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Ann Thorac Surg 1999;68:1983-1987
© 1999 The Society of Thoracic Surgeons

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II. Surgical Myocardial Protection

Heart preservation for transplantation: principles and strategies

^a Department of Surgery, University of Kentucky College of Medicine, Lexington, Kentucky, USA

Address reprint requests to Dr Jahania, Department of Surgery, University of Kentucky College of Medicine, MN 273, 800 Rose St, Lexington, KY 40536-0084
e-mail: sjahani{at}pop.uky.edu

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

Abstract

While transplantation is a proven modality for the treatment of end stage organ disease, an important determinant of outcome is the adequacy of organ preservation. Currently, heart preservation is limited to 4 to 6 hours of cold ischemic storage, and the effectiveness depends to a great extent on the solution and its temperature. The formulation of the solution is based on three basic principles: (a) hypothermic arrest of metabolism, (b) provision of a physical and biochemical environment to maintain viability of the structural components of the tissue during hypothermic metabolic slowing, and (c) minimization of reperfusion injury. This review presents the physiologic principles underlying the use of hypothermia and the chemical components of preservation fluids, specifically pertaining to preservation of the heart for transplantation. New approaches designed to protect the heart from surgical ischemic-reperfusion injury are presented as well. The object is to survey current strategies and generate insight into new and promising solutions designed to optimize donor heart preservation.

Successful organ preservation is an important component of transplantation and ensures the maintenance of organ viability until implantation into the recipient. Currently, heart preservation for transplantation is limited to 4 to 6 hours of cold ischemic storage, and longer periods of ischemia are known to adversely effect survival [1]. This is in contrast to preservation of the liver, kidney, and pancreas, which have been successfully preserved for 24 to 36 hours although graft function may be transiently compromised. A recent report on the patterns of usage of preservation fluids and related survival revealed that at least 167 different types of preservation fluids are used for heart transplantation in the United States, and their clinical popularity does not depend upon experimental proof of superiority. In most instances, related survival benefits are uncertain [2]. The object of this review is to describe current strategies and generate insight into new and promising strategies for novel solutions designed to optimize donor heart preservation. Improved preservation could lead to more time for immunologic matching of the donor with potential recipients. This, in turn could lead to a reduction in the incidence of rejection and the intensity of immunosuppression needed after transplantation and, ultimately, lower costs of care. Finally, since better preservation could allow longer ischemic times and facilitate distant procurement, the overall donor pool could be increased. This review presents the physiologic basis of two preservation techniques, specifically, continuous cold perfusion and cold ischemic storage.

Continuous cold perfusion

Perfusion storage involves the continuous infusion of a cold preservation fluid through the vasculature of the harvested organ [3]. Modifications of the cold ischemic storage fluids, in view of the unique physiologic environment of the continuous perfusion circuit permit the adaptation of the fluids for this use. Experimental studies have demonstrated the superiority of this method over cold ischemic storage [4, 5]. One study with isolated rabbit hearts documented return of greater than or equal to 93% of left ventricular developed pressure after 24 hours of cold continuous perfusion with modified University of Wisconsin Solution (UW) compared to recovery of only 35% of left ventricular developed pressure after 24 hours of cold ischemic storage [6]. However, the acceptable results with 3 to 4 hours of cold ischemic storage and the logistic difficulties associated with continuous perfusion systems, including cost, limit the use of this method despite strong evidence that this technique provides superior results.

Cold ischemic storage

The cornerstone of cold ischemic storage is hypothermia at 4° to 8°C and the chemical constituents of the fluid. Hypothermia decelerates metabolism and the ionic constituents facilitate rapid cessation of electrical activity. The formulation of the preservation solution is based on three principles: (a) hypothermic arrest of metabolism, (b) provision of a physical and biochemical environment that maintains viability of the structural components of the tissue during hypothermic metabolic arrest, and (c) minimization of the effects of reperfusion injury [7]. Cold storage solutions can be divided into two categories based on the concentration of Na⁺ and K⁺ ions. The addition of impermeants, free radical scavengers, metabolic nutrients, and various acid buffers is designed to minimize the deleterious effects of hypothermia and ischemia. Knowledge of organ-specific metabolic requirements permits customization of the fluids to meet the needs of the specific organ.

Hypothermia does not stop metabolism but it slows biochemical reaction rates and decreases the rate at which intracellular enzymes degrade essential cellular components necessary for organ viability [8]. Most enzymes of hypothermic animals show a 1.5 to 2.0-fold decrease in activity for every 10°C decrease in temperature. This effect is best described by Vant Hoff’s rule and expressed by the equation Q₁₀ = (k₂/k₁)^10/(t2–t1). Hypothermia also retards lysis of organelles like lysosomes that, in turn, release autolytic enzymes that cause cell death. Hypothermia remains one of the most important tools used to preserve organs today.

