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Ann Thorac Surg 1997;64:623-627
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Use of "Natural" Hibernation Induction Triggers for Myocardial Protection

Section of Thoracic Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, National Institute of Drug Abuse, Baltimore, Maryland and Department of Pathology, University of Kentucky, Lexington, Kentucky

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Hypothermic cardioplegia provides adequate myocellular protection, yet stunning and dysfunction remain significant problems. Interestingly, the subcellular changes of hibernation parallel the altered biology of induced cardiac ischemia, but are well tolerated by hibernating mammalian myocardium. Hibernation induction trigger (HIT) from winter-hibernating animal serum induces hibernation in active animals. Hibernation induction trigger is opiate in nature and is similar to the delta 2 opioids.

Methods. To determine whether HIT could improve myocardial recovery following global ischemia, we gave 37 isolated rabbit hearts either standard cardioplegia or cardioplegia containing summer-active woodchuck, hibernating woodchuck, or black bear HIT serum or a delta 2 opioid, D-Ala2-Leu5-enkephalin, before 2 hours of global ischemia.

Results. Hibernation induction trigger appeared not to have an active mechanism during ischemia, as all hearts had equal recovery. In contrast, when examining for a preischemia mechanism, 23 additional rabbits received 3 days pretreatment with summer-active woodchuck or HIT hibernating woodchuck or black bear serum, or were preperfused with D-Ala2-Leu5-enkephalin or D-pen2,5-enkephalin, a delta 1 opioid, again before 2 hours of global ischemia. Postischemic ventricular function, coronary flows, myocardial oxygen consumption, and ultrastructural preservation were all significantly improved with HIT and D-Ala2-Leu5-enkephalin pretreatment.

Conclusion. "Natural" HIT protection is superior to standard cardioplegia alone and may have clinical application.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Presently cardioplegia and hypothermia provide considerable myocardial protection during induced ischemia for cardiac operations; however, perioperative infarction, stunning, and ventricular dysfunction remain significant problems, especially in high-risk patients with poor preoperative function, recent myocardial infarction, or left ventricular hypertrophy. Interestingly, mammalian hibernation biology closely parallels the altered cardiac cellular physiology noted with hypothermic cardioplegic arrest. However, although similar subcellular and molecular changes are seen, such as intracellular acidosis, hypoxia, hypothermia, energy store depletion, and volume shifts, these alterations are well tolerated for months by the hibernated mammalian myocardium, whereas the present limit of surgically induced ischemia is 4 to 6 hours.

