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Ann Thorac Surg 2001;72:107-112
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

Backtable heat-enhanced preconditioning: a simple and effective means of improving function of heart transplants

Accepted for publication January 26, 2001.

Address reprint requests to Dr Menasché, Service de Chirurgie Cardiovasculaire B, Hôpital Bichat Claude Bernard, 46, rue Henri-Huchard, 75018 Paris, France
e-mail: ccv-bloc.sec3{at}bch.ap-hop-paris.fr

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Cardiac harvest teams are usually committed to immediately transfer the explanted donor heart into its cold storage solution. We tested the opposite hypothesis that a brief prestorage episode of heat-enhanced ischemic preconditioning could be protective.

Methods. Fifty-three isolated isovolumic rat hearts underwent 4 hours of cold (4°C) storage in the Celsior preservation solution and 2 hours of reperfusion. Control hearts were immediately immersed after arrest. In the 3 treated groups, 2 customized thermal probes were first applied onto the left ventricular free wall of the explanted heart at 22°C, 37°C or 42.5°C for 15 minutes before immersion. Each of the selected temperatures were monitored at the probe-tissue interface by a thermocouple.

Results. Whereas base line end-diastolic pressure was set at 8 mm Hg in all groups, it increased during reperfusion (mean ± SEM) to 28 ± 3, 27 ± 3, 17 ± 1, and 18 ± 2 mm Hg in control, 22°C, 37°C and 42.5°C-heated hearts, respectively (37°C and 42.5°C: p < 0.05 versus controls and 22°C). Slopes of pressure-volume curves featured similar patterns. Likewise, reperfusion dP/dT (mm Hg/s^-1) was significantly lower in control and 22°C hearts (1,119 ± 114 and 1,076 ± 125, respectively) than in those undergoing prestorage heating to 37°C and 42.5°C (1,545 ± 109 and 1,719 ± 111, p < 0.05 and p < 0.01 versus controls and 22°C, respectively). Western blot analysis of LV samples did not demonstrate any upregulation of HSP 72 in either group. Conversely, the involvement of preconditioning was evidenced by the loss of protection in the 42.5°C-heated hearts when, in 2 additional groups, the storage solution was supplemented with either the protein kinase C and tyrosine kinase inhibitors chelerythrine (5 µmol/L) and genistein (50 µmol/L) or the mitochondrial K_ATP channel inhibitor 5-hydroxydecanoate (200 µmol/L).

Conclusions. A brief period of postexplant ischemia with enhancement by topical heating ("backtable preconditioning") could be a simple and effective means of improving the functional recovery of heart transplants.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Both ischemic [1] and pharmacologic [2, 3] preconditioning have been proposed as new strategies for improving recovery of heart transplants. Their clinical applicability, however, has remained plagued with several problems. Thus, an ischemic-type preconditioning stimulus, achieved by a transient period of aortic cross clamping before donor heart arrest, may be difficult to implement in often hemodynamically unstable patients and in the context of a multiorgan procurement. Likewise, pharmacologic preconditioning mimetics have failed to gain wide clinical acceptance. Adenosine has yielded mixed results when used according to a preconditioning protocol [4] and potassium channel openers raise their own concerns as nicorandil is not available in an injectable form (except in Japan), whereas diazoxide may be difficult to handle because of its markedly hypotensive effects.

An alternate means of triggering an endogenous adaptive response is to increase the myocardial content of heat shock proteins (HSPs). These compounds are involved in the proper folding and assembly of macromolecular protein complexes, intracellular protein trafficking and degradation of irreversibly damaged proteins [5]. These mechanisms account for the consistent finding that HSPs enhance cardiac functional recovery from ischemia [6]. However, upregulation of HSPs is usually achieved by whole-body hyperthermia 24 hours before the ischemic episode [7], a protocol which is clearly irrelevant to the clinical practice of heart transplantation.