The main purpose of the ionic ingredients in the preservation fluid is to induce rapid myocardial cellular membrane depolarization by reducing the transmembrane K⁺ gradient. This results in a cessation of cardiac electrical and mechanical activity. Secondarily, it minimizes the flux of intracellular ions down the concentration gradient into the extracellular space. Preservation fluids, which mimic the interior cellular ionic milieu, are called the intracellular type, whereas those with ionic concentrations similar to extracellular fluid are termed the extracellular type. Intracellular preservation fluids have a Na⁺ concentration less than 70 mmol/L and a K⁺ concentration ranging between 30 and 125 mmol/L (Table 1). Examples of intracellular preservation fluids include University of Wisconsin Solution (UW standard), Roe Solution, Collins Solution, and Intracellular Stanford Solution. Extracellular preservation fluids generally have a Na⁺ concentration greater than or equal to 70 mmol/L and K⁺ concentration between 5 and 30 mmol/L. Celsior Solution, Krebs Solution, and St. Thomas Hospital Solution are examples of extracellular type fluids. The benefits of intracellular fluids include rapid cardiac mechanical arrest and less intracellular edema. Several clinical studies report superior results with intracellular solutions over the extracellular type [9]. A retrospective study of 9,401 patients transplanted in the USA between 1987 and 1992 concluded that the adjusted 1-month odds ratio for mortality was less for patients whose donor hearts had been preserved with intracellular solutions [2]. The benefits of intracellular type fluids may be due to their ability to induce more rapid and complete cardiac arrest and prevention of deleterious changes in membrane ionic flux during hypothermia.

While hypothermia and cold ischemic storage delay cell death, certain processes are activated that ultimately can be deleterious to the preserved organ. These include: (a) cellular swelling, (b) extracellular edema, (c) cellular acidosis, (d) depletion of metabolic substrate, (e) reperfusion injury, (f) calcium overload, and (g) endothelial injury. Cooling also reduces glucose utilization, adversely alters intracellular hydrogen regulation and slows tissue oxygen uptake. It induces shift to the left in the hemoglobin-oxygen dissociation curve and thus severely inhibits the ability of hemoglobin to unload oxygen in the hypoxic tissues. Below 12°C, hemoglobin loses its ability to contribute to oxygen delivery [10]. Enzymatic activity of mitochondrial enzymes like adenine nucleotide translocase is reduced as well. This may cause a decline in levels of mitochondrial adenosine diphosphate (ADP) and leads to an abundance of ADP in the cytoplasm. In this compartment, adenylate kinase converts ADP into adenosine monophosphate (AMP) and the net result is a depletion of mitochondrial ATP. This decline in high-energy phosphates compromises the ability of the cell to maintain normal ionic homeostasis.

Cellular swelling
Normally cells are bathed in an extracellular solution high in Na⁺ and low in K⁺. This ratio is maintained by the Na-K ATPase pump, which uses energy (ATP) derived from oxidative phosphorylation in mitochondria. The total intracellular colloid osmotic pressure derived from the intracellular proteins and impermeable anions is about 110 to 140 mOsm/kg. Anaerobic-hypothermic preservation suppresses the Na⁺ pump and decreases the plasma membrane potential. Sodium and chloride enter the cell down the concentration gradient and the water that follows leads to cell swelling. Colloids are added to the preservation solution to generate the same amount of osmotic pressure present in the intracellular compartment and counterbalance the tendency for cell swelling. Impermeants are also used for this purpose and are either saccharides like lactobionate, raffinose, glucose, and mannitol, or anions such as citrate, phosphate, sulfate, and gluconate.

Intracellular acidosis
It is well known that tissue acidosis is deleterious to normal cell function and is related in part to the accumulation of lactic acid due to anaerobic glycolysis. During ischemia, anaerobic glycolysis is stimulated (the Pasteur effect). In addition to the usual pathway for lactic acid production, pyruvate is also metabolized to lactic acid by lactic dehydrogenase (LDH). Lactic acid concentrations of 16 to 20 µmols not only injure cellular organelles but also can activate macrophages. This, in turn, can lead to cytokine production and the initiation of an inflammatory response. Since various LDH isoenzymes are sensitive to pH, efforts at limiting cellular acidosis include the addition of various concentrations of hydrogen ion buffers to the preservation solutions. Glucose is the preferred additive for preservation of organs with the isoenzyme of LDH that is inhibited by low pH. It is not the preferred additive for preservation of other organs where LDH is more active at an acidic pH. Methods to prevent acidosis include the provision of glucose in large concentrations or the addition of hydrogen ion buffers. Hydrogen ion buffers used for cardiac preservation include potassium phosphate, sodium bicarbonate, magnesium sulfate, and histidine.

