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Ann Thorac Surg 1996;62:1397-1403
© 1996 The Society of Thoracic Surgeons

Original Article: Cardiovascular

Preconditioning Improves Cardiac Function After Global Ischemia, But Not After Cold Cardioplegia

Guro Valen, MD, Shigeto Takeshima, MD, Jarle Vaage, MD

Department of Thoracic Surgery, Karolinska Hospital, Stockholm, Sweden

Accepted for publication June 14, 1996.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Ischemic preconditioning reduces infarct size and cardiac dysfunction during reperfusion. Preconditioning may offer myocardial protection in open heart operations.

Methods. The effect of preconditioning before ischemia and cardioplegia was investigated in Langendorff-perfused rat hearts in the following groups. First, group 1 received two episodes of 3-minute ischemia and 5-minute reperfusion before 25 minutes of global (37°C) ischemia and 60 minutes of reperfusion. Group 2 served as ischemic controls to group 1. Groups 3, 5, and 7 were preconditioned as described, before 3.5, 4, or 5 hours of cold (6° to 8°C) St. Thomas' II cardioplegia and 1 hour of reperfusion (37°C). Groups 4, 6, and 8 were cardioplegic controls to groups 3, 5, and 7 (n = 17 in groups 1 and 2, and n = 10 in groups 3 to 8).

Results. Preconditioning before warm ischemia attenuated the ischemia-induced increase of left ventricular end-diastolic pressure (3 ± 1 versus 17 ± 4 mm Hg; p < 0.01) (mean ± standard error of the mean), the reduction of coronary flow (14 ± 1 versus 9 ± 0.5 mL/min; p < 0.001) and heart rate (252 ± 19 versus 198 ± 18 beats/min; p < 0.04), and the incidence of ventricular fibrillation (2 of 17 versus 10 of 17 hearts; p < 0.04) at the start of reperfusion. However, preconditioning did not influence postischemic cardiac function or the release of lactate dehydrogenase in any of the cardioplegia groups.

Conclusions. Ischemic preconditioning improved postischemic cardiac function after warm global ischemia, but did not protect cold cardioplegic hearts, perhaps because of the time span used.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Brief episodes of ischemia before a longer ischemic insult, termed preconditioning, have cardioprotective effects [1, 2]. Ischemic preconditioning limits infarct size, attenuates ischemia-induced as well as reperfusion-induced arrhythmias, and improves postischemic ventricular function [1, 2]. Most of the studies conducted have investigated the effects of preconditioning on regional myocardial ischemia. Increasing evidence suggests that preconditioning improves cardiac function also in models of global ischemia [3–6].

Despite regimens of myocardial protection, postcardioplegic cardiac failure is an important cause of morbidity and mortality in cardiac operations [7]. Ischemic preconditioning before cardioplegia may offer additional cardiac protection. Reports on the effects of preconditioning in conjunction with hypothermia or cardioplegia are few, but controversial [8–14].

The purpose of this study was to investigate whether preconditioning improves postischemic cardiac function in a model of cold cardioplegia in isolated rat hearts.


   Material and Methods
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Heart Perfusion
The study was approved by the Ethics Committee for Animal Research at the Karolinska Institute, and the animals were cared for according to the "Principles of Laboratory Animal Care" by the National Society for Medical Research.

