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Ann Thorac Surg 1995;59:428-432
© 1995 The Society of Thoracic Surgeons

Hypoxic Preconditioning Enhances Functional Recovery After Prolonged Cardioplegic Arrest

Daniel T. Engelman, MD, Chang-zhi Chen, MD, Masazumi Watanabe, MD, Pankaj Kulshrestha, MD, Dipak K. Das, PhD, John A. Rousou, MD, Joseph E. Flack, III, MD, David W. Deaton, MD, Richard M. Engelman, MD

Department of Surgery, University of Connecticut School of Medicine, Farmington, Connecticut

Accepted for publication October 5, 1994.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
The purpose of this study was to assess the ability of hypoxic preconditioning to improve myocardial salvage after prolonged hypothermic cardioplegic arrest. Isolated working rat hearts were arrested at 4°C with St. Thomas' Hospital cardioplegic solution and immersion stored for 4 or 6 hours. Two groups were studied, control and hypoxically preconditioned (HP) hearts. After 4 hours' preservation, aortic flow, coronary flow, and the first derivative of aortic pressure were 8.7 ± 1.6 mL/min, 17.8 ± 1.6 mL/min, and 2,064 ± 123 mm Hg/s, respectively, in control hearts (n = 11) and 25.7 ± 2.5 mL/min, 27.1 ± 2.5 mL/min, and 2,655 ± 93 mm Hg/s, respectively, in HP hearts (n = 11) (p < 0.05). After 6 hours' preservation, aortic flow, coronary flow, and the first derivative of aortic pressure were 3.5 ± 1.2 mL/min, 18.8 ± 0.4 mL/min, and 1,622 ± 226 mm Hg/s, respectively, in control hearts (n = 6) and 21.5 ± 3.2 mL/min, 25.5 ± 2.3 mL/min, and 2,439 ± 239 mm Hg/s, respectively, in HP hearts (n = 6) (p < 0.05). After 6 hours' preservation, adenine nucleotides and creatine phosphate levels were not significantly different between the two groups, but lactate dehydrogenase release was significantly increased (p < 0.05) in control versus HP hearts (4.66 ± 0.58 IU/L versus 1.98 ± 0.28 IU/L). We conclude that hypoxic preconditioning reduces cellular necrosis and preserves myocardial function after prolonged hypothermic cardioplegic arrest.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Brief periods of ischemia have been found to render the heart more tolerant of a subsequent ischemia-reperfusion injury. First described by Murry and colleagues [1] in 1986, this phenomenon is known as ``ischemic preconditioning.'' We [2] have recently demonstrated that brief hypoxic perfusion can substitute for ischemia as a preconditioning stimulus in an isolated working normothermic rat heart. Although the ability of these phenomena to limit ischemia-reperfusion injury in laboratory animals is widely published, their clinical applicability has been limited.

Published data regarding the use of preconditioning prior to cardioplegic arrest [3] or profound hypothermia are limited. Preconditioning, however, may have a role in donor heart preservation prior to transplantation. The aim of this study was to use hemodynamic variables to evaluate the ability of hypoxic preconditioning to protect isolated working rat hearts from postischemic injury after prolonged hypothermic storage and reperfusion. Because a reduction in the rate of adenosine triphosphate (ATP) utilization may contribute to myocardial protection after ischemic preconditioning [4], we also assessed high-energy phosphate content before and after hypothermic storage.


   Material and Methods
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 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Perfusion Technique
Male Sprague-Dawley rats weighing 320 to 360 g were anesthetized with an intraperitoneal injection of sodium pentobarbital (Nembutal) (80 mg/kg) and heparin sodium (500 IU/kg) intravenously. 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 no. 85-23, revised 1985). After thoracotomy, the hearts were excised and placed in ice-cold perfusion buffer. The aorta was cannulated, and the heart was perfused by the Langendorff method at a constant perfusion pressure of 100 cm H2O [5]. The perfusion medium consisted of a modified Krebs-Henseleit bicarbonate buffer (KHB) (millimolar concentration: NaCl, 118; NaHCO3, 24; KCl, 4.7; KH2PO4, 1.2; MgSO4, 1.2; CaCl2, 1.7; and glucose, 10), gassed with 95% O2 and 5% CO2, with a pH of 7.4 and a temperature of 37°C. This solution was filtered through a 5-µm filter to remove any particulate contaminants.

