HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): James K. Kirklin David C. McGiffin Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kirklin, J. K. Articles by McGiffin, D. C. Search for Related Content PubMed PubMed Citation Articles by Kirklin, J. K. Articles by McGiffin, D. C.

Ann Thorac Surg 1999;68:1978-1982
© 1999 The Society of Thoracic Surgeons

---

II. Surgical Myocardial Protection

Control of the inflammatory response in extended myocardial preservation of the donor heart

^a Division of Cardiothoracic Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA

Address reprint requests to Dr Kirklin, Department of Surgery, University of Alabama at Birmingham, 739 Zeigler Bldg, 703 So 19th St, Birmingham, AL 35294
e-mail: jkirklin{at}uab.edu

Presented at the International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, Sep 21–24, 1997.

Abstract

The damaging effects of inflammation after prolonged myocardial ischemia are typically manifest during the period of reperfusion. The imbalance between free radical generation and availability of natural free radical scavengers during postischemic reperfusion set the stage for free radical injury. Calcium overload may convert reversible ischemic damage to fatal myocyte contracture. Complement activation and neutrophil activation, adhesion, and diapedesis are central components of the damaging inflammatory response. Cytokines such as tumor necrosis factor and IL1 simulate IL8 synthesis which is also a potent chemoattractant for neutrophils. The endothelial contribution to ischemic-reperfusion injury results from an imbalance between the production of naturally occurring vasodilators, such as prostacycline and nitric oxide, and vasoconstrictor products, such as endothelin, thromboxane A2, and angiotensin 2. Knowledge of these basic mechanisms has stimulated the formulation of preservation solutions and strategies to ameliorate the inflammatory response during reperfusion.

The reintroduction of blood flow after the period of ischemia during transport and implantation may induce further damage to cells that were reversibly injured during the ischemic period, providing a potent stimulus for a localized inflammatory response (Fig 1). The basic components of this process are discussed in this section.

View larger version (43K): [in this window] [in a new window]   Fig 1. Proposed mechanisms of donor cardiac ischemic and reperfusion injury.

During the initial phase of myocardial reperfusion with oxygenated blood after the period of prolonged ischemia, potentially toxic oxygen species called oxygen-derived free radicals are generated which can induce direct myocardial injury. Free radicals are neutral molecular species which contain an unpaired electron in their outer electron shell. They are unstable, exist mainly as short-lived intermediates, and are particularly reactive against electron-rich double bonds. There are numerous sources of intracellular free radicals, including endoplasmic reticulum, nuclear membrane and mitochondrial electron transport systems, plasma membranes, and soluble enzymes.

Under physiologic conditions, about 5% of available oxygen is diverted toward a "univalent reduction pathway," in which oxygen gains electrons in a sequential fashion, leading to the formation of free radicals. These free radicals generated in limited amounts under normal aerobic conditions are rapidly neutralized by intracellular enzymatic free radical scavengers which acts as the natural antioxidant defense. The main components of this defense include cytochrome oxidase, superoxide dismutase, catalase, glutathione peroxidase, vitamin E, and vitamin C. When inadequately controlled, oxygen-derived free radicals are typically cytotoxic by attacking the bi-lipid layer of cell membranes through reactions with unsaturated fatty acid side chains to form lipid peroxides which can decompose in the presence of transition metals, such as iron, to form unstable (and toxic) peroxy radicals. Malondialdehyde, a by-product of lipid peroxidation, can initiate damaging cross-linking reactions in plasma membrane proteins. The hydroxyl radical is particularly reactive and destructive, promoting marked cellular swelling, mitochondrial disruption, and breaks within the sarcolemmal membrane [1]. The hydroxyl radical is especially dangerous if produced in excessive quantities, since there is no effective natural scavenging system for this radical.

Although free radicals are generated during ischemia (particularly through the mitochondrial electron transport system and the arachidonic acid pathway) [2], their production is especially pronounced during reperfusion with the respiratory burst initiated by the sudden increase in oxygen tension [3] and by free radical generation and release by activated neutrophils. The potential for cellular damage is increased by the relative mismatch between free radical generation and availability of natural scavengers such as reduced glutathione, superoxide dismutase, catalase, and peroxidase, which are depleted during ischemia.