Male Sprague Dawley rats (200 to 300 g) were anesthetized with diethyl ether, and 200 IU heparin was injected into the femoral vein. The hearts were rapidly excised through a median sternotomy and placed in ice-cold buffer during preparation for aortic cannulation. Retrograde perfusion with gassed (5% CO2, 95% O2) Krebs-Henseleit buffer (NaCl, 118.5 mmol/L; NaHCO3, 25.0 mmol/L; KCl, 4.7 mmol/L; KH2PO4, 1.2 mmol/L; MgSO4 • 7H2O, 1.2 mmol/L; glucose • H2O, 11.1 mmol/L; CaCl2 • 2H2O, 1.8 mmol/L) was performed in a modified Langendorff model. Perfusion pressure was kept constant at 100 cm H2O. A balloon was inserted into the left ventricle through the left atrium for isovolumetric recording of left ventricular systolic pressure (LVSP) and end-diastolic pressure (LVEDP). Coronary flow (CF) was measured by timed collections of the coronary effluent. Heart rate (HR) was counted from the pressure curves. Only major arrhythmias such as ventricular fibrillation (VF) were recorded. The VF ratio was calculated as the number of hearts with VF divided by the number of hearts in the groups. Time to onset of pressure-generating beating during reperfusion (ie, end of VF) was registered in experiment series 2. Rate-pressure product (RPP) was calculated as: RPP = LVSP x HR. Water jackets around the perfusate reservoirs and heart chamber kept the temperature at 37°C during stabilization, the preconditioning period, and reperfusion in series 2, and throughout the experiments in series 1. Global ischemia was induced by clamping the inflow tubing. Hypothermia was initiated by switching rapidly from the 37°C water bath to a heater-cooler (Sarns Inc, Ann Arbor, MI), which kept the temperature in the water jacket around the heart chamber between 4° and 8°C. Cold (4° to 6°C) St. Thomas' II cardioplegia solution was infused through a side arm in the aortic cannula at a pressure of 70 cm H2O for 5 minutes to induce cardioplegic arrest. A single infusion of cardioplegic solution was given. The core temperature of the hearts (assessed by a thermistor probe in the left ventricle) was maintained between 6° and 8°C during cardioplegia.

Experimental Protocol
The hearts were stabilized for 20 minutes before the start of the experiments. Only hearts with LVSP between 60 and 160 mm Hg, LVEDP 0 mm Hg, CF 8 to 15 mL/min, and HR 240 to 340 beats/min at the end of stabilization were included. The following groups were studied (Fig 1Go).



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  		Fig 1. . Experimental protocol. Rat hearts were perfused in a retrograde manner for a 20-minute stabilization period (stab), and then preconditioned (precond) with two episodes of 3-minute global ischemia and 5-minute reperfusion (top) before 25 minutes of warm ischemia (n = 17) or 3.5, 4, or 5 hours of cardioplegia (n = 10 to 11 in each group). Control hearts were time perfused during the preconditioning episodes (bottom) before the same interventions (same number in each group).

 
SERIES 1: NORMOTHERMIC ISCHEMIA.
Group 1 (n = 17) included preconditioned hearts. This group received two episodes of global ischemia for 3 minutes followed by 5 minutes of reperfusion before 25 minutes of global ischemia and 60 minutes of reperfusion. Group 2 (n = 17) was given control perfusion with ischemia and reperfusion as in group 1.1.

Measurements of LVSP, LVEDP, CF, and HR were performed at the end of stabilization and immediately before ischemia. The same measurements and calculation of VF ratio were done 2, 5, 10, 15, 20, 40, and 60 minutes after the start of reperfusion. Calculations of RPP and VF ratio in the two groups were conducted at the same time points.

SERIES 2: COLD CARDIOPLEGIA.
Groups were as follows: (1) preconditioning before 3.5 hours of cold cardioplegic arrest and 1 hour of reperfusion (n = 10), (2) cardioplegic controls to group 1 (n = 10), (3) preconditioning before 4 hours of cardioplegia (n = 10), (4) cardioplegic controls to group 3 (n = 10), (5) preconditioning before 5 hours of cardioplegia (n = 11), and (6) cardioplegic controls to group 5 (n = 11).

Measurements of LVSP, LVEDP, CF, and HR were performed at the end of stabilization, as well as 8 and 16 minutes before cardioplegic arrest (at the end of each preconditioning episode). The same measurements were conducted 5, 10, 20, 40, and 60 minutes after the start of reperfusion. Calculations of RPP and VF ratio were conducted at the same time points. Samples of the coronary effluent (4 mL) for measurement of lactate dehydrogenase were collected at the end of stabilization and after 20 and 40 minutes of reperfusion. Lactate dehydrogenase was measured with a Cobas Bio centrifugal analyzer (Hoffman-La Roche, Switzerland) and a commercial reagent kit (Cat. no. 19153; Boehringer Mannheim, Germany) and is presented as the amount released per minute (U/min = U/mL x CF mL/min) in percentage of the initial value.

