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Ann Thorac Surg 2004;78:1362-1370
© 2004 The Society of Thoracic Surgeons
a University of Maryland School of Medicine and Veterans Affairs Medical Center at Baltimore, Division of Cardiac Surgery, Baltimore, Maryland, USA
b Organ Recovery Systems, Inc, Des Plaines, Illinois, USA
Accepted for publication February 18, 2004.
* Address reprint requests to Dr Poston, Department of Surgery, Division of Cardiac Surgery, N4W94 22 S Greene St, Baltimore, MD, USA 21201
rposton{at}smail.umaryland.edu
Presented at the Fiftieth Annual Meeting of the Southern Thoracic Surgical Association, Bonita Springs, FL, Nov 13–15, 2003.
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Abstract |
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 Top Abstract IntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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METHODS: Dog hearts underwent cold static storage (CS) for 8 hours (n = 8) or 24 hours (n = 2) or CP for 24 hours with cold asanguinous, oxygenated solution (n = 8). Myocardial systolic and diastolic function and oxygen and lactate consumption were assessed at base line, during CP, and after Langendorff blood reperfusion. Base line endothelial function was evaluated by the percentage transcoronary change ([coronary sinus – aorta]/aorta) in myeloperoxidase and by platelet function and coronary flow reserve after 20 seconds of coronary artery occlusion. During CP, the endothelium was assessed by transcoronary protein release and coronary resistance. Edema was assessed by weight gain and histology.
RESULTS: Base line systolic and metabolic functions showed no relation to post-Langendorff function. Compared with CS, CP resulted in a greater recovery in systolic function (87% ± 35% vs 65% ± 15% of baseline; p = 0.05) and a shorter interval required for lactate consumption to exceed production (7.0 ± 6.8 minutes vs 15.0 ± 8.9 minutes; p = 0.06). Endothelial function was heterogeneous: coronary flow reserve, 2.7 ± 0.7; percentage change in myeloperoxidase, –8.4% ± 6.8%; and change in platelet function, 4.3% ± 3.5%, as determined by thromboelastography angle at base line. Protein release during CP for 24 hours was 8.3 ± 7.1 g. Two factors predicted more than 75% systolic pressure generation recovery: use of CP and normal endothelial function (p = 0.05; Fisher's exact test). However, CP led to edema according to histology, weight gain (72 ± 29 g), and impaired diastolic function versus CS (end-diastolic pressure-volume relationship, 1.4 ± 0.4 mm Hg/mL vs 0.8 ± 0.3 mm Hg/mL; p = 0.08).
CONCLUSIONS: Better systolic function despite 16 hours' more preservation than cold storage corroborates the idea that CP supports aerobic metabolism at physiologically important levels. Viability analysis focused on endothelial function and identified organs that were able to tolerate this 24-hour preservation interval.
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Introduction |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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As the donor pool expands to include less-optimal donors at longer procurement intervals, interest in CP has been renewed. My colleagues and I investigated the optimal preservation of dog hearts by using a modified version of CP currently in clinical use to preserve kidneys at our institution. The CP interval was extended in these studies to 24 hours and was followed by reperfusion in an isolated heart (ie, Langendorff) preparation to test the following questions:
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Material and Methods |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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Experimental Procedure
Operation
Anesthesia was induced in the dogs by using intramuscular ketamine sodium 20 mg/kg followed by endotracheal intubation with isoflurane titrated for anesthesia maintenance. An external iliac artery catheter was placed for pressure monitoring and blood draws. Median sternotomy allowed exposure of the heart. Before donor cardiectomy, base line graft function was assessed in situ by using the assays described below followed by IV heparin 300 IU/kg. To arrest the heart, a timed infusion of 1 L of Celsior cardioplegia (Sangstat Corp, Fremont, CA) was initiated at an aortic root pressure of 65 mm Hg by a 16-gauge aortic cannula, with the heart vented through the superior vena cava and right pulmonary veins. After arrest, the hearts were excised in standard fashion and weighed, and biopsy specimens were obtained. Donor blood was harvested in citrate-phosphate-dextrose transfusion bags.
