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Ann Thorac Surg 1998;66:1991-1997
© 1998 The Society of Thoracic Surgeons

Original Articles

Heat shock improves recovery and provides protection against global ischemia after hypothermic storage

Ashok Gowda, MSa,d, Chunjie Yang, MDa, Gregory K. Asimakis, PhDb, Sohi Rastegar, PhDd, Massoud Motamedi, PhDa,c

a Biomedical Engineering Center, The University of Texas Medical Branch, Galveston, TX, USA
b Division of Cardiothoracic Surgery, Department of Surgery, The University of Texas Medical Branch, Galveston, TX, USA
c Division of Cardiology, Department of Medicine, The University of Texas Medical Branch, Galveston, Texas, USA
d Bioengineering Program, Texas A&M University, College Station, Texas, USA

Accepted for publication June 3, 1998.

Address reprint requests to Dr Motamedi, Jennie Sealy Hospital, Rt D56, University of Texas Medical Branch at Galveston, Room #625, 301 University Boulevard, Galveston, TX 77555


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Improved methods of donor heart preparation before preservation could allow for prolonged storage and permit remote procurement of these organs. Previous studies have shown that overexpression of heat-shock protein 72 provides protection against ischemic cardiac damage. We sought to determine whether rats subjected to heat stress with only 6-hour recovery could acquire protection to a subsequent heart storage for 12 hours at 4°C.

Methods. Three groups of animals (n = 10 each) were studied: control, sham-treated, and heat-shocked rats (whole-body hyperthermia 42°C for 15 minutes). After 12-hour cold ischemia hearts were reperfused on a Langendorff column. To confirm any differences in functional recovery, hearts were then subjected to an additional 15-minute period of warm global ischemia after which function and lactate dehydrogenase enzyme leakage were measured.

Results. Heat-shocked animals showed marked improvements compared with controls in left ventricular developed pressure (63 ± 4 mm Hg versus 44 ± 4 mm Hg, p < 0.05) heart rate x developed pressure (13,883 ± 1,174 beats per minute x mm Hg versus 8,492 ± 1,564 beats per minute x mm Hg, p < 0.05), rate of ventricular pressure increase (1,912 ± 112 mm Hg/second versus 1,215 ± 162 mm Hg/second, p < 0.005), rate of ventricular pressure decrease (1,258 ± 89 mm Hg/second versus 774 ± 106 mm Hg/second, p < 0.005). Diastolic compliance and lactate dehydrogenase release were improved in heat-shocked animals compared with controls and sham-treated animals. Differences between heat-shocked animals and control or sham-treated animals were further increased after the additional 15-minute period of warm ischemia. Western blot experiments confirmed increased heat-shock protein 72 levels in heat-shocked animals (> threefold) compared with sham-treated animals and controls.

Conclusions. Heat shock 6 hours before heart removal resulted in marked expression of heat-shock protein 72 and protected isolated rat hearts by increased functional recovery and decreased cellular necrosis after 12-hour cold ischemia in a protocol mimicking that of heart preservation for transplantation. Protection was further confirmed after an additional 15-minute period of warm ischemia.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Cells exposed to environmental stresses respond by increased synthesis of heat-shock proteins (HSPs) [1, 2]. Accumulation of HSPs in the cell has been shown to provide protection against an otherwise lethal stress condition [3]. Their expression in cardiac tissue has been shown to provide protection against both warm and cold ischemia reperfusion [4–9] and cold ischemic heart transplantation protocols [10–12]. Various forms of stress have been used to induce HSPs in the heart, including ischemia [13], hypoxia [14], hemodynamic overload [15], and hyperthermia (heat shock) [4, 6, 7, 10, 11, 16, 17]. Most of the previous studies using whole-body hyperthermia to induce HSPs have waited 24 to 48 hours after heat shock for accumulation of HSPs before subjecting the heart to ischemia. More recent studies have shown that HSPs can be expressed rapidly in the heart after hyperthermic [9] and hypoxic conditions [18] and that their expression continues during hypothermic cardioplegic storage [5, 19]. Upregulation of endogenous protective mechanisms before organ procurement might result in increased functional recovery after reperfusion. Additionally, hearts protected against cold ischemia could be stored for longer times and therefore the number of donor hearts available for transplantation would increase.