Statistics
A Mann-Whitney test for independent samples was used to evaluate differences between groups. The VF ratio was evaluated with a {chi}2 test. Values from hearts with VF were excluded from hemodynamic comparisons. Values are presented as mean ± standard error of the mean; p < 0.05 was considered significant.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Warm Ischemia
VENTRICULAR FIBRILLATION RATIO.
A majority of control hearts had VF at the start of reperfusion (10 of 17 and 8 of 17 after 5 and 10 minutes, respectively) (Fig 2Go). Although the incidence of VF improved during reperfusion, the ratio was 5 of 17 from 20 minutes onward. Preconditioning reduced the VF ratio after 5 minutes (2 of 17; p < 0.02) and 10 minutes (2 of 17; p < 0.04) of reperfusion, and the ratio was 1 of 17 after 40 minutes (not significant) (see Fig 2Go).



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  		Fig 2. . Ventricular fibrillation (VF) ratio as number of hearts with ventricular fibrillation divided by number of hearts in the groups during reperfusion of Langendorff-perfused rat hearts with (open bars) or without (closed bars) preconditioning before global warm ischemia. (*p < 0.05.)

 
LEFT VENTRICULAR SYSTOLIC PRESSURE.
Values of LVSP tended to increase at the start of reperfusion and then decreased in the ischemic controls (Table 1Go). Preconditioning reduced LVSP before the subsequent ischemia (p < 0.002) but did not influence LVSP during reperfusion (see Table 1Go).


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  		Table 1. . Left Ventricular Systolic Pressure, Heart Rate, and Rate-Pressure Product in Langendorff-Perfused Rat Hearts Without or With Preconditioning Before 25 Minutes of Global (37°C) Ischemiaa
 
LEFT VENTRICULAR END-DIASTOLIC PRESSURE.
The LVEDP increased from 0 to a maximum of 17 ± 4 mm Hg after 2 minutes of reperfusion in the controls, and thereafter gradually recovered to 3 ± 1 mm Hg after 60 minutes (Fig 3Go). Preconditioning attenuated the increase of LVEDP at all times during reperfusion (p < 0.03) (see Fig 3Go).



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  		Fig 3. . Left ventricular end-diastolic pressure (LVEDP, mean ± standard error of the mean) in Langendorff-perfused rat hearts with (circles) or without (squares) preconditioning before global warm ischemia. (BI = before ischemia; BPC = before preconditioning; *p < 0.05.)

 
CORONARY FLOW.
Preconditioning increased CF before the subsequent ischemia (15 ± 1 versus 10 ± 1 mL/min; p < 0.001) and after 2 minutes (p < 0.001) and 5 minutes (p < 0.001) of reperfusion compared with ischemic controls (Fig 4Go). Thereafter, no difference occurred between the groups.



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  		Fig 4. . Coronary flow (CF, mean ± standard error of the mean) in Langendorff-perfused rat hearts with (circles) or without (squares) preconditioning before global warm ischemia. (BI = before ischemia; BPC = before preconditioning; *p < 0.05.)

 
HEART RATE.
Preconditioning increased HR during reperfusion compared with controls, and the difference was significant after 2 minutes (p < 0.04) and 10 minutes (p < 0.04) (see Table 1Go).

RATE-PRESSURE PRODUCT.
The only significant influence of preconditioning on RPP was a reduction immediately before 25 minutes of ischemia (p < 0.001) (see Table 1Go).

Cold Cardioplegia
3.5 HOURS OF CARDIOPLEGIC ARREST.
Cardioplegia reduced LVSP, HR, CF, and RPP and increased LVEDP during reperfusion (Table 2Go). There was no difference between controls and preconditioned hearts at any time in any of the measurements, or in the VF ratio during reperfusion (see Table 2Go).


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  		Table 2. . Left Ventricular Systolic and End-Diastolic Pressures, Coronary Flow, Heart Rate, and Rate-Pressure Product in Langendorff-Perfused Rat Hearts Subjected to 3 Hours of Cold (4°C) Cardioplegic Arrest Without or With Preconditioning Before Cardioplegiaa
 
4 HOURS OF CARDIOPLEGIC ARREST.
Cardioplegia reduced LVSP, RPP, HR, and CF and increased LVEDP during reperfusion. There was no effect of preconditioning at any time (Table 3Go).


