HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Eliot R. Rosenkranz Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rosenkranz, E. R. Search for Related Content PubMed PubMed Citation Articles by Rosenkranz, E. R.

Ann Thorac Surg 1995;60:797-800
© 1995 The Society of Thoracic Surgeons

---

II: Surgical Myocardial Protection

Substrate Enhancement of Cardioplegic Solution: Experimental Studies and Clinical Evaluation

Division of Cardiothoracic Surgery, The Children's Hospital of Buffalo and School of Medicine, The State University of New York at Buffalo, Buffalo, New York

Abstract

Background. The development of myocardial protective strategies depends on a complete understanding of the pathophysiology of myocardial ischemia and reperfusion. This article reviews the rationale for inclusion of metabolic substrates in cardioplegic solutions on the basis of our current understanding of the underlying pathophysiologic pathways and speculates on the inclusion of future additives that await further investigation.

Methods. The pathophysiology of myocardial ischemia and reperfusion was evaluated from an extensive review of the pertinent literature. Experimental and clinical studies supporting the inclusion of metabolic substrates in clinical cardioplegic solutions were reviewed and summarized. Speculation on possible future additives to these formulas was made on the basis of encouraging, albeit preliminary, experimental data.

Results. Sound experimental and clinical evidence supports the inclusion of glucose, amino acids, calcium chelators, and oxygen as fundamental substrate additives to current cardioplegic solutions. Antioxidants, calcium-channel blockers, and tricarboxylic acid cycle intermediates may be of value. Adenosine, potassium--adenosine triphosphate channel modulators, and nitric oxide may join these lists after further research.

Conclusions. Substrate enhancement of clinical cardioplegic solutions is based on physiologic principles that have been confirmed in the clinical setting. Further definition of the intricacies of myocardial ischemia and reperfusion promises to expand the current list of additives.

The strategy and methods of intraoperative myocardial protection have changed vastly over the last 30 years. From the early ``ice age,'' we have emerged to become ``gourmet chefs,'' preparing the heart a sumptuous repast, supplemented with numerous spices and served at a pleasing temperature. This review will outline how several of these cardioplegic ``recipes'' have been developed based on the aerobic and anaerobic metabolism of the heart. Several of these components have been carefully studied in the laboratory and subsequently applied clinically. The role of other supplements remains controversial, whereas some simply tempt the palate for future consideration.

Myocardial Substrate Metabolism

Carbohydrate is metabolized by the heart (Fig 1) during both aerobic and anaerobic states through glycolysis, yielding pyruvate and lactate as end products. Acetyl coenzyme A is formed by the deamination of glutamate, yielding ketoglutarate, which provides an alternative pathway for entry of substrate into the tricarboxylic acid (TCA) cycle, the major generator of nicotinamide adenine dinucleotide (reduced form) (NADH). Other amino acids including aspartate and fumarate can also enter the TCA cycle by way of intermediates and yield adenosine triphosphate (ATP) and NADH as by-products (Fig 2). The NADH is then oxidized by the respiratory chain, yielding ATP as well as oxygen free radicals as a toxic waste product. The ATP utilized by the heart for mechanical work yields additional oxygen radicals during adenine nucleotide metabolism. The concentration of ATP within the cell may also play a role in preconditioning the heart for subsequent ischemic episodes [1].

View larger version (28K): [in this window] [in a new window]   Fig 1. . Myocardial metabolic pathways. (Ac CoA = acetyl coenzyme A; AICAR = 5-aminoimidazole-4-carboxamide riboside or acadesine; a kg = alpha ketoglutarate; AMP = adenosine monophosphate; ATP = adenosine triphosphate; K-ATP = adenosine triphosphate--sensitive potassium; NADH = nicotinamide adenine dinucleotide [reduced form]; O2- = superoxide anion; SOD = superoxide dismutase; TCA = tricarboxylic acid.)

