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Ann Thorac Surg 1996;62:469-474
© 1996 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Influence of Preconditioning on Rat Heart Subjected to Prolonged Cardioplegic Arrest

Hitoshi Ogino, MD, Ryszard T. Smolenski, MD, Marek Zych, MD, Anne-Marie L. Seymour, PhD, Magdi H. Yacoub, FRCS

Department of Cardiothoracic Surgery, National Heart and Lung Institute, Harefield Hospital, Harefield, United Kingdom

Accepted for publication March 1, 1996.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Ischemic preconditioning (IP) can reduce lethal injury to the myocardium induced by prolonged ischemia. However, little is known about the effect of preconditioning on the heart subjected to cardioplegic arrest and hypothermic preservation. We evaluated the effect of IP on myocardial metabolism, mechanical performance, and coronary endothelial function after cardioplegic arrest and prolonged hypothermic preservation.

Methods.An isovolumic Langendorff perfused rat heart model was used, and hearts were divided into two groups. The first group (IP, n = 14) was preconditioned by 5 minutes of global normothermic (37°C) ischemia followed by 10 minutes of normothermic reperfusion before 6 hours of cold (4°C) preservation, followed by 60 minutes of reperfusion. The second group (control, n = 15) was subjected to 6 hours of cold preservation followed by 60 minutes of reperfusion without preconditioning. Mechanical function was assessed using left ventricular balloon by constructing pressure-volume curves in two ways: at defined left ventricular volumes or at defined left ventricular end-diastolic pressures. Initially, the volume of the balloon was increased incrementally from 0 to 150 µL in 25-µL steps. Measurements were then repeated with loading balloon to achieve left ventricular end-diastolic pressure of 5, 10, 15, or 20 mm Hg. Myocardial function was assessed before ischemia and at 15 or 60 minutes of reperfusion. Metabolic status of the heart was evaluated by measuring the release of purine catabolites during the initial 15 minutes of reperfusion and concentrations of myocardial nucleotides at the end of reperfusion. Endothelium-mediated vasodilatation was evaluated using 10 µmol/L 5-hydroxytryptamine before and after ischemia.

Results.Left ventricular end-diastolic pressure values were significantly lower in the IP group, by 20% to 40%, during the reperfusion phase at each volume of the balloon compared with the control group. The rate-pressure product was more favorable during reperfusion in the IP than in the control group because of a 15% increased heart rate in the IP group. The release of purine catabolites from the heart during the reperfusion phase was reduced (p< 0.01) in the IP group (0.66 ± 0.04 µmol) relative to the control group (0.92 ± 0.06 µmol). No difference in the recovery of systolic function, myocardial adenosine triphosphate concentration, or endothelial function was observed between the groups.

Conclusions.Under conditions of cardioplegic arrest and hypothermic preservation, IP can offer additional protection for the heart by preventing an increase in diastolic stiffness. However, metabolic improvement or better preservation of the systolic or endothelial function was not observed in this model.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Since Murry and associates [1] first demonstrated the phenomenon of preconditioning, many studies have confirmed that brief periods of myocardial ischemia followed by reperfusion enhance the tolerance of the myocardium to subsequent, more prolonged ischemic episodes. In models of regional or global ischemia, preconditioning results in reduced infarct size, improved contractility, and decreased incidence of reperfusion arrhythmias [2–9]. There is also clinical evidence that, during percutaneous transluminal coronary angioplasty or coronary artery bypass grafting, brief periods of ischemia similar to preconditioning may protect the heart from subsequent prolonged coronary occlusion and can reduce the incidence of myocardial infarction or severe myocardial dysfunction [10–12]. An important clinical area in which preconditioning could be applied is myocardial protection during open heart procedures. However, little is known about the combined effect of ischemic preconditioning (IP) and cardioplegic arrest with hypothermic preservation.

In this study, we evaluated the effect of preconditioning induced by 5 minutes of ischemia followed by 10 minutes of reperfusion on the recovery of mechanical, endothelial, and metabolic function of the rat heart subjected to 6 hours of preservation at 4°C using an isolated rat heart preparation.


   Material and Methods
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
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). Male Wistar rats weighing 300 to 350 g (Harlan-Olac, UK) were used in this study. Animals were anesthetized by an intraperitoneal injection of pentobarbital sodium (60 mg/kg). Sodium heparin (1,000 IU/kg) was then administered intravenously. The heart was excised and quickly placed in cold Krebs-Henseleit buffer consisting of: 118.5 mmol/L NaCl, 25 mmol/L NaHCO3, 1.2 mmol/L MgSO4, 4.8 mmol/L KCl, 1.2 mmol/L KH2PO4, 1.36 mmol/L CaCl2, and 11 mmol/L glucose. Hearts were perfused in the Langendorff mode with Krebs-Henseleit buffer gassed continuously with 95% O2/5% CO2 at 37°C at a constant perfusion-pressure equivalent to 100 cm H2O.

