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Right arrow Myocardial protection

Ann Thorac Surg 2002;73:682-690
© 2002 The Society of Thoracic Surgeons

Review

Endothelial damage during myocardial preservation and storage

Alessandro Parolari, MD, PhD*a, Patrizia Rubini, MD, PhDb, Aldo Cannata, MDa,b, Luigi Bonati, MDb, Francesco Alamanni, MDa, Elena Tremoli, PhDc, Paolo Biglioli, MDa

a Department of Cardiac Surgery, University of Milan, Centro Cardiologico, Fondazione Monzino IRCCS, Milan, Italy
b Institute of General Surgery and Organ Transplantation, University of Parma, Parma, Italy
c Department of Pharmacological Sciences, University of Milan, Milan, Italy

* Address reprint requests to Dr Parolari, Department of Cardiac Surgery, University of Milan, Centro Cardiologico, Fondazione Monzino IRCCS, Via Parea, 4, 20138, Milan, Italy
e-mail: alessandro.parolari{at}cardiologicomonzino.it


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Ischemia-reperfusion injury
 Endothelial injury from...
 Mechanical forces in endothelial...
 Endothelial injury from...
 Endothelial injury from...
 Conclusions
 Acknowledgments
 References
 
Preservation and storage techniques represent two major issues in routine cardiac surgery and heart transplantation. Historically, these methods were conceived to prevent ischemic injury to myocardium after cardiac arrest during heart operations. Evidence shows that endothelium plays a critical role in the maintenance of normal heart function after cardiac operation, mainly by controlling the coronary circulation. Methods for preservation and storage, developed initially to protect cardiomyocyte function, may be deleterious for vascular endothelium and compromise myocardial protection. In this review article the present knowledge about endothelial injury secondary to preservation and storage techniques is discussed.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Ischemia-reperfusion injury
 Endothelial injury from...
 Mechanical forces in endothelial...
 Endothelial injury from...
 Endothelial injury from...
 Conclusions
 Acknowledgments
 References
 
Myocardial preservation and storage techniques were initially conceived mainly to protect cardiomyocytes. It is now becoming clear that endothelial cell integrity is critical for myocardial function [1]. Endothelial cell damage can lead to increased capillary permeability and organ edema, to vasospasm after the release of vasoactive compounds, and to microvascular hypoperfusion and early organ dysfunction [2]. In addition, the effects of preservation-related endothelial cell injury in heart transplantation are not limited to early organ dysfunction but may result in late events, eg, graft rejection and chronic transplant arteriopathy [3–5].

The aim of this article is to review data concerning the mechanisms underlying endothelial damage occurring during myocardial preservation and storage.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Ischemia-reperfusion injury
 Endothelial injury from...
 Mechanical forces in endothelial...
 Endothelial injury from...
 Endothelial injury from...
 Conclusions
 Acknowledgments
 References
 
A comprehensive literature search was performed (MEDLINE 1966 to 2000) for English literature pertinent to endothelial damage secondary to cardioplegic preservation and storage techniques, using the following "free text" search string:

[(endothelium OR endothelial) AND (damage OR injury OR trauma OR dysfunction)] AND (cardioplegia OR cardioplegic OR transplant OR storage OR preservation).

In addition, perusal of references of all the relevant papers was performed. The closing date of the search was December 30, 2000.


   Ischemia-reperfusion injury
Top
 Abstract
 Introduction
 Material and methods
 Ischemia-reperfusion injury
Endothelial injury from...
 Mechanical forces in endothelial...
 Endothelial injury from...
 Endothelial injury from...
 Conclusions
 Acknowledgments
 References
 
Ischemia-reperfusion injury to endothelium may occur in each cardiac surgical procedure despite the use of cardioprotective measures, and hypoxic ischemia and reperfusion each contribute to the damage, reperfusion prevailing in the extent of damage.

Ischemia/hypoxia
The hypoxic insult to endothelium caused by heart storage duration does not result in widespread endothelial cell death. Prolonged severe hypoxia, however, somehow affects viability of endothelium in vitro, as the viability of endothelial cells exposed to hypoxic environment varies from 80% [6] to 98% [7] after 24-hour exposure. In addition, up to one fourth of endothelial cells show apoptotic changes during 24-hour hypoxia [8], whereas after 48 hours viability drops to 55% [6].