We sought to determine whether isolated hearts from rats subjected to whole-body hyperthermia 6 hours before heart removal and a prolonged hypothermic storage of 12 hours would express HSP72 and be protected from postischemic injury as measured by functional recovery and enzyme release. To confirm any acquired protection observed during reperfusion and to access irreversible cellular injury as measured by lactate dehydrogenase (LDH) washout levels, we tested the ability of these hearts to withstand a subsequent 15-minute application of warm global ischemia.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Experimental groups
Forty-seven male Sprague-Dawley rats weighing 300 to 350 g were divided into three experimental groups, control (n = 15), sham treated (n = 16), and heat shocked (n = 16) (Fig 1). All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985). Heat-shocked rats were anesthetized with ketamine (100 mg/kg) and xylazine (40 mg/kg) given intraperitoneally, then wrapped in a heating blanket while body temperature was monitored by a thermocouple placed rectally. Temperatures were recorded using a computer-based data acquisition system (Omega Engineering, Stamford, CT). Core temperature of heat-treated animals was increased to between 42° and 43°C for 15 minutes. Supplemental hydration was given by subcutaneous injection of 4 to 5 mL of 0.9% saline solution. Sham-treated animals were anesthetized and hydrated similarly while wrapped in the heating blanket but were maintained at normal body temperature (37°C). Control rats did not undergo any treatment. All treated animals were returned to their cages and allowed to recover for 6 hours.



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  		Fig 1. Experimental protocol. Myocardial function (heart rate, developed pressure, rate of ventricular pressure increase, rate of ventricular pressure decrease, and coronary flow were measured at 20 minutes after the initial reperfusion and after an additional 15-minute period of warm global ischemia (n = 10/group). Additional animals were used to evaluate HSP72 expression at 6 hours of recovery (control, n = 2; sham-treated, n = 3; heat-shocked, n = 3), and after 6 hours of recovery and 12 hours at 4°C (control, n = 3; sham-treated, n = 3; heat-shocked, n = 3). (Hr = hours; LDH = lactate dehydrogenase; Min = minutes.)

 
Heart storage
After the 6-hour recovery period, animals were given heparin (5 mg, intraperitoneally) 20 minutes before they were reanesthetized with pentobarbital (25 to 30 mg, intraperitoneally). A median sternotomy was performed and the hearts were rapidly excised and immersed in chilled (4°C) St. Thomas’ cardioplegic solution (concentration: NaCl, 110; KCl, 16; MgCl2, 16; CaCl2, 1.2; and NaHCO3, 10 mmol/L). Hearts were secured to a polyethylene aortic cannula, and a single infusion of 15 mL of cardioplegia solution was used before 12 hours of storage at 4°C (n = 10 per group). Before its use, all cardioplegia solution was filtered through a 0.45-µm filter to remove any particulate contaminants. Additional groups of hearts were sectioned along the intraventricular septum and the left ventricles were snap frozen in liquid nitrogen after 6-hour recovery (n = 2 control, 3 sham treated, and 3 heat treated), or after 6-hour recovery and 12-hour storage at 4°C (n = 3 per group). These hearts were subsequently stored at -80°C before HSP72 analysis.

Perfusion technique
After 12 hours of cold storage at 4°C, hearts were perfused retrogradely with Krebs-Henseleit buffer using a nonrecirculating Langendorff preparation. The concentrations of constituents of the buffer were 4.7 mmol/L KCl, 1.2 mmol/L CaCl2, 1.25 mmol/L MgCl2, 1.25 mmol/L KH2PO4, 25 mmol/L NaHCO3, 118 mmol/L NaCl, and 10 mmol/L glucose. The buffer was filtered through 0.45-µm cellulose filters immediately after preparation to remove any particulate matter. The temperature of the buffer was kept constant at 37°C in a water-jacketed column and gased continuously with a 95% oxygen, 5% carbon dioxide mixture. The perfusion pressure was kept constant at 100 cm H2O.

A small incision was made in the center of the left atrium. An apical stab was made through the left ventricle with a 14-gauge needle to drain any fluid in the ventricle. A latex balloon was then inserted into the left ventricle through the left atrium and tied securely in place. The balloon was connected to a fluid-filled pressure transducer by polyethylene tubing. The pressure transducer was connected to a data acquisition system (Heart Performance Analyzer; MicroMed, Louisville, KY) and interfaced with a personal computer.

Reperfusion protocol
After 12 hours of storage, all hearts were reperfused at 37°C for 20 minutes before baseline recovery hemodynamic data were taken. Balloon volume was adjusted to give an end-diastolic pressure (EDP) of 10 mm Hg, and data consisting of peak developed pressure, EDP, heart rate, and rates of ventricular pressure increase and decrease were obtained. Timed collection of coronary effluent was performed for baseline coronary flow and assessment of LDH release by the enzymatic assay method using an LDH assay kit (Sigma Diagnostics, St. Louis, MO). The absorbance was read at 340 nm using a Kontron Uvicon 860 spectrophotometer (Kontron Instruments, Everett, MA). Diastolic compliance was assessed by measuring the EDP at different balloon volumes. The volume of the balloon was increased in 50-µL increments and data were collected 1 minute after each volume addition. Balloon volumes were incrementally increased until either 300 µL had been added or an EDP of 90 mm Hg had been attained.