Extracellular edema
During the process of organ procurement and storage, interstitial fluid accumulation results in extracellular edema. This may occur as a result of excessive hydrostatic force generated during the flushing of the organ vasculature with the preservation solution. This extracellular edema can impede the flow of the flush solution by causing collapse of the capillaries in the tissue. This may also result in an uneven distribution of the preservative fluid. Impermeants like hydroxyethyl starch, and other nontoxic colloids are added to preservation fluids to prevent the accumulation of fluid in the interstitial space by exerting colloidal oncotic pressure in the intravascular space.

Reperfusion injury
When blood flow and the supply of oxygen is reestablished, the availability of oxygen to tissues that have accumulated anaerobic metabolites leads to the production of harmful oxygen free radicals. These free radicals include superoxide anion, hydrogen peroxide, hypochlorous acid, and the hydroxyl radical. The production of free radicals occurs via the hypoxanthine-xanthine oxidase reaction, and can contribute to cell injury by participating in lipid peroxidation, polymerization of mucopolysaccharides, and oxidation of protein sufhydryl groups. These radicals can cross-link membrane proteins, cleave peptide bonds, alter the function of glycosaminoglycans, and promote DNA disruption. In addition, prolonged ischemia can deplete the tissue of protective antioxidants. Administering exogenous antioxidants like glutathione has long been known to play an important role in protecting the ischemic tissue from reperfusion injury. Several preservation fluids include glutathione as a specific additive to limit oxygen free radical injury. Reduced glutathione combines with reactive oxygen species and free radicals to minimize the oxidative injury to tissues. Other antioxidants and free radical scavengers used in various preservation fluids include superoxide dismutase, allopurinol, prostaglandin synthesis inhibitors, and vitamin E (lipid soluble antioxidant). It has been reported that oxygen free radicals derived from white blood cells (WBC) are major contributors to reperfusion injury. One study reported that eliminating leukocytes from reaching the reperfused myocardium could prevent this aspect of reperfusion injury [11]. This suggests that WBC-filtration prior to reperfusing the donor heart could be beneficial in limiting myocardial stunning associated with cold ischemic storage.

Calcium overload
Intracellular Ca²⁺ overload may also play an important role in reperfusion injury. Physiologic levels of [Ca²⁺]i range from approximately 100 nmol/L during end-diastole to approximately 1,000 nmol/L during peak systole. Sustained presence of supraphysiologic levels of [Ca²⁺]i can lead to activation of Ca²⁺-dependent phospholipases and proteases. Normal Ca²⁺ homeostasis is accomplished by several sarcolemmal transport enzymes, and other exchangers and pumps. Return of normal levels of [Ca²⁺]i at reperfusion can be lethal to the cells if the Na–Ca exchanger (which in the normal forward mode exchanges intracellular Ca²⁺ for the extracellular Na⁺) is reversed and accommodates Ca²⁺ influx and Na⁺ efflux. In addition to Ca²⁺ entry via the sarcolemmal Ca²⁺ channels, there is additional influx via the sodium-calcium exchanger. The sarcoplasmic reticulum Ca²⁺ pump, compromised by the lower intracellular ATP levels, may be unable to accommodate the additional excess of Ca²⁺ and diastolic Ca²⁺ levels increase markedly, resulting in Ca²⁺ overload and cellular injury. Several methods have been proposed to minimize Ca²⁺ overload and include the addition of calcium channel blockers and enhancement of endogenous adenosine levels.

Adenosine (Ado) has been extensively studied for its cardioprotective properties and is utilized in heart preservation fluids. This agent is a potent systemic and coronary vasodilator and has been reported to preserve myocardial phosphorylation potential. It has also been suggested to be a scavenger of oxygen free radicals and may inhibit platelet aggregation. Experimentally, addition of Ado to preservation fluids has been shown to improve recovery of explanted animal hearts after cold ischemic storage over extended periods of time. This effect appears to be mediated via activation of the Ado A₁ receptor [12, 13]. Nucleoside transport inhibition has been shown to increase myocardial Ado levels and is associated with decreased release of creatine kinase and lactate dehydrogenase. While the signal transmission pathways involved in the cardioprotective effects of Ado have not been delineated, the mechanism of action may be related to decreased production of oxygen free radials and prevention of Ca²⁺ overload by improved sarcolemmal Ca²⁺ handling.

Endothelial injury
The hyperkalemic composition of intracellular fluids has been reported by several laboratory studies to be detrimental to the functional and structural integrity of endothelial cells [14, 15]. Normally the endothelium synthesizes compounds that induce vascular smooth muscle relaxation. These compounds include endothelium-dependent nitric oxide (EDNO), endothelium-dependent hyperpolarization factor (EDHF), and prostacyclin. Hyperkalemic endothelial injury may reduce EDNO, which is a vasodilator and acts via the cyclic guanosine monophosphate pathway. EDHF is likely a cytochrome P450 monooxygenase metabolite of arachidonic acid and normally causes vascular smooth muscles to relax via Ca²⁺ activated K⁺ channels and prolonged membrane depolarization. Hyperkalemic injury to endothelial cells may inhibit the formation of EDHF. Hyperkalemia also results in the release of tissue plasminogen activator, fibronectin, interleukin-1, nitric oxide, and endothelin, which may be involved in various stages of cold ischemic storage mediated cellular injury. However, a recent study demonstrated that preservation of organs with a typical hyperkalemic solution like UW preserves endothelial and smooth muscle function [16]. This study documented the preservation of both basal and stimulated endothelial release of nitric oxide (NO) after preservation of canine hearts in hypothermic UW solution for 24 hours. Nitric oxide is capable of affecting vascular tone and possesses properties that may be beneficial for preservation of allograft function after cold ischemic storage. It may serve as a scavenger of oxygen free radicals and may prevent platelet aggregation and vascular smooth muscle proliferation [17]. To summarize, preservation of functional endothelium may be just as important as myocardial preservation. The contribution of endothelial injury, to morbidity and mortality, however, as an unwanted side effect of hyperkalemic preservation, remains controversial. Experimental evidence exists to support both sides of the argument. Further experimental and clinical data is required to resolve this controversy.

Opioid agonists and hibernation induction trigger

Several studies have demonstrated that opioid-like agents can impact significantly on the ability of cardiac tissue to tolerate periods of ischemia and hypoxia [18]. Activation of the delta subtype opioid receptors can result in improved functional recovery following ischemia-reperfusion [19]. Delta opioid peptides have also been shown to inhibit beta-adrenergic signaling pathways via G_i/o proteins involved in adenylate cyclase production [20]. This mechanism of action is not unlike that of adenosine and adenosine-like agents that have been implicated in the preconditioning phenomenon. Studies indicate that the interaction between opioid and adrenergic receptors occurs proximal to the point of activation of adenosine-dependent actions on protein kinases involved in the beta adrenergic intracellular signaling pathway [21]. It has also been demonstrated that the ATP-gated potassium channels may play an important role in this mechanism [20]. Opioid receptor activation can exert cardioprotective effects which are similar to ischemic and adenosine-induced preconditioning [22]. In addition, it has been suggested that peptides recovered from the plasma of hibernating animals have opioid-like properties and may enhance the ability of the heart to tolerate ischemic cold storage [19, 23]. These peptides, called hibernation induction triggers (HIT), are thermolabile, protease-sensitive, and nuclease-insensitive proteins that have been reported to induce physiologic changes that mimic hibernation, upon administration to non-hibernating animals. These changes include bradycardia, increased ATP preservation, decreased coronary flow, and decreased oxygen utilization. While the signaling processes involved in these phenomena are not understood, it has been suggested that opioid receptor activation is involved since these peptides are chemically similar to the delta opioid d-Ala2-Leu5-enkephalin (DADLE) and their effects can be attenuated by specific opioid antagonists.

In conclusion, cold ischemic storage is an effective and commonly used method for preserving the human heart for 4 to 6 hours. The cornerstone of this technique is hypothermia and the chemical composition of the preservation fluids. The two main types of preservation fluids can be classified as either intracellular or extracellular based on their ionic composition. Retrospective analysis suggests that intracellular type of fluids offer better preservation and improved survival but deleterious effects over time are observed with both preservative fluid types. Continued efforts to improve organ preservation are needed if consistent effective long-term storage is to be achieved.

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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): Juan A. Sanchez Robert D. Lasley Robert M. Mentzer, Jr Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jahania, M. S. Articles by Mentzer, R. M. Search for Related Content PubMed PubMed Citation Articles by Jahania, M. S. Articles by Mentzer, R. M., Jr