Ann Thorac Surg 1996;62:910-914
© 1996 The Society of Thoracic Surgeons
Current Review
The Scientific Basis for Hypocalcemic Cardioplegia and Reperfusion in Cardiac Surgery
Ray H. Chen, MD
Department of Cardiovascular and Thoracic Surgery, Texas Heart Institute, Houston, Texas
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Abstract
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The scientific rationale for avoiding the use of calcium-enriched cardioplegic solutions and calcium supplementation during cardioplegic induction and the early phase of reperfusion in open heart surgical procedures is reviewed. The role of the extracellular and intracellular free ionized calcium concentrations during ischemia and reperfusion is explored and the biochemical effects of ischemia on calcium fluxes, adenosine triphosphate levels, and mitochondrial function are discussed. The role of calcium in causing myocardial stunning and the biochemical basis of reperfusion injury are also addressed. Both prolonged ischemia and an increased concentration of Ca2+ during reperfusion have proved to be deleterious. I conclude on the basis of my review that there is no justification for the use of calcium chloride before and during the early phase of reperfusion and that hypocalcemic perfusion is an effective and easily controllable means of myocardial protection.
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Introduction
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In June 1808, Humphry Davy discovered a grayish white metal that he called calcium, after the Latin calx for "lime" [1]. In studies conducted from 1882 to 1894, Sidney Ringer further found that calcium is required for the normal contraction of a frog's heart, the development of fertilized eggs and tadpoles, and cell adhesion [1]. The calcium concentration is usually about 10 mmol/L in sea water and 2.5 mmol/L in human serum [1].
The pioneering work of Shen and Jennings [2] drew attention to the potential role of calcium in the pathogenesis of ischemic cardiac injury. They characterized the effects of ischemia on cardiac ultrastructure and demonstrated that cellular injury is accelerated during reperfusion after transient periods of ischemia. They were the first to show the correlation between cardiomyocyte injury and an overload and accumulation of calcium in the mitochondria.
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Mechanisms of Intracellular Ca2+ Overloading
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Physiologically, after an action potential, the small Ca2+ influx through voltage-gated calcium channels can increase the intracellular Ca2+ concentration ([Ca2+]i) to within 0.1 to 0.6 µmol/L in 1 ms. This increase then triggers the release of more calcium from the sarcoplasmic reticulum (SR) through the ryanodine receptor. This calcium-induced release of calcium causes a peak in the [Ca2+]i of from 0.8 to 1 µmol/L [3]. The second binding site of troponin C then becomes saturated and is activated to facilitate actin-myosin cross-bridging for contraction [4].
Although Ca2+ uptake in the sarcoplasmic reticulum decreases in ischemia, the effect of this on Ca2+-release channels in the sarcoplasmic reticulum is controversial. The mechanical dysfunction associated with ischemia and reperfusion does not involve a primary abnormality of sarcoplasmic reticulum function. The sarcoplasmic reticulum has a limited role in calcium overloading during prolonged ischemia as compared with extracellular Ca2+ entry [5].
During and after ischemia, the entry of calcium causes the increase in the [Ca2+]i [6–8]. Two well-defined pathways that could mediate Ca2+ entry include the voltage-gated Ca2+ channels and the Na+/Ca2+ exchanger [8]. When used prophylactically, calcium channel antagonists can slow the early rise in the [Ca2+]i and the ischemia-induced loss of adenosine triphosphate (ATP) and its precursors [9]. Because the calcium current through calcium channels is markedly reduced or disappears within 10 to 20 minutes [10] of ischemia as the result of the low pH and ATP levels [10], more investigators now believe that Ca2+ entry does not occur primarily by means of l-type Ca2+ channels [8]. Many of the studies reviewed by Silverman and Stern [8] have shown that Ca2+ loading after ischemia or hypoxia occurs principally through the Na+/Ca2+ exchanger. The intracellular Na+ concentration ([Na+]i) rises during hypoxia, which leads to cellular Ca2+ overloading and cell destruction via the Na+/Ca2+ exchanger. Measurements of the [Na+]i have indicated that the developed tension is proportional to the sixth or seventh power of the [Na+]i [11]. Thus, interventions that have only a small effect on [Na+]i can have a disproportionately large effect on the strength of cardiac contraction. The Na+/Ca2+ exchanger plays a central role in mediating these effects [11]. An increase in the Ca2+ concentration has been directly shown to cause accelerated phospholipid degradation, especially when the ATP store is depleted [12, 13]. This depletion to less than 5 to 10 nmol/mg of protein (normal value, 35 to 40 nmol/mg) causes phospholipid membranes to be destabilized, with a resulting exponential release of arachidonates [12, 13].