View larger version (32K): [in this window] [in a new window]   Fig 2. . Amino acid and tricarboxylic acid cycle (TCA) intermediate metabolism in the heart. (ADP = adenosine diphosphate; ATP = adenosine triphosphate; Co-A = coenzyme A; CO2 = carbon dioxide; Co ASH = coenzyme A radical; FAD = flavin adenine dinucleotide; FADH2 = flavin adenine dinucleotide [reduced form]; GDP = guanosine 5`-diphosphate; GTP = guanosine 5`-triphosphate; NAD = nicotinamide adenine dinucleotide; NADH = nicotinamide adenine dinucleotide [reduced form]; Pi = inorganic phosphate.) (From Pearl et al [13]; reprinted with permission from The Society of Thoracic Surgeons [Ann Thorac Surg 1994;57:1636--41].)

Amino acid metabolism has gained increasing notice in recent years as a means of providing energy-yielding substrate during periods of myocardial ischemia and reperfusion. As noted earlier, glutamate is involved in the transamination of pyruvate to alanine, yielding ketoglutarate, which can enter the TCA cycle and result in substrate level ATP production. Similarly, aspartate and fumarate can participate in the oxidation of NADH to nicotinamide adenine dinucleotide (NAD) by way of the malate-aspartate shuttle, which also carries reducing equivalents into the mitochondria for further substrate level ATP production (see Fig 2).

Numerous amino acids can participate in these reactions either through direct conversion to glutamate, aspartate, or pyruvate or through conversion to TCA cycle intermediates [4]. Julia and co-workers [5] have demonstrated consumption of aspartate and glutamate and generation of their end products (succinate and alanine) during periods of myocardial ischemia in both adult and pediatric experimental models. Similar amino acid consumption has been demonstrated clinically in patients undergoing coronary revascularization [6].

The recognition that amino acids played an important role in ischemic myocardial metabolism led us to the development of glutamate-enriched and subsequently glutamate and aspartate--enriched blood cardioplegic solutions for myocardial protection in hearts where substantial myocardial energy depletion had occurred [7--9]. In the experimental models, ischemia-reperfusion injury resulted in very marked depression of ventricular function. Standard cold blood cardioplegia resulted in incomplete recovery of function. Blood cardioplegia enriched with glutamate and aspartate, initially administered at a warm temperature, resulted in nearly complete recovery of preischemic stroke work index (Fig 3).

View larger version (16K): [in this window] [in a new window]   Fig 3. . Benefit of glutamate and aspartate enrichment of blood cardioplegia on postreperfusion ventricular function in adults. (LAP = left atrial pressure; SWI = stroke work index.) (Reprinted with permission from Rosenkranz ER, Okamoto F, Buckberg GD, Robertson JM, Vinten-Johansen J, Bugyi H. Safety of prolonged aortic clamping with blood cardioplegia. III. Aspartate enrichment of glutamate-blood cardioplegia in energy-depleted hearts after ischemic and reperfusion injury. J Thorac Cardiovasc Surg 1986;91:428--35.)

These and other studies led to our application of amino acid--enriched blood cardioplegia clinically in patients undergoing coronary revascularization after myocardial infarction. This treatment strategy resulted in improvement in postreperfusion ventricular function [9, 14]. A similar benefit of amino acid--enriched blood cardioplegia was demonstrated by Beyersdorf and associates [15], who found a substantial improvement in wall motion scores in patients undergoing emergency coronary artery bypass grafting after myocardial infarction.

Calcium Metabolism

Although calcium itself is not a metabolic substrate for the heart, it plays a critical role in myocardial function and reperfusion injury. The benefit of reducing the calcium concentration in reperfusion solutions has been demonstrated by several investigators including Follette and colleagues [16], who in 1981 reported that optimal postreperfusion myocardial function occurred when reperfusate blood calcium concentration was reduced to less than 1 mEq/L by chelation with citrate-phosphate-dextrose solution. Similar results have been demonstrated by others [17, 18] who approached this problem by preventing calcium entry into the cell by pharmacologic blockade of the slow calcium channels.