Myocardial Preservation
The excised hearts were pump-perfused or statically stored in iced (0° to 4°C) Celsior solution in 1 of 3 groups: CP for 24 hours (n = 8) or CS for 8 hours (n = 8) or 24 hours (n = 2). The portable perfusion system (Fig 1) included a bubble oxygenator to maintain partial pressure of arterial oxygen between 200 and 400 mm Hg, a pressure-controlled perfusion pump (Organ Recovery Systems, Des Plaines, IL) to maintain a constant 15-mm Hg aortic pressure, and 1 L of asanguinous perfusate (KPS-1; Organ Recovery Systems) enriched with 10 mmol of fructose bisphosphate (Sigma Chemical, St. Louis, MO) [9]. KPS-1 includes CaCl2 0.5 mmol/L, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid 10 mmol/L, KPO4 25 mmol/L, mannitol 30 mmol/L, glucose 10 mmol/L, insulin 10 U, sodium gluconate 80 mmol/L, magnesium 5 mmol/L, ribose 5 mmol/L, hydroxyethyl starch 50 g, glutathione 3 mmol/L, and adenine 5 mmol/L. The osmolarity of this solution was 365 to 375 mOsm. The temperature, coronary flow, and resistance were continually recorded during CP. Coronary arterial and sinus (ie, transcoronary) perfusates were sampled every hour for analyses of metabolic and endothelial status.
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Graft Function
Endothelial Integrity
The inflammatory and coagulant functions of the endothelium were assayed from evaluation of myocardial biopsy samples and transcoronary blood and perfusate samples. Blood samples were serially assessed for transcoronary differences in myeloperoxidase (MPO) and by using fresh whole blood and citrated blood samples. Transcoronary ([coronary sinus – aorta]/aorta) MPO activity, determined by using the guaiacol assay (Sigma Chemical), was used as an indirect indicator of endothelial inflammation [10]. Transcoronary platelet function (
) was assayed by using the thromboelastography angle (TEG-
), determined by the line in the middle of the TEG tracing and the line tangential to the maximum slope of the developing curve [11] (Fig 2). This variable was used to indicate a procoagulant endothelium. Endothelial inflammation was also assessed during pump perfusion by transcoronary total protein and von Willebrand's factor (vWF) release (
). Transcoronary release of protein was determined by a Micro Protein kit (Sigma-Aldrich, St. Louis, MO). The vWF was measured after 4 hours of CP by Western blot with a polyclonal sheep anti-dog vWF/Ag primary antibody at 1:1,000 dilution (Cedarlane Laboratories Ltd, Hornby, ONT, Canada) and quantitatively by enzyme-linked immunosorbent assay (ELISA; vWF/Ag ELISA 96 T; Technoclone, Sydney, Australia). Coronary vasoreactivity was determined by coronary flow reserve (CFR) in response to 20 seconds of occlusion of the left anterior descending artery; hyperemic and base line flow were determined by using a transit time flowmeter (Transonic, Inc, Ithaca, NY). A ratio of 2.5 or greater was assigned as the normal cutoff [12]. Coronary resistance was calculated from the aortic pressure/perfusion flow rate; aortic pressure was held at 65 and 15 mm Hg during cardioplegic arrest in situ and during CP ex vivo, respectively.
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The lack of hemoglobin during CP simplified the equation to 
. The time required for the aortic lactate concentration to equal or exceed that in the coronary sinus was recorded. Myocardial edema formation was assessed by total measured weight gain and percentage wet weight in myocardial biopsy samples before and after CP and after Langendorff reperfusion. In addition, edema was judged on the basis of blinded interpretation of hematoxylin and eosin–stained biopsy specimens.
Left Ventricular Function
Left ventricular pressure was measured by using an intraventricular 9F Millar catheter placed directly through the apex during donor harvest and inside a fluid-filled latex balloon placed across the mitral valve during reperfusion. Rate of systolic pressure generation (dP/dt) was measured at 40 mL of balloon inflation, and the end-systolic pressure-volume relationship was determined at balloon inflations of 10, 20, and 40 mL. Values during reperfusion were expressed as a percentage of the base line. Diastolic left ventricular function was assessed from the end-diastolic pressure to volume ratio. Data were continuously recorded with a Powerlab data-acquisition system (ADInstruments, Inc, Colorado Springs, CO) interfaced with the Millar catheter and flowmeter (Transonic).