When the extracellular K+ concentration exceeds 19 mmol/L, such as occurs during cardioplegic induction in cardiac surgical procedures, the membrane potential becomes more positive than -45 mV [14] and the fast sodium channel, with an activation threshold at -60 mV, is inactivated [14, 15]. On the contrary, the l-type calcium channel with an activation threshold of around -20 to -30 mV can still be readily activated [15, 16] and more Ca2+ can move intracellularly across the >10,000 electrochemical gradient, especially in the initial minutes. The Ca2+ influx is also greatly potentiated when the increased cyclic adenosine monophosphate level phosphorylates the C-terminal tail of the 
-1 subunit of the l-type channel [16], such as that brought about by the administration of ß-1 agonists. Therefore, theoretically, hyperkalemic cardioplegia alone cannot prevent the ongoing increase in the [Ca2+]i during ischemia.
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Role of Mitochondria in Ischemia and Reperfusion
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Although endothelial cells, smooth muscle cells, and neurons can meet their energy needs through anaerobic glycolysis, prolonged oxygen depletion in cardiomyocytes reduces energy reserves, disturbs ion homeostasis, and eventually causes structural damage [17]. The electron transfer taking place within the inner membrane pumps protons outward and builds a transmembrane potential of -150 to -200 mV that powers ATP synthesis [18]. During ischemia and hypoxia, the electron flow is reduced and approaches zero, with a consequent loss of the electrochemical gradient. Anaerobic glycolysis produces only two molecules of ATP per mole of glucose, whereas the mitochondrial aerobic pathway produces 36 additional molecules of ATP [19].
The mitochondrial Ca2+ concentration ([Ca2+]m) has an important regulatory function in the enzymatic activities of the Krebs cycle [17, 18]. Under normal resting conditions, both the [Ca2+]i and [Ca2+]m are approximately 0.1 to 0.2 µmol/L [20]. An increase in the [Ca2+]i beyond 0.25 to 0.5 µmol/L [20, 21] can initiate mitochondrial Ca2+ accumulation by increasing the driving force through the Ca2+ uniporter and inhibiting the Na+-dependent efflux pathway [22]. Mitochondria accumulate a considerable amount of Ca2+ when the [Ca2+]i remains persistently above the threshold of 1 to 2 µmol/L [22, 23]. Therefore, mitochondria produce less ATP and may eventually become depolarized because of profound Ca2+ overloading, especially during reoxygenation and reperfusion [17, 18, 24, 25]. Experimentally, this condition can be minimized by administering cyclosporin A, ruthenium red, and oligomycin through their respective mechanisms of "pore" closing, Ca2+ uniporter deactivation, and mitochondrial ATPase deactivation [17].