Oxygen Radical Scavengers

As noted earlier, oxygen radicals are generated normally by several metabolic pathways. Blood reperfusion of the ischemic heart results in a burst of oxygen radical release by white blood cells, vascular endothelium (by way of xanthine oxidase nucleotide catabolism), and myocyte oxidative metabolism of substrate. Blood as a vehicle for a cardioplegic solution contains several endogenous oxygen radical scavengers including hemoglobin, superoxide dismutase, catalase, and glutathione. Julia and associates [19] clearly demonstrated that blockade of these endogenous oxygen radical scavenger mechanisms results in a substantial reduction in postreperfusion regional wall motion.

Other investigators [20, 21] found that supplementation of crystalloid or blood cardioplegic solutions with free radical scavengers including ascorbate, methionine, glutathione, and deferoxamine was of benefit in reducing postreperfusion myocardial injury. Similarly, enhancement of superoxide anion and hydroxyl radical breakdown by superoxide dismutase and catalase have also shown effectiveness in preventing reperfusion damage [22]. Finally, Vinten-Johansen and associates [23] demonstrated that allopurinol enrichment of blood cardioplegia improved postreperfusion functional recovery by reducing the generation of superoxide anion through the ATP metabolic cascade.

Adenine Nucleotides

Adenine nucleotide supplementation of the postischemic myocardium has been attempted in several ways. Robinson and associates [24] added ATP and creatine phosphate to crystalloid cardioplegic solution and demonstrated an improvement in aortic flow recovery after ischemia. How these agents worked is unclear, because they are large, charged molecules that cannot permeate the intact cell membrane. Several investigators [25--27] have supplemented cardioplegic solutions with acadesine (5-aminoimidazole-4-carboxyamide riboside), a purine nucleoside analogue that enters the de novo purine biosynthetic pathway, and have demonstrated improvement in postreperfusion ventricular function. Once again, however, the mechanism of action is uncertain because an increase in tissue adenine nucleotide concentration, including ATP, has not been consistently demonstrated [27].

Adenosine and the Potassium--ATP Channel

There is growing experimental evidence that adenine nucleotides and their precursors, including acadesine, act by increasing the tissue adenosine concentration in the myocardium. Although the mechanism for the action of adenosine is as yet incompletely defined, the adenosine A₁ and A₂ receptors appear to be critical links. The adenosine A₁ receptor seems to mediate the chronotropic and inotropic effects of adenosine on the ischemic heart and may act through activation of the ATP--sensitive potassium channel (K--ATP channel) [26, 27]. The adenosine A₂ receptor mediates reperfusion damage after ischemia by preventing neutrophil activation [28] and by promoting adenosine-associated vasodilation.

There is increasing evidence that the K--ATP channel is a key link in the mechanism of ischemic preconditioning and may represent an important new avenue for investigating improved methods of myocardial protection. This channel hyperpolarizes the cell membrane, decreases calcium entry into the cell, decreases contractility, and therefore reduces ATP utilization both during ischemia and during reperfusion. Gross and Auchampach [29] demonstrated that inhibition of the K--ATP channel with glibenclamide significantly impaired the preconditioning response in dogs. Similarly, opening the K--ATP channel with the agent aprikalim significantly improved postischemic function even without a period of preconditioning (Fig 4). Cohen and colleagues [30] demonstrated that supplementation of potassium cardioplegia with aprikalim also enhanced postischemic recovery. The clinical application of K--ATP openers is premature until we further understand their potential for precipitating postischemic arrhythmias.

View larger version (16K): [in this window] [in a new window]   Fig 4. . Potassium--adenosine triphosphate channel and ischemic preconditioning (IP) of the heart. RP52891 is aprikalim. (LV = left ventricle.) (Modified from Gross and Auchampach [29] and reprinted by permission of the American Heart Association.)