Complement activation

Complement plays a central role in the inflammatory response to infection and injury through a series of reactions called the humeral amplification system, consisting of the coagulation, fibrinolytic, bradykinin-kallikrein, and complement cascades. Activation of the complement cascade results in the elaboration of the potent anaphylatoxins C_3a and C_5a, which act as inflammatory mediators by increasing vascular permeability, inducing vascular smooth muscle contraction, mediating leukocyte chemotaxis, and promoting leukocyte adhesion and activation. The alternative pathway of complement is activated by cardiopulmonary bypass (Fig 2) [4] with resultant activation of neutrophils by C_5a. C_5a is a potent neutrophil chemoattractant, and elaboration of C_3bi from the damaged endothelial cell surface induces CD11b/CD18 dependent neutrophil adhesion [5]. Neutrophils further activate complement through the action of protease and oxygen free radicals released from activated neutrophils. Complement is also activated by myocardial protease elaborated from disrupted myocytes and by the interaction between C₁ and damaged mitrochondrial membranes [6]. Complement derived products may also induce left ventricular dysfunction by mechanisms independent of neutrophil activation.

View larger version (17K): [in this window] [in a new window]   Fig 2. Plasma levels of C3a in patients undergoing cardiopulmonary bypass. (Reprinted with permission from Chenoweth DE, Cooper SW, Hugli TE, Stewart RW, Blackstone EH, Kirklin JW. Complement activation during cardiopulmonary bypass. N Engl J Med 1981;304:497–503.)

A central component of the inflammatory response to postischemic reperfusion is the neutrophil, which enters the cardiac vasculature during reperfusion. Leukocyte chemotaxis following myocardial ischemia is facilitated by at least two mediators: complement activation and products of the arachidonic acid cascade. The initial "rolling" of neutrophils along the endothelium is mediated by the selectin adhesion molecules, including E-selectin, L-selectin, and P-selectin (Fig 3). E-selectin is expressed on endothelial cells following stimulation by inflammatory cytokines such as TNF. L-selectin is a leukocyte surface molecule which is rapidly shed after neutrophil activation. P-selectin is stored in platelets and also expressed on endothelial cell surfaces after exposure to various inflammatory mediators. P-selectin may be the most rapidly available adhesion molecule, in that it is stored in cytoplasmic vacuoles (Weibel Palade bodies) and can rapidly reach the luminal surface for activation by exocytosis [7]. C_5a is a potent agonist for P-selectin endothelial surface expression and may play a pivotal role in rapid neutrophil recruitment. Neutrophils express beta 2 integrins, which are surface glycoproteins that contain a common beta 2 chain and one of three separate alpha chains (CD11a, CD11b, or CD11c). Neutrophil activation produces transient upregulation of CD11b/CD18 on the neutrophil surface. Integrins bind to the endothelial intracellular adhesion molecule-1 (ICAM-1) which is the principal ligand for neutrophil CD11b/CD18 (Fig 4) [8]. This binding process between neutrophil and endothelial cell is necessary for neutrophil attachment to the endothelium and subsequent diapedesis. Neutrophil accumulation along the endothelial surfaces may also plug small capillaries and contribute to the no-reflow phenomenon [9].

View larger version (22K): [in this window] [in a new window]   Fig 3. Model of the sequential steps in adhesion of neutrophils to the endothelium and the underlying molecular mechanisms. (Reprinted from Hansen PR. Role of neutrophils in myocardial ischemia and reperfusion. Circulation 1995;91:1872–85 with permission.)

View larger version (41K): [in this window] [in a new window]   Fig 4. Endothelial cells produce and secrete several factors under normal circumstances to maintain the vessel integrity. During ischemia or injury, there is a decrease in the production of nitric oxide and prostacyclin but an increase in the production of endothelin. There is also an activation of leukocytes and an increase in the presence of endothelial adhesion molecules. In reperfusion injury, there is leukocyte adherence, movement through vascular intima, capillary leakage, and production of cytokines, prostanoids, and superoxides that cause further cellular damage, edema, and fluid sequestration. (Reprinted with permission from McMillen MA, Huribal M, Sumpio B. Common pathway of endothelial-leukocyte interaction in shock, ischemia, and reperfusion. Am J Surg 1993;166:557–62.)