Statistical Analysis
Data are expressed as the mean ± standard deviation. Statistical analysis was performed with a statistical software package (InStat 3.05 and Prism 4.0; GraphPad, Inc, San Diego, CA). Student's t tests were used to test differences in variables between groups. Correlations were examined with Fisher's exact test for nonparametric and linear regression for parametric data. Differences were considered to be significant at p less than 0.05.
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Results |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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After excision, CS x 8 hours hearts demonstrated a maximum of 65% ± 15% recovery of base line systolic function during 2 hours of whole-blood reperfusion. Despite a preservation interval that was 16 hours longer, CP x 24 hours hearts demonstrated 87% ± 35% recovery of dP/dt (p = 0.05 vs CS; Fig 3) and showed trends toward significant improvement in the end-systolic pressure volume relationship (3.1 ± 0.8 mm Hg/mL vs 2.4 ± 0.5 mm Hg/mL; p = 0.08). However, CP for 24 hours led to edema (judged by histologic examination) and 72 ± 29 g of weight gain during perfusion (163.4 ± 12.8 g at base line and 235.1 ± 35.8 g after perfusion; p = 0.01). The end-diastolic pressure to volume ratio after reperfusion was impaired after CP for 24 hours compared with CS for 8 hours (1.4 ± 0.4 mm Hg/mL vs 0.8 ± 0.3 mm Hg/mL; p = 0.08). In contrast, the 2 hearts exposed to 24 hours of CS did not demonstrate any appreciable recovery in systolic function (dP/dtmax, 34 ± 54 mm Hg/s; end-systolic pressure-volume relationship, 1.1 ± 0.8 mm Hg/mL) and did not reach the lactate crossover point during the 2 hours of blood reperfusion.
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CS Versus CP: Endothelial Function
In contrast to the myocardial and metabolic variables, endothelial function varied widely at base line (percentage change in MPO, –8.4% ± 6.8%; TEG-, 4.3% ± 3.5%; CFR, 2.7 ± 0.7; coronary resistance during cardioplegic arrest, 0.43 ± 0.3; n = 17). An equally wide distribution of protein (8.3 ± 7.1 g) and vWF (0.08 ± 0.05 U/mg protein; n = 17) release during 24 hours of continuous pump perfusion was also seen. However, no marked difference in any base line variable of endothelial function was seen in the CP x 24 hours versus CS x 8 hours groups.
After whole-blood reperfusion, endothelial function was preserved better in the CP x 24 hours group. Procoagulant and proinflammatory endothelial changes were more evident in the CS x 8 hours group according to the percentage change in MPO (–15.5% ± 5.5% vs –9.9% ± 4.3%; p = 0.04, CS vs CP; n = 8 per group) and TEG- (9.3% ± 3.1% vs 6.1% ± 3.6%; p = 0.05; n = 8 per group). However, postreperfusion CFR (1.2 ± 0.3 vs 1.4 ± 0.5; not significant) and coronary resistance (0.43 ± 0.12 vs 0.48 ± 0.26; not significant) were not different.
Good Versus Poor Recovery After CP: Ventricular and Metabolic Variables
Postreperfusion myocardial function recovery of hearts in the CP group was heterogeneous. Some hearts (CP-A; n = 5) showed good recovery (ie, > 70% of base line dP/dt), whereas others (CP-B; n = 3) showed poor recovery. Postreperfusion metabolic function mirrored the myocardial function during Langendorff reperfusion (oxygen consumption, 95% ± 10% vs 43% ± 12% of base line; 1-hour transcoronary lactate level, +1.7 ± 1.9 mmol/L vs –2.0 ± 1.4 mmol/L for CP-A vs CP-B). There were no base line differences in the maximal venous oxygen consumption, transcoronary lactate, or dP/dt of CP-A versus CP-B. During CP, oxygen consumption during the first 4 hours was appreciably increased for CP-A versus CP-B (233.16 ± 43.9 vs 128.89 ± 13.6 mL of oxygen per 100 g of heart, respectively; p < 0.02; Fig 4). The transcoronary difference in lactate was minimal during all CP time points and was therefore similar between CP-A and CP-B (0.11 ± 0.07 mmol/L vs 0.13 ± 0.11 mmol/L at 24 hours).