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Severity of Ischemic and Reperfusion Injury
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The cessation of blood flow to the intact heart results in rapid depression and then arrest of contraction. In addition to the loss of myocyte distention (the "garden hose" effect), which directly affects the Frank-Starling curve, contraction is also depressed because of the effects of accumulating inorganic phosphates and protons early in hypoxia [6, 26, 27]. In a single-cell cardiomyocyte model, hypoxia and glucose deprivation have been observed to cause spontaneous cellular shortening (rigor contracture) before the [Ca2+]i increases [6]. The [Ca2+]i increases immediately thereafter, probably by entry through the sarcolemma. If cardiomyocytes are depleted of oxygen and glucose for 15 to 30 minutes and then reoxygenated, the number of viable rod-shaped cells declines rapidly and many rounded, hypercontracted cardiomyocytes develop [6]. This situation would certainly differ from that in the intact heart, in which the sarcolemma of some cardiomyocytes would probably rupture and the cells would die as they hypercontracted and tore away from their sites of attachment to neighboring cells [8]. Stern and colleagues [28] also observed in the single-cell model that the contracture relengthens in cells that are reoxygenated soon after hypoxic rigor develops, and the cells retain a clear sarcomere pattern and the ability to respond to electrical stimulation. Cells that are reoxygenated more than 20 minutes after the occurrence of hypoxic rigor hypercontract into rounded forms containing disordered myofilaments and sarcolemmal blebs and can no longer contract [28]. This finding indicates that reoxygenation injury depends on a preliminary period of sustained ATP depletion. In addition, cells survive and relengthen if they are reoxygenated before the [Ca2+]i exceeds 2 to 3 µmol/L, whereas cells hypercontract immediately if the [Ca2+]i exceeds 5 µmol/L [6]. Therefore, both the prolonged ATP depletion and the increased [Ca2+]i have a deleterious effect on the recovery of myocardial function upon reoxygenation. Of course, the heterogeneous distribution of collateral flows in different areas can produce heterogeneous injury patterns [17]. This is in stark contrast to the shorter period of ischemia (less than 10 minutes) before reperfusion, during which the myocardium can recover without ionic, functional, and structural sequelae [2]. Between these two extremes, 15 to 20 minutes of ischemia can result in a milder form of reperfusion injury, a phenomenon referred to as myocardial stunning [29–31].
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Stunned Myocardium and Lethal Reperfusion Injury
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In the mid-1970s, Heyndricks and colleagues [30] described their unexpected observation of severely depressed regional myocardial function after a short episode of ischemia of less than 20 minutes despite normal perfusion and an absence of cell necrosis. Widespread attention to this observation was catalyzed in 1982 by Braunwald and Kloner when they coined the term stunned myocardium to refer to the phenomenon [30, 31]. Because stunned myocardium responds to catecholamines and to an increase in the extracellular Ca2+ concentration ([Ca2+]o), it would seem that the [Ca2+]i is decreased in this setting. However, Marban [32] and Kusuoka and associates [33] recently showed that the [Ca2+]i peaks at 1.03 to 1.57 µmol/L in stunned myocardium within the first 100 ms, compared with a concentration of 0.61 to 0.65 µmol/L in control myocardium. Because the diastolic [Ca2+]i only changes from between 0.08 and 0.18 µmol/L to between 0.22 and 0.24 µmol/L, the timed-averaged [Ca2+]i can misleadingly fail to show an obvious difference. Bakker and co-workers [34] demonstrated the presence of a high ratio of surface densities of contact sites between the inner and outer mitochondrial membrane; this finding lends credibility to the hypothesis that stunning increases the [Ca2+]i and energy demand. Therefore, the reduction in the development of pressure in the stunned myocardium does not result from a decrease in the [Ca2+]i. This can only occur as a result of downstream mechanisms that shift the range of activation (myofilament Ca2+ desensitization) [33] and decrease the amplitude of the maximal Ca2+-activated pressure response [35]. There is also evidence indicating that the decrease in myofilament Ca2+ responsiveness is an aftereffect of the transient increase in the [Ca2+]i during ischemia and early reperfusion in the stunned myocardium [33].
The most telling evidence is the finding that a transient calcium overload, even in the absence of ischemia, mimics myocardial stunning physiologically, metabolically, and histologically [36]. Oxygen consumption is much higher in stunned myocardium than in control myocardium when the degree of force generation is normalized, and ATP hydrolysis is actually increased in the stunned myocardium, despite the decrease in force generation [33]. The therapeutic use of catecholamines and calcium chloride is necessary in established stunned myocardium to improve myocardial contraction, but it also causes more energy to be consumed and creates an arrhythmogenic potential. However, a sound myocardial protection strategy may prevent the myocardium from becoming stunned.
It seems unlikely that all injury occurs during ischemia, because at the beginning of reperfusion there is often a period of normal contractility, or even hypercontractility, that precedes the loss of contractility [37]. The spectrum of reperfusion injury has been classified into four categories [38–40]. The last three categories, microvascular reperfusion injury, stunned myocardium, and reperfusion arrhythmias, are uniformly accepted on the basis of consistent experimental and clinical data, but Kloner [40] considers the first category, lethal reperfusion injury, controversial. Nevertheless, Harper and associates [41] found unequivocal evidence for a model of reperfusion-induced cell death in isolated neonatal myocardium.
