ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Spinale, F. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Spinale, F. G.

Ann Thorac Surg 1999;68:1934-1941
© 1999 The Society of Thoracic Surgeons

I. Pathophysiology of Ischemic Reperfusion Injury

Cellular and molecular therapeutic targets for treatment of contractile dysfunction after cardioplegic arrest

Francis G. Spinale, MD, PhDa

a Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina, USA

Address reprint requests to Dr Spinale, Division of Cardiothoracic Surgery, Medical University of South Carolina, 770 MUSC Complex, Rm 625, 171 Ashley Ave, Charleston, SC 29425

Presented at the International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, Sept 21–24, 1997.

Abstract

Transient left ventricular (LV) dysfunction can occur after hypothermic hyperkalemic cardioplegic arrest. This laboratory has developed an isolated LV myocyte system of simulated cardioplegic arrest and rewarming in order to examine cellular and molecular events that may contribute to the LV dysfunction after cardioplegic arrest. Contractile function was examined using high-speed video microscopy after reperfusion and rewarming. After cardioplegic arrest and reperfusion, indices of myocyte contractility were reduced by over 40% from normothermic control values. The capacity of the myocyte to respond to an inotropic stimulus was examined through ß-adrenergic receptor stimulation with isoproterenol. After cardioplegic arrest, the contractile response to isoproterenol was reduced by over 50% from normothermic values. The next series of studies focused upon preventing these changes in myocyte contractile processes after cardioplegic arrest. First, the cardioplegic solutions were augmented with adenosine or an ATP-sensitive potassium channel opener, aprikalim. Both adenosine and aprikalim augmentation significantly improved myocyte function compared with cardioplegia alone values. A potential intracellular mechanism for the protective effects of either adenosine or the ATP-sensitive potassium channel is the activation of protein kinase C (PKC). A brief period of PKC activation before cardioplegic arrest provided protective effects on myocyte contractility with subsequent reperfusion and rewarming. In another set of studies, the potential protective effects of the active form of thyroid hormone (T3) were examined. In myocytes pretreated with T3, myocyte contractile function and ß-adrenergic responsiveness were significantly improved after hypothermic cardioplegic arrest and rewarming. Thus, endogenous means of providing improved myocardial protection during prolonged cardioplegic arrest can be achieved through a brief period of PKC activation or pretreatment with T3. Future studies, which more carefully deduce the basis for these pretreatment effects, will likely yield novel methods by which to protect myocyte contractile processes during cardioplegic arrest.

Over one-half million cardiac surgical procedures are performed in the United States alone, and the majority of these procedures require cardiopulmonary bypass and cardioplegic arrest. An important method for achieving myocardial quiescence is through the delivery of a hypothermic, hyperkalemic solution. However, transient left ventricular (LV) dysfunction can occur after reperfusion and may be due to this prolonged hyperkalemic environment. It is estimated that 10% of patients undergoing elective coronary bypass procedures have significant LV dysfunction in the early period after cardioplegic arrest and rewarming requiring inotropic agents and/or intraaortic balloon pump support [1, 2]. With respect to health care costs, at least 1 billion dollars are spent each year on immediate postcardiac surgical complications [2]. The fundamental contractile unit of the heart is the myocyte, and would be an appropriate target for developing strategies to improve LV function in the cardiac surgical setting. The purpose of this review will be to examine the direct effects of hyperkalemic cardioplegic arrest on myocyte contractile processes. Next, potentially unique strategies to prevent changes in myocyte contractile processes that occur after cardioplegic arrest will be discussed. Specifically, the effects of pretreatment with a potassium channel opener (PCO) or adenosine before cardioplegic arrest with respect to myocyte function will be reviewed. Furthermore, a potential intracellular mechanism for the protective effects of adenosine or PCO activation with cardioplegic arrest, the activation of protein kinase C (PKC), will be discussed. Finally, the potential for using the active form of thyroid hormone (T3) as a preemptive treatment strategy in preventing myocyte contractile function in the setting of cardioplegic arrest and rewarming will be reviewed.