Hibernation induction trigger (HIT) obtained from serum of certain winter-hibernating mammals, such as woodchucks, 13-lined ground squirrels, brown cave bats, and black bears, can induce hibernation in these animals, even when summer active. Hibernation induction trigger has also been able to induce hibernation-like behavior in nonhibernators. The exact chemical identity of HIT is elusive, but a proto-opiate nature of HIT is well established as HIT can be reversed or retarded by opiate antagonists. Physical chemistry indicates that the HIT molecule is similar to the delta 2 opioid D-Ala2-Leu5-enkephalin (DADLE), which can mimic natural hibernation. D-Ala2-Leu5-enkephalin may initiate its metabolic effects through specific membrane opioid receptors to alter or stabilize membrane geometry. There is evidence to suggest that DADLE influences adenosine triphosphate preservation, thereby potentially augmenting myocardial ischemic tolerance. Finally, cellular assays of DNA and protein synthesis have noted profound alteration with DADLE use. Because of these potentially favorable actions during cardiac ischemia, the present study undertook to test whether HIT or DADLE could improve myocardial functional recovery after global ischemia in a nonhibernating mammalian model.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Preparation of Isolated Heart
Rabbits (male or female, 2.2 to 2.7 kg body weight) were anesthetized with sodium pentobarbital (45 mg/kg, intravenously) and heparinized (700 U/kg, intravenously). The heart was rapidly excised and immersed in ice-cold physiologic salt solution, pH 7.4, containing 118.0 mmol/L NaCl, 4.0 mmol/L KCl, 22.3 mmol/L NaHCO₃, 11.1 mmol/L glucose, 0.66 mmol/L KH₂PO₄, 1.23 mmol/L MgCl₂, and 2.38 mmol/L CaCl₂. The aorta was cannulated in the Langendorff mode and the heart was perfused with physiologic salt solution that was equilibrated with 95% O₂–5% CO₂ at 37°C and passed twice through filters with 3.0-µm pore size. Perfusion pressure was maintained at 90 mm Hg. An incision was made in the left atrium, and a fluid-filled latex balloon was passed through the mitral orifice and placed in the left ventricle. The balloon was connected to a pressure transducer for continuous measurement of left ventricular pressure and its first derivative, dP/dt. The caudal vena cava, the left and right cranial vena cava, and the azygous vein were ligated. The pulmonary artery was cannulated to enable timed-collection measurements of coronary flow and the cannula was connected to an oxygen meter (Diamond Electro-Tech, Inc, Ann Arbor, MI) for continuous measurement of the oxygen partial pressure. The analog signals were continuously recorded on a pressurized ink-chart recorder (model 2600S, Gould, Inc., Cleveland, OH) and digitized to an online computer (AST Premium/386, AST Research Inc, Irvine, CA). To characterize cardiac function, developed pressure is defined as peak systolic pressure minus end-diastolic pressure. Myocardial oxygen consumption was calculated by the following formulas: Myocardial oxygen consumption = [coronary flow (mL • min^-1 • g^-1)] x [difference in partial pressure of O₂ (mm Hg) between perfusate and coronary effluent] x [Bunsen solubility coefficient of O₂ at 37°C (22.7 µL O₂ • atm^-1 • mL^-1 perfusate)/760]. The partial pressure of O₂ of the perfusate was 665 mm Hg. Coronary flow was measured by performing timed collections of the pulmonary effluent flow with a graduated cylinder. Oxygen extraction was calculated as myocardial O₂ consumption divided by O₂ content in the perfusate. Wet weight of the heart was determined at the conclusion of each experiment after trimming the great vessels and fat and blotting the heart dry with nine-layer cotton gauze. The left ventricular wall was weighed, desiccated for 48 hours at 65°C, and reweighed. Water content was determined using the formula (1 - dry weight/wet weight)/100%. A section of the left ventricle was prepared for histopathology.

After instrumentation was completed and calibrations were performed, left ventricular balloon volumes were varied over a range of values to construct modified left ventricular function curves. In this manner, it is possible to define a specific balloon volume that is associated with a developed pressure from 100 to 140 mm Hg. This volume was maintained the same during baseline and reperfusion conditions. Baseline data were obtained after an equilibration period of 30 minutes. During the baseline period, data were obtained with hearts maintained at 37°C by a water-jacketed organ bath. A Khuri Regional Tissue pH Monitor—intramural pH electrode (Vascular Technology, Chelmsford, MA) was placed in the left ventricular free wall to observe pH changes. To induce the 2 hours of ischemia, the physiologic salt solution infusion was stopped and 60 mL of 4°C solution was injected into the aorta at a rate of 1 mL/sec to begin the 34°C 2-hour ischemia.

Hearts were randomly assigned to groups. To determine whether HIT could improve myocardial recovery after global ischemia, 37 hearts received standard cardioplegia (controls), cardioplegia with 5 mL of summer-active woodchuck, hibernating woodchuck, or black bear serum, or cardioplegia with 1 mg/kg DADLE. To examine for a preischemia profactor or receptor mechanism, we gave 25 additional rabbits 3 days of pretreatment with 1 mL/kg per day of summer-active woodchuck, hibernating woodchuck, or hibernating black bear serum before ischemia, or hearts were preperfused with DADLE or DPDPE, D-pen2,5-enkephalin, a delta I opioid, administered for 15 minutes at 2 mmol/L (22.7 mg/20 mL physiologic salt solution), before standard cardioplegic-induced ischemia. The cardioplegia contained 109.0 mmol/L NaCl, 25.0 mmol/L KCl, 21.9 mmol/L NaHCO₃, 16.0 mmol/L MgCl₂, and 0.8 mmol/L CaCl₂. When the 34°C 2-hour ischemic period was ended, hearts were reperfused with oxygenated physiologic salt solution at 37°C. Hemodynamic data were recorded every 15 minutes for 45 minutes to compare with baseline data and to determine the degree of functional recovery.

The Statview 5.01 program (Abacus Concepts, Inc, Berkeley, CA) was used for statistical analysis. Data were evaluated with analysis of variance (Scheffé's test). Differences were considered significant when p values were less than 0.05. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research. All work was performed in the section of Thoracic Surgery, University of Michigan Medical Center, Ann Arbor, MI.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
There were no differences in any functional or metabolic indices during preischemia between groups. Table 1 summarizes the postischemic metabolic and functional recovery results. Hibernation induction trigger appeared not to have an active mechanism during ischemia, as hearts perfused with cardioplegia alone returned to 38% of preischemic developed pressure, whereas all other groups with HIT or DADLE given in the cardioplegia had between 33% and 38% recovery (not significant). However, when HIT, DADLE, or DPDPE were given before ischemia to examine for a preischemic profactor or receptor mechanism, hearts perfused with HIT-containing serum from both woodchuck and black bear, and DADLE, but not DPDPE, a delta 1 opioid, demonstrated significantly improved postischemic function (Table 1). Serum from summer-active animals, containing no HIT, had no effect either given in the cardioplegia or as pretreatment. Ultrastructural preservation was significantly improved with HIT and DADLE pretreatment, as compared with controls or summer-active serum treatment. There were no significant differences in interstitial pH, heart weight, or water content between groups.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

Dawe and Spurrier [7] were the first investigators to present evidence for the presence of a hibernation "trigger" in the plasma of hibernating 13-lined ground squirrels (Citellles tridecemlineatus) that could induce a similar state when injected into either summer-active ground squirrels or woodchucks (Marmota monax). However, the identification of this hibernation trigger has been slow, owing to the necessity of using a bioassay requiring induction of hibernation in summer-active animals. Recently, protein-resolving techniques have provided clues to the chemical identity of the HIT molecule, a small, thermolabile, protease-sensitive, nuclease-insensitive protein. Hibernation induction trigger is associated with albumin and its physiologic role in hibernators may be dependent on seasonally changing albumin concentrations [8, 9].

Although the HIT molecule has been shown to be highly effective in specially adapted hibernating species, nonhibernating primate studies also indicate that HIT derived from winter-hibernating, but not summer-active woodchucks, initiates opiatelike behavioral modifications [10, 11] and profound physiologic depression, resembling a hibernationlike state including hypothermia, bradycardia, and hypophagia [12]. Furthermore, the opiate nature of HIT has been established as most of the behavioral and physiologic depressions noted in primates are blocked or retarded by infusion of the opiate antagonists, naloxone and naltrexone. Evidence indicates that the HIT molecule initiates its potent metabolic inhibitory effects through specific membrane opioid receptors. The HIT molecule may be either an opiate or a neuropeptide hormone that initiates its action through, most probably, a delta opioid receptor [13, 14]. It has been shown that the opioid antagonist naloxone [15], the potent synthetic kappa agonist U69593 [16], the mu agonists, morphine and morphiceptin, as well as the naturally occurring kappa brain opioid agonist, dynorphin, all of which can occupy the delta opioid receptor site, can block hibernation induced by HIT when infused in summer-active ground squirrels [17, 18]. Only the delta 2 opioid D-Ala2-Leu5-enkephalin (DADLE) induces hibernation in summer-active ground squirrels [14].