The cytoskeleton proteins that help anchor actin filaments to the sarcolemma (particularly viculin and -actinin) and the Z band of the sarcomere can be damaged, thereby disrupting the attachment of the actin filaments to the sarcolemma. The resultant disruption further causes the rate of calcium leakage through the membrane to be increased [8]. The extent to which the alterations in structural proteins depend on changes in the [Ca2+]i is currently unknown [8]. It is well known, however, that the high [Ca2+]i can sensitize the myofilaments and set the stage for hypercontractility during reperfusion [8, 42, 43]. Elz and Nayler [42] were able to inhibit reperfusion injury by pretreatment with 2, 3-butanedionemonoxime, which inhibited cross-bridge function at the myofilament level. Piper and colleagues [43] emphasized the importance of preventing contracture-induced injury and the channeling of ATP during the early phase of reoxygenation to ensure repair and recovery. This concept matches the clinical strategy of controlled reperfusion espoused by Buckberg [44, 45].
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The Rationale for Hypocalcemic Perfusion
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The important role of Ca2+ was reemphasized by Zimmerman and Hulsmann [46], who coined the phrase calcium paradox to refer to the detrimental effect during ischemia of a calcium-free solution followed by reperfusion with a 2.5-mmol/L Ca2+ solution. The introduction of calcium-enriched St. Thomas' solution no. 1 [47] was a milestone in cardiac surgery; at one point, it was used by 40% of the cardiac surgery units throughout the world [48]. The calcium concentration was set at 2.2 mmol/L on the basis of the formulation of Ringer's solution. Later, a concentration of 1.2 mmol/L was discovered to be more appropriate, and this concentration was used in St. Thomas' solution No. 2 [49]. However, this determination was made in hearts subjected to normothermic global ischemia. Studies of hypothermic (below 20°C) ischemia revealed that the calcium concentration for St. Thomas' solution No. 2 should be 0.6 mmol/L [50].
The erroneous impulse to add excessive Ca2+ should be rectified in light of the important findings of Rich and Langer [51]. They noted that the so-called calcium paradox could be prevented by lowering the temperature to 18°C or by adding as little as 50 µmol/L of divalent cations, especially calcium, during Ca2+-free perfusion. The deleterious effect of the physiologic [Ca2+]o has been further recognized and characterized in recent years [52–54]. Baker and associates [53] have found the optimal level of [Ca2+]o to occur at 0.3 mmol/L, and Tani and Neely [55] have found the optimal level to occur at 0.15 mmol/L.
On the basis of the evidence in these reports, Plegisol (Abbott Pharmaceuticals, Abbott Park, IL), the only cardioplegic solution based on the St. Thomas' solution No. 2 formulation approved by the United States Food and Drug Administration, is not necessarily the best choice for either crystalloid or blood cardioplegia in hypothermic cardiac surgical procedures because of its excessive concentration of Ca2+. A Ca2+ concentration of 0.15 to 0.25 mmol/L and a K+ concentration of 20 mmol/L during induction and reperfusion [45] is more scientifically sound and has proved to be effective clinically [45, 56, 57]. Resuscitation with warm blood and substrate enrichment for the energy-depleted heart, as well as optimizing cardiac protection by minimizing the actual ischemic time, are also important techniques [45, 57].
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Conclusion
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The free [Ca2+]i of resting cardiomyocytes is maintained at 0.1 µmol/L against a 10,000-fold electrochemical gradient. Any change in the [Ca2+]i has significant physiologic and even pathologic consequences. Cardiac myofilaments can be either desensitized or overstimulated, and mitochondria can be damaged if ischemia lasts for more than 15 to 20 minutes and the [Ca2+]i rises above a threshold level, especially if followed by uncontrolled reperfusion. Therefore, it is imperative to minimize the actual ischemic time and there is no justification for the use of calcium chloride before and in the early phase of reperfusion in cardiac surgical procedures. This practice can only increase the already high [Ca2+]i and worsen the reperfusion injury. Conversely, hypocalcemic reperfusion in conjunction with hyperkalemia can divert the newly available ATP for the repair and recovery of cardiomyocytes. Without such controlled reperfusion, the premature electromechanical activities of the myocardium will unnecessarily waste energy and may disrupt the sarcolemma and possibly cause more severe reperfusion injury.
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Acknowledgments
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I thank Dr David Abramson, from the Department of Anesthesiology, the University of Texas Houston Health Science Center, for his encouragement and editorial assistance with the manuscript.
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Footnotes
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Address reprint requests to Dr Chen, 1303 McCullough, Suite 429, San Antonio, TX 78212.
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References
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- Campbell AK. Intracellular calcium-its universal role as regulator. New York: John Wiley, 1983:1–22.
- Shen AC, Jennings RB. Myocardial calcium and magnesium in acute ischemic injury. Am J Pathol 1972;67:417–40.[Medline]
- Isenberg G. Cardiac excitation-contraction coupling: from global to microscopic models. In: Sperelakis N, ed. Physiology and pathophysiology of the heart. Boston: Kluwer Academic, 1995:289–308.
- Strauss JD, Ruegg C. Lues I. In search of calcium sensitizer compounds; from subcellular models of muscle to in vivo positive inotropic action. In: Lee JA, Allen DG, eds. Modulation of cardiac calcium sensitivity-a new approach to increasing the strength of the heart. Oxford: Oxford University Press, 1993:37–66.
- Mubagwa K. Sarcoplasmic reticulum function during myocardial ischemia and reperfusion. Cardiovasc Res 1995;30:166–75.[Medline]
- Allshire A, Piper HM, Cuthbertson KSR, Cobbold PH. Cytosolic free Ca2+ in single rat heart cells during anoxia and reoxygenation. Biochem J 1987;244:381–5.[Medline]
- Koomen JM, Schevers JAM, Noordhoek J. Myocardial recovery from global ischemia and reperfusion: effects of pre- and/or post-ischemic reperfusion with low-Ca2+. J Mol Cell Cardiol 1983;15:383–92.[Medline]
- Silverman HS, Stern MD. Ionic basis of ischemic cardiac injury: insights from cellular studies. Cardiovasc Res 1994;28:581–97.[Free Full Text]
- Nayler WG. The ischemic myocardium and calcium antagonists. In: Opie LH, ed. Myocardial protection by calcium antagonists. New York: Wiley-Liss, 1994:46–61.
- Sperelakis N. Regulation of calcium slow channels of cardiac muscle by cyclic nucleotides and phosphorylation. J Mol Cell Cardiol 1988;20(S2):75–105.[Medline]
- Reeves JP. Cardiac sodium-calcium exchange system. In Sperelakis N, ed. Physiology and pathophysiology of the heart, 3rd ed. Boston: Kluwer Academic, 1995:309–18.
- Buja LM, Willerson JT. Role of membrane dysfunction and altered calcium homeostasis in the pathogenesis of irreversible myocardial injury. In: Fiskum G, ed. Cell calcium metabolism-physiology, biochemistry, pharmacology, and clinical implications. New York: Plenum Press, 1989:551–560.
- Gunn MD, Sen A, Chang A, Willerson JT, Buja LM, Chien KR. Mechanisms of accumulation of arachidonic acid in cultured myocardial cells during ATP depletion. Am J Physiol 1985;249:H1188–94.
- Fleckenstein A. Calcium antagonism in heart and smooth muscle–experimental facts and therapeutic prospects. New York: John Wiley, 1983:57–95.
- Sperelakis N. Basis of the cardiac resting potential. In: Sperelakis N, ed. Physiology and pathophysiology of the heart, 3rd ed. Boston: Kluwer Academic, 1995:55–76.
- Opie LH. Fundamental properties of calcium antagonists including classification and molecular action. In: Opie LH, ed. Myocardial protection by calcium antagonists. Boston: Wiley-Liss; 1994:1–28.
- Piper HM, Noll T, Siegmund B. Mitochondrial function in the oxygen depleted and reoxygenated myocardial cell. Cardiovasc Res 1994;28:1–15.[Free Full Text]
- Gunter TE, Pfeiffer DR. Mechanisms by which mitochondria transport calcium. Am J Physiol 1990;258:C755–86.[Abstract/Free Full Text]
- Voet D, Voet JG. Electron transfer and oxidative phosphorylation. In: Voet D, Voet JG, eds. Biochemistry. New York: John Wiley, 1990:528–60.
- Miyata H, Silverman HS, Sollot SJ, Lakatta EG, Stern MD, Hansford RG. Measurement of mitochondrial free Ca2+ concentration in living single rat cardiac myocytes. Am J Physiol 1991;261:H1123–34.[Abstract/Free Full Text]
- Miyata H, Lakatta EG, Stern MD, Silverman HS. Relation of mitochondrial and cytosolic free calcium to cardiac myocyte recovery after exposure to anoxia. Circ Res 1992;71:605–13.[Abstract/Free Full Text]
- McCormack JG, Halestrap AP, Denton RM. Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev 1990;70:391–425.[Free Full Text]
- Hansford RG. Relation between mitochondrial calcium transport and control of energy metabolism. Rev Physiol Biochem Pharmacol 1985;102:1–72.[Medline]
- Walsh LG, Tormey JM. Subcellular electrolyte shifts during in vitro myocardial ischemia and reperfusion. Am J Physiol 1988;255:H917–28.[Abstract/Free Full Text]
- Walsh LG, Tormey JM. Cellular compartmentation in ischemic myocardium: indirect analysis by electron probe. Am J Physiol 1988;255:H929–36.[Abstract/Free Full Text]
- Bertoni AG, Adrian S, Mankad S, Silverman HS. Impaired posthypoxic relaxation in single cardiac myocytes: role of intracellular pH and inorganic phosphate. Cardiovasc Res 1993;27:1983–90.[Abstract/Free Full Text]
- Kusuoka H, Weisfeldt ML, Zweier JL, Jacobus WE, Marban E. Mechanism of early contractile failure during hypoxia in intact ferret heart: evidence for modulation of Ca2+-activated force by inorganic phosphate. Circ Res 1986;59:270–82.[Abstract/Free Full Text]
- Stern MD, Chien AM, Capogrossi MC, Lakatto EG. Direct observation of the "oxygen paradox" in single rat ventricular myocytes. Circ Res 1985;56:899–903.[Abstract/Free Full Text]
- Bolli R. Mechanisms of myocardial "stunning."Circulation 1990;82:723–38.[Abstract/Free Full Text]
- Heyndricks GR, Vatner SF. Stunned myocardium. Historical perspective. In: Kloner RA, Przyklenk K, eds. Stunned myocardium. Properties, mechanisms, clinical manifestations. New York: Marcel Dekker, 1993:3–15.
- Braunwald E. Kloner RA. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation 1982;66:1146–9.[Abstract/Free Full Text]
- Marban E. Myocardial stunning and hibernation. The physiology behind the colloquialisms. Circulation 1991;83:681–8.[Free Full Text]
- Kusuoka H, Koretsune Y, Chacko VP, Weisfeldt ML, Marban E. Excitation-contraction coupling in postischemic myocardium. Does failure of activator Ca2+ transients underlie stunning? Circ Res 1990;66:1268–76.[Abstract/Free Full Text]
- Bakker A, Thone F, Borgers M, Jacob W. Contact sites between the inner and outer mitochondrial membranes in the stunned versus hibernating myocardium. Cardiovasc Pathol 1995;4:195–202.
- Kusuoka H, Porterfield JK, Weisman HF, Weisfeldt ML, Marban E. Pathophysiology and pathogenesis of stunned myocardium: depressed Ca2+ activation of contraction as a consequence of reperfusion-induced cellular calcium overload in ferret hearts. J Clin Invest 1987;79:950–61.
- Kitakaze M, Weisman HF, Marban E. Contractile dysfunction and ATP depletion after transient calcium overload in perfused ferret hearts. Circulation 1988;77:685–95.[Abstract/Free Full Text]
- Opie LH. Myocardial stunning–are calcium antagonists useful? Cardiovasc Drugs Ther 1994;8:533–41.