Finally, several new mechanisms hold promise for future investigation. Nitric oxide--dependent vasodilation and inhibition of neutrophil activity appear to play prominent roles in prevention of reperfusion damage after ischemia. Pearl and associates [31] demonstrated that failure to preserve endothelial cell--dependent, nitric oxide--mediated vasodilation during reperfusion resulted in a significant decrease in postreperfusion myocardial blood flow. Several nitric oxide donors might be considered as supplements to future cardioplegic solutions, including L-arginine, which can also enter the amino acid metabolic pathways described earlier. Other modes of inhibiting neutrophil activation, such as suppressors of neutrophil adhesion molecule expression or function or both, hold future promise.

What then should be included in today's cardioplegic solution? It is important to base these decisions on physiologic principles that have been carefully tested in the laboratory as well as in the clinical setting. Good evidence suggests that glucose, amino acids, calcium chelators, and oxygen are important components of a cardioplegic solution and that blood as a vehicle is physiologically sound. Antioxidants, calcium-channel blockers, and TCA cycle intermediates such as fumarate may also be of benefit, although further clinical testing is necessary. More laboratory study is necessary before we can consider the addition of adenosine, K--ATP channel modulators, nitric oxide, and other mediators to our clinical solutions.

Footnotes

Presented at the International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, Sep 25--28, 1994.

Address reprint requests to Dr Rosenkranz, Division of Cardiothoracic Surgery, The Children's Hospital of Buffalo, 219 Bryant St, Buffalo, NY 14222.