Experimental Protocol
The experimental protocol for the group subjected to IP and the control group is shown in Figure 1Go. After an initial 15 minutes of Langendorff perfusion, baseline left ventricular function was evaluated using a balloon catheter introduced into the left ventricle through the left atrium. Subsequently, endothelial function was assessed by measuring the changes in coronary flow after infusion of 5-hydroxytryptamine (5-HT), as described later. In the IP group (n = 14), hearts were then subjected to 5 minutes of global ischemia followed by 10 minutes of reperfusion, and were arrested by infusion of cold (4°C) St. Thomas' Hospital cardioplegic solution No. 1 (Martindale Pharmaceuticals, UK) at a constant pressure of 60 cm H2O for 2 minutes. Finally, the hearts were immersed in cardioplegic solution and stored for 6 hours at 4°C. In the control group (n = 15), hearts were arrested by cardioplegic infusion as described and stored for 6 hours without prior preconditioning. At the end of preservation period, the hearts were reperfused with Krebs-Henseleit buffer, and the same balloon catheter was inserted into the ventricle 10 minutes after reperfusion. Coronary effluent was collected throughout the 15 minutes of reperfusion; the volume was recorded and small aliquots (1 mL) were taken after mixing for determination of purine release from the myocardium. The effluent was collected also during 3 minutes of reperfusion after 5 minutes of IP and analyzed for purine catabolite loss. After 15 and 60 minutes of reperfusion, mechanical function was evaluated. Endothelial function was determined after 30 minutes of reperfusion. At the end of the perfusion protocol, the hearts were freeze-clamped for analysis of nucleotide concentrations. Six additional hearts were freeze-clamped after 20 minutes of Langendorff perfusion without ischemia to determine initial metabolite concentrations. Hearts with a rate less than 250 beats/min under baseline perfusion conditions were excluded from the study.



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  		Fig 1. . Experimental protocol in the ischemic preconditioning group (IP) and the control group (C). (C = cardioplegic fluid infusion; EF = endothelial function evaluation; FA = functional assessment; I = ischemia; LP = Langendorff perfusion; RP = reperfusion.)

 
Assessment of Endothelial Function
Coronary flow was monitored continuously with an in-line electromagnetic flow probe (FF-070T; Nihon-Kohden Co, Japan) connected to an MFV 3200 Nihon-Kohden flow meter. Flow meter recordings were verified by volumetric measurements. To evaluate endothelial function, we infused 100 µmol/L 5-HT dissolved in oxygenated perfusion buffer into the side arm of the perfusion cannula with the infusion pump at 10% of the coronary flow, to give a final concentration of 10 µmol/L. Perfusion temperature was maintained at 37°C. Infusion of 5-HT was continued until a steady-state flow rate was achieved (between 5 and 7 minutes). Subsequently, the increase of coronary flow rate was calculated as percentage of the baseline flow before infusion of 5-HT. This procedure was repeated after 30 minutes of reperfusion to evaluate the effects of hypothermic cardioplegic storage and ischemia.

Evaluation of Mechanical Function
Mechanical function assessment was performed using a balloon catheter inserted into the left ventricle to determine systolic pressure and diastolic pressure-volume relations [13–15]. The balloon was loaded with water in a stepwise manner to achieve specific end-diastolic volumes ranging from 0 to 150 µL in 25-µL steps. The zero volume was defined as the point at which left ventricular end-diastolic pressure (LVEDP) was zero. Left ventricular systolic pressure and LVEDP were recorded at each loading of the balloon. Subsequently, the balloon was deflated for 5 minutes and loaded again to achieve an LVEDP value of 0, 5, 10, 15, or 20 mm Hg. This value was then subtracted from the measured left ventricular systolic pressure to calculate left ventricular developed pressure. The rate-pressure product was calculated by multiplying the left ventricular developed pressure value at each LVEDP set by the heart rate. The rate of recovery was evaluated by functional measurement at the early stage (15 minutes) and late stage (60 minutes) of reperfusion.

Metabolic Determinations
The coronary effluent was collected during the first 15 minutes of reperfusion (or after IP), and an aliquot was taken to evaluate purine catabolite release. Nucleotide content was determined in hearts freeze-clamped at the end of the experiment. Samples were analyzed subsequently by high-performance liquid chromatography. Coronary effluent samples were injected directly into the chromatograph. Freeze-clamped hearts were freeze-dried; subsequently, about 40 mg of freeze-dried tissue was extracted with 1 mL of 0.6 mol/L perchloric acid using a glass homogenizer. After centrifugation to remove protein precipitates, the supernatant was neutralized with 2 mol/L potassium hydroxide. After a second centrifugation to remove potassium perchlorate, samples were injected into the chromatograph. The reverse-phase chromatographic procedure has been described previously [16, 17].

Statistical Analysis
All results are expressed as mean ± standard error of the mean. Student's unpaired t test was used to assess the level of statistical significance of the difference between the IP and control groups.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Mechanical Function
Before preservation, systolic and diastolic function in the two groups were similar (Fig 2Go). During the reperfusion phase, the end-diastolic pressure-volume relation, which reflects stiffness of the ventricle, showed a sharper slope for the control group (Fig 3Go). Values of LVEDP after 15 and 60 minutes of reperfusion at each volume load in the balloon were lower in the IP group. Comparison of the recovery of mechanical function expressed as left ventricular systolic pressure or developed pressure showed no significant difference between the groups. Heart rates were significantly higher during reperfusion in the IP group (Table 1Go). Consequently, the rate-pressure product was significantly greater in the IP group at each end-diastolic pressure load (see Table 1Go).



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  		Fig 2. . Systolic pressure-volume relation of the rat heart before and 15 or 60 minutes after 6 hours of hypothermic ischemia. (C = control group; IP = ischemic preconditioning; LVSP = left ventricular systolic pressure.) Values are mean ± standard error of the mean, n = 14 (IP) or n = 15 (C).

 


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  		Fig 3. . End-diastolic pressure-volume relation of the rat heart before and after 6 hours of hypothermic ischemia. Values are mean ± standard error of the mean, n = 14 (IP) or n = 15 (C). (C = control group; IP = ischemic preconditioning; LVEDP = left ventricular end-diastolic pressure; *p < 0.05; **p < 0.01 compared with ischemic preconditioning.)

 

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  		Table 1. . Rate-Pressure Product Evaluated as Percentage Recovery of Preischemic Valuea
 
Metabolic Recovery
The adenosine triphosphate (ATP) concentration and levels of other metabolites are presented in Figure 4Go. There was a 25% decrease in the ATP concentration and the adenine nucleotide pool after 6 hours of ischemia, but no differences were observed between the IP and control groups. There were no differences in the concentrations of any other metabolites between the groups. Release of purine catabolites from the heart during the first 15 minutes of reperfusion was 30% lower in the IP group (0.66 ± 0.04 µmol) than in the controls (0.92 ± 0.06 µmol) (Fig 5Go). However, degradation and loss of nucleotide precursors were observed also after IP (0.16 ± 0.02 µmol).



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  		Fig 4. . Myocardial concentration of nucleotide and creatine (Creat) metabolites in the heart at the end of the protocol involving 6 hours of hypothermic (4°C) ischemia and 60 minutes of reperfusion with ischemic preconditioning (IP) or without (C). Values are mean ± standard error of the mean, n = 14 (IP) or n = 15 (C). (ADP = adenosine diphosphate; AMP = adenosine monophosphate; ATP = adenosine triphosphate; GTP = guanosine triphosphate; NAD = nicotinamide adenine dinucleotide; NADP = nicotinamide adenine dinucleotide phosphate; PCr = phosphocreatine; TAN = total adenine nucleotide.)

 


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  		Fig 5. . Release of purine catabolites from the heart during reperfusion after prolonged hypothermic ischemia in the control (C) and ischemic preconditioning (IP) groups or after 5 minutes of preconditioning ischemia in the ischemic preconditioning group. Values are mean ± standard error of the mean, n = 14 (IP) or n = 15 (C). (Ado = adenosine; Hx = hypoxanthine; Ino = inosine; TP = total purine; UA = uric acid; X = xanthine; *p < 0.05; **p < 0.01 compared with control.)

 
Endothelial Function
The extent of coronary flow increase induced by 5-HT before and after preservation was similar in both groups (Fig 6Go). The percentage increases in coronary flow were 32% ± 7% and 37% ± 9% before ischemia and 18% ± 7% and 24% ± 4% after ischemia in the IP and control groups, respectively.



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  		Fig 6. . Endothelial function evaluated as vasodilatory response to the infusion of 10 µmol/L 5-hydroxytryptamine evaluated before and after 30 minutes of reperfusion following prolonged hypothermic ischemia in the control (C) and ischemic preconditioning (IP) groups. Values are mean ± standard error of the mean, n = 9 (IP) or n = 10 (C).

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
We have demonstrated that IP can produce an additional cardioprotective effect in combination with cardioplegic arrest and hypothermia. However, the extent of added protection from preconditioning is relatively small in comparison to that observed after unprotected normothermic ischemia [2, 5, 8, 9]. This beneficial effect was reflected by improved preservation of diastolic function of the heart, but no change in systolic functional recovery was observed (see Figs 2, 3GoGo). Diastolic function has been reported to be more sensitive to ischemic damage, and its deterioration occurs earlier than systolic dysfunction [13]. One of the important factors involved in the decline of diastolic function after ischemia is interstitial edema, which may occur especially with the "extracellular" type of crystalloid cardioplegic solutions [18], as used in this study. The mechanism of the protective effect of preconditioning on diastolic function remains unknown. Such an effect could be due to reduction of edema or improved metabolic function of the myocardium.

The rate-pressure product has been used widely as an index of both mechanical function of the heart and myocardial energy turnover. In our experiments, this index recovered better after IP as the result of increased heart rate in the IP group. This result suggests that both the impulse-generating system and contractile cells are better preserved after IP. In line with this interpretation, the spontaneous recovery from ventricular fibrillation during reperfusion was quicker in hearts subjected to IP (data not shown). This is in agreement with previous studies showing that preconditioning can reduce reperfusion arrhythmias [19].

The release of purine catabolites during reperfusion was 30% lower after IP, but there was no difference in ATP concentration in the IP group at the end of the protocol. Purine catabolite release, and particularly inosine in crystalloid perfusion systems, provides a very sensitive measure of ischemic damage, which correlates closely with the extent of adenine nucleotide pool depletion in the heart [20, 21]. One could thus conclude that the decrease of the adenine nucleotide pool during cardioplegic preservation was slower in the IP group. Lack of differences in ATP concentration at the end of the protocol may have resulted from a loss of the nucleotide pool during the preconditioning phase (see Fig 5Go). The question thus remains whether this slower decrease of the adenine nucleotide pool during cold ischemia in the IP group could be interpreted as evidence of improved protection. We believe that in addition to a lower starting value of the nucleotide pool, other mechanisms were involved in this reduced purine production, including changes in myocardial energetics [22] or alterations in enzymes of purine degradation. This observation still indicates improved protection.

Preservation of the coronary endothelium is another important target for protection of the heart during cardiac operations. Poor preservation of coronary endothelium results in increased resistance of coronary vessels and insufficient perfusion, observed as the no-reflow phenomenon [23]. A very sensitive marker of endothelial function is 5-HT. In the intact endothelium, 5-HT causes vasodilation mediated by nitric oxide release, whereas if the endothelium is damaged, 5-HT exerts its effect directly on smooth muscle cells, causing vasoconstriction [24, 25]. In our experimental setting, the endothelium-mediated vasoactive response to 5-HT was unchanged by IP (see Fig 5Go). It is important to note that even a short period of ischemia such as the preconditioning phase may exert detrimental effects on the endothelium [26]. The similar outcome of endothelial function in the IP and control groups indicates that preconditioning neither reduces nor exacerbates ischemic endothelial damage in this model.

One important consideration is the method of induction of IP. Our experimental design was based on the observations of Li and Kloner [27] and Downey [28], who reported that for rabbits and rats, a single 5-minute ischemic period is sufficient to produce IP. Alkhulaifi and colleagues [7] suggested that the minimum period of reperfusion necessary to induce IP is between 30 seconds and 1 minute. On the other hand, it was demonstrated that if the reperfusion time after preconditioning exceeds 2 hours, the beneficial effect of preconditioning is lost [28]. In a preliminary series of experiments, in addition to the final protocol, we have also used three periods of 5-minute ischemia with 10-minute reperfusion intervals to induce preconditioning, but the ATP level was lower and functional outcome was not significantly different from that in the group without preconditioning (not shown). Because of these findings, we chose a single 5-minute ischemic period and 10 minutes of reperfusion.

Despite the clear evidence of improvement of diastolic function in the IP group, the extent of protection appears to be smaller compared with preconditioning in other experimental settings that do not include hypothermia or cardioplegia [2, 5, 8, 9]. Several mechanisms may be responsible for this. Cardioplegic arrest with or without hypothermia may act by protective mechanisms similar to those involved in preconditioning. Another consideration may be the short time of protection produced by preconditioning, which may not be sustained throughout the prolonged period of cardioplegic preservation.

In conclusion, preconditioning as an adjunct to cardioplegic arrest and hypothermia can exert an additional protective effect, which results in improvement of diastolic function and heartbeat frequency. Development of pharmacologic methods of inducing preconditioning that could avoid the negative aspects of brief periods of ischemia may further enhance this effect.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
We thank The Harefield Heart Transplant Trust and The British Heart Foundation for financial support.


   Footnotes
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 Footnotes
Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Address reprint requests to Prof Yacoub, Department of Cardiothoracic Surgery, National Heart and Lung Institute, Harefield Hospital, Harefield, Middlesex UB9 6JH, United Kingdom.


   References
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 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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