The pulmonary vein was cannulated and the Langendorff perfusion discontinued. The preparation was converted to the working heart as described by Tosaki and co-workers [6]. The experimental setup is seen in Figure 1Go. The conversion to the working heart mode was accomplished by opening clamps 1 and 2 and closing clamp 3. Essentially, it is a left-heart preparation in which oxygenated KHB at 37°C enters the cannulated left atrium at a filling pressure of 17 cm H2O. The perfusion fluid passes to the left ventricle, from which it is ejected spontaneously through the aortic cannula against a pressure equivalent to 100 cm H2O. In this mode, contractility, aortic flow, and coronary flow can be measured.



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  		Fig 1. . Experimental working heart apparatus. The Langendorff perfusion was converted to the working heart mode by opening clamps 1 and 2, and closing clamp 3.

 
Experimental Design
After conversion to the working heart mode, the hearts were perfused for 5 minutes with KHB gassed with a mixture of 95% O2 and 5% CO2 (oxygen tension >= 600 mm Hg). Baseline contractile function was measured, and the effluents from the hearts were collected for subsequent assay of lactate dehydrogenase (LDH). Langendorff perfusion was then begun for the hypoxically preconditioned (HP) group with 10 minutes of KHB gassed with a 95% N2 and 5% CO2 mixture (oxygen tension <= 50 mm Hg) followed by 5 minutes of aerobic perfusion. The control group underwent 15 minutes of continuous Langendorff perfusion with the 95% O2 and 5% CO2 (aerobic) mixture. After conversion to the working heart mode for an additional 5 minutes, contractile function was measured, and LDH samples were again collected.

Cardioplegic arrest was obtained by clamping the aortic and atrial cannulas and infusing cardioplegic solution into a sidearm of the aortic cannula at a perfusion pressure of 60 cm H2O for 2 minutes. The hearts were then immersed in cardioplegic solution maintained at 4°C for either a 4-hour (n = 11 in both groups) or 6-hour period (n = 6 in both groups). The hearts were randomly assigned to each protocol. After ischemic arrest, all hearts were reperfused with oxygenated KHB at 37°C by the Langendorff method for 10 minutes and then converted to the working mode for 20 minutes. Contractile function was obtained after 10 and 20 minutes of working heart reperfusion.

Cardioplegic Solution
A single infusion of St. Thomas' Hospital cardioplegic solution (millimolar concentration: NaCl, 110; KCl, 16; MgCl, 16; CaCl2, 1.2; and NaHCO3, 10) was used for myocardial preservation. This solution was filtered through a 5-µm filter to remove any particulate contaminants before infusion.

Indices of Myocardial Function
The aortic flow rate was measured by a calibrated rotameter, and the coronary flow rate was measured by timed collection of the coronary effluent. Direct measurements of heart rate, developed pressure (defined as aortic end-systolic pressure - aortic end-diastolic pressure), and the first derivative of aortic pressure were made at each time point. All data were recorded and analyzed in real time using the Cordat II data acquisition, analysis, and presentation system (Data Integrated Scientific Systems, Pinckney, MI; Triton Technologies, Inc, San Diego, CA).

Biochemical Analysis
Lactate dehydrogenase samples were obtained after 4 and 6 hours of arrest and 10 minutes of Langendorff reperfusion. One milliliter of the coronary effluent was collected with each sampling. Quantification of LDH release was determined by the enzymatic assay method using an LDH assay kit (Sigma Diagnostics, St. Louis, MO). The absorbance was read at 340 nm using a Beckman DU-8 spectrophotometer [7].