The present study was therefore designed to assess whether the combination of a brief prestorage ischemic episode with topical heating of the explanted heart could trigger an endogenous cardioprotective pathway which would translate into an improved recovery of function. It was reasoned that if such a protocol was successful, its simplicity should facilitate its clinical acceptance in the context of cardiac transplantation.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Experimental preparation
Fifty-three male Wistar rats weighing 300 to 350 g were used in this study. They were anesthetized with pentobarbital sodium (60 mg/kg IP). After heparinization, the heart was excised and rapidly mounted on a nonrecirculating Langendorff perfusion column. Retrograde perfusion was instituted at a constant pressure of 100 cm H₂0 with ultrafiltered (5 µm pore filter), oxygenated (95% oxygen and 5% carbon dioxide), normothermic (37°C) Krebs-Henseleit buffer solution (pH: 7.3 to 7.4). The pulmonary outflow tract was incised to allow drainage of the coronary venous effluent while the Thebesian flow was drained via a transapical left ventricular catheter. A latex balloon was introduced into the left ventricle through a left atriotomy. Left ventricular pressure was continuously recorded online with a pressure transducer (TSD104, BIOPAC Systems Inc, Santa Barbara, CA) connected to the data acquisition unit (MP100A). Data were then processed with a Power Macintosh 6100/66 computer with AcqKnowledge III software (BIOPAC Systems Inc). Left ventricular developed pressure was calculated as the difference between peak systolic pressure and left ventricular end-diastolic pressure (LVEDP). The first derivative (dP/dT) was calculated with the software. Coronary flow was measured by timed collection of the coronary venous effluent. Left ventricular pacing was instituted at a constant rate of 320 beats/min throughout the control and reperfusion periods.

All rats were cared for in compliance with Principles of Laboratory Animal Care formulated by the National Society of Medical Research and Guidelines for the Care and Use of Laboratory Animals published by the National Institutes of Health (National Institutes of Health publication No. 86 to 23, revised 1985).

Experimental protocol
The hearts were allowed to equilibrate for 15 minutes, after which the left ventricular balloon was inflated to the volume that gave an end-diastolic pressure of 8 mm Hg. Contractile function and coronary flow were then measured in triplicate under these isovolumic conditions. In addition, a left ventricular pressure-volume curve was constructed by incremental inflation of the balloon volume by 0.02-mL aliquots. Two sets of pressure-volume measurements were generated, the first of which was discarded because of small balloon shifts. Zero volume was defined as the point at which the LVEDP was zero.

At the end of the control period, all hearts were arrested with 50 mL of the heart preservation solution Celsior, delivered at 4°C under a pressure of 100 cm H₂0. Hearts were then removed from the perfusion apparatus and allocated to one of the 6 experimental groups (see below). Regardless of the treatment protocol, they were stored for 4 hours at 4°C in plastic containers filled with Celsior solution and surrounded with crushed ice.

On completion of the storage interval, hearts were transferred back to the Langendorff column. The balloon catheter was reinserted into the left ventricular cavity and reinflated to the same volume as during the preischemic period. Hearts were reperfused for 2 hours at 37°C. Reperfusion was started at a pressure of 50 cm H₂0 for the initial 15 minutes, after which it was raised back to 100 cm H₂0. Pacing was reinstituted at 320 beats/min once a regular rhythm had resumed. Isovolumic measurements of contractile indices and diastolic pressure were performed at 60 and 120 minutes of reperfusion. At these time points, 2 pressure-volume curves (the first of which was discarded) were again generated over the same range of balloon volumes as during the preischemic period.

At the end of the reperfusion period, hearts were snap-frozen and stored at -80°C until processing for HSP expression by Western blot analysis.

Immunoblot analysis of HSP 72 expression
The technique has been previously described [8]. In brief, rat left ventricular tissue samples (50 mg) were rapidly powdered, suspended, and homogenized in 500 µL of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) sample buffer containing 20% glycerol, 6% SDS, and 1.4% Tris-HCl (pH 6.8). 2-Mercaptoethanol (10%) was added to the samples and heated at 100°C for 10 minutes. Samples were cooled and centrifuged at 11,000g for 5 minutes. They were then assayed using a Pierce BCA Protein Assay Reagent kit (Pierce & Warriner, Chester, UK) for protein quantification. Eight-percent of bromophenol blue was added to the supernatant and samples were stored at -20°C. A total of 80 µg of proteins were electrophoretically separated on a 12.5% SDS-PAGE gel. Proteins were transferred electrophoretically onto nitrocellulose membranes (Hybond-C, Amersham, Buckinghamshire, UK) overnight at 180 mA at 4°C. Blots were stained with Ponceau solution (Sigma Chemical Co, St. Louis, MO) to confirm normalization of protein loading before blocking. Membranes were blocked in blot buffer (phosphate buffer saline, pH 7.2, containing 0.05% Tween 20 and 0.1% dried milk powder) for 1 hour to block nonspecific binding sites. The membranes were then probed with a primary antibody (mouse monoclonal immunoglobulin G) cross-reactive to HSP 72 (StressGen, York, UK) at 1:1000 dilution for 1 hour followed by three washes in the same buffer as above, but without milk. A rabbit antimouse immunoglobulin G secondary antibody (P260, Dako, Cambridgeshire, UK) at 1:2500 dilution was used for a further 1 hour probing. The filters were then developed using an enhanced chemiluminescence detection system (Amersham).

Experimental groups
The hearts were divided into 6 groups. The control group consisted of hearts that underwent immediate postarrest immersion into the cold storage solution. In the 5 other groups, the heart was removed from the Langendorff apparatus, placed in a Celsior-containing beaker, and 2 thermal probes (see below) were applied onto the anterior left ventricular wall for 15 minutes before the onset of the cold storage period (Fig 1). In one group, the probes were simply kept at room temperature (22°C) to assess whether any effect of the procedure could be mechanically related to the application of the probes. In 2 other groups, the temperature of the probes was increased to 37°C and 42.5°C respectively. In the remaining 2 groups, the temperature of the probes was also raised to 42.5°C but the cold arrest solution was supplemented with either the protein kinase C and tyrosine kinase inhibitors chelerythrine (5 µmol/L) and genistein (50 µmol/L) or with the mitochondrial adenosine triphosphate-sensitive potassium channel (K_ATP) blocker 5-hydroxydecanoate (5-HD, 200 µmol/L). These compounds were only used as additives to the arrest solution, ie, before the heating procedure, and were therefore not included thereafter in the storage medium.

View larger version (46K): [in this window] [in a new window]   Fig 1. Diagram showing the application of the thermal probes on the anterior wall of the left ventricle.

Solutions and drugs
The Krebs-Henseleit buffer was prepared fresh, the day of use, and contained (in mmol/L): NaCl 118; KCl 4.7; MgSO₄ 1.2; NaHCO₃ 25; KH₂PO₄ 1.2; CaCl₂ 2.5, and glucose 11. The Celsior solution (provided by Imtix-Sangstat, Lyon, France) had the following composition: potassium 15; sodium 100; magnesium 13; calcium 0.26; chloride 41.5; histidine 30; glutamate 20; lactobionate 80; mannitol 60, and reduced glutathione 3. Chelerythrine, genistein, and 5-HD were obtained from Sigma Chemical Company.

Statistics
Functional data were compared by 2-factor ANOVA with repeated measures. Intergroup differences were specified by post hoc t test with Bonferroni’s correction for multiple comparisons. Left ventricular compliance curves were assessed by linear regression analysis of LVEDP data to calculate slope. A value of p less than 0.05 was considered significant. Data are reported as mean ± SEM.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Left ventricular diastolic and systolic functions
Base line functional data were not significantly different among the 6 groups (Table 1). After 2 hours of reperfusion, control hearts demonstrated a fourfold increase in LVEDP over preischemic values. Application of the probes at room temperature resulted in a roughly similar degree of contracture. Conversely, prestorage heating to 37°C or 42.5°C yielded postischemic LVEDP values which only increased 2 times over base line levels and were thus significantly (p < 0.05) lower than in nonheated hearts. However, the preservation of LVEDP seen in the 42.5°C-heated group was abolished when heating was preceded by donor heart arrest with the solution containing either the kinase inhibitors or mitochondrial K_ATP blocker. Similar patterns were seen when LVEDP was analyzed in relation to balloon volume. Thus, the base line slopes of the pressure-volume curves were not different among the 6 groups: 586 ± 22, 510 ± 37, 557 ± 38, 495 ± 95, 540 ± 62, and 510 ± 38 mm Hg/mL in control, 22°C, 37°C, 42.5°C, 42.5°C + chelerythrine and genistein, and 42.5°C + 5-HD groups, respectively. After storage, all hearts demonstrated an increase in LVEDP measured at a given balloon volume compared with the corresponding preischemic values. However, the upward shift of the postarrest compliance curves was less pronounced in hearts heated to 37°C and 42.5°C than in those where the probes were kept at 22°C or not used at all (controls). Thus, the slopes of reperfusion pressure-volume curves were increased to 806 ± 63 mm Hg/mL in control hearts and 805 ± 96 mm Hg/mL in hearts exposed to the probes at 22°C whereas they were reduced to 632 ± 34 mm Hg/mL and 618 ± 54 mm Hg/mL in 37°C- and 42.5°C-heated hearts, respectively. Addition of chelerythrine and genistein to the storage solution before heating to 42.5°C resulted in a dramatic loss in compliance reflected by an increase of the pressure-volume slope to 1085 ± 41 mm Hg/mL (p < 0.01 versus 42.5°C). The effects of 5-HD on the curve slope (646 ± 92 mm Hg/mL) were less pronounced than under isovolumic conditions where LVEDP was increased more than 2 times compared with the 42.5°C group (Table 1).

Immunoblot analysis of HSP 72 expression
As shown in Figure 2, there was no evidence for upregulation of HSP 72 over basal expression in any of the experimental groups topically exposed to the probes. In particular, heating to 37°C or 42.5°C failed to induce greater HSP 72 expression than that seen when the probes were kept at room temperature. Overall, these patterns were not different from that yielded by hearts undergoing immediate postarrest storage without an intervening period of probe application (internal controls).

View larger version (7K): [in this window] [in a new window]   Fig 2. Western blot analysis of left ventricular samples. From left to the right are blots from hearts undergoing immediate postarrest storage without any probe application (internal controls, A) and hearts which were topically exposed to the probes at room temperature (B), 37°C (C) and 42.5°C (D). Note a similar basal expression of HSP 72 which is not further upregulated in any group (although some lanes appear darker than others, laser densitometry analysis failed to detect significant differences between blots).

	Comment

Top Abstract Introduction Material and methods Results Comment References

Increasing the myocardial content of HSPs is a strategy which has been shown to accelerate recovery of stunned myocardium [9] and could therefore be relevant to preservation of cardiac allografts. However, aside from gene transfection procedures [10, 11], upregulation of HSPs has usually been achieved by systemic (total body) warming 24 hours before the ischemic episode. In addition to being difficult to implement clinically, this whole-body hyperthermia can have adverse effects, possibly on blood-borne elements, that can outweigh any benefit derived from myocardial HSP synthesis [12]. Conversely, increasing the HSP content by topical heating of the explanted donor heart immediately before its immersion into the cold storage solution would better match the practical constraints of a transplantation procedure. We were encouraged in testing this hypothesis by the results of previous studies demonstrating the feasibility of increasing the myocardial content of HSPs by selective (as opposed to systemic) heating of the heart, either by the application of thermal probes similar to those used in the present study [13] or by coronary perfusion with hyperthermic blood [14] or buffer [15]. Of note, the HSP upregulation reported in these previous studies could consistently be correlated with an enhanced cardioprotection manifest as either a reduction in infarct size [13] or an improvement in postischemic function [14, 15].

Our data diverge from those of these studies in that the significant improvement of function occurring after the heat stress (at 37°C or 42.5°C) was not paralleled by an increased HSP content in any of these 2 groups. A first hypothesis to account for this finding is that the time frame of our experiments (in which reperfusion was limited to 2 hours) was too short for HSP synthesis to become detectable. However, in the porcine [14] and rat [15] models in which hyperthermic (42.5°C) blood [14] or buffer [15] was selectively delivered for 15 minutes before cardioplegic arrest [14] or unprotected global ischemia [15], HSP 71–72 upregulation in myocardial tissue could be demonstrated within 15 [14] to 50 minutes [15] following the heat stress. Alternatively, the hypothermic conditions prevailing during the storage interval could have blocked HSP synthesis. However, several lines of evidence argue against this hypothesis: (a) HSP 71 synthesis triggered by an hyperthermic stimulus has been shown to continue during cold ischemia [16]; (b) In the previously mentioned porcine study [14], the use of hypothermia did not preclude HSP 71 upregulation which increased progressively throughout the period of cold cardioplegic arrest (a more recent study in immature rabbit hearts also shows an increased synthesis of HSP 72–73 after whole-body hyperthermia followed by 60 minutes of normothermic recovery and 2 hours of cold cardioplegia [17]); (c) Likewise, HSP 72 ribonucleic acid messenger has been shown to increase in patients undergoing cold crystalloid cardioplegic arrest [18]; and (d) Cold, by itself, has been identified as one of the stressors that can trigger HSP upregulation [19, 20]. However, in comparing our data with those of previous studies, it should be noted that these experiments have involved selective heating of either nonischemic in situ beating [13] or isolated perfused [15] hearts or of ischemic but in situ hearts [14]. Conversely, in the present study, topical heating was implemented in a totally ischemic, arrested, ex vivo heart. Severe zero-flow ischemia similar to the situation of our explanted hearts during heating has been reported to cause a shutdown of HSP 70 ribonucleic acid messenger expression [21] and, it is therefore possible that the metabolic status of our heated hearts might have altered the extent, nature or kinetics of HSP expression.

Regardless of the reason why improved functional recovery in the 42.5°C-heated group could be dissociated from HSP upregulation, this finding suggests the involvement of an alternate cardioprotective mechanism which we presume to be classic preconditioning. There is now compelling evidence that this pathway involves a coordinated interaction between various kinases and mitochondrial K_ATP channels. Opening of these channels causes an intramitochondrial influx of potassium ions which may attenuate the membrane potential across the inner mitochondrial membrane and consequently decrease the driving force for calcium influx [22] and the related reperfusion contracture. That this chain of events could account for the improved recovery yielded by our 37°C- and 42.5°C-heated hearts is supported by 2 lines of evidence: (a) These hearts demonstrated a dramatic preservation of their postarrest compliance whereas, (b) Protection afforded by 42.5°C heating was completely abolished when the heat stress was preceded by a pharmacologic blockade of either the kinase cascade (chelerythrine and genistein groups) or the mitochondrial K_ATP channels (5-HD group).

The lack of functional improvement in the 22°C shows that neither ischemia nor the local stress induced by probe application were sufficient alone to trigger a cardioprotective response. This response actually required the ischemic stimulus to be ' sensitized by heat, which is consistent with the concept that multiple stressors may have to be simultaneously present to reach the level of protein kinase C stimulation required for triggering cardioprotection [23]. As hypothermia has been shown to increase the threshold for eliciting the infarct-limiting effect of ischemic preconditioning [24], it is sound to postulate that, at the opposite, heat may facilitate the preconditioning pathway to be turned on by the ischemic stress.

Although the results of this study are relatively straightforward, some limitations should be acknowledged. First, the reperfusion period was limited to 2 hours and, as previously discussed, this time frame may have prevented the demonstration of a delayed HSP upregulation. Should such a phenomenon have occurred, it could still not explain the improved functional recovery yielded by heat-stressed hearts during the early reperfusion phase. Nevertheless, additional experiments involving longer reperfusion periods are clearly mandated to ascertain whether the topical thermal stress induces a late HSP response that might be temporally linked to a "second window"-type of protection. Furthermore, the study has been performed in normal rat hearts and, thus, it remains to be determined whether our results are reproducible in other species and in situations where the heart has already incurred some damage as a consequence of brain death. Secondly, the lack of increased expression of HSP 70 does not preclude upregulation of other stress proteins, in particular HSP 27. This protein has been shown to play a major role in stabilizing the actin cytoskeleton [25] and it has recently been shown by Yellon’s group that pharmacologic inducement of the second window of protection with an adenosine receptor agonist is related to the phosphorylation state of HSP 27 in the in vivo rabbit [26]. A possible upregulation of HSP 27 would still be consistent with our findings implicating preconditioning as the primary mechanism of protection since HSP 27 synthesis might be linked to mitochondrial K_ATP channels through channel activation-induced acceleration of respiration rate [27], subsequent production of free radicals and oxidative activation of the kinase cascade. This "backtable" preconditioning has been designed to be simple, inexpensive, and user-friendly. It now requires to be validated in a large animal model of orthotopic transplantation to assess to what extent it might be relevant to the clinical practice of heart, and possibly, other organ transplantation, in particular in the context of prolonged organ storage or marginal donors.

	References

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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): Philippe Menasché Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kevelaitis, E. Articles by Menasché, P. Search for Related Content PubMed PubMed Citation Articles by Kevelaitis, E. Articles by Menasché, P. Related Collections Transplantation - heart