A myocyte model of cardioplegic arrest and rewarming

A direct causal relation between changes in myocyte contractile processes and LV function after hypothermic cardioplegic arrest and rewarming has been difficult to establish in light of the associated changes that occur in systemic loading conditions and neurohormonal systems [1, 3–7]. Thus, direct determination of myocyte contractile performance in vivo after hypothermic cardioplegic arrest and rewarming can be problematic. Accordingly, this laboratory developed an isolated myocyte system in order to examine the fundamental contributory mechanisms that directly influence the contractile properties of the myocyte under control conditions, after cardioplegic arrest, as well as with the development of LV dysfunction [8–20]. Using this unique myocyte system, studies can be performed that allow: (1) examination of contraction and relaxation properties of myocytes independent from the effects of the extracellular matrix; (2) the removal of in vivo hemodynamic and neurohormonal influences; (3) independence from coronary perfusion and capillary diffusion capacity; and (4) careful control of the extracellular milieu [21–24]. Through the use of isolated myocyte function studies, the effects of hypothermic arrest and crystalloid potassium cardioplegia upon myocyte contractility were directly examined. Porcine myocytes were harvested from the region of the LV free wall using techniques developed by this laboratory previously [8–21]. Using this isolation technique, a high yield (> 70%) of rod-shaped, intracellular free calcium (Ca2+) tolerant myocytes are routinely obtained [8–24]. Myocyte contractile function was examined using computer-assisted high-speed video microscopy developed by this laboratory [21–24]. Indices of contractile function computed from the digitized myocyte contraction profile include the percent and velocity of shortening, and the velocity of relengthening. After baseline, steady-state measurements, myocytes were randomly assigned to one of two treatment groups: (1) normothermic control group: isolated myocytes were incubated in oxygenated normothermic cell culture media and then stored for 2 hours at 37°C in a 95% oxygen environment; (2) cardioplegia group: isolated myocytes were incubated with 4°C Ringer’s solution containing 24 mEq/L potassium and 5 mEq/L HCO3-, then stored at 4°C for 2 hours and subsequently rewarmed in normothermic oxygenated (pO2 > 300 torr) cell culture media. The effects of this simulated 2-hour period of hyperkalemic cardioplegic arrest with rewarming have been summarized for over 1,000 myocytes in Table 1. Myocyte percent and velocity of shortening were reduced by over 40% from normothermic baseline values. In addition, isolated myocyte velocity of relengthening, which reflects energy dependent Ca2+ resequestration, was significantly reduced from normothermic control values. These results demonstrated that hyperkalemic cardioplegic arrest with subsequent reperfusion and rewarming caused negative effects on myocyte contractile function.


View this table:
[in this window]
[in a new window]
  		Table 1. Myocyte Contractile Function in Normothermic Control State and After Simulated Cardioplegic Arrest

 
Hyperkalemic cardioplegic arrest: ß-adrenergic responsiveness and Ca2+ homeostasis

When LV pump dysfunction occurs in the period after hyperkalemic cardioplegic arrest, inotropic support is commonly initiated by ß-receptor activation [3–5]. Furthermore, ß-receptor agonists are commonly used to facilitate separation from cardiopulmonary bypass [5, 7]. However, defects in ß-adrenergic receptor transduction occur after cardioplegic arrest [3, 25]. For example, Schwinn and colleagues demonstrated that the early reperfusion and rewarming period after cardioplegic arrest was associated with ß-receptor desensitization as evidenced by diminished isoproterenol stimulated cAMP production [3]. The results from this past report, as well as others [25], suggest that the mechanism for the diminished inotropic responsiveness that can occur after hyperkalemic cardioplegic arrest is due to defects in the ß-receptor transduction pathway. In order to more carefully examine this issue, myocyte contractility was examined in the presence of the ß-receptor agonist, isoproterenol (25 nM). As shown in Table 1, myocyte contractile function after ß-receptor stimulation significantly increased from baseline values. However, myocyte function remained depressed from normothermic values in the cardioplegia and rewarming group. In order to more closely examine whether the blunted myocyte ß-adrenergic response was associated with possible defects in cAMP generation or enhanced degradation, a series of studies was performed using the phosphodiesterase inhibitor, amrinone (50 nmol/L) [8]. This concentration of amrinone was chosen based upon preliminary dose-response studies. In the presence of amrinone, myocyte velocity of shortening was 84 ± 6 µm/s in control myocytes, but was 65 ± 6 µm/s with cardioplegic arrest and rewarming (p < 0.05). Thus, potentiation of cAMP levels within the myocyte after cardioplegic arrest failed to normalize myocyte function. These findings suggest that contributory mechanisms for the abnormalities in ß-adrenergic responsiveness occur beyond this transduction system.

Based upon the observations described in the preceding paragraphs, we suspected that the prolonged membrane depolarization due to hyperkalemic cardioplegic arrest caused increased myocyte [Ca2+]i. Accordingly, we developed a system by which to monitor time dependent changes in myocyte [Ca2+]i within the same myocyte during cardioplegic arrest and rewarming [17]. Porcine LV myocytes (n = 30) were loaded with the Ca2+-specific dye, Fura-2, as described previously by this laboratory [10, 17]. Measurements were sequentially recorded in the same myocyte during normothermia (cell media, 15 minutes, 37°C), hyperkalemic cardioplegia (hypothermic hyperkalemic crystalloid cardioplegic arrest, 60 minutes, 12°C, 24 mEq K+), and subsequent reperfusion (cell media, 15 minutes, 37°C). The results from this study are summarized in Figure 1. Steady-state normothermic [Ca2+]i was 85 ± 6 nmol/L and is consistent for this myocyte preparation [26]. With the initiation of a hyperkalemic environment, myocyte [Ca2+]i rapidly increased by twofold and remained elevated throughout the period of cardioplegic arrest. With reperfusion and rewarming, myocyte [Ca2+]i levels returned to normothermic control values. Thus, hyperkalemic cardioplegic arrest caused a prolonged elevation in myocyte intracellular Ca2+ and is associated with myocyte contractile dysfunction with reperfusion and rewarming.