Other pathways elicited during hypoxia may contribute to endothelial damage, which are reversible when hypoxia is applied for a relatively short time. Among these are (1) reduction of protein synthesis and adenosine triphosphate levels, which results in the depletion of intracellular energy [9]; (2) increase of anaerobic metabolism [7], which causes acidosis, both intracellularly and extracellularly; and (3) increase in the release from endothelium of interleukin-1{alpha}, which promotes the expression of neutrophil adhesion molecules such as E-selectin and intercellular adhesion molecule-1 [10], as well as the release of interleukin-8, a potent chemoattractant [11]. Moreover, hypoxia affects the production of oxygen-derived free radicals also at very low oxygen tensions. The consequent reduction in the availability of tissue antioxidants [12] may cause endothelial cell activation or disruption.

The impairment of endothelial barrier function [7, 13] may thus result in perivascular and tissue edema with consequent alterations in the distribution of cardioplegic or storage solutions, as well as reduction of coronary flow after reperfusion, promoting graft dysfunction. In addition, hypoxic endothelial cells expressing a procoagulant phenotype trigger microvascular thrombosis, an event that is exacerbated by reperfusion (Fig 1).



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  		Fig 1. Effects of ischemia on the procoagulant phenotype of the endothelial cell. (ADO = adenosine; AT-III = antithrombin III; GAG = glycosaminoglycans; NO = nitric oxide; PAF = platelet-activating factor; PAI-1 = plasminogen activator inhibitor-1; PGI2 = prostacyclin; t-PA = tissue plasminogen activator; TBM = thrombomodulin; TFPI = tissue factor pathway inhibitor.)

 
Reperfusion
When blood flow and oxygen delivery to myocardium are restored after ischemia, the damage to endothelium markedly increases and often becomes irreversible because of the occurrence of the so-called oxidative stress. A burst of free radicals occurs 15 seconds after the onset of reperfusion [14]. They induce a generalized damage to vascular endothelium, increasing the biosynthesis of vasoactive lipids such as platelet-activating factor. This phospholipid derivative activates both vascular endothelium and blood cells, eg, platelets and leukocytes, thus amplifying the inflammatory reaction [15]. Consequent to endothelial injury is recruitment and adhesion of neutrophils, which peaks within 2 to 3 hours after reperfusion. Activated neutrophils release oxygen-derived free radicals and proteolytic enzymes, which destroy viable cells as well as extracellular matrix. These processes result in the break down of the barrier function of the endothelium and lead to swelling and functional impairment of both endothelium and cardiomyocytes [16].

It has been recently reported that in nonpreconditioned reperfused myocardium, an overwhelming oxidative stress results in the activation of the transcription factor nuclear factor-kappa B (NF-{kappa}B) from cytoplasm to the nucleus through a specific mechanism (tyrosine phosphorylation of I{kappa}B{alpha}) [17, 18]. This transcription factor binds to specific sequences present in the promoter regions of a variety of proinflammatory, procoagulant, and vasoactive genes, thus contributing to ischemia-reperfusion injury [19]. This activation pathway elicited by oxidative stress consequent to ischemia-reperfusion recognizes a different activation mechanism with respect to other stimuli such as infection and inflammation (serine phosphorylation of I{kappa}B{alpha}) [17, 20]. Therefore, the modulation of this event is theoretically possible without interference with other protective endothelial responses. Nuclear factor-kappa B activation, however, does not always induce detrimental effects to endothelium: it has been reported that an oxidative stress of mild entity, such as during preconditioning, induces NF-{kappa}B–dependent transcription of antiinflammatory and antiapoptotic proteins with cytoprotective effects [19]. Thus, NF-{kappa}B seems to be a convergence point between different intracellular pathways of endothelial activation in ischemia-reperfusion injury.

Finally, during this process the balance between vasodilation and vasoconstriction markedly shifts toward vasoconstriction, which adds a further ischemic component to reperfusion injury, as shown in Figure 2.