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  		Table 3. . Left Ventricular Systolic and End-Diastolic Pressures, Coronary Flow, Heart Rate, and Rate-Pressure Product in Langendorff-Perfused Rat Hearts Subjected to 4 Hours of Cold (4°C) Cardioplegic Arrest Without or With Preconditioning Before Cardioplegiaa
 
5 HOURS OF CARDIOPLEGIC ARREST.
Preconditioning did not attenuate the reduction of LVSP, CF, HR, or RPP induced by cardioplegia. Furthermore, preconditioning did not influence the VF ratio (Table 4Go).


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  		Table 4. . Left Ventricular Systolic and End-Diastolic Pressures, Coronary Flow, Heart Rate, and Rate-Pressure Product in Langendorff-Perfused Rat Hearts Subjected to 5 Hours of Cold (4°C) Cardioplegic Arrest Without or With Preconditioning Before Cardioplegiaa
 
TIME TO ONSET OF PRESSURE-GENERATING BEATING.
Ischemic preconditioning did not reduce the time to onset of pressure-generating beating during reperfusion after any interval of cardioplegia. Time to onset of pressure-generating beating was slightly longer after 4 hours than after 3.5 hours of cardioplegia in the controls, and was longer after 5 hours than after 4 hours (p < 0.02) (Fig 5Go).



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  		Fig 5. . Seconds to onset of pressure-generating beating (mean ± standard error of the mean) during reperfusion of isolated rat hearts subjected to 3.5, 4, or 5 hours of cold (4°C) cardioplegic arrest without (closed bars) or with (open bars) preconditioning before cardioplegia. There was no difference between preconditioned and control hearts. (*p < 0.05 for comparison between 4 and 5 hours in controls.)

 
RELEASE OF LACTATE DEHYDROGENASE.
Baseline release of lactate dehydrogenase at the end of stabilization was 19 ± 2, 14 ± 2, 25 ± 5, 16 ± 2, 12 ± 1, and 15 ± 2 U/min in cold cardioplegia groups 1 to 6, respectively. Release of lactate dehydrogenase after cardioplegia was not significantly influenced by preconditioning (Fig 6Go).



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  		Fig 6. . Release of lactate dehydrogenase as percentage of initial value in the coronary effluent of Langendorff-perfused rat hearts subjected to 3.5, 4, or 5 hours of cold cardioplegic arrest without (closed bars) or with (open bars) preconditioning before cardioplegia. Values before preconditioning (0) and after 20 and 40 minutes of reperfusion are shown (mean ± standard error of the mean). There were no differences between preconditioned and control hearts.

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Preconditioning attenuated the incidence of VF, the increase of LVEDP, and the reduction of CF and HR seen during reperfusion after normothermic global ischemia. These findings are in accordance with previous studies in similar models [3–6] and demonstrate that our model of preconditioning was cardioprotective. However, preconditioning was not cardioprotective after cold cardioplegia. We used three different intervals of cardioplegia to ensure that the lack of effect of preconditioning was not due to an overly short or long time of arrest.