View larger version (20K):
[in this window]
[in a new window]
  		Fig 1. Intracellular Ca2+ concentration was measured in the same myocyte during cardioplegic arrest (4°C Ringer’s solution containing 24 mEq/L potassium) and with reperfusion (n = 30), as well as in normothermic control myocytes (n = 30). A significant increase in intracellular Ca2+ was observed during the hyperkalemic cardioplegic arrest interval, which persisted during the period of reperfusion and rewarming. Thus, hyperkalemic cardioplegic arrest caused a prolonged elevation in myocyte intracellular Ca2+ and is associated with myocyte contractile dysfunction with reperfusion and rewarming. See text for further details. (Reproduced from Dorman BH, Hebbar L, Hinton RB, Roy RC, Spinale FG. Preservation of myocyte contractile function after hypothermic cardioplegic arrest by activation of ATP-sensitive potassium channels. Circulation 1997;96:2376–84, [17] with permission from the American Heart Association.)

 
Preconditioning and cardioplegia: relation to adenosine and the KATP channel

Preconditioning describes a phenomenon in which myocardium made transiently ischemic becomes more tolerant to a subsequent and prolonged period of ischemia [27–33]. Murry and associates reported that myocardium subjected to a brief period of coronary occlusion preceding a more prolonged ischemic interval significantly decreased the size of myocardial infarction compared with hearts subjected to a single prolonged ischemic episode [33]. In a recent study, Illes and associates demonstrated that preconditioning in the rabbit heart improved LV pump function after hypothermic cardioplegic arrest and rewarming [30]. Potential contributory mechanisms for preconditioning include activation of the adenosine A1-receptor and/or stimulation of the ATP-sensitive potassium (KATP) channels [28–43]. A study by Liu and associates demonstrated that adenosine was equivalent to preconditioning in limiting infarct size in isolated rabbit hearts [35]. Gross and Auchampach have shown that blockade of the KATP channel prevented preconditioning in dogs [40]. Recent studies have provided strong evidence that the role of adenosine and the KATP channel are closely integrated in the preconditioning phenomenon [28, 29, 35]. Specifically, adenosine receptor activation leads to mobilization of PKC and, in turn, causes activation of KATP channels. Mitchell and colleagues have reported that the preconditioning phenomenon is mediated by PKC [44]. Accordingly, a series of studies have been performed by this laboratory in which the potential protective effects of adenosine or PCO-augmented cardioplegic arrest on myocyte contractile processes as well as determine intracellular mechanisms for these effects [15–18].

Isolated porcine LV myocytes were incubated in cardioplegic solution augmented with adenosine at a concentration of 200 µmol/L. This dose of adenosine was selected in previously performed dose-response studies [16]. Damiano and colleagues demonstrated that the potent ATP-sensitive potassium channel opener aprikalim (100 µmol/L) in crystalloid cardioplegia improved postischemic functional recovery in isolated rabbit hearts, as assessed by LV peak developed pressure [45–47]. Accordingly, isolated myocytes were incubated in cardioplegic solution augmented with aprikalim at a concentration of 100 µmol/L. Myocyte contractile function was examined after simulated cardioplegic arrest and rewarming with adenosine or aprikalim augmented cardioplegia at steady-state and after ß-adrenergic receptor stimulation, and the results are summarized in Table 2. LV myocyte contractile function and ß-receptor responsiveness was significantly improved with either adenosine or PCO-augmented cardioplegic arrest. Taken together, these findings as well as recently completed studies from other laboratories provide the basis for a working hypothesis with respect to a molecular mechanism for myocyte protection in the setting of cardioplegic arrest (Fig 2). Specifically, adenosine receptor or KATP channel activation operate through a common transduction pathway: increased activity of PKC. The activation state of PKC directly influences ionic homeostasis such as intracellular Ca2+ release, Na+ flux, and intracellular pH [48–51], all of which have particular relevance with respect to myocardial protection and cardioplegic arrest.


View this table:
[in this window]
[in a new window]
  		Table 2. Myocyte Contractile Function After Simulated Cardioplegic Arrest and Rewarming: Effects of Adenosine and Aprikalim Augmented Cardioplegia

 


View larger version (27K):
[in this window]
[in a new window]
  		Fig 2. A hypothetical model of the mechanism of myocyte preconditioning in the setting of cardioplegic arrest. Adenosine augmentation or activation of the ATP-sensitive potassium channel provided similar protective effects on myocyte contractile processes with cardioplegic arrest and rewarming. Therefore, adenosine augmentation or activation of the ATP-sensitive potassium channel may operate through a common transduction pathway. The adenosine A1 receptor is coupled to an inhibitory guanine nucleotide binding protein complex (Gi) [34]. Increased adenosine levels activate the adenosine A1 receptor, with subsequent activation of phospholipase C (PLC) [48, 64, 65]. In turn, phospholipase C increases the activity of protein kinase C (PKC) [65], which activates the ATP-sensitive potassium channel [53]. ATP-sensitive potassium channels can be directly activated by potassium channel openers (PCOs). Thus, ATP-sensitive potassium channel activation either by adenosine A1 receptor stimulation or by a PCO maintains a hyperpolarized membrane potential [42, 66] and may therefore play a role in mediating the protective effects of preconditioning on myocyte contractile processes with cardioplegic arrest and rewarming. (Reprinted from Handy JR, Dorman BH, Cavallo MJ, et al. Direct effects of oxygenated crystalloid or blood cardioplegia on isolated myocyte contractile function. J Thorac Cardiovasc Surg 1996;112:1064–72, with the permission of the publisher.)

