents no-reflow phenomenon. Our goal was to develop a guidewire platform comprising a nondisruptive hydrophilic coating that allows continuous delivery of adenosine throughout a percutaneous coronary intervention. Methods and Results: We developed a guidewire with spaced coils to increase surface area for drug loading. Guidewires were plasma treated to attach hydroxyl groups to metal surfaces, and a methoxy-polyethylene glycol-silanol primer layer was covalently linked to hydroxyl groups. Using polyvinyl alcohol, polyvinyl pyrrolidone, and polyvinyl acetate, a drug layer containing jet-milled adenosine was hydrogen-bonded to the polyethylene glycol-silanol layer and coated with an outer diffusive barrier layer. Coatings were processed with a freeze/thaw curing method. In vitro release studies were conducted followed by in vivo evaluation in pigs. Coating quality, performance, and stability with sterilization were also evaluated. Antiplatelet properties of the guidewire were also determined. Elution studies with adenosine-containing guidewires showed curvilinear and complete release of adenosine over 60 minutes. Porcine studies demonstrated that upon insertion into a coronary artery, adenosine-releasing guidewires induced immediate and robust increases (2.6-fold) in coronary blood flow velocity, which were sustained for ≈30 minutes without systemic hemodynamic effects or arrhythmias. Adenosine-loaded wires prevented and reversed coronary vasoconstriction induced by acetylcholine. The wires significantly inhibited platelet aggregation by \u3e80% in vitro. Guidewires passed bench testing for lubricity, adherence, integrity, and tracking. Conclusions: Our novel drug-releasing guidewire platform represents a unique approach to prevent/treat no-reflow phenomenon during percutaneous coronary intervention

Pharmacologic perturbation of neutrophils by Fluosol results in a sustained reduction in infarct size in the canine model of reperfusion

AbstractPrevious studies have demonstrated that intravenous administration of large doses of Fluosol, a perfluorochemical preparation, reduced infarct size 24 h after reperfusion, an effect that was associated with reduced neutrophil infiltration. The effect of a clinically tolerable dose of Fluosol on infarct size after a prolonged period of reperfusion and its mechanism of action on neutrophils remain unknown.Twenty-one anesthetized closed chest dogs were subjected to 90 min of proximal left anterior descending coronary artery occlusion and 72 h of reperfusion. An additional five dogs that did not undergo regional myocardial ischemia were utilized to explore the mechanism of action of Fluosol on neutrophil function. In the infarct study, animals were randomized to receive either intravenous Fluosol (n = 10) or an equivalent volume of Ringer's lactate solution (control; n = 11) at 15 ml/kg body weight during the last 30 min of occlusion and for the 1st 30 min of reperfusionFluosol significantly reduced infarct size when expressed as percent area at risk 72 h aller reperfusion (13.7 ± 2.7% vs. 38.3 ± 4.5%, respectively, p < 0.001). This reduction was associated with significant improvement in regional wall motion (18.4 ± 2.3% vs. 5.5 ± 2%, p < 0.001). Endocardial blood fiow in the ischemic bed was significantly higher 3 h after reperfusion in Fluosol-treated dogs (0.63 ± 0.08 vs. 0.34 ± 0.07 ml/min per g, p = 0.01). Reduced capillary plugging by neutrophils with relative preservation of endothelial cell structure was observed in Fluosol-treated animals. Infusion of Fluosol produced a marked transient decrease in peripheral neutrophil and platelet counts in both ischemic and nonischemic dogs and was associated with a significant reduction in total hemolytic complement levels. Studies of neutrophil function ex vivo revealed a reduction in chemotaxis and lysozyme degranulation after infusion of Fluosol. In vitro experiments showed that Fluosol produced a rapid and sustained activation of neutrophils determined by superoxide anion production.These data demonstrate that low dose intravenous Fluosol produces a sustained reduction in infarct size in the canine model. The beneficial effect may be in part due to the suppression of various neutrophil functions in the reperfused myocardium subsequent to peripheral activation by Fluosol. Such interventions may offer a novel therapy to enhance myocardial salvage by sequestration of circulating neutrophils during the critical early reperfusion period

Electrocardiographic changes associated with isolated right ventricular infarction

Isolated infarction of the right ventricle is an extremely rare entity. A patient is described with diffuse interstitial lung disease who developed ST segment elevation in inferior and anterior leads on a routine electrocardiogram and at autopsy was found to have an isolated right ventricular infarct involving approximately 70% of the right ventricular circumference without involvement of the left ventricle and septum. This case illustrates that isolated right ventricular infarction in the presence of cor pulmonale and right ventricular hypertrophy can produce an injury current in the limb and precordial leads of the electrocardiogram which mimics that seen in typical transmural infarction of the left ventricle