Additional warm ischemia
To confirm any protection upon recovery, balloon volumes were emptied and hearts were subjected to an additional 15-minute period of global warm ischemia. At the time of reperfusion, after the 15-minute warm ischemia period, timed collection of coronary effluent was taken each minute for the first 5 minutes and LDH release was assessed as described previously. After an additional 5 minutes of recovery (10 minutes after reperfusion), diastolic compliance was assessed again as before. The experimental protocol was concluded by setting the EDP to 10 mm Hg and assessing functional variables.

Heat-shock protein 72 analysis
Western blot analysis was used to determine the expression of the inducible HSP70 (HSP72) in all myocardial samples. Tissues were weighed and diced into small slices with a razor blade. The slices were thawed in 3 mL/mg of cold lysis buffer and homogenized with a Polytron Homogenizer and stored on ice for 30 minutes. After centrifugation at 15,000 g for 20 minutes at 4°C the supernatant was removed and centrifuged again. Equal amounts of proteins were resolved by electrophoresis on a 0.1% sodium dodecyl sulfate 12% polyacrylamide gel under denaturing conditions. The proteins were transferred electrophoretically to a nitrocellulose membrane. After blocking in 10 mmol/L Tris HCl (pH = 8.0), 150 mmol/L sodium chloride, and 5% (w/v) nonfat dry milk, the membranes were treated with a primary antibody that recognizes the inducible HSP72 (SPA-810 AP, StressGen, Victoria, British Columbia) for 90 minutes, followed by incubation with peroxidase-conjugated secondary antibody for 45 minutes (Kirkegaard & Perry Laboratories, Inc, Gaithersburg, MD). The immunocomplexes were detected using a chemoluminescence reagent kit (Amersham, Arlington Heights, IL).

Statistical analysis
The values for myocardial function and LDH release are expressed as the mean plus or minus standard error of the mean. A one-way analysis of variance was used to test for any differences between groups. If significant differences were established, post hoc analysis using the Bonferroni procedure was carried out. Significance was considered at a p value of less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Figure 2 shows a typical temperature history for animals who had whole-body heat shock as well as the temperature of heated water being circulated through the heating pad. Animals were heated at a rate of approximately 0.2°C/minute. Core temperature reached 42°C within 20 minutes and was maintained for 15 minutes. Animals recovered to normal body temperature 30 minutes after removal from the heating pad. There were no complications resulting from the heating protocol.



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  		Fig 2. Typical core temperature and heating pad temperature recorded from an animal subjected to whole-body heating (heat-shock group). Heat-shocked animals were anesthetized and wrapped in a heating blanket. Temperatures were recorded by a thermocouple placed rectally. Core temperature was increased to between 42° and 43°C for 15 minutes.

 
Table 1 gives functional data observed at reperfusion and after the additional 15-minute period of warm ischemia. There were no statistically significant differences between variables in control and sham-treated groups at either baseline reperfusion or after warm ischemia. Heat-shocked animals, however, demonstrated marked improvements in left ventricular developed pressure, heart rate x developed pressure, and rate of ventricular pressure increase (dP/dt) and decrease (negative dP/dt) compared with controls. These differences were more significant after the 15-minute period of warm ischemia. Although heart rate and coronary flow were higher in heat-shocked animals at both time points, these differences were not statistically significant. Diastolic compliance, as assessed by the slope of the EDP-volume relationships, was improved (less steep slope) in heat-shocked animals but not significantly different compared with both sham-treated and control animals at both time points. Heat-shocked animals had a significant reduction of the x-intercept (shift of EDP-volume curve up and to the left) compared with sham-treated and control animals after the additional period of warm ischemia (Table 1). When diastolic compliance was assessed according to individual end-diastolic pressures for a given balloon volume, significant differences were found between heat-shocked animals and sham-treated or control animals before (Fig 3) and after global ischemia (Fig 4) at all three balloon volumes used to generate linear regressions on EDP versus volume points. Lactate dehydrogenase release was significantly different between control and heat-treated animals at baseline reperfusion and at all time points greater than 1 minute after reperfusion from warm ischemia (Fig 3). Although heat-treated animals showed lower levels of LDH release at all time points measured, there were no significant differences compared with levels measured in sham-treated animals (Fig 5).