 
Activation of PKC and cardioplegic arrest

Recent studies have demonstrated that activation of the serine-threonine PKC may be an intracellular triggering mechanism for the preconditioning phenomenon [28, 44, 52]. However, whether and to what extent direct activation of PKC at the level of the myocyte provides protective effects in the setting of cardioplegic arrest and rewarming remained unclear. Accordingly, we tested the central hypothesis that a short interval of PKC activation before a prolonged period of hypothermic hyperkalemic cardioplegic arrest would improve myocyte contractile function upon reperfusion and rewarming [18]. For these studies, PKC activation was achieved using the phorbol ester PMA (phorbol 12-myristate 13-acetate). Isolated myocytes were randomly assigned to one of the following treatment groups: 1) incubation in oxygenated, normothermic media (37°C) for 3 minutes; 2) incubation in oxygenated, normothermic media containing PMA (10-9 mol/L) for 3 minutes; or 3) incubation in oxygenated, normothermic media-containing vehicle (Krebs buffer solution containing equivalent concentrations of ethanol) for 3 minutes. All myocytes were then subjected to simulated cardioplegic arrest as described in the previous section and steady-state myocyte contractile function examined with reperfusion and rewarming (Table 3). Pretreatment with PMA before cardioplegic arrest and rewarming resulted in improved indices of myocyte contractile function with subsequent reperfusion and rewarming. Specifically, myocyte percent shortening, shortening velocity, and velocity of relengthening were significantly increased from cardioplegia alone values. More importantly, these indices of contractile function with PMA pretreatment were similar to normothermic control values (p > 0.60). However, myocyte total duration of contraction, time to peak contraction, and time to 50% relaxation were prolonged with PMA pretreatment and cardioplegic arrest when compared with normothermic values. These results suggest that pretreatment with PMA before simulated cardioplegic arrest protected indices of myocyte contractile function with subsequent reperfusion and rewarming, but defects in the temporal aspects of myocyte contractile process persisted. Coincubation with chelerythrine, an inhibitor of PKC, abolished the protective effects of PKC pretreatment [18].


View this table:
[in this window]
[in a new window]
  		Table 3. Steady-State Myocyte Contractile Function After Cardioplegic Arrest and Rewarming: Effects of Protein Kinase C Activation Before Cardioplegic Arrest

 
Taken together, the results from the studies outlined here build upon past reports [28, 44] and provide direct evidence that induction of PKC activation in isolated myocytes immediately before cardioplegic arrest will result in improved contractile function with subsequent reperfusion and rewarming. In the present study, a brief (3-minute) interval of PKC activation before the induction of cardioplegic arrest normalized myocyte percent and velocity of shortening with subsequent reperfusion and rewarming. This observation suggests that activation of PKC within the myocyte provided protective effects on myocyte homeostatic processes during the period of cardioplegic arrest. Activation of PKC results in a number of intracellular events within the myocyte, which include influencing ion exchange systems and pumps, activity of mitogen-activated protein kinases, phosphorylation states of contractile proteins, and cytoskeletal protein conformation. The activation of PKC has also been shown to influence gene expression and myocardial growth properties [48–53]. The isolated myocyte results presented here demonstrated significant protective effects after only a brief period of PKC activation. Therefore, the acute effects of PKC activation that were observed were probably not due to changes in transcriptional or translational processes, but more likely due to alterations in intracellular ionic homeostasis and phosphorylation states. PKC activational status has been demonstrated to influence the activity of the Na+/H+ exchanger, which will cause intracellular alkalinization [51, 54]. PKC activation has also been demonstrated to influence intracellular Ca2+ levels by modulating the function of the L-type Ca2+ channel on the myocyte sarcolemma [55] as well as the sarcoplasmic reticulum Ca2+-ATPase [51]. Thus, it is likely that PKC activation in isolated LV myocytes changed intracellular pH and Ca2+ levels, which provided a protective effect when subjected to prolonged hypothermic, hyperkalemic cardioplegic arrest. However, future studies that directly measure intracellular pH and Ca2+ with PKC activation during cardioplegic arrest will be necessary to directly examine this possibility.