Evidence that HIT can induce cardiac metabolic changes in nonhibernating species was demonstrated by Swan and Schatte [19], who obtained subcortical brain extracts from both winter-hibernating and summer-active ground squirrels. These protein-containing extracts were injected into rats, a nonhibernating animal. Although rats injected with summer-active ground squirrel brain extracts had no change in metabolism, the rats injected with winter-hibernator brain extracts were noted to have suppression of metabolic rate, particularly myocardial oxygen consumption, which decreased to 65% of control at 30 minutes. Other investigators have noted this alteration in myocardial oxygen consumption and used HIT to enhance myocardial preservation. Burt and Copeland [20] reported severe functional deterioration of control isolated hearts stored for 24 hours. However, when HIT-containing bear plasma was used before and during 24-hour preservation storage in hearts, contractile function was much better preserved. Hearts from the group that received HIT resumed beating after 24 hours of preservation with a very short period of reperfusion [5].

Recent studies have revealed that HIT may play a role in maintaining cellular energy status and membrane integrity during hibernation, which could provide for "natural" cellular and myocardial protection for cardiac surgery. As evidence, plasma from deeply hibernating woodchucks containing an HIT molecule or the delta opioid DADLE, which mimics natural hibernation, have been used to extend survival time of multiorgan autoperfusion systems [21–23]. Furthermore, successful lung transplantations from HIT-treated organ blocks, following 24 hours of ex vivo preservation, have been performed [23]. Additionally, in concordance with the results from the present study, a recent previous study from this laboratory also demonstrated markedly enhanced return of function after 18 hours of storage in a cardiac transplant model using HIT [24].

The specific action of the HIT molecule remains hypothetical and may be through multiple pathways. Hibernation induction trigger may initiate its potent metabolic inhibitory effects through specific membrane opioid receptors and may alter membrane geometry and potentially may be a membrane stabilizing agent [5]. Our study concurs with the time course appropriate to a receptor mechanism. There is also evidence to suggest that the HIT molecule and the delta opioid DADLE may influence adenosine triphosphatases and preservation of ATP during ischemia, thereby potentially augmenting cellular and myocardial ischemic tolerance [24]. Interestingly, in vitro cellular assays monitoring DNA and protein synthesis have noted depression of turnover and altered neosynthesis with HIT use [10, 11]. Furthermore, recent reports have provided indirect evidence that delta opioid receptors may be involved in ischemic preconditioning in rat myocardium [25, 26]. Hibernation induction triggers may protect and stabilize membranes against oxygen free radicals, alter calcium handling, or ion channel opening [27–30]. Finally, DADLE has been shown to increase the level of inositol 1,4,5-triphosphate and release of calcium from sarcoplasmic reticulum in rat ventricular cardiac myocytes [29]. Although the exact mechanism of HIT is unknown at present, it is important to note that DADLE exerts its action not through an inotropic mechanism. Although opioid receptors have been thought to be linked to adenylate cyclase activation [28], in preliminary data from our laboratory when DADLE was given to normal, beating nonischemic rabbit hearts in concentrations from 0.01 to 100 mmol/L, there was no inotropic effect and no alteration in pH or myocardial O₂ consumption.

In conclusion, mammalian hibernation biology closely parallels the altered cardiac cellular physiology seen with hypothermic global ischemia used during cardiac operations. However, the drastic subcellular and molecular changes seen with hypothermic mammalian hibernation are well tolerated by hibernating animals, and in particular by the mammalian myocardium. Hibernating animals can conserve up to 90% of the energy required during normal metabolism. The exact mechanism of this energy conservation during hibernation is currently unknown. However, the HIT molecule and the synthetic delta opioids, which appear to work by the same mechanism, have been shown to produce profound physiologic and metabolic inhibitory effects favoring survival at the organ and cellular level. This natural approach to cardiac preservation is exciting and may have clinical application.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This work was supported in part by grant 95008730 from the American Heart Association.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Presented at the Poster Session of the Thirty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Feb 3–5, 1997.

Address reprint requests to Dr Bolling, Section of Thoracic Surgery, The University of Michigan Hospitals, 1500 E. Medical Center Drive, 2120D Taubman Center, Box 0344, Ann Arbor, MI 48109-0344 (e-mail: sbolling{at}umich.edu).

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract 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): Steven F. Bolling Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bolling, S. F. Articles by Harlow, H. H. Search for Related Content PubMed PubMed Citation Articles by Bolling, S. F. Articles by Harlow, H. H.