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  		Fig 2. Imbalance between vasodilation and vasoconstriction after ischemia-reperfusion injury in coronary vessels. (eNOS = endothelial nitric oxide synthase; NO = nitric oxide.)

 

   Endothelial injury from hypothermia
Top
 Abstract
 Introduction
 Material and methods
 Ischemia-reperfusion injury
 Endothelial injury from...
Mechanical forces in endothelial...
 Endothelial injury from...
 Endothelial injury from...
 Conclusions
 Acknowledgments
 References
 
The current strategies for heart preservation and storage during cardiac operations primarily involve the slowing of myocardial metabolism with hypothermia. It should be noted that hypothermia theoretically exerts protective effects by limiting the increase of permeability induced by hypoxia in cultured endothelial cells [21], and by delaying endothelial cell activation [22, 23]. There are several potentially deleterious effects, however, induced by hypothermia. First, hypothermia is not sufficient to induce a full metabolic standstill, as some degree of metabolic activity is detectable even at 4°C. Consequently, hypothermic tolerance to ischemia is time-limited and inversely related to temperature. Hypothermia reduces oxygen consumption and high-energy phosphate depletion, which is essential for cell viability [24, 25], and delays the occurrence of degradation or disruption of endothelial cell structures. The rate of reparative processes, however, is also impaired, as well as the extent of adenosine triphosphate–generating reactions. The activity of ionic pumps is markedly lowered, and this facilitates the loss of transmembrane ionic gradients: sodium and chloride flow into the cell down a concentration gradient, increasing intracellular osmolarity and promoting endothelial swelling [25]. The increased intracellular sodium concentration reverses sodium/calcium antiport, lowering the intracellular sodium concentration through an increase of extracellular calcium influx [26]. This increases endothelial sensitivity and susceptibility to calcium overload and consequent damage at reperfusion by activation of phospholipases, proteases and endonucleases, and calcium-sensitive adenosine triphosphatases, and by uncoupling oxidative phosphorylation [27].

One of the potential benefits of hypothermia already described is the temporary inhibition of the expression of proinflammatory genes involved in endothelial activation (eg, leukocyte-specific adhesion molecules and tissue factor) both in vitro [22] and in vivo [28]. This effect, however, fades away at rewarming [22, 28]. In addition, the temporary inhibition of endothelial cell activation pathways induced by hypothermia does not affect NF-{kappa}B [23], the final common pathway in endothelial cell activation caused by a variety of noxious stimuli; thus, some degree of endothelial activation can theoretically take place even during hypothermic storage.

Morphologic studies suggest that endothelial cells tolerate short-term (3 hours) storage at 4°C [29]. Prolonged hypothermic storage, however, both in culture medium and in preservation solutions, causes an increased fusion of microvilli, with consequent blebbing of the plasma membrane, chromatin condensation and margination, ruffling of the nuclear membrane, and DNA fragmentation, ultimately leading to loss of cell-to-cell connections and to cell detachment [29, 30]. The presence of blebbing as a prominent ultrastructural feature observed on plasma membranes and of nuclear fragmentation suggests apoptosis as the most likely mechanism responsible for hypothermic endothelial injury and cell death.


   Mechanical forces in endothelial injury
Top
 Abstract
 Introduction
 Material and methods
 Ischemia-reperfusion injury
 Endothelial injury from...
 Mechanical forces in endothelial...
Endothelial injury from...
 Endothelial injury from...
 Conclusions
 Acknowledgments
 References
 
The endothelium is directly exposed to various types of biomechanical stimuli resulting from pulsatile blood flow. These stimuli include fluid shear stress and hydrostatic pressure. Biomechanical forces are sensed by endothelium, modulating both structure and function of endothelial cells. Biomechanical forces induce the release of cytokines, growth factors, nitric oxide, or hormones. They increase vascular permeability, the expression of leukocyte adhesion molecules, monocyte recruitment, and lipoprotein accumulation and modulate endothelial cell proliferation and repair [31]. Flow-sensitive receptors transduce mechanical stress into the nucleus through distinct signaling cascades, eventually inducing gene transcription. These processes are regulated by the activation of several transcriptional factors, including NF-{kappa}B, which bind to shear stress–responsive elements within promoter regions of genes responsive to biomechanical forces (platelet-derived growth factor A and B, transforming growth factor-ß, and vascular cell adhesion molecule-1).

Biomechanical forces experimentally applied to endothelium induce structural changes of both cell surface topography and intracellular architecture. Exposure of endothelium to shear stress promotes gross modification of cell shape and orientation, caused by the rearrangement of cytoskeleton [32]. Shear stress–induced changes in cell shape alter endothelial barrier function. Indeed, this process requires the partial disassembly and reassembly of the adherens junctions, a cadherin-based protein complex that mediates cell–cell adhesion. Reassembly is completed within 24 to 48 hours after shear stress is imposed. Moreover, endothelial cells may exhibit discontinuous adherens junctions under steady-state shear stress. Disassembly of junctions increases endothelial cell permeability with the consequent reduction of barrier function observed at vascular sites exposed to shear stress [33].

During cardiac operation, in addition to shear stress, the endothelium of coronary arteries is exposed to infusion pressure of solutions used for preservation and storage. As almost all experimental studies have been necessarily performed on whole hearts, the effect of infusion pressure on endothelium cannot be discriminated from that occurring in the overall vessel wall. Existing evidence, however, suggests that excess infusion pressure of cardioplegic solutions, as well as overdistension of vein grafts, during coronary surgical procedures may induce endothelial damage, which in turn may contribute to poor postischemic myocardial recovery [34–36]. In vivo experimental studies performed by intermittently infusing cold crystalloid cardioplegic solutions show that an infusion pressure of 75 mm Hg exerts better myocardial protection than one of 175 mm Hg, even when they are infused for long time periods [37]. In addition, coronary flow recovery at reperfusion is better with infusion pressures ranging from 70 and 110 mm Hg compared with those at 22 and 175 mm Hg [38]. During heart storage, arterial autoregulation is inhibited, and this renders more critical the infusion pressure [39]. Moreover, high potassium concentrations may be better tolerated if the perfusion pressure is low and the time of exposure is short [34].

In addition, some studies have documented that it is possible to increase the time of heart storage by continuous infusion of storage solutions in the graft. Also, in these conditions good heart protection occurs in a defined range of infusion pressures, and protection is progressively lost for infusion pressures over or under such a range [40, 41].

Thus, these studies suggest that infusion pressure and hence presumably the rate of flow affect optimal myocardial or graft preservation. Moreover, the infusion pressure is critical, as high or extremely low pressures may be detrimental to endothelium, thus reducing cardiac protection.


   Endothelial injury from preservation solutions
Top
 Abstract
 Introduction
 Material and methods
 Ischemia-reperfusion injury
 Endothelial injury from...
 Mechanical forces in endothelial...
 Endothelial injury from...
Endothelial injury from...
 Conclusions
 Acknowledgments
 References
 
Organ preservation solutions can be classified as extracellular (nondepolarizing) or intracellular (depolarizing) depending on ionic composition: extracellular solutions contain 70 mEq/L or greater sodium, whereas solutions with sodium concentration less than 70 mEq/L sodium are defined as intracellular type.

At least 167 different types of preservation solutions for heart preservation are currently used in the United States [42]. Data, however, in favor of one preservation solution with respect to the others in clinical practice are still lacking. Also, the potential clinical benefits of intracellular solutions can actually be equated by extracellular formulations when the latter are supplemented with impermeants. In a study performed on 9,401 patients receiving transplants between 1987 and 1992 in the United States, the risk of early mortality after heart transplant was reported to be lower when the donor heart was preserved with intracellular solutions [42]. This study, however, was biased by the fact that extracellular St. Thomas II/Plegisol (ST) solution was also used, which can be inappropriate for cold storage because it does not contain impermeants.