Pretreatment of T3 improves myocyte function after cardioplegic arrest

Past clinical and experimental studies have reported an improvement in LV pump function after administration of the active form of thyroid hormone (T3) [56–58]. However, it remained unclear whether preemptive treatment with T3 would exert beneficial effects on myocyte contractile performance after hypothermic cardioplegic arrest and rewarming. Accordingly, a series of studies was performed in order to more carefully examine the direct effects of T3 pretreatment on myocyte contractile performance under normothermic conditions and after hypothermic cardioplegic arrest and rewarming [10, 20, 59]. Contractile function in isolated pig LV myocytes was examined after the following treatment protocols: (1) normothermic incubation for 2 hours with T3 (80 pmol/L) followed by 2 hours of hyperkalemic, hypothermic cardioplegic arrest ([K+]: 24 mmol/L; 4°C) and subsequent rewarming; and (2) normothermic incubation for 2 hours with no T3 followed by 2 hours of hyperkalemic, hypothermic cardioplegic arrest, and rewarming. The pretreatment interval and the concentration of T3 used in these studies were determined by previously performed dose-response studies [10, 20]. The results from this study are summarized in Table 4. Cardioplegic arrest and subsequent rewarming caused a significant reduction in myocyte function from normothermic values. However, in myocytes pretreated with T3, myocyte contractile function was significantly higher after hypothermic cardioplegic arrest and rewarming. In a second series of experiments, ß-adrenergic responsiveness was examined after pretreatment with T3 (Table 4). In the presence of the ß-adrenergic agonist isoproterenol (25 nmol/L), myocyte contractile function was increased by 26% in the T3-treated myocytes. However, the results from these experiments must be put in context with the findings from the recent clinical study by the Duke T3 Study Group [60]. In this past clinical study, treatment of patients with T3 undergoing cardioplegic arrest and cardiopulmonary bypass did not improve indices of LV pump function in the postoperative period. Results from our laboratory suggest that pretreatment with T3 may have particular beneficial effects in the setting of LV dysfunction [20, 61]. Thus, future clinical studies are necessary in order to determine whether T3 pretreatment before cardioplegic arrest in patients with preexisting LV dysfunction may provide beneficial effects in the postoperative period.


View this table:
[in this window]
[in a new window]
  		Table 4. Myocyte Contractile Function After Simulated Cardioplegic Arrest and Rewarming: Effects of Pretreatment With Triiodothyronine

 
Summary

The most common method for achieving myocardial quiescence during cardiac surgery has been the use of a hyperkalemic cardioplegic solution that causes rapid membrane depolarization and a quiescent heart. As the external potassium activity is increased by infusion of a hyperkalemic cardioplegic solution, the myocyte resting membrane potential becomes more positive and causes depolarization. This depolarization at high external potassium concentrations causes a rapid cessation of contractile activity and thereby reduces metabolic demands within the myocyte. However, the same mechanism that causes rapid depolarization of the membrane has also been shown to have significant consequences on cellular metabolic processes, particularly during reperfusion [62]. Specifically, extracellular hyperkalemia results in sodium influx, which in turn causes an influx of calcium through the sodium-calcium exchanger. Furthermore, the membrane depolarization induced by hyperkalemia causes a leakage of calcium from the sarcoplasmic reticulum and an influx of calcium by way of the "window current." Thus, a prolonged hyperkalemic environment with subsequent reperfusion may play a contributory role in abnormal regulation and activation of intracellular second messenger and enzyme systems, and alterations in contractile performance [63]. While hyperkalemic cardioplegia solutions have been the historical choice for myocardial arrest, this approach is directly associated with alterations in myocyte contractile processes, which in turn may result in a complicated postoperative course after cardiac operation, particularly in patients with preexisting LV dysfunction. The studies outlined in this review suggest that activation of specific intracellular transduction pathways within the LV myocyte, such as stimulation of PKC or the KATP channel, may hold promise as preemptive protective strategies that will result in improved contractile performance after cardioplegic arrest.

Acknowledgments

The studies outlined in this project were supported by National Institutes of Health grants HL-45024 and HL-56603, a Grant-in-Aid from the American Heart Association, and the Thoracic Surgery Foundation for Research and Education. The studies described in this review were carried out with the direct participation of surgical residents Jennifer D. Walker, Barry R. Hird, Seung-Jun O, and Monty H. Cox, and anesthesiology fellow Latha Hebbar. The invaluable assistance and dedication of Rupak Mukherjee is greatly appreciated. Jennifer D. Walker was a Nina S. Braunwald Research Fellow during the execution of these studies. Francis G. Spinale is an Established Investigator of the American Heart Association.