Six nonischemic hearts were perfused in the working mode for 5 minutes as already described and then rapidly frozen in liquid nitrogen and stored at -70°C for subsequent baseline high-energy phosphate measurements. Six other hearts were similarly perfused in the working mode for 5 minutes, hypoxically preconditioned for 10 minutes, and reoxygenated for 10 minutes before -70°C storage. These hearts were used for preischemic measurements after the preconditioning stimulus. After 6 hours of ischemia and 30 minutes of reperfusion, HP hearts (n = 7) and control hearts (n = 6) were similarly frozen and stored. Adenine nucleotides (adenosine monophosphate [AMP], adenosine diphosphate [ADP], and ATP) and creatine phosphate (CP) were separated by high-performance liquid chromatography as described elsewhere [8]. Using the method of Atkinson [9], the adenylate charge was calculated as follows: ([ATP] + 1/2[ADP])/[ATP] + [ADP] + [AMP]).

Statistical Analysis
The values for myocardial function, LDH, ATP, and CP are expressed as the mean ± the standard error of the mean. A two-way analysis of variance (Scheffé's) was carried out first to test for any differences between groups. If differences were established, the values were compared using Student's t test for paired data. Significance was considered at a p value of less than 0.05.


   Results
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 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Myocardial Function and LDH Release
There was no significant difference between 20 and 30 minutes' reperfusion for heart rate, developed pressure, first derivative of aortic pressure, aortic flow, or coronary flow in either the 4-hour or 6-hour cardioplegic arrest groups. Mean hemodynamic data and LDH release at baseline, after preconditioning, and after 30 minutes of reperfusion are shown in Table 1Go. Ten minutes of hypoxic perfusion had no measurable effect on heart rate, developed pressure, first derivative of aortic pressure, aortic flow, coronary flow, or LDH release. Immediately after the hypoxic preconditioning stimulus, there was a transient decline in cardiac function. However, this decline is not apparent in our data because after reoxygenation, myocardial function had returned to baseline values by the 10-minute measurement. After both 4 hours and 6 hours of hypothermic storage, the HP hearts had a significant (p < 0.05) improvement in the first derivative of aortic pressure, aortic flow, and coronary flow and reduced LDH release compared with control hearts.


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  		Table 1. . Hemodynamic Data and Release of Lactate Dehydrogenasea
 
Myocardial Adenine Nucleotide Levels
There was no significant change in any adenine nucleotide or CP level before and immediately after the preconditioning stimulus. After 6 hours of immersion storage and 30 minutes of reperfusion, however, all of the adenine nucleotides were significantly reduced from baseline levels (Fig 2Go). The CP levels, on the other hand, were not significantly changed from baseline values in either group. The adenylate charge was also unchanged from a baseline value of 0.82 ± 0.02 to 0.82 ± 0.02 and 0.85 ± 0.01 for the control and HP groups, respectively. There were no significant differences in either adenylate charge, adenine nucleotide levels, or CP levels between control and HP hearts at 30 minutes' reperfusion after 6 hours of storage.



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  		Fig 2. . Adenine nucleotide and creatine phosphate (CP) levels for control (CON) and hypoxically preconditioned (HP) hearts at baseline (n = 6), after preconditioning (n = 6), and after 6 hours of storage (n = 6 for CON group and 7 for HP group). Adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) levels were significantly reduced after storage and reperfusion. There was no significant difference between CON and HP hearts in any of the high-energy phosphates. Data are shown as the mean ± the standard error. (*p < 0.05 versus baseline.)

 

   Comment
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 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
The present study has shown that hypoxic preconditioning can preserve postischemic function in a model of prolonged hypothermic storage that simulates the method used prior to heart transplantation. This protection was afforded after both the 4-hour and the 6-hour time periods. Many investigators have sought the ideal storage method for donor hearts. Prolongation of preservation time has been obtained by altering cardioplegic solutions [10] and using continuous [11] and intermittent perfusion [12] during storage. In a novel experiment, heat shock was used 24 hours before prolonged cardioplegic arrest to improve postischemic recovery [13].