View larger version (41K): [in this window] [in a new window]   Fig 5. Schematic representation of important inflammatory mediators with cardiotoxic potential released from activated neutrophils. O2- = superoxide anion; HOCl = hypochlorous acid; H2O2 = hydrogen peroxide; MPO =myeloperoxidase; E = elastase; C = collagenase; LTB4 = leukotriene B4; PAF = platelet-activating factor. (Reprinted from Hansen PR. Role of neutrophils in myocardial ischemia and reperfusion. Circulation 1995;91:1872–85 with permission.)

The cytokine system also contributes to the local inflammatory response. Tumor necrosis factor (TNF) and IL-1 are activated by tissue breakdown and stimulate IL-8 synthesis by endothelial cells. IL-8 is a potent chemoattractant which can induce transendothelial neutrophil migration [12]. These and other mediators promote amplification of the inflammatory response. Other cytokine–endothelial interactions are discussed in the next section.

Endothelial response to ischemia-reperfusion injury

Endothelial cells, which cover the lumenal surface of capillaries, play a pivotal role in reperfusion injury through regulation of vasomotor tone and expression of adhesion molecules (Fig 4). Normally, endothelial cells synthesize several important vasodilators: prostacyclin (also produced by platelets and monocytes), a direct smooth muscle relaxant, and nitric oxide (endothelial derived relaxation factor, EDRF) [13]. ERDF is synthesized by endothelial cells from L-arginine, and prostacyclin is a product of arachadonic acid metabolism. Endothelial cells are also a potent source of adenosine, which promotes vasorelaxation. Endothelial cells also produce an important vasoconstrictor called endothelin, which is generated mainly by injured or ischemic endothelium [14]. Endothelin, a 21 amino acid peptide, has four known isoforms, the first two (ET-1 and ET-2) of which are mainly in peripheral, coronary, and renal vessels. Endothelial cells also produce thromboxane A₂ and angiotensin II, which are potent vasoconstrictors.

As ischemia-reperfusion injury progresses, competing forces promoting vasodilation (with greater local blood flow but also greater damaging neutrophil accumulation) versus vasoconstriction (with decreased local blood flow) yield an unpredictable outcome in the stages when injury is still potentially reversible. Local vasodilation is promoted by production of carbon dioxide, lactate, hydrogen ions, histamine, and adenosine in ischemic tissues; loss of sympathetic neuronal control; and systemic infusion of platelet derived serotonin, histamine released from most cells, kinins released from plasma proteins, and prostaglandins produced by cell membrane phospholipids [8]. Local vasoconstriction is promoted by the increased endothelial production of endothelin; impaired nitric oxide and prostacyclin production; impaired nitric oxide-induced vasorelaxation by oxygen free radicals; systemic catecholamines and angiotensin; decreased lumen size secondary to endothelial cell swelling; and "no-reflow" lesions induced by capillary plugging. The damage is amplified by neutrophil adherence and chemotaxis followed by additional neutrophil migration into the ischemic zone [13].

Injured endothelial cells act as a source of platelet-derived growth factor, and basic fibroblast growth factor, which stimulates smooth muscle proliferation in the media, can be detected within 24 hours of endothelial injury [15]. Smooth muscle cell proliferation is known to be an important component of allograft vasculopathy.

Components of preservation solutions to reduce reperfusion injury

A major advance in organ preservation occurred with the development of a flush and storage solution by Wahlburg, Southard, and Belzer at the University of Wisconsin (UW) for pancreatic transplantation [16] and successfully extended to liver, kidney, heart, and lung preservation. UW Solution (pentafraction, 50 g/L; lactobionic acid, 100 mmol; potassium phosphate monobasic, 25 mmol; magnesium sulfate heptahydrate, 5 mmol; raffinose pentahydrate, 30 mmol; adenosine, 5 mmol; allopurinol, 1 mmol/L; gluthathione reduced, 3 mmol; potassium hydroxide, q.8; soldium hydroxide, adjust to pH 7.4; and water for injection, Qs) is an intracellular based solution (sodium concentration about 20 meq/l) which contains the impermeants lactobionate, raffinose, and pentastarch to prevent cellular swelling, adenosine as a precursor for adenosine triphosphate (ATP) generation during reperfusion, magnesium sulfate to retard calcium influx, glutathione as an antioxidant, and allopurinol to potentially reduce free radical generation. There currently is an extensive clinical experience with UW Solution in heart transplantation for neonates, children, and adults.