The use of preservation and storage solutions, either intracellular or extracellular type, however, cannot completely prevent endothelial damage. The majority of studies evaluating morphology and cell viability (Table 1) documents some advantages of the University of Wisconsin solution with respect to other preservation solutions that have been routinely used in the last decade (Bretschneider, Euro-Collins, Stanford, and ST solutions), especially for longer storage times. University of Wisconsin solution–stored endothelia show improved viability, ultrastructural integrity, and reduced cell apoptosis, separation, or detachment. Evidence about Celsior solution, recently introduced in clinical practice, is still scarce. A study from our group documented that hypothermic exposure and reperfusion of cultured endothelium to Celsior and University of Wisconsin solutions provide similar postexposure viability rates, which are substantially higher with respect to Euro-Collins and ST solutions (A. Parolari, unpublished data). University of Wisconsin and Bretschneider solutions spare some functional properties of the endothelium to a greater extent with respect to Euro-Collins or ST solutions (Table 2). There is still some debate, however, about the capability of University of Wisconsin solution to completely maintain endothelium-dependent vasodilation. Optimal preservation of endothelium-dependent relaxation with University of Wisconsin solution [51, 66] has been reported, but this finding was not confirmed in other studies [58, 62, 67, 68]. Indeed the relatively high potassium concentration of this solution may represent a limiting factor, and the reduction of potassium from 129 to 25 mEq/L has been shown to preserve endothelial function [63].


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  		Table 1. Endothelial Effects of Storage Solutions: Morphology and Viability Studies

 

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  		Table 2. Effects of Storage Solutions on Endothelium: Functional Studies

 
There is now substantial agreement about the role of potassium in the induction of poststorage endothelial dysfunction. Even potassium concentrations usually present in extracellular preservation solutions can sensibly affect endothelium. Earlier reports documented that potassium concentrations as low as 10 or 25 mEq/L have adverse effects on endothelial-dependent relaxation [69, 70]. Potassium of at least 40 mEq/L can impair prostacyclin production and release [71]. He and colleagues [72–76] have shown that potassium concentrations of at least 20 mEq/L cause selective impairment of endothelium-derived hyperpolarizing factor–dependent relaxation. As the significance of endothelium-derived hyperpolarizing factor–mediated vasorelaxation is becoming increasingly recognized in human arteries, especially in microvessels [77, 78], the impairment of this pathway may be critical by itself as well as when other endothelial-dependent relaxation pathways are impaired (ie, impairment of nitric oxide after ischemia-reperfusion).

Finally, studies from Kevelaitis and associates [79, 80] have shown good preservation of endothelial properties using relatively new Celsior solution, but further studies are needed to confirm this evidence.


   Endothelial injury from cardioplegic solutions
Top
 Abstract
 Introduction
 Material and methods
 Ischemia-reperfusion injury
 Endothelial injury from...
 Mechanical forces in endothelial...
 Endothelial injury from...
 Endothelial injury from...
Conclusions
 Acknowledgments
 References
 
Cardioplegic protection during routine nontransplant cardiac surgical procedures may also cause endothelial damage. Both temperature (10°C to 20°C) and preservation time (usually less than 2 hours) usually adopted during this kind of operation differ from those used for heart transplantation. For these reasons the results and conclusions reached using simulations of transplantation procedures cannot be simply transferred into routine cardioplegic protection, and specific studies are necessary to assess the effects of cardioplegic solutions on endothelium.

Carpentier and coworkers [81] in 1981 evaluated the toxicity of several cardioplegic solutions, documenting that 3-hour incubation of human endothelial cells and fetal fibroblasts with several cardioplegic solutions at 19°C followed by reperfusion with culture medium negatively affects cell viability. In addition, there is a marked heterogeneity in terms of cell toxicity among the solutions tested, and two of the solutions, which still have a widespread diffusion (Bretschneider and ST solutions) preserve cell viability. Marked hypothermic conditions (4°C, those usually achieved during transplant storage), however, worsen the effect of ST solution on endothelial cell viability. Interestingly, Carpentier and associates [81] initially documented that the addition of blood to cardioplegic solutions improves cell viability.

The contribution of ischemia-reperfusion to endothelial dysfunction, in terms of functional changes, is even more important than that of the cardioplegic solutions [82, 83]. In fact, temperatures reached during myocardial protection during routine heart operations (10°C to 20°C) are substantially higher than those reached during heart storage during transplant procedures (4°C).

Other factors, however, may contribute to the occurrence of endothelial dysfunction. As mentioned previously, hyperkalemia (>= 20 mEq/L) impairs endothelial function by affecting endothelium-derived hyperpolarizing factor both in humans and in experimental animals [72–76]. A potassium concentration of 20 mEq/L, however, does not represent a cutoff level for this phenomenon. Factors such as temperature and duration of exposure may both influence the effects of potassium. In fact, cardioplegic solutions containing 16 mEq/L potassium infused for a relatively long time (120 minutes) have been shown to impair endothelium-derived hyperpolarizing factor [84], whereas they have been shown to preserve endothelium-derived hyperpolarizing factor–dependent vasorelaxation when infused for shorter time (< 1 hour) [36].

Addition of either blood or albumin to cold crystalloid cardioplegic solutions improves preservation of endothelium-dependent relaxation [85], and cold blood cardioplegia provides better protection of endothelium-dependent relaxation than crystalloid cardioplegia [86]. Moreover, continuous warm blood cardioplegia infusion is associated with improved preservation of endothelial function with respect to multidose crystalloid cardioplegia (ST solution) after 120 minutes of ischemia [84]. It is not clear by now, however, which type of blood cardioplegia (continuous warm versus intermittent warm or intermittent cold) or which administration protocol has the best performance in improving endothelial preservation.

The protective effects of blood cardioplegia, both warm and cold, on vascular endothelium may derive from the counterbalance of the effects of ischemia-reperfusion, rather than from a reduced toxicity. In fact, blood is a potent inhibitor of oxygen-derived free radicals that may be released on initiation of reperfusion. In addition, soluble O2 from the oxygenated blood may provide an additional amount of oxygen (greater in case of warm cardioplegia) to the cells, thus reducing the ischemic damage. Finally, blood has favorable rheologic features with respect to crystalloid solutions [87]. Similar mechanisms (improved protection from ischemia-reperfusion damage rather than reduced toxicity) may explain the beneficial effects on endothelial function observed with addition of free-radical scavengers [88] or adenosine [89] to crystalloid solutions.


   Conclusions
Top
 Abstract
 Introduction
 Material and methods
 Ischemia-reperfusion injury
 Endothelial injury from...
 Mechanical forces in endothelial...
 Endothelial injury from...
 Endothelial injury from...
 Conclusions
Acknowledgments
 References
 
The endothelium has a pivotal role in the control of the coronary circulation by modulating vascular permeability, hemostasis, leukocyte adhesion, and vascular tone. Therefore, the maintenance of endothelial structural and functional integrity is essential for continuous myocardial supply of oxygen and metabolites.

The available methods of preservation and storage of explanted hearts, and of protection of hearts undergoing routine nontransplant heart operation, specifically designed for cardiomyocytes, have deleterious effects on the endothelium, an effect that may counterbalance their benefits on myocardial protection.

It is now clear that hypoxia-reperfusion, hypothermia, mechanical stress, and exceedingly hyperkalemic (>= 30 mEq/L) cardioplegic solutions exert a variable degree of injury to endothelium, which is strictly dependent on cation concentrations and time of exposure. None of the available preservation solutions has proven to be superior, even if the University of Wisconsin solution exerts a smaller impairment of endothelial integrity compared with the others. Further studies are still required to identify new strategies that display not only myocardium-protective but also endothelium-protective effects, so that we can shift from myocardial protection to cardiac protection.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Ischemia-reperfusion injury
 Endothelial injury from...
 Mechanical forces in endothelial...
 Endothelial injury from...
 Endothelial injury from...
 Conclusions
 Acknowledgments
References
 
This work was supported in part by grants from The Italian Ministry of Health (ICS 49.2/RF97-24 and ICS 030.6/RF00-45) and by a grant from Fondazione Cassa di Risparmio di Parma.


   References
Top
 Abstract
 Introduction
 Material and methods
 Ischemia-reperfusion injury
 Endothelial injury from...
 Mechanical forces in endothelial...
 Endothelial injury from...
 Endothelial injury from...
 Conclusions
 Acknowledgments
 References
 

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