To date, preconditioning may provide the most powerful form of endogenous protection against lethal myocyte injury after moderate ischemia [14]. A similar phenomenon can be induced by a variety of stimuli other than ischemia. Hypoxia [15–17], calcium [18], adenosine agonists [19], {alpha}1-adrenergic agents [20], muscarinic agonists [21], and stretch [22] have each been used to induce a tolerance of a subsequent ischemic episode. Under normothermic conditions, the protective effects of ischemic preconditioning can be lost after 60 to 90 minutes of ischemia [23, 24]. However, under moderate hypothermic conditions (20°C), ischemic preconditioning has afforded myocardial protection after up to 3 hours of ischemia [25]. In this study, using hypoxic preconditioning and cardioplegic arrest, we have extended the period of protection to up to 6 hours under profound hypothermic conditions.

If we assume all preconditioning has a common mechanism, theories regarding ischemic preconditioning, including adenosine pathways [26], inhibitory G (Gi) proteins [27], and Katp channels [28], may be applicable. Preconditioning may also slow energy metabolism [4], which in turn could inhibit the activation of phospholipases, thereby preserving membrane lipids [29]. Preconditioning has been found to stabilize membrane functions through the inhibition of sarcolemmal phospholipid loss and accumulation of lipids [30], which could reduce the oxidative stress produced during ischemia and reperfusion [31].

Following both 4 hours and 6 hours of immersion storage, all hearts exhibited a substantial increase in LDH release and reduced mechanical function. Other researchers [3, 25] have documented similar findings. Human hearts transplanted with less than 4 hours of ischemia have been associated with myocardial ultrastructural injury on reperfusion [32] and significantly elevated creatine kinase release from the coronary sinus after 5 minutes and 10 minutes of reperfusion [33]. This suggests that early reperfusion of human transplanted hearts may be associated with elevated enzyme leakage without clinically significant cell necrosis, and that the rat model remains applicable in this setting.

Postischemic functional impairment can be due to myocardial stunning, necrosis, or both. We have shown that hypoxic preconditioning significantly reduced enzyme leakage and also improved function after immersion storage. This suggests that preconditioning functions by decreasing cellular damage and maintaining sarcolemmal integrity. However, as histologic confirmation of reduced cellular necrosis in HP hearts could not be obtained, these conclusions cannot be confirmed. The significantly preserved coronary flow seen in the HP hearts may suggest that hypoxic preconditioning also has a beneficial effect on endothelial function. Enhanced nitric oxide release has been found to augment graft survival after prolonged preservation [34].

Our ability to extend the preconditioning window may be due to a further reduction in energy utilization afforded by a greater degree of hypothermia [35]. Hypothermia conserves tissue glycogen, stabilizes lysosomal enzymes, and reduces ATP depletion, lactate accumulation, and glucose utilization [36, 37]. The addition of cardioplegia further reduces myocardial oxygen demand by interrupting metabolic processes [38]. Our data agree with that of others [25], however, that preconditioning prior to hypothermic storage does not increase adenine nucleotide content. No correlation was observed between energy storage and postischemic myocardial function. Hence, a further reduction in high-energy phosphate utilization does not appear to be an underlying mechanism.

The precise mechanism responsible for hypoxic preconditioning remains speculative. Recent work in our laboratory [2] has suggested that hypoxic preconditioning may function through preservation of the endogenous myocardial antioxidant enzyme system. Our laboratory has also demonstrated that transient ischemia induces the sequential upregulation of mitochondrial genes responsible for ATP synthesis, which may contribute to ultimate myocardial adaptation [39].

It can be hypothesized that brief hypoxic blood perfusion before human donor heart explantation may extend the period of viable cold storage. However, before the clinical application of this phenomenon, the specific mechanisms underlying the hypoxic preconditioning response must first be ascertained. Ideally, a direct manipulation that leads to enhanced endogenous myocardial protection may result in improved donor heart preservation.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This research was supported by grants HL 22559-14 and HL 34360-07 from the National Institutes of Health.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Address reprint requests to Dr Daniel T. Engelman, Surgical Research Center, University of Connecticut School of Medicine, 263 Farmington Ave, Farmington, CT 06030-1110.


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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