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J Thorac Cardiovasc Surg 1996;111:613-620
© 1996 Mosby, Inc.

CARDIOPULMONARY BYPASS,
MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

TRANSIENT REPERFUSION WITH ACIDIC SOLUTION AFFECTS POSTISCHEMIC FUNCTIONAL RECOVERY: STUDIES IN THE ISOLATED WORKING RAT HEART

Takeki Ohashi, MD*, Fumio Yamamoto, MD, Hiroshi Yamamoto, MD, Hajime Ichikawa, MD, Toshihiko Shibata, MD, Yasunaru Kawashima, MD

From the Department of Cardiovascular Surgery, National Cardiovascular Center, Osaka, Japan.

Received for publication Sept. 2, 1994 Accepted for publication June 1, 1995. Address for reprints: Fumio Yamamoto, MD, Department of Cardiovascular Surgery, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565, Japan.

Abstract

This isolated working rat heart study was designed to investigate the effect of duration of reperfusion and degree of acidity of the reperfusate on myocardial protection. The experimental time course was as follows: 20 minutes of perfusion with the heart working, 3 minutes of infusion with the St.Thomas' Hospital cardioplegic solution followed by global ischemia for 33 minutes at 37º C, and 20 minutes of Langendorff reperfusion followed by 20 minutes of working perfusion. During the initial 3 minutes of Langendorff reperfusion, the pH of the reperfusate was changed to 5.6, 6.8, and 7.5 by addition of sodium hydroxide into Krebs-Henseleit nonbicarbonate HEPES buffer. A respiratory acidic reperfusate was used for the initial 0.5, 1, 2, 3, 5, and 15 minutes during reperfusion. The results were as follows: (1) Reperfusion with a mildly acidic solution (i.e., pH 6.8) yielded better recovery than reperfusion with solutions having pH levels of 5.8 or 7.5. (2) Reperfusion for less than 3 minutes with a reperfusate having a pH level of 6.8 provided better recovery, although reperfusion for longer than 3 minutes exacerbated reperfusion injury. In conclusion, the effects of reperfusion with acidic solution were influenced by degree and duration with biphasic response characteristics. (J THORAC CARDIOVASC SURG 1996;111:613-20)

Reperfusion injury of ischemic myocardium is an important problem in clinical and surgical situations. In cardiac surgery, modification of reperfusate to protect against reperfusion injury is thought to be one of the important strategies to avoid reperfusion injury.Go Go 1-9 Recently, protective effects of transient reperfusion with acidic solution have been reported by some investigators,Go Go 10,11 although whether acidic reperfusion is protective is still controversial. The effects of acidosis on myocardium involve many factors such as ion exchange, ion channels, energy metabolites, and affinity of calcium to troponin.Go Go 12-15 These factors might affect more complicated influenceson myocardium especially during reperfusion. Therefore the aim of this study of the isolated working rat heart was to investigate the optimal modification of the acidic reperfusate in terms of the degree of acidity and the duration of reperfusion. The current study showed that transient acidic reperfusion affected postischemic functional recovery with degree (pH level) and duration response characteristics.

Materials and methods

Experimental model(Fig. 1)
Hearts were obtained from male Wistar rats (270 to 320 gm body weight). The isolated perfused working heart model is a left heart preparation in which oxygenated perfusion medium at 37º C enters the cannulated left atrium at a pressure equivalent to 15 cm H2O and is passed to the left ventricle. It is spontaneously ejected (electrical pacing was not used inthis study) from the left ventricle through an aortic cannula against a hydrostatic pressure equivalentto 100 cm H2O. Coronary effluent exits from the right side of the heart and can be sampled for biochemical analysis or pooled and recirculated with the aortic flow.



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  		Fig. 1. Experimental model. The isolated perfused working heart model is a left heart preparation in which oxygenated perfusion medium enters the cannulated left atrium at a pressure equivalent to 15 cm H2O and is passed to the left ventricle. It is spontaneously ejected from the left ventricle via an aortic cannula against a hydrostatic pressure equivalent to 100 cm H2O. Coronary effluent exits from the right side of the heart and can be sampled for biochemical analysis or pooled and recirculated with the aortic flow. In the Langendorff mode, the left atrial cannula and arterial tube connected to the arterial chamber were clamped and the heart was perfused in a retrograde fashion arterially from a reservoir located 100 cm above the heart. Ischemic cardiac arrest was induced by clamping the aortic cannula and left atrial cannula.