- Opie LH. Proposed role of calcium in reperfusion injury. Int J Cardiol 1989;23:159–64.[Medline]
- Hearse DJ. Reperfusion-induced injury: a possible role for oxidant stress and its manipulation. Cardiovasc Drugs Ther 1991;5:225–36.
- Kloner RA. Does reperfusion injury exist in humans? J Am Coll Cardiol 1993;21:537–45.[Abstract]
- Harper IS, Bond JM, Chacon E, Reece JM, Herman B, Lemasters JJ. Inhibition of Na+/H+ exchanger preserves viability, restores mechanical function and prevents the pH paradox in reperfusion injury to rat myocytes. Basic Res Cardiol 1993;88:430–42.[Medline]
- Elz J, Nayler WG. Contractile activity and reperfusion-induced calcium gain after ischemia in the isolated rat heart. Lab Invest 1988;58:653–9.[Medline]
- Piper HM, Siegmund B, Schluter KD. Severe ischemic injury and the oxygen paradox. In: Piper HM, Preusse CJ, eds. Ischemia-reperfusion in cardiac surgery. Boston: Kluwer Academic, 1993:41–66.
- Follette DM, Fey K, Buckberg GD, et al. Reducing postischemic damage by temporary modification of reperfusate calcium, potassium, pH and osmolarity. J Thorac Cardiovasc Surg 1981;82:221–38.[Abstract]
- Buckberg GD, Beyersdorf F, Allen BS, Robertson JM. Integrated myocardial management: background and initial application. J Card Surg 1995;10:68–89.[Medline]
- Zimmerman ANE, Hulsmann WC. Paradoxical influence of calcium ions on the permeability of the cell membranes of the isolated rat heart. Nature 1966;211:646–7.[Medline]
- Braimbridge MV, Chayen J, Bitensky L, Hearse DJ, Jynge P, Cankovic-Darracott S. Cold cardioplegia or continuous coronary perfusion? Report on preliminary clinical experience as assessed cytochemically. J Thorac Cardiovasc Surg 1977;74:900–6.[Abstract]
- Chambers DJ, Braimbridge MV. Cardioplegia with an extracellular formulation. In: Piper HM, Preusse CJ, eds. Boston: Kluwer Academic, 1993:135–79.
- Yamamoto F, Braimbridge MV, Hearse DJ. Calcium and cardioplegia. J Thorac Cardiovasc Surg 1984;87:908–12.[Abstract]
- Robinson LA, Harwood DL. Lowering the calcium concentration in St. Thomas' Hospital cardioplegic solution improves protection during hypothermic ischemia. J Thorac Cardiovasc Surg 1991;101:314–25.[Abstract]
- Rich TL, Langer GA. Calcium depletion in rabbit myocardium. Circ Res 1982;51:131–40.[Abstract/Free Full Text]
- Boggs BR, Torchiana DF, Geffin GA, et al. Optimal myocardial preservation with an acalcemic crystalloid cardioplegic solution. J Thorac Cardiovasc Surg 1987;93:838–46.[Abstract]
- Baker EJ IV, Olinger GN, Baker EJ. Calcium content of St. Thomas' II cardioplegic solution damages immature myocardium. Ann Thorac Surg 1991;52:993–9.[Abstract]
- Allen BS, Okamoto F, Buckberg GD, et al. Reperfusate composition: benefits of marked hypocalcemia and diltiazem on regional recovery. J Thorac Cardiovasc Surg 1986;92:564–72.[Abstract]
- Tani M, Neely JR. Mechanisms of reduced reperfusion injury by low Ca2+ and/or high K+. Am J Physiol 1990;258:H1025–31.[Abstract/Free Full Text]
- Loop FD, Higgins TL, Panda R, Pearce G, Estafanous FG. Myocardial protection during cardiac operations. Decreased morbidity and lower cost with blood cardioplegia and coronary sinus perfusion. J Thorac Cardiovasc Surg 1992;104:608–18.[Abstract]
- Kirklin JW, Barratt-Boyes BG. Myocardial management during cardiac surgery with cardiopulmonary bypass. In: Kirklin JW, Barratt-Boyes BG, eds. Cardiac surgery. New York: Churchill Livingstone, 1993:129–165.
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Abstract
Introduction