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  		Table 1. Postischemic Functional Recovery After 12 Hours at 4°C and 15 Minutes of Warm Ischemiaa

 


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  		Fig 3. End-diastolic pressure (EDP) versus balloon volume for all three groups at baseline reperfusion after cold ischemia (12 hours at 4°C). Heat-shocked animals demonstrated significant differences in EDP at all three balloon volumes between both sham-treated and control groups. (a = p < 0.05 versus sham and control; b = p < 0.005 versus sham and control.)

 


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  		Fig 4. End-diastolic pressure (EDP) versus balloon volume for all three groups after 15 minutes of additional warm global ischemia. Heat-shocked animals demonstrated significant differences in EDP at all three balloon volumes between both sham-treated and control groups. (a = p < 0.001 versus sham and control; b = p < 0.0001 versus sham and control.)

 


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  		Fig 5. Lactate dehydrogenase (LDH) enzyme leakage measured at baseline reperfusion and at 1-minute intervals after the additional warm ischemic period. Enzyme leakage was significantly different at all time points greater than 1 minute measured between heat-shocked and control animals. Although enzyme leakage of heat-shocked animals was lower than that of sham-treated animals at all time points, these differences were not statistically significant. (a = p < 0.05 versus control.)

 
Western blot analysis confirmed increased expression of HSP72 in rats subjected to whole-body hyperthermia in samples of left ventricle tissue taken after 6 hours of recovery and after an additional 12 hours of cold ischemia compared with those of sham-treated and control animals (Fig 6A). Densitometric analysis of immunoblots showed a marked difference in the expression HSP72 between heat-shocked animals and both control groups. There was greater than threefold (p < 0.005) difference between heat-shocked animals and control groups both before and after storage for 12 hours at 4°C (Fig 6B).



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  		Fig 6. (a) Total cell lysates from rat hearts were dissolved on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotted with an antibody specific for HSP72. Study groups above included heat-shocked (1), sham-treated (2), and control (3) animals, with 6 hours of recovery and 12 hours of storage at 4°C, and heat-shocked (4), sham-treated (5), and control (6) animals with only 6 hours of recovery. (b) Bar graphs showing densitometric analysis of autoradiographs from all groups studied. Heat shock followed by 6 hours of recovery (before storage) and 6 hours of recovery and 12 hours of storage at 4°C resulted in a significant difference (a = p < 0.005) when compared with both sham-treated and control groups.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
The present study showed that hearts from rats subjected to heat shock only 6 hours before removal and 12 hours of hypothermic storage demonstrated marked expression of HSP72 and improved recovery of mechanical function in a protocol similar to that of cardiac preservation before transplantation. Our experiments demonstrated improved recovery of developed pressure, heart rate x developed pressure, rates of ventricular pressure increase and decrease, end-diastolic compliance, and reduced LDH release at reperfusion in heat-shocked animals compared with untreated controls. Additionally, protection was further confirmed by no detectable decrease in functional indicators in heat-treated animals after a subsequent 15-minute warm ischemic period as well as by decreased LDH release compared with controls.

Previous studies confirmed the protective effects of heat shock for prolonged hypothermic storage. Amrani and associates [12] showed that animals heat shocked 24, 26, or 30 hours before 4 hours of hypothermic (4°C) storage demonstrated better recovery of both mechanical and endothelial function. This protection was correlated with the maximum expression of the inducible HSP 70 protein. Zhang and colleagues [10] demonstrated improved recovery of developed pressure, coronary flow, adenine nucleotides, and reduced release of creatine kinase in animals heat shocked 24 hours before 8 hours of storage at 0°C. Amrani and associates [12] were unable to show any improvement in mechanical function at time points earlier than 24 hours after heat shock with a 4-hour cold ischemic period. We chose a much shorter recovery period (6 hours) and longer time of cold ischemia (12 hours), because other studies have shown protein expression early after exposure to hyperthermia [5] with continued expression during cold ischemia [5, 19]. Liu and associates [5] found significant improvements in global and regional left ventricular function and reduced creatine kinase release in porcine hearts treated with hyperthermic blood cardioplegia (42°C) immediately before 2 hours of intermittent, hypothermic (4° to 6°C) crystalloid cardioplegia. Increased levels of HSPs were found as early as 15 minutes after heat-shock pretreatment, and levels increased progressively after 1 and 2 hours of hypothermic cardioplegic arrest. McCully and colleagues [9] showed that rapid expression of HSP72 after brief retrograde hyperthermic (42°C) perfusion was able to provide enhanced myocardial functional recovery after warm global ischemia in an isolated rat heart model. These results suggest that it might not be necessary to wait for extended periods of time after heat shock for sufficient accumulation of HSPs, which makes the procedure more feasible from a clinical point of view.