References

  1. Weisel R.D. Myocyardial stunning after coronary bypass surgery. J Card Surg 1993;8:242-244.[Medline]
  2. Mangano D.T. Cardiovascular morbidity and CABG surgery—a perspective. J Card Surg 1995;10:366-368.[Medline]
  3. Schwinn D.A., Leone B.J., Spahn D.R., et al. Desensitization of myocardial ß-adrenergic receptors during cardiopulmonary bypass. Circulation 1991;84:2559-2567.[Abstract/Free Full Text]
  4. Roberts A.J., Spies S.M., Sanders J.H., et al. Serial assessment of left ventricular performance following coronary artery bypass grafting. J Thorac Cardiovasc Surg 1981;81:69-84.[Abstract]
  5. Mangano D.T. Biventricular function after myocardial revascularization in humans. Anesthesiology 1985;62:571-577.[Medline]
  6. Breisblatt Wn., Stein K.L., Wolfe C.J., et al. Acute myocardial dysfunction and recovery. J Am Coll Cardiol 1990;15:1261-1269.[Abstract]
  7. Phillips H.R., Carter J.E., Okada R.D., et al. Serial changes in left ventricular ejection fraction in the early hours after aortocoronary bypass grafting. Chest 1983;83:28-34.[Abstract/Free Full Text]
  8. Dorman B.H., Cavallo M.J., Roy R.C., Spinale F.G. Direct and interactive effects of phosphodiesterase inhibition and ß-adrenergic stimulation on myocyte contractile function following hypothermic cardioplegic arrest. Anesth Analg 1995;81:925-931.[Abstract]
  9. Handy J.R., Spinale F.G., Mukherjee R., Crawford F.A. Hypothermic potassium cardioplegia impairs myocyte contractility and inotropy. J Thorac Cardiovasc Surg 1994;107:1050-1058.[Abstract/Free Full Text]
  10. Walker J.D., Crawford F.A., Mukherjee R., Spinale F.G. The direct effects of 3,5,3 triiodo-1-thyronine (T3) on myocyte contractile processes. J Thorac Cardiovasc Surg 1995;110:1369-1380.[Abstract/Free Full Text]
  11. Cavallo M.J., Dorman B.H., Spinale F.G., Roy R.C. Myocyte contractile responsiveness following hypothermic cardioplegic arrest. Anesthesiology 1995;82:926-939.[Medline]
  12. Dorman B.H., Cavallo M.J., Hinton R.B., Roy R.C., Spinale F.G. Preservation of myocyte contractile function following hypothermic, hyperkalemic cardioplegic arrest with 2, 3-butanedione monoxime. J Thorac Cardiovasc Surg 1996;111:621-629.[Abstract/Free Full Text]
  13. Handy J.R., Dorman H., Cavallo M.J., et al. Direct effects of oxygenated crystalloid or blood cardioplegia on isolated myocyte contractile function. J Thorac Cardiovasc Surg 1996;112:1064-1072.[Abstract/Free Full Text]
  14. Zellner J.L., Hebbar L., Crawford F.A., Mukherjee R., Spinale F.G. Preconditioning has direct and beneficial effects on myocyte contractile processes with cardioplegic arrest and rewarming. Ann Thorac Surg 1996;61:558-564.[Abstract/Free Full Text]
  15. O S.J., Zellner J.L., Cox M.H., et al. Contributory mechanisms for the beneficial effects of myocyte preconditioning following cardioplegic arrest. Circulation 1996;94:389-397.
  16. Cox M.H., O S.J., Hebbar L., Mukherjee R., Crawford F.A., Spinale F.G. Protective and dose dependent effects of adenosine on myocyte contractile processes during simulated cardioplegic arrest. Ann Thorac Surg 1997;63:981-987.[Abstract/Free Full Text]
  17. Dorman B.H., Hebbar L., Hinton R.B., Roy R.C., Spinale F.G. Preservation of myocyte contractile function after hypothermic cardioplegic arrest by activation of ATP-sensitive potassium channels. Circulation 1997;96:2376-2384.[Abstract/Free Full Text]
  18. O S.J., Cox M.H., Crawford F.A., Spinale F.G. Protein kinase C activation prior to cardioplegic arrest. J Thorac Cardiovasc Surg 1998;114:651-659.[Abstract/Free Full Text]
  19. Spinale F.G., Fulbright B.M., Mukherjee R., et al. Relationship between ventricular and myocyte function with tachycardia induced cardiomyopathy. Circ Res 1992;71:174-187.[Abstract/Free Full Text]
  20. Walker J.D., Crawford F.A., Mukherjee R., Zile M.R., Spinale F.G. The novel effects of 3,5,3 triiodo-1-thyronine upon myocyte contractile function and ß-adrenergic responsiveness in dilated cardiomyopathy. J Thorac Cardiovasc Surg 1994;108:672-679.[Abstract/Free Full Text]
  21. Mukherjee R., Crawford F.A., Hewett K.W., Spinale F.G. Cell and sarcomere contractile performance from the same cardiocyte using video microscopy. J Appl Physiol 1993;74:2023-2033.[Abstract/Free Full Text]
  22. Spinale F.G., Mukherjee R., Fulbright B.M., Hu J., Crawford F.A., Zile M.R. Contractile properties of isolated porcine ventricular myocytes. Cardiovasc Res 1993;27:304-311.[Abstract/Free Full Text]