Prevention of calcium overload
Maintenance of cell membrane integrity and prevention of cellular swelling coupled with a low ionized calcium concentration in the initial flush solution and reperfusion solution offers the best protection against calcium overload. A potential disadvantage of extracellular flushing solution relates to the likely participation of the Na⁺–Ca⁺⁺ exchange mechanism in the reestablishment of the ionic gradient during the period of ischemia-reperfusion. The high intracellular sodium is exchanged for extracellular calcium promoting accumulation of intracellular calcium. Additional conditions which retard calcium influx include a high magnesium concentration, slightly acidic pH, and the presence of calcium chelators (possibly lactobionate) [17].

Free radical scavengers
Increasingly, initial flush solutions have been designed to include antioxidants for the inactivation of free radicals generated during ischemia and for the provision of scavengers to the intravascular and possibly interstitial compartments that will be available during initial reperfusion.

Reduced glutathione (GSH) is one of the most effective naturally occurring scavengers [18]. GSH is a low molecular weight antioxidant shown to improve recovery when administered as part of the cardioplegia solution or in the reperfusate. Allopurinol has improved myocardial recovery in some experimental preparations, but the antioxidant effects of allopurinal in the human heart may relate to its ability to scavenge hydroxyl radicals rather than through the inhibition of xanthine oxidase, which has a very low concentration in human cardiac muscle.

Preservation of energy substrate
Preservation of ATP levels during ischemia likely translates into greater preservation of membrane integrity. Enhancement of flush solutions with Krebs’ cycle substrate, such as glutamate, has improved ATP preservation in experimental [19] and clinical cardioplegia solutions [20].

Additional strategies to limit reperfusion injury

Role of amino acids during reperfusion
With the onset of ischemia, myocytes undergo conversion from aerobic to anaerobic glycolysis [21] with depletion of L-glutamate (which undergoes deamination to form alpha-ketoglutarate), an intermediate in the Krebs’ cycle which is necessary for oxidative metabolism. The provision of L-glutamate and aspartate to the reperfusion solution improves recovery after cardiac surgery [19] and likely enhances recovery after the prolonged ischemic time in cardiac transplantation.

Prevention of neutrophil-induced reperfusion injury
The modalities for neutrophil depletion or neutralization of neutrophil-induced toxicity are not yet a routine part of clinical myocardial preservation, and their discussion is currently largely experimental and theoretical. The proposed methods of decreasing neutrophil-induced reperfusion injury are: (1) neutrophil depletion, (2) inhibition of complement activation, (3) inhibition of neutrophil adhesion, and (4) inhibition of neutrophil inflammatory mediators. However, several lines of investigation suggest that preventing neutrophil adhesion and diapedesis would provide a major increment in recovery following reperfusion. Filtering of leukocytes (three parallel pall filters) during a 10-minute period of reperfusion in a neonatal piglet heart model [22] provided a further increment in myocardial recovery. Others have also demonstrated benefit with neutrophil filtering during reperfusion [23].

The second major method of decreasing neutrophil-induced reperfusion injury is through prevention of neutrophil adhesion and diapedesis. Effective reduction in neutrophil-endothelial adhesion in experimental models has been reported by inhibition of neutrophil CD11b/CD18 up-regulation by monoclonal antibodies against CD18, pharmacologic blockade of the CD11b/CD18 [24] and administration of acadesine or adenosine [25]. Reduction in postischemic reperfusion injury has also been demonstrated experimentally with monoclonal antibodies against L-selectin, P-selectin [26], and ICAM-1.

Inhibition of complement activation with synthetic soluble complement receptors has been demonstrated in rodent models to decrease neutrophil accumulation in postischemic myocardium. Inhibition of neutrophil inflammatory mediators by inhibitors of elastase, lipoxygenase, cyclooxygenase, and platelet activating factor have all shown promise in experimental preparations for the blunting of neutrophil-induced postischemic injury.