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(2.1% ± 2.9% vs 6.8% ± 2.1%; p = 0.05) and base line CFR (2.9 ± 0.8 vs 1.7 ± 0.4; p = 0.05). Although linear correlations were not established, a marked difference was demonstrated on a contingency analysis for CP-A versus CP-B by using normal cutoff values of less than 5 for percentage change TEG- and 2.5 or greater for CFR (Fig 5). Trends toward significance were seen in base line percentage change of MPO (2.3% ± 1.6% vs 5.4% ± 2.1%; p = 0.08). During pump perfusion, CP-A showed less total protein release (Fig 4) and transcoronary vWF on both Western blot (Fig 6) and ELISA (Fig 4). Other than CFR, assays for graft vasoreactivity did not differentiate CP-A from CP-B. Coronary resistance measured during cardioplegic arrest (0.45 ± 0.15 vs 0.42 ± 0.1) showed no significant differences in CP-A and CP-B. Two factors were noticeably associated with a postreperfusion recovery of dP/dt more than 70%: (1) use of CP and (2) "normal" endothelial function, defined as TEG- less than 5%, CFR 2.5 or greater, coronary resistance during CP less than 0.25 mm Hg · s–1 · mL–1, 24-hour protein release less than 5 g, and 4-hour vWF release less than 0.075 U/mg of protein (p = 0.04; Fisher's exact test).
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Comment |
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Still, the results with CP were incomplete and inconsistent. Diastolic function, an important factor in primary graft failure clinically [14], was not well preserved after CP. A third of the hearts developed primary systolic dysfunction despite harvesting from an "ideal donor" with consistently good base line systolic and metabolic function. Although coronary sinus lactate at the end of CP for 24 hours was uniformly low (0.12 ± 0.11 mmol/L), further clearance was evident by a sharp increase in the coronary sinus lactate level on the initial analysis after blood reperfusion of the isolated hearts (4.5 ± 1.7 mmol/L). In addition, transcoronary PO2 differences measured during CP were found to correlate with recovery of systolic function. Taken together, these data likely reflect inhomogeneous tissue perfusion during CP as either a cause or effect of poor myocardial preservation in our study and indict our choice of 15 mm Hg as a suboptimal coronary perfusion pressure—a key determinate of oxygen delivery to the myocardium [15]. Prior studies have used perfusion pressures ranging from 10 mm Hg [16] to 25 mm Hg [17] in attempts to balance oxygen delivery against edema formation. A recent modification of our heart perfusion pump allows pulsatility, which may increase myocardial perfusion compared with nonpulsatile flow [18]. In addition, titration of myocardial perfusion pressure according to an end point of resuscitation such as tissue pH or tissue PO2 may optimize organ preservation, enhance graft viability assessment, and minimize edema.
Although the hearts for this study were obtained from apparently healthy animals, analyses performed at base line and during CP demonstrated a considerable variation in endothelial function that correlated with myocardial systolic recovery after CP for 24 hours. Similar to humans, "healthy" dogs demonstrate a biological variability in inflammatory and coagulation markers, potentially because of prevalent asymptomatic infections such as parvovirus [19], and variability in the their responses to anesthesia and operation. The presence of dysfunctional endothelium in a perfused heart would likely exacerbate the inhomogeneous delivery of perfusate. It has been established that endothelial activation in hearts before procurement markedly influences graft function after ischemia and reperfusion [20]. Organs for clinical transplantation are taken from donors who have experienced brain death, which leads to endothelial activation and further increases the risk of primary graft dysfunction [21]. In addition, CP hearts demonstrated better endothelial function after blood reperfusion than hearts preserved by CS. Early posttransplantation abnormalities in vascular phenotype, as represented by vasoconstrictive [22] and procoagulant [23] endothelium, correlate with chronic graft vascular disease in patients.
Because vascular phenotype is a difficult variable to quantify in the dog model, we chose unconventional assays to determine endothelial activation. Demonstrating endothelial activation on myocardial biopsy or by assaying the release of soluble markers (soluble E-selectin, soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1) requires monoclonal antibodies that are not readily available for the dog. Regional (ie, coronary sinus) activation of platelets [24] and neutrophils [10] is an established surrogate marker of endothelial dysfunction that has been shown to predict poor graft function after kidney [25] and liver [26] transplantation. Although flow cytometry and aggregometry are considered the gold standards for assessing neutrophil and platelet activation, they have remained restricted to the laboratory because of their technical complexity. Whole-blood viscoelasticity measured by TEG provides a clinically meaningful and quantifiable analysis of platelet activity. In preliminary studies, our group has found an increased base line transcoronary change in the angle of TEG- to be a strong predictor of primary graft dysfunction after clinical heart transplantation [27]. MPO is also an established and reproducible assay to measure neutrophil activation. These reasons served as the rationale for us to evaluate transcoronary changes in the TEG and MPO as our method of evaluating coronary activation.
This study used healthy, "ideal" donors as a first step in determining the safety and feasibility of donor heart CP. CS of ideal donor hearts yields an incidence of primary graft dysfunction of less than 2% with a transport time less than 6 hours [1]. The widespread distribution of heart transplantation centers in the United States makes it unlikely that a more prolonged preservation period would be required for an ideal heart. Instead, the future of this expensive and technically demanding technology is with the "extended criteria" donor heart that is occasionally used with good clinical results yet demonstrates an enhanced sensitivity to prolonged cold ischemic times [28]. In multivariate analysis, CP of donor kidneys from extended-criteria donors eliminated the influence of total transport period on posttransplantation clinical outcome [29]. Prolonging the allowable procurement time would also promote donor heart allocation on the basis of human leukocyte antigen matching, which on retrospective analysis demonstrates a long-term survival influence for heart transplantation similar to that seen in kidneys [30].
In addition to the limitations of CP described previously, there were study design factors that restricted our ability to reach definitive conclusions. Although the Langendorff isolated heart preparation is a well-established transplantation simulation, cytokines and other metabolites that accumulate are not easily eliminated from the circuit, and this complicates the evaluation of postreperfusion endothelial function. This likely played a role in the persistent vasodilatory state documented in all grafts during Langendorff reperfusion. Second, the acceptable ranges of normal versus abnormal for the percentage of transcoronary change in TEG- and MPO have not been established. We favored these transcoronary assays given their point-of-care nature. These tests are easy to perform and provide information for immediate decision making while the heart is still being perfused before committing to transplantation. Finally, all conclusions reached in this study should be considered as hypothesis generating, given the low statistical power that resulted from the small number of animals used.
In conclusion, hearts continuously perfused with a cold asanguinous solution for 24 hours demonstrated better recovery of systolic, but not diastolic, function after blood reperfusion compared with a group exposed to 8 hours of CS in Celsior. Before proceeding to clinical trial, further efforts are required to improve the consistency of preservation and minimize potentially toxic edema formation. Unlike CS, CP offers the chance for dynamic assessment of the organ before committing to transplantation. Organ utilization is maximized while recipient risk is minimized with the incorporation of CP into a procurement strategy that objectively screens extended criteria grafts at high risk for primary dysfunction.
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Discussion |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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I think you said you used a nonblood perfusate, and of course you do have a certain amount of edema and diastolic dysfunction. In our studies several years ago, it seemed that addition of blood to the perfusate made a big difference in myocardial edema and diastolic function, even if it wasn't a normal hematocrit, but some addition of blood. Of course, adding blood complicates the issue because then you have to decide where the blood will come from. But I wonder about your ideas about at least some part of blood perfusate.
Finally, I wonder exactly how you plan to use this. It appears that it is not quite so unwieldy that you couldn't transport it all right, but just how will you specifically go about deciding? What if the donor heart, for example, seemed to have poor viability? What steps would you take then as opposed to when it seemed quite viable?
DR POSTON: We used an asanguinous solution in order to perfuse at a temperature (six degrees) which does not depart from our current clinical temperature achieved with cold storage. Blood perfusion increases the perfusion complexity by forcing perfusion at higher temperatures due to the viscosity of blood which therefore requires higher pump flows and pressure. The other issue for blood perfusion is where to get it. While harvesting the blood from the donor would be simple, it would keep the heart in the hostile cytokine environment of the brain dead donor that you mentioned.