  23. Wang Z., Mukherjee R., Lam C.F., Spinale F.G. Spatial characterization of contracting cardiac myocytes by computer assisted high speed image processing. Am J Physiol 1996;270:H769-H779.[Abstract/Free Full Text]
  24. Wang Z., Lam C.F., Mukherjee R., Hebbar L., Wang Y., Spinale F.G. Relation between external load and isolated myocyte contractile function. Am J Physiol 1997;42:H183-H191.
  25. Schranz D., Droege A., Broede A., et al. Uncoupling of human cardiac ß-adrenoceptors during cardiopulmonary bypass with cardioplegic cardiac arrest. Circulation 1993;87:422-426.[Abstract/Free Full Text]
  26. Zile M.R., Mukherjee R., Clayton C., Kato S., Spinale F.G. Effects of chronic supraventricular pacing tachycardia on relaxation rate in isolated cardiac muscle cells. Am J Physiol 1995;268:H2104-H2113.[Abstract/Free Full Text]
  27. Przyklenk K., Kloner R.A., Yellon D.M. In: Przyklenk K., Kloner R.A., Yello D.M., eds. Ischemic preconditioning. Boston: Kluwer Academic Publishers, 1994:153-170.
  28. Speechly-Dick M.E., Grover G.J., Yellon D.M. Does ischemic preconditioning in the human involve protein kinase C and the ATP-dependent K+ channel?. Circ Res 1995;77:1030-1035.[Abstract/Free Full Text]
  29. Tan H.L., Mazon P., Verberne H.J., et al. Ischemic preconditioning delays ischemia induced cellular electrical uncoupling in rabbit myocardium by activation of ATP sensitive potassium channels. Cardiovasc Res 1993;27:644-651.[Abstract/Free Full Text]
  30. Illes R.W., Wright J.K., Inners-McBride K., Yang C.J., Tristan A. Ischemic preconditioning improves preservation with crystalloid cardioplegia. Ann Thorac Surg 1994;58:1481-1485.[Abstract]
  31. Shizukuda Y., Mallet R.T., Lee S.C., Downey H.F. Hypoxic preconditioning of ischemic canine myocardium. Cardiovasc Res 1992;26:534-542.[Medline]
  32. Kolocassides K.G., Galinanes M., Hearse D.J. Ischemic preconditioning, cardioplegia, or both. J Mol Cell Cardiol 1994;26:1411-1414.[Medline]
  33. Murry C.E., Jennings R.B., Reimer K.A. Preconditioning with ischemia. Circulation 1986;74:1124-1135.[Abstract/Free Full Text]
  34. Thornton J.D., Liu G.S., Olsson R.A., Downey J.M. Intravenous pretreatment with A1-selective adenosine analogues protects the heart against infarction. Circulation 1992;85:659-665.[Abstract/Free Full Text]
  35. Liu G.S., Thornton J.D., Van Winkle D.M., Stanley A.W.H., Olsson R.A., Downey J.M. Protection against infarction afforded by preconditioning is mediated by A1-adenosine receptors in rabbit heart. Circulation 1991;84:350-356.[Abstract/Free Full Text]
  36. Bolling S.F., Bies L.E., Gallagher K.P., Bove E.L. Enhanced myocardial protection with adenosine. Ann Thorac Surg 1989;47:809-815.[Abstract]
  37. Van der Lee C., Huizer T., Janssen M., et al. Adenosine, added to St Thomas Hospital cardioplegic solutions, improves functional recovery and reduces irreversible myocardial damage. Cardioscience 1994;5:269-274.[Medline]
  38. Ely S.W., Mentzer R.M., Lasley B.A., Lee B.K., Berne R.M. Functional and metabolic evidence of enhance myocardial tolerance to ischemia and reperfusion with adenosine. J Thorac Cardiovasc Surg 1985;80:549-556.
  39. Coetzee W.A. ATP dependent potassium channels and myocardial ischemia. Cardiovasc Drug Ther 1992;6:201-208.[Medline]
  40. Gross G.J., Auchampach J.A. Role of ATP dependent potassium channels in myocardial ischaemia. Cardiovasc Res 1992;26:1011-1016.[Abstract/Free Full Text]
  41. Edwards G., Weston A.H. Structure-activity relationships of K+ channel openers. Trends Pharmacol Sci 1990;11:417-422.[Medline]
  42. Kakei M., Noma A., Shibasaka T. Properties of adenosine-triphosphate-regulated potassium channels in guinea-pig ventricular cells. J Physiol 1985;363:441-462.[Abstract/Free Full Text]
  43. Galinanes M., Shattock M.J., Hearse D.J. Effects of potassium channel modulation during global ischaemia in isolated rat heart with and without cardioplegia. Cardiovasc Res 1992;26:1063-1068.[Medline]
  44. Mitchell M.B., Meng Z., Ao L., Brown J.M., Harken A.H., Banerjee A. Preconditioning of isolated rat heart is mediated by protein kinase C. Circ Res 1995;76:73-81.[Abstract/Free Full Text]
  45. Cohen N.M., Wise R.M., Wechsler A.S., Damiano R.J. Elective cardiac arrest with a hyperpolarizing adenosine triphosphate sensitive potassium channel opener. J Thorac Cardiovasc Surg 1993;106:317-328.[Abstract]
  46. Damiano R.J., Cohen N.M. Hyperpolarized arrest attenuates myocardial stunning following global surgical ischemia. J Cardiac Surg 1994;9(Suppl):517-525.[Medline]