References

1. Nichols CG, Lederer WJ. Adenosine triphosphate--sensitive potassium channels in the cardiovascular system. Am J Physiol 1991;261:H1675–86.[Medline]
2. Flaherty JT, Glower DD, Kanter KR, Gardner TJ, Jacobus WE. Use of an isolated heart model to test utilization of substrates for inclusion in cardioplegic solutions. Adv Microcardiol 1982;3:563–9.
3. Wikman-Coffelt J, Wagner S, Wu S, Parmley W. Alcohol and pyruvate cardioplegia. Twenty-four hour in situ preservation of hamster hearts. J Thorac Cardiovasc Surg 1991;101:509–16.[Abstract]
4. Shug AL, Madsen D, Dobbie R, Paulson DJ. Protection of mitochondrial and heart function by amino acids after ischemia and cardioplegia. Life Sci 1994;54:567–77.[Medline]
5. Julia PL, Kofsky ER, Buckberg GD, Young HY, Bugyi HI. Studies of myocardial protection in the immature heart. 1. Enhanced tolerance of immature versus adult myocardium to global ischemia with reference to metabolic differences. J Thorac Cardiovasc Surg 1990;100:879–87.[Abstract]
6. Svedjeholm R, Ekroth R, Joachimsson PO, Ronquist G, Svensson S, Tyden H. Myocardial uptake of amino acids and other substrates in relation to myocardial oxygen consumption four hours after cardiac operations. J Thorac Cardiovasc Surg 1991;101:688–94.[Abstract]
7. Rosenkranz ER, Okamoto F, Buckberg GD, Vinten-Johansen J, Robertson JM, Bugyi H. Safety of prolonged aortic clamping with blood cardioplegia. II. Glutamate enrichment in energy-depleted hearts. J Thorac Cardiovasc Surg 1984;88:402–10.[Abstract]
8. Rosenkranz ER, Okamoto F, Buckberg GD, Robertson JM, Vinten-Johansen J, Bugyi H. Safety of prolonged aortic clamping with blood cardioplegia. III. Aspartate enrichment of glutamate-blood cardioplegia in energy-depleted hearts after ischemic and reperfusion injury. J Thorac Cardiovasc Surg 1986;91:428–35.[Abstract]
9. Rosenkranz ER, Buckberg GD, Laks H, Mulder DG. Warm induction of cardioplegia with glutamate-enriched blood in coronary patients with cardiogenic shock who are dependent on inotropic drugs and intra-aortic balloon support. J Thorac Cardiovasc Surg 1983;86:507–18.[Abstract]
10. Kofsky ER, Julia P, Buckberg GD, Young H, Tixier D. Studies of myocardial protection in the immature heart. V. Safety of prolonged aortic clamping with hypocalcemic glutamate/aspartate blood cardioplegia. J Thorac Cardiovasc Surg 1991;101:33–43.[Abstract]
11. Bolling SF, Childs KF, Ning X-H. Amino acid substrate preloading and postischemic myocardial recovery. J Surg Res 1992;53:342–8.[Medline]
12. Rousou JA, Engelman RM, Anisimowicz L, et al. Metabolic enhancement of myocardial preservation during cardioplegic arrest. J Thorac Cardiovasc Surg 1986;91:270–6.[Abstract]
13. Pearl JM, Hiramoto J, Laks H, Drinkwater DC Jr, Chang PA. Fumarate-enriched blood cardioplegia results in complete functional recovery of immature myocardium. Ann Thorac Surg 1994;57:1636–41.[Abstract]
14. Allen BS, Buckberg GD, Schwaiger M, et al. Studies of controlled reperfusion after ischemia. XVI. Early recovery of regional wall motion in patients following surgical revascularization after eight hours of acute coronary occlusion. J Thorac Cardiovasc Surg 1986;92:636–48.[Abstract]
15. Beyersdorf F, Mitrev Z, Sarai K, et al. Changing patterns of patients undergoing emergency revascularization for acute coronary occlusion. Importance of myocardial protection techniques. J Thorac Cardiovasc Surg 1993;106:137–48.[Abstract]
16. 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]
17. Flameng W, Borgers M, Van der Vusse G, et al. Cardioprotective effects of lidoflazine in extensive aorta-coronary bypass grafting. J Thorac Cardiovasc Surg 1983;85:758–68.[Abstract]
18. Mori F, Miyamoto M, Tsuboi H, Noda H, Esato K. Clinical trial of nicardipine cardioplegia in pediatric cardiac surgery. Ann Thorac Surg 1990;49:413–8.[Abstract]
19. Julia PL, Buckberg GD, Acar C, Partington MT, Sherman MP. Studies of controlled reperfusion after ischemia. XXI. Reperfusate composition: superiority of blood cardioplegia over crystalloid cardioplegia in limiting reperfusion damage--importance of endogenous oxygen free radical scavengers in red blood cells. J Thorac Cardiovasc Surg 1991;101:303–13.[Abstract]
20. Chambers DJ, Astras G, Takahashi A, Manning AS, Braimbridge MV, Hearse DJ. Free radicals and cardioplegia: organic antioxidants as additives to the St. Thomas' Hospital cardioplegic solution. Cardiovasc Res 1989;23:351–8.[Medline]
21. Menasché P, Grousset C, Gauduel Y, Mouas C, Piwnica A. Prevention of hydroxyl radical formation: a critical concept for improving cardioplegia. Protective effects of deferoxamine. Circulation 1987;76(Suppl 5):180–5.
22. Greenfield LJ, Hess ML. Enhancement of crystalloid cardioplegic protection against global normothermic ischemia by superoxide dismutase and catalase but not diltiazem in the isolated, working rat heart. J Thorac Cardiovasc Surg 1988;95:799–813.[Abstract]
23. Vinten-Johansen J, Chiantella V, Faust KB, et al. Myocardial protection with blood cardioplegia in ischemically injured hearts: reduction of reoxygenation injury with allopurinol. Ann Thorac Surg 1988;45:319–26.[Abstract]
24. Robinson LA, Braimbridge MV, Hearse DJ. Enhanced myocardial protection with high-energy phosphates in St. Thomas' Hospital cardioplegic solution. Synergism of adenosine triphosphate and creatine phosphate. J Thorac Cardiovasc Surg 1987;93:415–27.[Abstract]
25. Bolling SF, Groh MA, Mattson AM, Grinage RA, Gallagher KP. Acadesine (AICA-riboside) improves postischemic cardiac recovery. Ann Thorac Surg 1992;54:93–8.[Abstract]
26. Toombs CF, McGee DS, Johnston WE, Vinten-Johansen J. Myocardial protective effects of adenosine. Infarct size reduction with pretreatment and continued receptor stimulation during ischemia. Circulation 1992;86:986–94.[Abstract/Free Full Text]
27. Vinten-Johansen J, Nakanishi K, Zhao Z-Q, McGee DS, Tan P. Acadesine improves surgical myocardial protection with blood cardioplegia in ischemically injured canine hearts. Circulation 1993;88(Suppl 2):350–8.
28. Cronstein BN, Rosenstein ED, Kramer SB, Weissman G, Hirschorn R. Adenosine: a physiologic modulator of superoxide anion by human neutrophils: adenosine acts via an A₂ receptor on human neutrophils. J Immunol 1985;135:1366–71.[Abstract]
29. Gross GJ, Auchampach JA. Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ Res 1992;70:223–33.[Abstract/Free Full Text]
30. Cohen NM, Wise RW, Wechsler AS, Damiano RJ Jr. Elective cardiac arrest with a hyperpolarizing adenosine triphosphate--sensitive potassium channel opener. J Thorac Cardiovasc Surg 1993;106:317–28.[Abstract]
31. Pearl JM, Laks H, Drinkwater DC, et al. Loss of endothelium-dependent vasodilatation and nitric oxide release after myocardial protection with University of Wisconsin solution. J Thorac Cardiovasc Surg 1994;107:257–64.[Abstract/Free Full Text]

This article has been cited by other articles:

				V. Venugopal, A. Ludman, D. M. Yellon, and D. J. Hausenloy 'Conditioning' the heart during surgery Eur. J. Cardiothorac. Surg., June 1, 2009; 35(6): 977 - 987. [Abstract] [Full Text] [PDF]

				Q. Yang and G.-W. He Effect of Cardioplegic and Organ Preservation Solutions and Their Components on Coronary Endothelium-Derived Relaxing Factors Ann. Thorac. Surg., August 1, 2005; 80(2): 757 - 767. [Abstract] [Full Text] [PDF]

				N. King, H. Williams, J. D McGivan, and M.-S. Suleiman Characteristics of L-aspartate transport and expression of EAAC-1 in sarcolemmal vesicles and isolated cells from rat heart Cardiovasc Res, October 1, 2001; 52(1): 84 - 94. [Abstract] [Full Text] [PDF]

				M. Caputo, W.C. Dihmis, A.J. Bryan, M.-S. Suleiman, and G.D. Angelini Warm blood hyperkalaemic reperfusion (`hot shot') prevents myocardial substrate derangement in patients undergoing coronary artery bypass surgery Eur. J. Cardiothorac. Surg., May 1, 1999; 13(5): 559 - 564. [Abstract] [Full Text] [PDF]

				M. Caputo, A.J. Bryan, A.M. Calafiore, M.-S. Suleiman, and G.D. Angelini Intermittent antegrade hyperkalaemic warm blood cardioplegia supplemented with magnesium prevents myocardial substrate derangement in patients undergoing coronary artery bypass surgery Eur. J. Cardiothorac. Surg., December 1, 1998; 14(6): 596 - 601. [Abstract] [Full Text] [PDF]

				L. A. Rivetti and S. M. A. Gandra Initial Experience Using an Intraluminal Shunt During Revascularization of the Beating Heart Ann. Thorac. Surg., June 1, 1997; 63(6): 1742 - 1747. [Abstract] [Full Text]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Eliot R. Rosenkranz Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rosenkranz, E. R. Search for Related Content PubMed PubMed Citation Articles by Rosenkranz, E. R.