 
In the Langendorff nonworking mode, the atrial cannula is clamped and perfusion fluid at 37ºC is allowed to flow into the aorta from a reservoir located 100 cm above the heart. This preparation, originally described by Langendorff, will continue to beat but does not perform external work, which is a condition similar to that produced by total cardiopulmonary bypass during cardiac operations. Ischemic cardiac arrest can be induced in this preparation by clamping the aortic cannula. Short periods of preischemic coronary infusion (at 37º C) of cardioplegic solution can be achieved by the use of a reservoir located 60 cm above the heart and attached to a side arm of the aortic cannula. During the period of global ischemia the heart is maintained in a sealed, temperature-regulated (37º C) chamber.

Perfusion solution
The perfusion solution was the standard Krebs-Henseleit bicarbonate buffer solution containing (in millimoles per liter) NaCl, 118.5; NaHCO3, 25; KCl, 4.8; KH2PO4, 1.2; MgSO4, 1.2; 2.5 CaCl2, 2.5; and glucose, 11. The control solution was adjusted to a pH of 7.5 by equilibration with a gas mixture containing 5% carbon dioxide and 95% oxygen. Bicarbonate-free solution, which was replaced by sodium chloride, contained a 10 mmol/L concentration of N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) and was titrated with sodium hydroxide at 37º C to a pH of 7.4, 6.8, or 5.6. Also, the bicarbonate-free solution was saturated with 100% oxygen. Respiratory acidic solution was changed to pH 6.8 by equilibration with a gas mixture containing 25% carbon dioxide and 75% oxygen. The cardioplegic solution was St. Thomas' Hospital cardioplegic solution No. 2 containing(in millimoles per liter) NaCl, 110; NaHCO3, 10; KCl, 16; MgCl2, 16; and CaCl2, 1.2.

Basic protocol
Hearts were subjected to 5 minutes of Langendorff perfusion, 20 minutes of aerobic working perfusion, 3 minutes of cardioplegic infusion (at 37º C) with St. Thomas' Hospital cardioplegic solution, and 33 minutes of ischemic arrest at 37º C. Hearts were then reperfused in theLangendorff mode for 20 minutes and then in the working mode for 20 minutes (37º C).

Experimental protocol(Fig. 2)
1. Pilot study
To exclude the possibilities of irreversible harmful effects of acidosis on the normoxic perfused heart, we perfused the hearts with respiratory acidic solution for 15 minutes followed by normal perfusion.



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  		Fig. 2. Experimental protocol. Hearts were subjected to 20 minutes of aerobic working perfusion, 3 minutes of cardioplegic infusion with St. Thomas' Hospital cardioplegic solution, and 33 minutes of ischemic arrest at 37º C. Hearts were then reperfused in the Langendorff mode for 20 minutes and then in the working mode for 20 minutes. During reperfusion, conditions of acidic reperfusion were modified in terms of pH level and duration. In the pH study, the pH of the reperfusion solution during the initial 3 minutes of reperfusion was changed to 7.5, 6.8 and 5.6 of the bicarbonate-free HEPES buffered solution. In the duration study, duration of initial high carbon dioxide respiratory acidic reperfusion was changed to 0.5, 1, 2, 3, 5, and 15 minutes. L, Langendorff perfusion; W, working perfusion; S, 3 minutes of infusion with St. Thomas' Hospital cardioplegic solution.

 
2. pH study
During the initial 3 minutes of reperfusion after 33 minutes of normothermic ischemia, during which the hearts were preserved with St. Thomas' Hospital cardioplegic solution, hearts were reperfused with HEPES buffered solution at three different pH levels (5.6, 6.8, and 7.5). We selected bicarbonate-free HEPES buffer to maintain the concentration of bicarbonate and carbon dioxide when pH was changed.

3. Duration study
The duration of initial reperfusion with respiratory acidic solution (pH 6.8) was divided into six groups—0.5, 1, 2, 3, 5, and 15 minutes—and the results were compared with those in the control reperfusion group. We selected a Krebs-Henseleit bicarbonate buffer solution high in carbon dioxide, because this respiratory acidic solution has a rapid effect on myocardial pH.Go 16

Measurement
Cardiac indices such as aortic flow, coronary flow, cardiac output, aortic pressure, heart rate, and stroke work were measured before and after the working period, and functional recoveries were expressed as percentage of initial functional performances. Cardiac output was derived from the sum of the aortic flow and the coronary flow, and stroke work was calculated by multiplying the cardiac output by the aortic pressure divided by the heart rate. Creatine kinase leakage into the coronary effluent during the initial 20-minute reperfusion period was measured by the Oliver U.V. method.Go 17

Statistical analysis
Nine rats and 10 rats were used for the control group in the pH study and the duration study, respectively, and six rats were used for the other groups. Results were expressed as means ± standard error of the mean. All levels of statistical significance were calculated by means of analysis of variance in each study, and Dunnett's t tests were then performed. Values of p < 0.05 were considered to be significant.

Results

1. Pilot study
Hearts subjected to acidic solution for 15 minutes recovered to pretreatment baseline levels and had no leakage of creatine kinase.

2. pH study
GoTable I shows the preischemic cardiac function in the pH study.No significant differences were detected among these groups.GoTable II shows the functional recoveries of cardiac indices and creatine kinase leakage during reperfusion in the pH study.The hearts subjected to reperfusion with HEPES buffered solution at pH levels of 5.6, 6.8, and 7.5 for the initial 3 minutes recovered to 50.9% ± 3.2%, 65.9% ± 1.8%, and 57.8%± 1.5% of preischemic cardiac output, respectively(Fig. 3). The percent recovery of cardiac output was highest in the hearts reperfused at a pH of 6.8 and lowest in those reperfused at a pH of 5.6. The changes reach statistical significance. Creatine kinase leakage during the initial 15 minutes of reperfusion in the hearts reperfused at a pH of 6.8 was the lowest.


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  		Table I. Preischemic cardiac function (pH study)
 

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  		Table II. Postischemic functional recovery and creatine kinase leakage (pH study)
 


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  		Fig. 3. Percent recovery of cardiac output in the pH study.

 
3. Duration study
GoTable III shows preischemic cardiac function in the duration study. No significant differences were detected among these groups.GoTable IV shows the functional recoveries of cardiac indices and creatine kinase leakage during reperfusion.Varying the duration of reperfusion with respiratory acidic solution (pH 6.8) resulted in a biphasic time-response functional recovery. In the hearts reperfused with control Krebs-Henseleit bicarbonate buffer solution with a pH of 7.5, cardiac output recovered to 54.0% ± 0.7%. The hearts reperfused with acidic solution for an initial 0.5, 1, 2, 3, 5, or 15 minutes recovered to 51.7%± 3.3%, 64.5% ± 3.8% (p < 0.05 vs control), 59.8% ± 3.6%, 56.7% ± 1.9%, 43.1% ± 2.9% (p < 0.05 vs control), and 43.6% ± 2.4% (p < 0.05 vs control) of preischemic control values, respectively(Fig. 4). Recoveries of aortic flow in the hearts subjected to acidic reperfusion for 0.5, 1, 2, 3, 5 or 15 minutes were 44.8% ± 4.0%, 58.0% ± 4% (p < 0.05 vs control [45.7% ± 0.6%]), 55.8% ± 4.2% (p < 0.05 vs control [45.7% ± 0.6%]), 52.8% ± 2.7%, 37.1% ± 3.5% (p < 0.05 vs control [45.7% ± 0.6%]), and 35.7% ± 2.6% (p < 0.05 vs control [45.7% ± 0.6%]), respectively. When acidic reperfusion was used for less than 3 minutes, percent recovery of cardiac output was greater than with control reperfusion. However, in the hearts reperfused with acidic solution for more than 3 minutes, recovery was poorer than with control reperfusion. Creatine kinase leakage during 15 minutes of reperfusion was reflected by the percent recovery of cardiac function, although the difference was not statistically significant.


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  		Table III. Preischemic cardiac function (duration study)
 

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  		Table IV. Postischemic functional recovery and creatine kinase leakage (duration study)
 


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  		Fig. 4. Percent recovery of cardiac output in the duration study.

 
Discussion

During cardiac operations, optimizing the extracellular environment during reperfusion can help to avoid reperfusion injury.Go Go 1-9 Unlikecardioplegic solutions, whose compositions have been widely investigated,Go Go 18,19 the optimal pH of reperfusion solutions has not been widely investigated.Go Go Go 3,4,11 Our study was designed to evaluate the effects of extracellular modification of pH on ischemic myocardium preserved with St. Thomas' Hospital cardioplegic solution in terms of functional recovery and creatine kinase leakage.

The optimal pH of bicarbonate-free HEPES buffer solution for the initial 3 minutes of reperfusion to protect against reperfusion injury was 6.8. Recovery was better in the hearts reperfused with respiratory acidic solution within 3 minutes than in control hearts, but reperfusion for longer than 3 minutes was harmful. Thus for 3 minutes the effects of acidic reperfusion on postischemic hearts were significantly influenced by degree of acidosis (pH level) and duration of perfusion. In the pH study, we selected bicarbonate-free HEPES buffer to maintain the concentration of bicarbonate and carbon dioxide when pH was changed. In the duration study, we selected a Krebs-Henseleit bicarbonate buffer solution with a high carbon dioxide content, because this respiratory acidic solution has a rapid effect on myocardial pH.Go 16 The different types of acidic solutions might have different influences on myocardium.Go Go 20,21 In our previous study, we found that hearts reperfused with bicarbonate-free HEPES buffer recovered better than those reperfused with bicarbonate buffer. This suggests that bicarbonate-dependent intracellular pH regulation was one of the factors that alter reperfusion injury.Go 22 In this respect, if we had chosen the bicarbonate-free HEPES buffer instead of the respiratory acidic solution in the duration study, we would not have obtained the same results. However, we believe that we obtain almost the same biphasic duration-response characteristics with the acidic reperfusate.

Previous reports considering modification of pH in reperfusate
In the early 1980s Follette and coworkersGo Go 1,3 reported that raising pH to 7.8 in the reperfusate during the initial 5 minutes of reperfusion improved functional recovery of hypothermic ischemic dog hearts. It has since been widely accepted that the optimal and reasonable modification of extracellular pH to salvage the ischemic heart is to make the pH more alkaline, which immediately neutralizes the acidosis of the ischemic myocardium. Similarly, Menasché and coworkersGo 4 reported that in the isolated perfused rat heart after 2 hours of cardioplegic arrest, a glutamate-buffered reperfusate at pH 7.7 for 3 minutes provided better recovery of cardiac performance than the same buffer at pH 7.4. They also reported the protective effect of asanguineous reperfusion solutions in the clinical situation.Go 5 Milliken, Billingsley, and LaksGo 6 reported the protective effect of modified reperfusate (potassium 22 millimoles per liter, pH 7.8) for 10 minutes on a canine heart subjected to prolonged hypothermia. However recently, Kitakaze, Weisfeldt, and MarbanGo 10 demonstrated that transient acidic reperfusion (an initial 3 minutes at a pH of 6.6 and after 2 minutes at a pH of 7.0) prevented myocardial stunning in ferret hearts made ischemic for 15 minutes. Similarly, Avkiran and IbukiGo 11 reported that transient reperfusion with acidic solution helped to prevent reperfusion-induced arrhythmia. Hori and coworkersGo 23 observed that acidosis during staged reperfusion attenuated myocardial stunning in dogs. Harada and associatesGo 24 contributed the protective effect of acidic solution to prevent an increase in intracellular calcium during reperfusion.

The discrepancy in these results is attributable not only to a difference in experimental species and models but also to the many different conditions of acidic reperfusion. Our result, demonstrating that the effects of acidic reperfusion are influenced by the different conditions, is consistent with previous reports.

Protective effects of mildly acidic solutions and short periods of reperfusion
The possible mechanism of the protective effect of acidic solutions is thought to be the prevention of calcium overload during reperfusion. At the onset of reperfusion, a rapid increase in intracellular pH is associated with sodium intrusion by way of sodium-proton exchange.Go Go 25-28 An increase in the intracellular concentration of sodium ion that cannot be pumped out of a cell as a consequence of the depression of sodium potassium adenosine triphosphatase leads to massive calcium intrusion by a sodium-calcium exchange.Go Go 29,30 Consequently sodium-calcium exchange and sodium-proton exchange induced by proton extrusion from acidic myocardium play key roles in myocardial injury during reperfusion. This is called the pH paradox.Go Go 27,28 Acidosis, which is thought to inhibit both sodium-proton exchange and sodium-calcium exchange,Go 31 prevents an overload of sodium and calcium by inhibition of these exchanges.Go 24 In addition, acidosis influences the decrease in the accumulation of intracellular calcium via a calcium inward currentGo 32 and a calcium-induced calcium release from the sarcoplasmic reticulum.Go Go 14,33 Therefore slowing or delaying of pH recovery by acidic reperfusion is thought to help to prevent the pH paradox and to attenuate calcium overload.Go Go Go 10,11,26