  47. Cohen R.M., Damiano R.J., Wechsler A.S. Is there an alternative to potassium arrest?. Ann Thorac Surg 1995;60:858-863.[Abstract/Free Full Text]
  48. Marala R.B., Mustafa S.J. Modulation of protein kinase C by adenosine. Mol Cell Biochem 1995;145/150:51-58.
  49. Lahat-Singer D, Gershon E, Lotan H, et al. Modulation of the Ca+2 channels in Xenopus oocytes by protein kinase C. FEBS Lett 1992;11268;306:113–8.
  50. Bogoyevitch M.A., Parker P.J., Sugden P.H. Characterization of protein kinase C isotype expression in adult rat heart. Protein kinase C-{epsilon} is a major isotype present, and is activated by phorbol esters, epinephrine and endothelin. Circ Res 1993;72:757-767.[Abstract/Free Full Text]
  51. Sugden P.H., Bogoyevitch M.A. Intracellular signalling through protein kinases in the heart. Cardiovasc Res 1995;30:478-492.[Medline]
  52. Armstrong S., Downey J.M., Ganote C.E. Preconditioning of isolated rabbit cardiomyocytes. Cardiovasc Res 1994;28:72-77.[Abstract/Free Full Text]
  53. Hu K., Duan D., Li G.R., Nattel S. Protein kinase C activated ATP-sensitive K+ current in human and rabbit ventricular myocytes. Circ Res 1996;78:492-498.[Abstract/Free Full Text]
  54. Steinberg S.F., Goldberg M., Rybin V.O. Protein kinase C isoform diversity in the heart. J Mol Cell Cardiol 1995;27:141-153.[Medline]
  55. Dösemeci A., Dhallan R.S., Cohen N.M., Lederer W.J., Rogers T.B. Phorbol ester increases calcium current and simulates the effects of angiotensin II on cultured neonatal rat heart myocytes. Circ Res 1988;62:347-357.[Abstract/Free Full Text]
  56. Holland F.W., Brown P.S., Clark R.E. Acute severe postischemic myocardial depression reversed by triiodothyronine. Ann Thorac Surg 1992;54:301-305.[Abstract]
  57. Novitzky D., Cooper D.K., Barton C.I., et al. Triiodothyronine as an inotropic agent after open heart surgery. J Thorac Cardiovasc Surg 1989;98:972-978.[Abstract]
  58. Novitzky D., Human P.A., Cooper D.K. Inotropic effect of triiodothyronine following myocardial ischemia and cardiopulmonary bypass. Ann Thorac Surg 1988;45:50-55.[Abstract]
  59. Walker J.D., Crawford F.A., Spinale F.G. Pretreatment with 3,5,3 triiodo-L-thyronine. J Thorac Cardiovasc Surg 1995;110:315-327.[Abstract/Free Full Text]
  60. Bennett-Guerrero E., Jimenez J.L., White W.D., D’Amico E.B., Baldwin B.B.I., Schwinn D.A., Duke T3 Study Group. J Am Med Ass 1996;275:687-692.[Abstract/Free Full Text]
  61. Walker J.D., Crawford F.A., Spinale F.G. 3,5,3 triiodo-L-thyronine treatment prior to hypothermic cardioplegic arrest improves myocyte contractile processes in the setting of left ventricular dysfunction. Ann Thorac Surg 1995;60:292-299.[Abstract/Free Full Text]
  62. Gay W.A. Potassium-induced cardioplegia. Ann Thorac Surg 1989;48:441-443.[Abstract]
  63. Damiano R.J. The electrophysiology of ischemia and cardioplegia. J Card Surg 1995;10:445-453.[Medline]
  64. Spielman W.S., Klotz K.N., Arend L.J., Olson B.A., Le Vier D.G., Schwabe U. Characterization of adenosine A1 receptor in a cell line (28A) derived from rabbit collecting tubule. Am J Physiol 1992;263:C502-C508.[Abstract/Free Full Text]
  65. Schwiebert E.M., Karlson K.H., Friedman P.A., Dietl P., Spielman W.S., Stanton B.A. Adenosine regulates a chloride channel via protein kinase C and a G protein in rabbit cortical collecting duct cell line. J Clin Invest 1992;89:834-841.
  66. Daut J., Maier-Rudolph W., Von Beckerath N., Mehrke G., Günther K., Goedel-Meinin L. Hypoxic dilation of coronary arteries is mediated by ATP-sensitive potassium channels. Science 1990;247:1341-1344.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Thorac. Cardiovasc. Surg.Home page
D. M. Rudd and G. P. Dobson
Toward a new cold and warm nondepolarizing, normokalemic arrest paradigm for orthotopic heart transplantation.
J. Thorac. Cardiovasc. Surg., January 1, 2009; 137(1): 198 - 207.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
R. Mukherjee, W. M. Yarbrough, E. S. Reese, J. S. Leiser, J. A. Sample, J. T. Mingoia, A. E. Hardin, R. E. Stroud, J. E. McLean, J. W. Hendrick, et al.
Myocyte contractility with caspase inhibition and simulated hyperkalemic cardioplegic arrest
Ann. Thorac. Surg., May 1, 2004; 77(5): 1684 - 1689.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
K. Mubagwa and W. Flameng
Adenosine, adenosine receptors and myocardial protection: An updated overview
Cardiovasc Res, October 1, 2001; 52(1): 25 - 39.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Spinale, F. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Spinale, F. G.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS