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Right arrow Myocardial protection

Ann Thorac Surg 2003;75:S735-S739
© 2003 The Society of Thoracic Surgeons

II: Surgical myocardial protection

Aprotinin and preservation of myocardial function after ischemia-reperfusion injury

David A. Bull, MDa*, Jennifer Maurer, PhDb

a Department of Surgery, Division of Cardiothoracic Surgery, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
b Scientific Communications, Department of Clinical Services, Bayer Corporation, West Haven, Connecticut, USA

* Address reprint requests to Dr Bull, Division of Cardiothoracic Surgery, Room 3C127, Department of Surgery, University of Utah, 50 N Medical Dr, Salt Lake City, UT 84132, USA.
e-mail: david.bull{at}hsc.utah.edu

Presented at the 3rd International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, June 2–6, 2002.

Abstract

Ischemia-reperfusion injury, a complex process involving the generation and release of inflammatory cytokines, accumulation and infiltration of neutrophils and macrophages, release of oxygen free radicals, activation of proteases, and generation of nitric oxide (NO), may result in myocardial dysfunction and possible injury to other major organs. Aprotinin, a nonspecific serine protease inhibitor used to reduce the blood loss and transfusion requirements accompanying cardiac surgery, has dose-dependent effects on coagulation, fibrinolytic, and inflammatory variables. Data indicate that aprotinin may provide protection from ischemia-reperfusion injury. In myocardial tissue models of ischemia and reperfusion, aprotinin has been shown to reduce uptake of tumor necrosis factor-{alpha} (TNF-{alpha}), generation of NO, and accumulation of leukocytes. Improved myocardial function has been observed with aprotinin treatment in animal models of ischemia-reperfusion injury. In humans, data indicate that integrin expression associated with leukocyte transmigration as well as markers of myocardial damage are reduced in patients receiving aprotinin. Further, data suggest that patients who receive aprotinin may have a reduced need for inotropic support and a decreased incidence of postoperative atrial fibrillation. In all, review of this topic indicates that aprotinin may reduce aspects of ischemia-reperfusion injury and prospective clinical studies are needed to evaluate the impact of aprotinin on associated patient outcomes.


Doctor Maurer discloses that she has a financial relationship with Bayer Corporation.

 

Management of ischemia-reperfusion injury is integral to the practice of cardiac surgery. Both ischemia and reperfusion of myocardial tissue contribute to tissue damage [1]. The pathophysiology of ischemia-reperfusion injury is complex and involves the generation and release of inflammatory cytokines, accumulation and infiltration of neutrophils and macrophages, release of oxygen free radicals, activation of proteases, and generation of nitric oxide (NO) [1]. Aprotinin, a nonspecific serine protease inhibitor used to reduce the blood loss and transfusion requirements accompanying cardiac surgery, has known antiinflammatory properties. The current review will discuss data highlighting the antiinflammatory properties of aprotinin that may help preserve myocardial function after ischemia-reperfusion injury.

The generation and release of inflammatory cytokines contributes to myocardial dysfunction after ischemia-reperfusion injury. Tumor necrosis factor-{alpha} (TNF-{alpha}), in particular, is a primary contributor to myocardial dysfunction [2, 3]. Both myocardial macrophages and cardiac myocytes synthesize TNF-{alpha}, and cardiac myocytes have been shown to produce substantial amounts of TNF-{alpha} in response to ischemia [2]. TNF-{alpha} produced within myocardial tissue may contribute to postischemic myocardial dysfunction by directly depressing contractility and inducing apoptosis [2]. Temporally, the effects of TNF-{alpha} can be divided into an early NO-independent phase and a late NO-dependent phase [2]. The early phase, occurring within minutes of TNF-{alpha} release as TNF-{alpha} binds its receptors within the myocardium, leads to sphingosine-mediated disruption of calcium transients, subsequent depletion of ATP stores, depression of myocardial contractile efficiency, and systolic and diastolic dysfunction [2]. Clinically this manifests as contractile dysfunction immediately after reperfusion in the operating room. The late phase, occurring hours after TNF-{alpha} release, is correlated with induction of NO synthase, subsequent release of NO, myofilament desensitization to calcium, and sustained contractile dysfunction [2]. Clinically this delayed or persistent late contractile dysfunction manifests as an ongoing low cardiac output state in the intensive care unit after surgery.

Aprotinin is a pharmacologic agent with diverse properties [4] that inhibits an array of enzymes and activities that participate in coagulation, fibrinolytic, and inflammatory processes as well as others that fall outside of this realm. The use of aprotinin during cardiac surgery may improve patient outcomes, specifically through suppression of inflammatory mediators [5]. Clinically aprotinin has been shown to reduce TNF-{alpha} levels to varying degrees in CABG patients, depending on the studyprotocol and dosing regimens utilized [6–8]. Mechanistically aprotinin has been shown to inhibit cytokine-induced NO synthase expression, producing a dose-dependent inhibition of NO production by bronchial epithelial cells [9]. In cultured coronary microvascular endothelial cells, aprotinin inhibited calcium ionophore-induced nitrite accumulation (concentration 125 to 500 KIU/mL) [10]. In cultured rat coronary microvascular endothelial cells, aprotinin 250 KIU/mL was shown to down-regulate NO synthase mRNA and protein [11]. In a rabbit model of ischemia-reperfusion involving the renal artery, elevation of serum NO was more pronounced in controls compared with animals receiving aprotinin (30,000 KIU/kg bolus with 10,000 KIU/h intravenous infusion) [12]. Further, aprotinin (150 KIU/mL) has been shown to improve preservation of adenine nucleotides in canine hearts after ischemia and reperfusion after cold storage [13]. In sum these studies suggest that the antiinflammatory actions of aprotinin may be coupled to preservation of biochemical function after ischemia and reperfusion.

In our laboratory we hypothesized that aprotinin mediates preservation of myocardial biochemical function through inhibition of the release, uptake and activity of TNF-{alpha}. To test this hypothesis we specifically investigated whether aprotinin would preserve myocardial biochemical function during ischemic cold storage of the myocardium and whether this preservation of biochemical function was mediated through suppression of the release, uptake, and activity of TNF-{alpha}. Further we investigated whether aprotinin suppressed TNF-{alpha} induced nitric oxide production within the myocardium. Our studies specifically focused on the period of cold ischemia before reperfusion, as this would better assess the direct effect of aprotinin on the myocardium without the confounding variable of TNF-{alpha} release from circulating white blood cells after reperfusion [14]. Briefly, rat hearts precision cut into slices with a thickness of 200 µm were stored in crystalloid cardioplegia alone or crystalloid cardioplegia with one of the following additions: (1) aprotinin (200 KIU/mL), (2) TNF-{alpha} (100 pg/mL), (3) aprotinin plus TNF-{alpha}, (4) a monoclonal antibody to TNF-{alpha} (100 pg/mL), or (5) a polyclonal antibody to the TNF-{alpha} receptor (100 pg/mL). Myocardial biochemical function was assessed by ATP content and capacity for protein synthesis immediately after slicing and at intervals after storage (4°C). Compared with storage in cardioplegia solution alone, heart slices stored in solution containing aprotinin (200 KIU/mL) showed a significant increase in ATP content and capacity for protein synthesis, a significant decrease in intramyocardial generation of TNF-{alpha} as well as decreased uptake of TNF-{alpha}. Further, the presence of an anti-TNF-{alpha} antibody or anti-TNF-{alpha} receptor antibody in the cardioplegia solution also increased intramyocardial ATP content and protein synthesis. The addition of aprotinin, anti-TNF-{alpha} antibody, or anti-TNF-{alpha} receptor antibody to the cardioplegia solution significantly decreased NO levels within the myocardium after cold storage compared with storage in cardioplegia alone.

These experiments showed that aprotinin (200 KIU/mL) improved preservation of myocardial ATP content and capacity for protein synthesis during cold storage. This improvement in myocardial biochemical function in the presence of aprotinin is related to suppression of intramyocardial generation of TNF-{alpha}. Our experiments also showed that addition of TNF-{alpha} to crystalloid cardioplegia resulted in intramyocardial TNF-{alpha} levels higher than those measured during cold storage with cardioplegia alone, indicating that extracellular TNF-{alpha} is taken up into the myocardium during cold storage. This uptake of TNF-{alpha} into the myocardium was also suppressed in the presence of aprotinin. Overall we concluded that aprotinin mediates improvement in the preservation of myocardial biochemical function during cold storage through the suppression of the release, uptake, and activity of TNF-{alpha}. Further, aprotinin suppressed TNF-{alpha} induced NO production within the myocardium during cold storage, indicating that depression of myocardial biochemical function by TNF-{alpha} may be mediated through a NO-dependent pathway [14].

Clinically the generation of TNF-{alpha} within the myocardium after ischemia-reperfusion injury and cardiac surgery is complex. As Formigli and associates [15] have shown, while TNF-{alpha} levels within the myocardium rise during ischemia, the highest levels of TNF-{alpha} within the myocardium are measured after reperfusion. During ischemia the number of neutrophils and monocytes within the myocardium increases 2.5- to threefold compared with nonischemic myocardium. During reperfusion, the number of neutrophils and monocytes within the myocardium increases an additional threefold to 3.5-fold compared with the ischemic state before reperfusion [15, 16]. Ischemia with reperfusion, compared with ischemia alone, promotes rapid accumulation of leukocytes in the myocardium. These leukocytes are a source of additional TNF-{alpha} and can damage the myocardium directly, in part through the induction of myocyte apoptosis [2, 17–19]. In addition to its other properties aprotinin may help protect the myocardium by inhibiting this leukocyte mediated apoptosis [17–19].

In addition to awareness of direct effects on the myocardium, cardiothoracic surgeons should be cognizant that the infiltration of leukocytes into ischemic and reperfused tissues appears to be a global phenomenon. The lungs, brain, liver, and kidneys as well as other tissues have all been demonstrated to accumulate leukocytes after periods of ischemia and reperfusion [20–26]. As hypoperfusion and ischemia of other major organs can occur during and after cardiothoracic surgery, a therapy that reduces ischemia-reperfusion injury to the myocardium may have beneficial effects on other organ systems as well.

As this topic is reviewed, clinicians must appreciate that the effects of aprotinin, as with most pharmacologic agents, are concentration dependent. Dissociation constants (Ki) of enzyme-protease complexes of human enzymes are 6 x 10-11 M for trypsin, 9 x 10-11 M for plasmin, 3 x 10-8 M for plasma kallikrein, 1 x 10-7 for factor XIa, more than 1 x 10-6 M for factor XIIa, more than 1 x 10-6 M for factor Xa, more than 1 x 10-6 M for tissue plasminogen activator, and more than 1 x 10-6 M for leukocyte elastase [27]. As a result, a lower dose of aprotinin (50 to 125 KIU/mL) is needed to directly inhibit plasmin, while relatively higher doses are required to directly inhibit plasma kallikrein (>=200 KIU/mL), coagulation factors, and elastase [28, 29]. In using the full Hammersmith dose (2 x 106 KIU pre-CPB, 2 x 106 KIU in pump prime, 500,000 KIU/h during CPB) during CABG surgery, aprotinin plasma levels achieve kallikrein inhibition, peaking after onset of cardiopulmonary bypass (approximately 400 KIU/mL) and declining gradually during the course of surgery, maintaining levels of 200 KIU/mL or more until discontinuation of the aprotinin infusion [30]. It is also important to note that full-dose aprotinin, by directly inhibiting plasma kallikrein, indirectly reduces events that are downstream of contact activation, namely activation of coagulation and activation of fibrinolysis [31]. Recent clinical data reveal the dose dependency of the effect of aprotinin on the coagulation, fibrinolytic, and inflammatory cascades. In a cohort of CABG patients (n = 20) administered full-dose aprotinin or placebo, IL-6 levels were reduced significantly in the aprotinin group at 4 hours and 1 day postbypass compared with placebo [32]. In contrast, a cohort of 64 patients undergoing primary CABG randomly assigned to control or low-dose aprotinin (2 x 106 KIU in pump prime) showed no significant difference in perioperative inflammatory markers (including IL-6) between groups [33]. Similarly, in patients (n = 29) undergoing CABG prospectively randomly assigned to control or low-dose aprotinin (2 x 106 KIU in pump prime), reduced fibrinolysis was observed in patients treated with low-dose aprotinin relative to control whereas effects on coagulation were not significantly different between the groups [8]. Thus appreciation for the dose dependency of the effect of aprotinin, especially as it relates to coagulation, fibrinolytic, and inflammatory pathways, is important when evaluating the impact of the drug on indicators of ischemia-reperfusion injury.

Asimakopoulos and associates [34] have shown that full-dose aprotinin administered to patients undergoing primary CABG surgery reduces expression of leukocyte integrin CD11b/CD18 (Mac-1). They also demonstrated that aprotinin (>=200 KIU/mL) inhibits leukocyte transmigration in vitro in response to IL-8 and other chemoattractants and further, using intravital microscopy, showed aprotinin (40,000 KIU/kg load, 20,000 KIU/kg per hour infusion) inhibited chemoattractant-induced leukocyte extravasation [35]. Research by Buerke and associates [36–39] in rodent ischemia-reperfusion models has shown that aprotinin (10,000 to 20,000 KIU/kg) administered 5 minutes before reperfusion reduces infiltration of leukocytes into the myocardium. This reduction in leukocyte accumulation was accompanied by a reduction in myocardial injury with aprotinin treatment as measured by CK release [38]. Similarly, aprotinin has been shown to improve recovery of myocardial contractility (dose, 200 KIU/mL) [40] and decrease release of troponin T (dose, 10,000 KIU infusion) [41] relative to controls after ischemia-reperfusion in isolated Langendorff preparations. Interestingly, effects observed in isolated heart preparations may occur through direct drug action as leukocytes and plasma proteins are absent from the system. In a canine heart ischemia-reperfusion model McCarthy and associates [42] showed aprotinin-treated (30,000 KIU/kg and 7,000 KIU/kg per hour) animals had improved systolic function as measured by greater percent systolic shortening relative to controls. Aprotinin (2 x 106 KIU load, 500,000 KIU/h) also inhibits the reduction in wall-thickening fraction observed after minimally invasive coronary artery bypass surgery in an ovine model [43]. In this study aprotinin was more efficacious than cariporide in preserving myocardial function after coronary artery bypass grafting [43]. As aprotinin appears to have activity in models in the absence and presence of leukocytes, aprotinin may act through multiple mechanisms to impact ischemia-reperfusion injury variables.

Corroborating these preclinical findings to observations in the clinical setting, Wendel and associates [44] found that full-dose aprotinin reduced serum CK-MB and troponin T levels in patients at 1 and 3 days after CABG surgery compared with controls. As suggested by retrospective analysis of the Trasylol Proprietary Database, the ability of full-dose aprotinin to preserve myocardial function after ischemia-reperfusion may result in the decreased use of inotropic agents, vasopressors, and antiarrhythmic agents after coronary artery bypass grafting (Royston and associates, in preparation) [45]. Within a small cohort (n = 20) undergoing CABG surgery the use of full-dose aprotinin resulted in a significantly reduced incidence of postoperative atrial fibrillation [34]. Similarly within a small cohort of pediatric patients (n = 34), those treated with a high-dose regimen (28,000 KIU/kg bolus, 28,000 in pump prime, 7,000 KIU/kg per hour) required significantly less inotropic support relative to controls [46]. Olivencia-Yurvati and associates [47] in a recent study (n = 120) designed to investigate intraoperative strategies to reduce postoperative atrial fibrillation showed that patients treated with full-dose aprotinin plus leukocyte depleting filters during surgery had significantly reduced atrial fibrillation relative to control. Unfortunately most clinical studies to the present time have not been prospectively designed, powered, and conducted to separate the potential benefits of aprotinin on myocardial preservation from its known beneficial impact on blood loss and administration of blood products perioperatively.

In addition to its protective effects on the myocardium aprotinin may also help improve pulmonary function after ischemia-reperfusion injury. Aprotinin improves pulmonary function during reperfusion in an isolated lung model [48]. In a randomized prospective study aprotinin reduced lung reperfusion injury after cardiopulmonary bypass in coronary artery bypass graft patients [49]. Interestingly the addition of aprotinin to Euro-Collins and University of Wisconsin solutions improves lung preservation under conditions of hypoxic cold storage [50].

Taken in aggregate these studies demonstrate that the ability of aprotinin to suppress the endogenous release of TNF-{alpha} within the myocardium and suppress the infiltration of white blood cells into the myocardium and other tissues after ischemia-reperfusion injury results in preservation of myocardial biochemical function. The preservation of myocardial biochemical function manifests clinically as a decrease in myocardial injury, better preservation of systolic function, and possibly decreased need for inotropic, antiarrhythmic, and vasopressor therapy after cardiac surgery. While all of the studies reviewed provide insight as to the effect of aprotinin on myocardial preservation in the clinical setting, larger prospective studies are required to more fully understand the potential benefits of aprotinin in counteracting the effects of ischemia-reperfusion injury in the clinical practice of cardiothoracic surgery.

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