Stein and colleagues have shown experimentally that functional recovery after prolonged (24 hours) myocardial preservation can be importantly enhanced by controlled initial reperfusion with glutamate–aspartate enriched blood cardioplegia and leukocyte depletion after flushing with UW Solution at the time of harvest and storage at 4°C for 24 hours [21]. Functional recovery in a blood perfused working model was improved with either aspartate–glutamate controlled reperfusion or leukocyte-depleted reperfusion, but was superior with the combination of leukocyte-depletion and aspartate–glutamate modified reperfusion (100% recovery in this model).

In summary, current strategies in extended myocardial preservation for cardiac transplantation include the use of flush solutions, storage solutions, and reperfusion conditions aimed at minimizing ischemic injury during the period of harvesting and transport, followed by specific strategies to control the conditions of reperfusion in order to limit the associated inflammatory reaction. Although the current UW Solution represents a major advance in organ preservation, future solutions will add additional components aimed at further modifying the inflammatory response. Clearly, separate reperfusion strategies will focus on inhibition of neutrophil-mediated inflammatory responses.

References

1. Przyklenk K., Whittaker P., Kloner R.A. Direct evidence that oxygen free radicals cause contractile dysfunction in vivo. Circulation 1988;78(Suppl II):II264.
2. Hammond B., Hess M.L. The oxygen free radical system. J Am Coll Cardiol 1985;6:215-220.[Abstract]
3. Gauduel Y., Duvelleroy M.A. Role of oxygen radicals in cardiac injury due to reoxygenation. J Mol Cell Cardiol 1984;16:459-470.[Medline]
4. Chenoweth D.E., Cooper S.W., Hugli T.E., Stewart R.W., Blackstone E.H., Kirklin J.W. Complement activation during cardiopulmonary bypass. N Engl J Med 1981;304:497-503.[Abstract]
5. Marks R.M., Todd R.F., III, Ward P.A. Rapid induction of neutrophil-endothelial adhesion by complement fixation. Nature 1989;339:314-317.[Medline]
6. Rossen R.D., Michael L.H., Kagiyama A., et al. Mechanism of complement activation after coronary artery occlusion. Circ Res 1988;62:572-584.[Abstract/Free Full Text]
7. Wagner D.D. The Weibel Palade body. Thromb Haemost 1993;70:105-110.[Medline]
8. McMillen M.A., Huribal M., Sumpio B. Common pathway of endothelial–leukocyte interaction in shock, ischemia, and reperfusion. Am J Surg 1993;166:557-562.[Medline]
9. Engler R.L., Dahlgren M.D., Peterson M.A., Dobbs A., Schmid-Schonbein G.W. Accumulation of polymorphonuclear leukocytes during 3-h experimental myocardial ischemia. Am J Physiol 1986;2251:H93-H100.
10. Hansen P.R. Role of neutrophils in myocardial ischemia and reperfusion. Circulation 1995;91:1872-1885.[Abstract/Free Full Text]
11. Weiss S.J. Tissue destruction by neutrophils. N Engl J Med 1989;320:365-376.[Medline]
12. Lefer A.M., Tsao P.S., Lefer D.J., Ma X.L. Role of endothelial dysfunction in the pathogenesis of reperfusion injury after myocardial ischemia. FASEB J 1991;5:2029-2034.[Abstract]
13. Yanigasawa M., Kurihara H., Kimura S., et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411-415.[Medline]
14. Ross R., Glomset A. Atherosclerosis and arterial smooth muscle cells. Science 1973;180:1332-1339.[Free Full Text]
15. Belzer F.O., Southard J.H. Principles of solid-organ preservation by cold storage. Transplantation 1988;45:673-676.[Medline]
16. Bernard M., Menasché P., Canioni P., et al. Influence of the pH of cardioplegic solution on intracellular pH, high-energy phosphaates, and postarrest performance. J Thorac Cardiovasc Surg 1985;90:235-242.[Abstract]
17. Menasché P., Pradier F., Grousset C., et al. Improved recovery of heart transplants with a specific kit of preservation solutions. J Thorac Cardiovasc Surg 1993;105:353-363.[Abstract]
18. Kevelaitis E., Mouas C., Menasché P. Poststorage diastolic abnormalities of heart transplants. J Heart Lung Transplant 1996;15:461-469.[Medline]
19. Rosenkranz E.R., Okamoto F., Buckberg G.D., Vinten-Johansen J., Robertson J.M., Bugyi H. Safety of prolonged aortic clamping with blood cardioplegia. II. Glutamate enrichment in energy-depleted hearts. J Thorac Cardiovasc Surg 1984;88:402-410.[Abstract]
20. Gharagozloo F., Melendez F.J., Hein R.A., et al. The effect of amino acid L-glutamate on the extended preservation ex vivo of the heart for transplantation. Circulation 1987;76(Suppl V):V65.
21. Stein D.G., Drinkwater D.C., Laks H., et al. Cardiac preservation in patients undergoing transplantation. J Thorac Cardiovasc Surg 1991;102:657-665.[Abstract]
22. Wilson I.C., DiNatale J.M., Gillinov A.M., Curtis W.E., Cameron D.E., Gardner T.J. Leukocyte depletion in a neonatal model of cardiac surgery. Ann Thorac Surg 1993;55:12-19.[Abstract]
23. Gillinov A.M., Redmond J.M., Zehr K.J., et al. Inhibition of neutrophil adhesion during cardiopulmonary bypass. Ann Thorac Surg 1994;57:126-133.[Abstract]
24. Mathew J.P., Rinder C.S., Tracey J.B., et al. Acadesine inhibits neutrophil CD11B upregulation in vitro and during in vivo cardiopulmonary bypass. J Thorac Cardiovasc Surg 1995;109:448-456.[Abstract/Free Full Text]
25. Weyrich A.S., Ma X.-L., Lefer D.J., Albertine K.H., Lefer A.M. In vivo neutralization of P-selectin protects feline heart and endothelium in myocardial ischemia and reperfusion injury. J Clin Invest 1993;91:2620-2629.
26. Maruyama M., Farber N.E., Vercellotti G.M., Jacob H.S., Gross G.J. Evidence for a role of platelet activating factor in the pathogenesis of irreversible but not reversible myocardial injury after reperfusion in dogs. Am Heart J 1990;120:510-520.[Medline]

This article has been cited by other articles:

				A. S. Wechsler and J. Y. Kresh Of Mice and Men (and Effects of Gene Silencing) Circulation, September 22, 2009; 120(12): 1027 - 1028. [Full Text] [PDF]

				T Kofidis, H Baraki, H Singh, H Kamiya, M Winterhalter, V Didilis, M Emmert, F Woitek, A Haverich, and U Klima The minimized extracorporeal circulation system causes less inflammation and organ damage Perfusion, May 1, 2008; 23(3): 147 - 151. [Abstract] [PDF]

				L. Dvorak, J. Pirk, S. Cerny, and J. Kovar The role of leukocyte depleting filters in heart transplantation: early outcomes in prospective, randomized clinical trial. Eur. J. Cardiothorac. Surg., October 1, 2006; 30(4): 621 - 627. [Abstract] [Full Text] [PDF]

				Y. Lamarche, J. Gagnon, O. Malo, G. Blaise, M. Carrier, and L. P. Perrault Ventilation prevents pulmonary endothelial dysfunction and improves oxygenation after cardiopulmonary bypass without aortic cross-clamping Eur. J. Cardiothorac. Surg., September 1, 2004; 26(3): 554 - 563. [Abstract] [Full Text] [PDF]

				G. Plenz, H. Eschert, M. Erren, T. Wichter, M. Bohm, M. Flesch, H. H. Scheld, and M. C. Deng The interleukin-6/interleukin-6-receptorsystem is activated in donor hearts J. Am. Coll. Cardiol., May 1, 2002; 39(9): 1508 - 1512. [Abstract] [Full Text] [PDF]

				S. C. Stoica, M. Goddard, and S. R. Large The endothelium in clinical cardiac transplantation Ann. Thorac. Surg., March 1, 2002; 73(3): 1002 - 1008. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): James K. Kirklin David C. McGiffin Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kirklin, J. K. Articles by McGiffin, D. C. Search for Related Content PubMed PubMed Citation Articles by Kirklin, J. K. Articles by McGiffin, D. C.