Preconditioning neither improved functional recovery nor reduced the myocardial release of lactate dehydrogenase from the postcardioplegic rat heart. In a previous study, Illes and co-workers [10] found that preconditioning before cold (4°C) crystalloid cardioplegia improved left ventricular systolic and diastolic function and reduced the release of creatine kinase from isolated rabbit hearts. However, small groups (n = 6) and parametric statistics were used in the study [10]. In addition, there are major species differences in the mechanisms and effects of preconditioning [2], which may further explain the difference between the present and previous [10] findings. Two other studies combining preconditioning and cardioplegia at higher temperatures than ours (34°C and 37°C) in rat [12] or rabbit [13] hearts found no improvement of subsequent postcardioplegic function. In a rat model of moderate hypothermia (20°C) and cardioplegia, Cave and Hearse [9] found that preconditioning improved functional recovery and reduced leakage of creatine kinase during reperfusion. Preconditioning also improved the recovery of aortic flow during reperfusion after different durations of cold (20°C) global ischemia (without hyperkalemic cardioplegia) in working rat hearts [8]. The discrepancy of results in the present study and in previous reports [8–12] may imply that preconditioning offers only marginal protection in conjunction with cardioplegia. This is not because cardioplegia offers optimal myocardial protection, as functional, ultrastructural, and biochemical signs of ischemia-reperfusion injury are seen after release of the aortic cross-clamp in cardiac operations [7]. However, hypothermia, hyperkalemia, or a combination of the two may influence the mechanisms by which preconditioning protects. When combining preconditioning with intermittent cross-clamping with VF (37°C) in patients, Yellon and associates [13] found that brief episodes of aortic cross-clamping improved the myocardial content of adenosine triphosphate. The same procedure did not influence myocardial adenosine triphosphate content when the patients were cooled to 32°C [14]. Intermittent cross clamping improved postischemic ventricular function and myocardial content of adenosine triphosphate in dogs undergoing cardiopulmonary bypass (37°C) as compared with global ischemia and reperfusion in the same time span [15].

The mechanisms of preconditioning are not fully elucidated and vary among species [2]. Preservation of high-energy phosphates appears to be a mechanism of protection, as mentioned earlier. Release of endogenous cardioprotective substances such as adenosine and bradykinin may be important [2]. Activation of protein kinase C and adenosine triphosphate-sensitive potassium channels has been suggested as a mechanism, along with induction of protective proteins (heat shock proteins and antioxidants) [2]. Even if heat shock proteins are normally associated with "the second window of protection" afforded by preconditioning [2], their expression has been increased as early as 15 minutes after reperfusion following 120 minutes of cold (4°C) cardioplegia in pigs pretreated with heat shock. Pigs with expression of heat shock proteins had improved cardiac function [16]. However, as the time course of gene expression is unlikely to be consistent with the general biology of classic preconditioning, heat shock proteins are probably not important for modification of myocardial stunning [17]. In routine cardiac operations, no induction of heat shock proteins occurred in the interval between reperfusion after cold cardioplegia and 15 minutes after weaning from cardiopulmonary bypass [18].

Theoretically, the deep hypothermia in the present study stopped the biochemical reaction(s) necessary for the protective effects of preconditioning. However, recent work has shown that porcine myocytes could be preconditioned before 2 hours of hypothermic (4°C) cardioplegia [19]. A more likely explanation for the lack of preconditioning effect, therefore, is that cardioprotection by preconditioning disappears after 2 hours of reperfusion [20]. Whether this depends on the time of reperfusion or on the time span per se is uncertain. Possibly, cardioplegia in the present study lasted too long to achieve preconditioning. Preconditioning may have a role in cardioprotection when the time span is shorter. However, preconditioning may be more effective in preventing the irreversible injury of regional ischemia than the reversible injury of global ischemia.

In summary, ischemic preconditioning improved cardiac function during reperfusion of globally ischemic rat hearts. However, preconditioning before cold cardioplegia did not influence postischemic function or the release of lactate dehydrogenase.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This work was supported by a grant from the Swedish Society of Medicine, the Swedish Medical Research Council (11235), and the Karolinska Hospital and Institute. Per-Ove Sjöquist, Astra Hässle AB, Mölndal, Sweden, is gratefully acknowledged for measuring lactate dehydrogenase.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Address reprint requests to Dr Valen, Department of Thoracic Surgery, Karolinska Hospital, S-17176 Stockholm, Sweden.


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

  1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay in lethal injury in ischemic myocardium. Circulation 1986;74:1124–36.[Abstract/Free Full Text]
  2. Walker DM, Yellon DM. Ischemic preconditioning: from mechanisms to exploitation. Cardiovasc Res 1992;26:734–9.[Free Full Text]
  3. Cave AC, Collis CS, Downey JM, Hearse DJ. Improved functional recovery by ischaemic preconditioning is not mediated by adenosine in the globally ischaemic isolated rat heart. Cardiovasc Res 1993;27:663–8.[Abstract/Free Full Text]
  4. Moolman JA, Genade S, Winterbach R, Harper IS, Williams K, Lochner A. Preconditioning with a single short episode of global ischemia in the isolated working rat heart: effect on structure, mechanical function, and energy metabolism for various durations of sustained global ischemia. Cardiovasc Drugs Ther 1995;9:103–15.[Medline]
  5. Asimakis GK, Inners-McBride K, Conti C. Attenuation of postischaemic dysfunction by ischaemic preconditioning is not mediated by adenosine in the isolated rat heart. Cardiovasc Res 1993;27:1522–30.[Abstract/Free Full Text]
  6. Lasley RD, Anderson GM, Mentzer RM. Ischaemic and hypoxic preconditioning enhance postischaemic recovery of function in the rat heart. Cardiovasc Res 1993;27:565–70.[Abstract/Free Full Text]
  7. Vaage J, Valen G. Pathophysiology and mediators of ischemia-reperfusion injury with special reference to cardiac surgery. Scand J Thorac Cardiovasc Surg 1993;41(Suppl):1–18.
  8. Cave AC, Hearse DJ. Ischaemic preconditioning and contractile function: studies with normothermic and hypothermic global ischaemia. J Mol Cell Cardiol 1992;24:1113–23.[Medline]
  9. Cave AC, Hearse DJ. Ischemic preconditioning enhances post-ischemic function and reduces creatine kinase leakage in the rat heart even when used in conjunction with hypothermic cardioplegia [Abstract]. Circulation 1992;86(Suppl 1):31.
  10. Illes RW, Wright JK, Inners-McBride K, Yang C-J, Tristan A. Ischemic preconditioning improves preservation with crystalloid cardioplegia. Ann Thorac Surg 1994;58:1481–5.[Abstract]
  11. Bolling SF, Olszanski DA, Childs KF, Gallagher KP, Ning X-H. Stunning, preconditioning, and functional recovery after global myocardial ischemia. Ann Thorac Surg 1994;58:822–7.[Abstract]
  12. Kolocassides KG, Galinanes M, Hearse DJ. Ischemic preconditioning, cardioplegia, or both? J Mol Cell Cardiol 1994;26:1411–4.[Medline]
  13. Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet 1993;342:276–7.[Medline]
  14. Di Salvo C, Hemming A, Jenkins D, et al. Can the human myocardium be preconditioned with ischemia under hypothermic conditions? Proc Eur Assoc Cardiothorac Surg 1995:134.
  15. Abd-Elfattah AS, Ding M, Wechsler AS. Intermittent aortic crossclamping prevents cumulative adenosine triphosphate depletion, ventricular fibrillation, and dysfunction (stunning): is it preconditioning? J Thorac Cardiovasc Surg 1995;110:328–9.[Abstract/Free Full Text]
  16. Liu X, Engelman RM, Moraru II, et al. Heat shock. A new approach for myocardial preservation in cardiac surgery. Circulation 1992;86:II358–63.[Medline]
  17. Reimer KA, Vander Heide RS, Jennings RB. Ischemic preconditioning slows ischemic metabolism and limits myocardial infarct size. In: Das DK, ed. Cellular, biochemical, and molecular aspects of reperfusion injury. New York: Ann NY Acad Sci 1994;723:99–115.[Medline]
  18. McGrath LB, Locke M, Cane M, Chen C, Ianuzzo CD. Heat shock protein (HSP 72) expression in patients undergoing cardiac operations. J Thorac Cardiovasc Surg 1995;109:370–6.[Abstract/Free Full Text]
  19. Zellner JL, Hebbar L, Crawford FA, Mukherjee R, Spinale FG. Beneficial effects of myocyte preconditioning on contractile processes after cardioplegic arrest. Ann Thorac Surg 1996;61:558–64.[Abstract/Free Full Text]
  20. Van Winkle DM, Thornton JD, Downey DM, Downey JM. The natural history of preconditioning: cardioprotection depends on duration of transient ischemia and time to subsequent ischemia. Coronary Artery Dis 1991;2:613–9.



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