Second, an important possible protective mechanism of acidic reperfusion is the reduction of the calcium-binding ability of troponin.Go Go 34,35 During reperfusion, myocardial rigor caused by intracellular calcium overload might be prevented because of reduction of the calcium-binding ability of troponin.Go 13

Third, acidosis is thought to decrease the energy demand and reduce the use of adenosine triphosphate by reducing the heart contractility.Go Go 10,12

Since Bing, Brooks, and MesserGo 36 reported the protective effect of acidosis on the hypoxic rat heart, the protective effect of mild acidosis has been observed by many other investigators.Go Go 36-38Koop and PiperGo 37 demonstrated that mild acidosis (around pH7.0) had a prominent energy-saving effect on the hypoxic heart. Bak and IngwallGo 39 suggested that inhibition of 5'-nucleotidase by acidosis during ischemia preserved adenosine triphosphate and prevented reperfusion injury.

Harmful effects of severely acidic solutions and longer periods of reperfusion
The most important point in the current results is that reperfusion of acidic solution has biphasic and opposite effects on the heart after ischemia. Although acidic reperfusion has been reported to attenuate reperfusion injury, our observation showed that a severely acidic reperfusate or longer periods of acidic reperfusion had a detrimental effect on the reperfused heart. Acidosis in general suppresses many metabolic pathways that are essential to maintain homeostasis of myocardium, including sodium-potassium adenosine triphosphatase activity.Go 12 In this respect, the inhibition of a sodium pump by acidosis during reperfusion may have detrimental effects on postischemic myocardium. We observed that a long period of reperfusion with acidic solution was detrimental. Myocardial recovery is better if the start of pH recovery (pH paradox) is delayed for 3 minutes, although inhibition of metabolism for more than 3 minutes during reperfusion may be harmful.

Interestingly, Allen and OrchardGo 13 demonstrated that the response of myocardium to acidosis was influenced by duration. In the myocardium subjected to acidic perfusion at an early phase, a decrease of calcium binding to troponin and a decrease of calcium release from sarcoplasmic reticulum were observed. At a late phase, calcium overload caused by a calcium release from the troponin binding site replaced by hydrogen was observed. The bell-shaped duration response curve observed in our acidic reperfusion study supports their observation.

Limitation of this study
Several limitations of this study should be addressed. This study was conducted in the asanguineous isolated rat heart preparation. Recent workGo 40 suggested that a blood-perfused heart is more closely related to the clinical situation than a crystalloid-perfused heart. It is recognized that the blood-perfused heart is different from the crystalloid-perfused heart in terms of the buffering capacity, hormonal effect, viscosity, white blood cell count, and other blood-containing factors. However, the blood-containing factors may not have an adverse influence on the effect of acidic reperfusion, which is mainly mediated by ion exchange systems and intracellular functions, as discussed earlier. Further studies of a blood-perfused model and in vivo model will be necessary before this technique can be applied clinically. Furthermore, Krebs-Henseleit bicarbonate buffer used in this study has been widely used for cardiac research; however, the concentration of calcium (2.5 millimoles per liter) and pH (7.5) may not be relevant to the clinical situation. In addition, we used normothermic global ischemia with St. Thomas' Hospital cardioplegic solution as the myocardial protectant. It is conceivable that a different type of myocardial protection may produce different results.

Conclusion

After normothermic global ischemia of rat hearts and preservation with the St. Thomas' Hospital cardioplegic solution, transient reperfusion with acidic solution affected postischemic functional recovery with biphasic duration and degree response characteristics. Brief reperfusion (within 3 minutes) with mildly acidic solution (pH 6.8) had protective properties; prolonged reperfusion (more than 3 minutes) with severely acidic solution (pH 5.6) was harmful compared with control reperfusion. To our knowledge, no other reports assessing the modulation of acidic reperfusion have been published. As a result of our study, when we use reperfusion solution or terminal cardioplegia (hot shot) in patients, we must consider both duration of reperfusion and acidity of the solution.

Acknowledgments

We thank Dr. George Smith for assistance in preparing the manuscript.

Footnotes

*Present address: 197-4 Kannonji Kokuhu-cho, Tokushima-city 779-31, Japan. Back

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F. P. Tritto, J. Inserte, D. Garcia-Dorado, M. Ruiz-Meana, and J. Soler-Soler
Sodium/Hydrogen Exchanger Inhibition Reduces Myocardial Reperfusion Edema After Normothermic Cardioplegia
J. Thorac. Cardiovasc. Surg., March 1, 1998; 115(3): 709 - 715.
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