Regarding clinical application, this is an FDA-approved pump which is currently being used for preservation of kidneys for transplantation. The University of Maryland and Johns Hopkins kidney transplant divisions, the two biggest users of this technology, apply it towards extended criteria donors. Similar to the kidney docs, I see heart perfusion as a way of getting more aggressive with extended criteria donors that we are currently turning down. A heart with suboptimal ejection fraction would be used more confidently if more objective criteria such as a viability analysis while it is on the pump were available. The kidney grafts used with good pump parameters are functioning quite well despite the fact that the clinical criteria would suggest otherwise.
DR WILLIAM A. BAUMGARTNER (Baltimore, MD): Bob, that was a great presentation and really some very fine work. I, like you, believe this is the Holy Grail of heart transplantation because not only has it the potential of increasing the number of donor hearts that might be available to our patients, but I believe it also might actually ameliorate the accelerated coronary artery disease that occurs because you are going to have better endothelial cell preservation perhaps with this technique.
I had two questions. One, as you know, we have been working with this same system, and we have been impressed that you can almost predict the outcome when you lift that heart out of the device. The edema does provide a way to determine that these hearts don't do as well, and the times that we have seen this happen have been the times where the perfusion pressure has, for whatever reason, changed.
And I just wanted to ask you if you have seen a correlation, and I know you mentioned it in your conclusion slide, but how big of a correlation is it to the amount of edema and the function of your hearts and whether or not it has anything to do with perfusion pressure?
And my second question is, why did you pick eight hours of cold ischemic time as opposed to say what is probably the more average ischemic time that we see around the country clinically, somewhere in the range of hour fours? I really enjoyed the presentation.
DR POSTON: Edema had a clear impact on diastolic dysfunction. But in contrast to your orthotopic transplant model, cardiac edema development during continuous perfusion didn't seem to correlate with systolic function using the Langendorff model. My observations of the perfusion pump and feedback from the staff at Organ Recovery System that manages the heart perfusion is that every heart in my study was maintained at 15 mm Hg throughout the entire preservation interval. It is concerning to hear that there may be technical issues that remain with this pump prototype that causes some inconsistency in this important variable.
The 8 hour time point was chosen because prior Celsior studies have shown that dog hearts are well preserved at this time point.
DR FREDERICK L. GROVER (Denver, CO): I would like to compliment you on a very nice study. The issue of expanding the donor heart pool is very important because of the number of people dying annually on the waiting list. As we progress into the nonheartbeating donor area more and evaluate borderline donors, objective assessment of the organs becomes critically important. I am curious if you have this assessment clinically to evaluate donors? What is your timetable for clinical assessment implementation, and what is the osmolality of your perfusate solution, the content of that, and could you give us some detail on the amount of myocardial edema that occurs?
DR POSTON: This presentation represents preclinical data in anticipation of submitting FDA Investigational Device Exemption (IDE) and Institutional Review Board (IRB) applications prior to investigate clinical use. Approval should be a fairly smooth process given this Organ Recovery Systems pump has already been approved by the FDA for use in kidney transplantation.
Your second question regarding nonheartbeating donors is certainly a key application of the perfusion strategy. We predict that hearts that are irreversibly damaged from warm ischemia are likely going to respond to continuous perfusion differently than those that have reversible damage. How to demonstrate this difference is an area of active investigation in our lab. The perfusion pump provides an avenue to using both nonheartbeating and extended criteria donors that have not previously existed.
The osmolarity was adjusted between 300–350 using mannitol. Edema was quantified using percentage wet weight on biopsy and with total heart weight gained.
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Acknowledgments |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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This article has been cited by other articles:
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  M. J. Collins, S. L. Moainie, B. P. Griffith, and R. S. Poston Preserving and evaluating hearts with ex vivo machine perfusion: an avenue to improve early graft performance and expand the donor pool. Eur. J. Cardiothorac. Surg., August 1, 2008; 34(2): 318 - 325. [Abstract] [Full Text] [PDF]
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= good recovery (CP-A, n = 5); 
= poor recovery (CP-B, n = 3). (Ao = aorta; CP = continuous perfusion; CP-A = hearts that showed good recovery; CP-B = hearts that showed poor recovery; CS = coronary sinus; MVO2 = maximal oxygen consumption; vWF = von Willebrand's factor.)
