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Ann Thorac Surg 1999;68:1628-1634
© 1999 The Society of Thoracic Surgeons

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Original Articles

Increased temperature reduces the protective effect of University of Wisconsin solution in the heart

^a Cardiac Surgical Research Unit, Baker Medical Research Institute and Alfred Hospital, Melbourne, Australia
^b Department of Cardiothoracic Surgery, Alfred Hospital, Melbourne, Australia
^c Department of Pathology, School of Medicine, University of Auckland, Auckland, New Zealand

Address reprint requests to Dr Rosenfeldt, Baker Medical Research Institute, PO Box 6492, Melbourne, Victoria 8008, Australia

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. The protective effect of University of Wisconsin solution (UW) for hypothermic storage of donor hearts has been demonstrated in the laboratory. However, clinical usage is associated with occasional primary graft failures. We postulated that this could be related to adverse effects of UW on the coronary vasculature during cardiac implantation and rewarming. We therefore assessed recovery of contractile function and coronary flow in rat hearts after cardioplegic arrest using UW compared with St. Thomas’ solution (ST) at 4°C or 25°C.

Methods. Cardioplegia was induced in isolated rat hearts using either UW or ST at 4°C. Hearts were then maintained at 4°C or 25°C. In some hearts, UW at 4°C was used for inducing arrest followed by flushing with ST at 4°C and then rewarming to 25°C. After 40 minutes of arrest, recovery of function and coronary flow were measured. Nuclear track emulsion was used to assess microvascular competence.

Results. Compared with ST–treated hearts, UW–treated hearts showed significant reduction in recovery of function at 25°C (76.2% ± 4.0% versus 25.0% ± 4.1%; p < 0.01) but not at 4°C (88.0% ± 1.6% versus 87.1% ± 2.6%). Recovery of coronary flow in the UW–treated hearts at 25°C was significantly lower than that in the ST–treated hearts at 25°C (71.7% ± 3.0% versus 94.5% ± 6.3%; p < 0.01). At 25°C, microvascular competence was reduced in the UW group compared with the ST group. At 25°C, flushing out UW with ST resulted in greater recovery of function compared with UW throughout (73.4% ± 7.1% versus 25.0% ± 4.1%; p < 0.01).

Conclusions. University of Wisconsin solution provides effective donor heart protection under hypothermic conditions but can be deleterious at warmer temperatures.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
University of Wisconsin solution (UW) provides effective long-term preservation for the pancreas [1], the kidney [2], and the liver [3]. However, it has not achieved widespread application in cardiac transplantation [4]. Previous experimental studies [5–7] have suggested that UW provides myocardial protection comparable or superior to that conferred by St. Thomas’ solution (ST) and Stanford University solution during prolonged hypothermic storage. In contrast, in a rat heart model of hypothermic cardioplegia as used in transplantation, other investigators [8] found that UW was inferior to ST. Some clinical trials [9, 10] also indicated that UW is effective for human donor heart preservation. A higher rate of coronary atherosclerosis associated with the use of UW has been reported [11]. A possible reason for these variable results was suggested by Mankad and colleagues [12], who noted adverse effects of UW on the coronary circulation at 15°C and 20°C but not 4°C.

We postulated that the unfavorable clinical results reported with UW could be explained by the adverse effects it causes at the higher myocardial temperatures (20°C or more) that occur during cardiac allograft implantation. Therefore, in this study using the isolated rat heart, we mimicked the temperatures that can occur clinically during transport and implantation of donor hearts and assessed the efficacy of UW–based myocardial protection at these temperatures compared with that of an ST–based standard.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Sprague-Dawley rats weighing 250 to 300 g were anesthetized with 4% halothane in oxygen and given 200 units of heparin intravenously. The heart was then rapidly excised, mounted on an isolated working heart apparatus, and perfused with modified Krebs-Henseleit buffer gassed with 95% oxygen and 5% carbon dioxide at 37°C. The buffer had the following composition (millimoles per liter): NaCl, 118; KCl, 4.7; MgSO₄, 1.2; KH₂PO₄, 1.2; CaCl₂, 2.5; NaHCO₃, 25; and glucose 11; pH 7.4. After equilibration, hearts were subjected to 15 minutes of Langendorff perfusion and then converted to the working mode for 15 minutes at an aortic pressure of 100 cm H₂O and a left atrial pressure of 15 cm H₂O.

Each heart was rendered globally ischemic by clamping the aortic cannula and immediately arresting the heart by infusing cardioplegic solution through the aortic cannula at a pressure of 100 cm H₂O. The cardioplegic solution used was either UW or ST No. 2. The composition of these solutions is shown in Table 1. Twenty milliliters of cardioplegic solution was infused, and the time to arrest and the time to infuse solution were recorded. The hearts were then subjected to cardioplegic arrest and storage in the cardioplegic solution for 40 minutes at either 4°C or 25°C. Cardiac temperature was measured using a miniature thermocouple inserted into the right ventricular cavity through the pulmonary artery. After 40 minutes, the hearts were reperfused at 37°C with Krebs-Henseleit buffer in the Langendorff nonworking mode for 15 minutes before conversion to the working mode for 15 minutes.

ST 4°C (n = 5): ST infused at 4°C and the heart maintained at this temperature in the same solution throughout the cardioplegic period

UW 4°C (n = 5): UW infused at 4°C and the heart maintained at this temperature in the same solution throughout the cardioplegic period

ST 25°C (n = 10): ST infused at 4°C and the heart then warmed to 25°C by immersion in ST at 25°C to simulate the implantation phase of transplantation

UW 25°C (n = 12): UW infused at 4°C and the heart then warmed to 25°C by immersion in UW at 25°C

UW–ST 25°C (n = 6): heart arrested with UW at 4°C, then flushed with ST at 4°C, and rewarmed by immersion in ST at 25°C.

Physiologic and biochemical studies
Aortic perfusion fluid and coronary effluent were sampled for gas analysis. Systolic, diastolic, and mean aortic pressures and aortic and coronary flow rates were measured and recorded just before cardioplegic arrest and again after 30 minutes of reperfusion.

Work performed (power) was calculated as follows: Power (mJ · s^-1 · g^-1) = (Psys - LAP) x (CF + AF) x 0.0022/wet heart weight (g), where Psys = systolic aortic pressure, LAP = left atrial pressure, CF = coronary flow, AF = aortic flow, and 0.0022 is the factor for conversion to the International System of Units.

Myocardial oxygen consumption (MVO₂) was calculated as follows: MVO₂ (µL O₂ · min^-1 · g^-1) = (PaO₂ - PvO₂) x CF x 0.0315 x heart weight (g), where PaO₂ = partial pressure of arterial oxygen, PvO₂ = partial pressure of venous oxygen, and CF = coronary flow. The factor (0.0315) incorporates Boltzmann’s constant and a factor for conversion to the International System of Units.

To adjust for the differences in oxygen consumption due to differences in cardiac work, the efficiency of oxygen utilization was calculated by dividing the power output by the oxygen consumption, and expressing this as a percentage of the predicted energy equivalent of oxygen, which is 20.97 J/ml O₂.

At the end of the reperfusion working phase, the hearts were freeze-clamped and stored in liquid nitrogen for later extraction of metabolites. Frozen samples were homogenized with perchloric acid and centrifuged. The supernatant was neutralized with potassium hydroxide. The concentrations of adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, and lactate in these extracts were estimated using enzymatic methods [13]. Other samples of the left ventricle were weighed and then dried to constant weight for determination of water content.

All animal experiments were conducted under the guidelines of the National Health and Medical Research Council of Australia. Protocols were approved by the institutional ethics committee.

Morphology and microvascular function
Two nonischemic (control) hearts and 5 postreperfusion hearts (3 UW 25°C and 2 ST 25°C) were fixed by perfusion with 20 mL of 2.5% glutaraldehyde in 0.1 mol/L phosphate buffer (pH 7.4, 318 MOSM) at 37°C and 100 cm H₂O pressure, followed by immersion in the same solution for 10 minutes. To identify competent and incompetent myocardial blood vessels, the hearts were then perfused with 20 mL of 0.1 mol/L phosphate buffer, followed by 3 mL of nuclear track photographic emulsion diluted 1:1 with 0.1 mol/L phosphate buffer, also at 37°C and 100 cm H₂O pressure [14].

These hearts were cooled for 60 minutes at 4°C to solidify the gelatin of the nuclear track photographic emulsion and then cut transversely at 2 mm intervals across both ventricles midway between the apex and the atrioventricular sulcus. The slices were immersed in 2.5% buffered glutaraldehyde until prepared for microscopy. This involved postfixation in 1% osmium tetroxide in 0.1 mol/L cacodylate buffer (pH 7.4), dehydration in increasing concentrations of ethanol, and embedding in resin. Transmural sections 2 µm thick were stained with 1% toluidine blue and examined by light microscopy for histologic abnormalities and to calculate the proportion of competent capillaries in the subendocardial and subepicardial thirds of the left ventricular myocardium.

Statistical analysis
All values are expressed as the mean ± the standard error of the mean. Data in the four primary groups were subjected to two-way analysis of variance followed by multiple comparisons using the Student-Newman-Keuls method to separate the effects of temperature and solution composition. Values obtained before and after arrest were compared using the Student paired t test. To compare the UW–ST 25°C group and the UW 25°C group, the unpaired t test was used. A p value of less than 0.05 was considered to indicate significance.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Physiologic variables
Arrest was more rapid with UW than with ST (8.7 ± 0.4 seconds versus 22.9 ± 1.5 seconds; p < 0.01). However, the infusion time for UW was longer than that for ST (169.5 ± 7.2 seconds versus 77.1 ± 3.8 seconds; p < 0.01). In the hypothermic groups (ST 4°C and UW 4°C), the myocardial temperature remained lower than 4°C throughout the ischemic period. In the other groups (ST 25°C and UW 25°C), myocardial temperature fell rapidly to 4°C when the cardioplegic solution was infused but increased to 25°C within 35 seconds of subsequent immersion in warm cardioplegic solution.

In the 4°C groups, there was no significant difference in the recovery of power between UW and ST. In contrast at 25°C, recovery of power with UW was only one third of the value of ST–treated hearts (p < 0.01) (Table 2; Fig 1). At 4°C, there was no significant change in total coronary flow after 40 minutes of cardioplegia with either ST or UW (see Table 2). However, at 25°C, recovery of coronary flow in UW–treated hearts was significantly less than that in the ST group (p < 0.01) (see Table 2). The recovery to prearrest myocardial oxygen consumption after cardioplegia was similar in both UW and ST groups at 4°C. After arrest at 25°C, recovery of oxygen consumption with UW was significantly less than that with ST (p < 0.01) (Table 3). The efficiency of myocardial oxygen consumption showed a similar pattern. At 25°C, it was significantly impaired in UW–treated hearts (p < 0.01) (see Table 3).

View larger version (18K): [in this window] [in a new window]   Fig 1. Recovery of cardiac function after 40 minutes of cardioplegia with University of Wisconsin solution (UW) or St. Thomas’ solution (ST) at either 4°C or 25°C. In the reflush group (UW-ST), UW at 4°C was used to induce arrest and ST at 4°C, used to flush out UW before warming to 25°C. Recovery rates are expressed as a percentage of preischemic levels. (** = p < 0.01, versus ST group at same temperature; ++ = p < 0.01 versus corresponding value for UW group.)

Myocardial metabolites
Table 4 shows the concentrations of myocardial energy metabolites after reperfusion for the four primary groups of hearts. The levels of adenosine triphosphate in ST–treated and UW–treated hearts at 25°C were lower than for the corresponding groups at 4°C (p < 0.01). The adenosine triphosphate concentration was not significantly different in UW and ST hearts at 4°C. However, after storage at 25°C, the level was lower in the UW group than in the ST group (p < 0.05). Lactate levels were low in the 4°C groups. At 25°C in the ST group, myocardial lactate showed a twofold increase over the corresponding group at 4°C (p < 0.01). In the UW 25°C group, the lactate level had a tenfold increase compared with its 4°C counterpart (p < 0.01).

In the hearts arrested with ST at 25°C, most myocytes in all layers were well stained. In the subendocardial third, however, a few myocytes showed pale staining consistent with glycogen depletion, and a few (0.5%) were pale and swollen, findings indicating a low level of ischemia-reperfusion damage (Fig 2). The blood vessels were patent and structurally normal, and more than 90% of capillaries were competent.

View larger version (160K): [in this window] [in a new window]   Fig 2. Transversely sectioned subendocardial myocytes after 40 minutes of cardioplegia with St. Thomas’ solution at 25°C and reperfusion for 15 minutes at 37°C. The myocytes (M) are uniformly and densely stained, and virtually all of the intervening blood vessels have dilated lumina and contain silver granules (arrows) demonstrating their competence to transmit reperfusate. (Toluidine blue; x770 before % reduction.)

View larger version (138K): [in this window] [in a new window]   Fig 3. Transversely sectioned subendocardial myocytes after 40 minutes of cardioplegia with University of Wisconsin solution at 25°C and reperfusion for 15 minutes at 37°C. The majority of myocytes (M) are pale and swollen, and some contain dense bands (thin arrows) of myofilament (contraction bands). Only two blood vessels (open arrows) were able to transmit reperfusate containing silver grams at the end of the experiment; the remainder (arrowheads) do not contain silver grains. (Toluidine blue; x770 before % reduction.)

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
This study has clearly demonstrated that the efficacy of UW as a cardioprotective agent is markedly temperature dependent, with impaired protection at 25°C compared with 4°C. At 4°C, UW showed protection comparable to that of ST, but with UW at 25°C, arrest and reperfusion were followed by depressed function, decreased coronary flow, and a high myocardial lactate level. Flushing out UW after induction of arrest abolished this detrimental effect. Using the nuclear track photographic emulsion technique, we demonstrated that the loss of protection was associated with a decline in the ability of the microvasculature to adequately reperfuse the myocardium and prevent myocyte necrosis.

Role of temperature
Animal studies from our laboratory [5] and elsewhere [6, 7] have demonstrated the superiority of UW over other solutions for long-term cold storage of the heart. However, the clinical results with UW for donor heart preservation have been variable. Stein and associates [9] showed a slight improvement in preservation with UW compared with Stanford solution. Jeevanandam and co-workers [15] also found a slight superiority of UW over glucose-mannitol solution. Both these studies involved ischemic times of less than 3 hours. On the other hand, Demertzis and colleagues [10] found UW to be no better than ST. Kawai and coworkers [16] also reported no superiority of UW over a potassium-albumin-mannitol cardioplegic solution.

At the Alfred Hospital after our favorable experimental results in rat hearts using modified (starch-free) UW [5], we used modified UW in 6 human donor hearts with ischemic times of less than 4 hours and experienced two fatal primary graft failures and one death from accelerated coronary atherosclerosis in the first year after transplantation. This contrasted with our overall experience in more than 300 heart transplantations using aspartate-containing ST with an incidence of primary graft failure of only 6.6%.

It was difficult to reconcile the unfavorable clinical experience with UW for heart preservation with the favorable laboratory results. A likely explanation is the differing myocardial temperatures in the two situations and the effect this could have on the action of UW. Most laboratory studies of UW have been conducted using profound hypothermic conditions throughout, whereas in clinical practice, myocardial temperature usually increases during implantation of the donor heart because efficient topical cooling is difficult to achieve at this phase of the procedure. In our experience, during donor heart implantation, the myocardial temperature gradually increases to around 23°C. Prompted by clinical concerns about UW for human donor heart preservation, du Toit and associates [17] reported recently that in rat hearts under normothermic conditions, the high potassium level in UW causes depression of mechanical function and ischemic contracture.

Potentially deleterious effects of UW
Myocardial function and coronary flow were both markedly reduced by UW at 25°C. The lower coronary flow rate could be a result of the reduced work output of damaged myocytes. However, the much higher lactate concentration in these hearts indicated that myocardial ischemia (inadequate microvascular function) rather than reduced oxygen demand caused by primary myocyte damage was responsible. University of Wisconsin solution contains 125 mmol/L of potassium and 35 mmol/L of sodium, which is similar to the intracellular concentration of these ions. This solution was designed to be beneficial for long-term cold organ storage by reducing the energy requirement for maintaining ionic gradients across the cellular membrane when membrane ion pumps are inhibited by hypothermia [18].

However, in studies done with normothermic conditions, hyperkalemic solutions have long been recognized as being deleterious to the vascular endothelium [19]. Mankad and coworkers [7] showed that UW could cause endothelial dysfunction at 15°C and 20°C but not at 4°C in the rat. They suggested that a reduction in basal and stimulated nitric oxide release at the warmer temperatures was a factor contributing to UW–induced coronary vasoconstriction. In human endothelial cell culture preparations at normothermia, Von Oppell and associates [20] found that solutions of an intracellular type (Collins and UW) were cytotoxic, whereas ST was not. However, in the same preparations at 4°C to 10°C, UW and Collins solution were associated with improved cell survival compared with ST. The detrimental effects of UW on the vascular endothelium under normothermic conditions were found to be due to the low sodium and low chloride content of UW as well as its high potassium content.

Apart from its action on the endothelium, UW may have a direct constrictive effect on coronary vascular smooth muscle. Both a high potassium concentration [21] and a low sodium concentration [22] contribute to coronary vasoconstriction. It has been demonstrated that coronary vasoconstriction induced by Collins solution can be reduced by decreasing the potassium level or increasing the sodium concentration [23]. Although UW does not contain calcium, there is sufficient calcium present in the coronary vasculature and the interstitial space for Na⁺-Ca²⁺ exchange when UW is infused. Hypothermia can retard or prevent calcium transit across the cell membrane, whereas under warmer conditions, the phase transition in the membrane lipids toward a more liquid state results in an increase in Ca²⁺ permeability [24].

Morphologic findings
Our histologic findings, although taken from a small sample of hearts (3 receiving UW and 2 receiving ST), were consistent with those of previous studies that defined the contribution of ischemia and reperfusion to myocyte injury and microvascular dysfunction in general [14] and to failure of cardioplegic protection [25]. Although structural damage to endothelial cells was not evident, microvascular function was clearly compromised in those hearts that failed to recover adequate function.

Strategies to avoid deleterious effects of UW
Low-potassium UW
To avoid the adverse effects of standard UW in the heart, Drinkwater and colleagues [26] have advocated the use of a low-potassium UW. In isolated neonatal pig hearts, they found low-potassium UW to be comparable in efficacy to standard UW. However, in our previous studies in isolated rat hearts, we [5] found the high potassium concentration of UW to be essential for its efficacy. The protective effect of UW was significantly reduced when the potassium concentration was lowered to 30 mmol/L. Therefore we believe that the beneficial effects of the high potassium concentration in the UW solution under hypothermic conditions should be preserved and the deleterious effects at warmer temperatures, avoided.

Reflushing
One strategy to prevent UW–induced damage at warmer temperatures would be to replace the UW with ST before the heart rewarms during implantation. We tested the efficacy of flushing out the UW before rewarming the heart. Flushing out the solution immediately before increasing the myocardial temperature abolished the detrimental effect of UW and resulted in significantly improved functional recovery (see Fig 1). This suggests a possible clinical strategy for avoiding UW–induced damage, that is to flush out the UW before the implantation phase of the transplant procedure.

The efficacy of this approach for another high-potassium preservation solution, Collins solution, was elegantly demonstrated in a study of rat hearts by Toshima and associates [27]. These investigators also showed that recovery was greatly improved by first cooling and arresting the heart with an extracellular cardioplegic solution, then introducing an intracellular type of solution for the prolonged hypothermic storage period, and finally flushing out the intracellular solution with cardioplegic solution 30 minutes before reperfusion. As our study was conducted with asanguineous reperfusate, studies in large animals are indicated to confirm the safety and efficacy of reflushing after UW with crystalloid or blood cardioplegia before this strategy is tried in humans.

Conclusion
University of Wisconsin solution has deleterious effects on both the coronary microvasculature and the myocytes when myocardial temperatures are substantially higher than the hypothermic temperatures usual during donor heart storage and transport. We recommend when UW is used for donor heart preservation that before the heart warms up during implantation, UW be flushed out of the heart by a cold, extracellular, low-potassium cardioplegic solution.

	References

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