There are discrepancies in reports of the length of protection against ischemic injury, with recovery and subsequent expression of HSPs after heat shock. Amrani and associates showed that protection correlates with expression of the inducible HSP70 in a model mimicking preservation for heart transplantation. In contrast, Shipley and associates [20] found rapid induction and accumulation of HSP27 and HSP72 after heat shock, but no myocardial protection was observed until 24 hours after heat stress in a rat model of regional ischemia and reperfusion. In a similar model, Yamashita and colleagues [21] confirmed rapid expression of HSP72, reaching a maximum by 3 hours and remaining increased for 72 hours after heat shock, yet no protection was conferred until 48 hours after heat shock. In the present study we showed (1) rapid accumulation of HSP72 at 6 hours after heat shock, which remained increased after 12 hours of cold ischemia and (2) protection in heat-shocked animals compared with sham-treated and control animals at this time point. One possible reason for the differences between other studies and the present study could be the experimental models used, in vitro isolated heart versus in vivo blood perfused heart. There is evidence that factors released in the blood after whole-body hyperthermia might mitigate myocardial protection [16].

Another important factor in these experimental protocols could be the way in which the heat-shock protocol is performed. We have included data showing the temperature profile of heat-shocked animals along with the rate of heating in the present study (Fig 2). Although most whole-body hyperthermia protocols increase the core temperature to 42° to 43°C for 15 minutes, the rate at which the animals are brought to this temperature is usually not presented. Previous studies have shown that the rate of heating will likely affect the resulting protein synthesis [22, 23]. Flanagan and associates [22] found significantly greater expression of HSP72 in liver samples from rats heated at high heating rates of (0.166°C/minute) compared with rats heated at low heating rats (0.045°C/minute) at 4 hours after hyperthermia. Flanagan and associates also demonstrated tissue-specific expression of HSP72; therefore, this variable will also need to be studied in heart tissue before its relevance can be determined.

One notable difference in the results from the present study and previous studies is the lack of improvement in coronary flow observed in the present study. Both Amrani and associates [11] and Zhang and colleagues [10] observed increases in coronary flow during reperfusion after cold ischemia (4 hours and 8 hours, respectively) in heat-shocked rats in a protocol similar to that of the present study. There is evidence that this enhancement of endothelial function results from increases in antioxidant enzymes such as catalase [24]. This difference might be caused by the shorter recovery time in the present study (6 hours versus 24 hours) and the subsequent expression of antioxidant enzymes or by the longer cold storage time (12 hours) and the inability of HSPs to protect endothelial function against this extended period of ischemia. Because we were able to show increased mechanical function in heat-shocked animals, it is likely that there are different mediators responsible for protecting endothelial and mechanical function in similar experimental protocols.

The present study found improvements in functional recovery after the initial cold ischemic storage and an additional warm ischemic period in heat-shocked animals compared with controls. Heat-shocked animals demonstrated virtually no reduction in any functional variables measured, as well as decreased LDH release upon reperfusion from the additional warm ischemia, compared with baseline measurements made after the initial cold ischemic period. The present study used heat-shock to protect against both cold and warm ischemia in the same experimental protocol. Although this protocol lacks similarities to the clinical protocol of heart transplantation, it provides additional evidence to support the protective abilities of heat shock before prolonged hypothermic storage.

Recovery of sham-treated animals demonstrated intermediate results. Although the results were lower on average than those in heat-treated animals in all the variables measured, many of the results did not demonstrate statistical significance. These results are in agreement with similar previous studies in which results from sham-treated animals were intermediate between those of controls and heat-treated groups, suggesting that anesthesia alone might be stressful [10]. However we did not measure an increase in HSP72 from anesthesia alone. The protection seen in sham-treated animals might have been induced by a different family of heat-shock proteins or a different molecular mechanism. However, we can only speculate on this; additional experiments should be done to investigate these results.

In summary, heat shock 6 hours before heart removal protected isolated rat hearts by improving functional recovery after 12 hours of cold ischemia and an additional 15-minute period of warm ischemia in a protocol mimicking that of heart preservation for transplantation. Development of techniques for eliciting the heat-shock response might find clinical applications in transplantation or conventional cardiac bypass surgical procedures.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
We thank Kare Inners, BS, for her contributions to the study.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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