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Right arrow Myocardial protection

Ann Thorac Surg 2003;76:1240-1245
© 2003 The Society of Thoracic Surgeons

Original article: cardiovascular

Protection of myocardium by cyclosporin A and insulin: in vitro simulated ischemia study in human myocardium

Aviva Schneider, MSa, Niv Ad, MDb, Uzi Izhar, MDb, Igor Khaliulin, PhDa, Joseph B. Borman, MDa, Herzl Schwalb, PhDa*

a Joseph Lunenfeld Cardiac Surgery Research Center, Hadassah University Hospital, Jerusalem, Israel
b Cardiothoracic Surgery Department, Hadassah University Hospital, Jerusalem, Israel

Accepted for publication April 8, 2003.

* Address reprint requests to Dr Schwalb, Joseph Lunenfeld Cardiac Surgery Research Center, Hadassah University Hospital, PO Box 12000, 91120 Jerusalem, Israel.
e-mail: schwalb{at}hadassah.org.il


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: The efficacy of myocardial protection by cyclosporin A (CSA) and insulin was tested in human right atrial myocardial slices subjected to simulated ischemia and reoxygenation.

METHODS: Slices of right atrial trabeculae were obtained from patients undergoing elective cardiac surgery. Trabeculae were incubated with oxygenated glucose containing phosphate buffered saline (O2, G-PBS). After 30 minutes of stabilization the sections were exposed to 90 minutes of simulated ischemia (N2, PBS without glucose) followed by 90 minutes reoxygenation (O2, G-PBS). Cyclosporin A (0.2 µmol/L) or insulin (5 mU/mL) was added during the stabilization period prior the ischemia. Cell viability was measured by using 3-[4.5 dimethylthiazol 2-yl]-2,5-diphenyltetrazolium bromide (MTT), which is cleaved by active mitochondrial dehydrogenases of living cells.

RESULTS: The viability of untreated slices (control) was 30.45% ± 2.5% versus 52.65% ± 4.4% in the CSA treated slices, p less than 0.001. The extent of protection by CSA was affected by oral antiglycemic drugs (glibenclamide). The effect obtained by CSA was inhibited by 5-hydroxydecanoate (5HD), a specific blocker of mitochondrial KATP channels. Protection of the myocardial slices with insulin appears to be superior and not affected by the medication before surgery. This protection was maximal when insulin was present during both preischemic equilibration and reoxygenation periods (68.9% ± 9.3% viability with insulin versus 33.2% ± 6.9% in the control, p < 0.001).

CONCLUSIONS: Protection of right atrial trabeculae slices with insulin is superior to that obtained with CSA and is independent of preoperative medication.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Ischemic preconditioning is a phenomenon in which single or multiple brief periods of ischemia have been shown to protect the heart against prolonged ischemic insult, the result of which is a marked reduction in myocardial infarct size, severity of stunning, or incidence of cardiac arrhythmias [1]. The overwhelming majority of evidence suggests that the adenosine triphosphate (ATP)-sensitive potassium channel (KATP) may serve as the effecter in this process [2].

The cardioprotective effects of ischemic preconditioning have been shown in various species including humans [1, 3]. However its protective effect during open-heart surgery has been questioned [4]. An effective method for ischemic preconditioning during cardiac surgery is intermittent crossclamping but it may result in a relatively high incidence of intraoperative myocardial damage and cerebral embolic events. This emphasizes the need for pharmacologic mediators that safely and effectively will emulate the beneficial effects of preconditioning.

Cyclosporin A (CSA), a widely used immunosuppressive agent, inhibits T-cell activation through inhibition of the calcium/calmodulin-dependent PP2B, also known as calcineurin, by forming complexes with the cytoplasmic binding proteins cyclophilin [5]. Griffiths and colleagues [6] found that CSA preserved postischemic contractile function. They ascribed the protection to inhibition of a Ca2+-dependent mitochondrial transition pore (MTP) in heart. Others [7] noted that CSA treatment preserved postischemic function but their results suggested a nitric oxide dependent mechanism, mediated by endothelium. We demonstrated that CSA significantly enhanced recovery of contractile performance, oxygen consumption, ATP, and phosphocreatine content in postischemic reperfused hyperthyroid isolated rat hearts [8]. Minners and associates [9] and others demonstrated that CSA triggered "preconditioning" cardioprotection in the isolated rat heart.

Since the 1960s the regimen of glucose-insulin-potassium has been studied in several trials as a therapy for acute myocardial infarction with the rationale of providing both electrical stability and metabolic support to the myocardium. Recently these clinical trials have been reevaluated by meta-analysis [10]. The findings indicate that glucose-insulin-potassium therapy may have an important role in reducing the in-hospital mortality after acute myocardial infarction.

Studies in the early 1990s indicated that insulin and the insulin-like growth factor-1 inhibited apoptosis in various cell lines including hemopoietic cells [11]. Preischemic treatment with insulin triggers a cardioprotective infarct-limiting response in rabbit myocardium through activation of phosphatidylinositol 3- kinase (PI3K) [12]. Inhibition of either protein kinase C (PKC) by polymyxin B (0.05 mmol/L) or KATP channels by 5- hydroxydecanoate (5-HD, 0.1 mmol/L) failed to prevent protection by insulin. Ischemic preconditioning reduced infarction and still offered significant protection in the presence of wortmannin (selective inhibitor of phosphatidylinositol 3- kinase). Thus it was suggested that the mechanism of protection by insulin in the rabbit heart involves activation of PI3K but not PKC or KATP channels [12].

In the present study we used sections of right atrial trabeculae obtained from patients undergoing elective cardiac surgery in a model of simulated ischemia and reoxygenation and investigated the effect of CSA and insulin on tissue viability. The involvement of KATP channels was tested with 5HD, a specific inhibitor of mitochondrial KATP.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Cyclosporin A was purchased from Calbiochem (La Jolla, CA). The 5-hydroxydecanoic acid sodium salt (5HD) was purchased from Research Biologicals (Natick, MA). The 3-[4,5-dimethythiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), and diazoxide were obtained from Sigma (Sigma-Aldrich Co, St. Louis, MO). Regular human insulin (100 U/mL) was purchased from Lilly France S.A. (Fegersheim, France).

Incubation medium
Glucose-phosphate buffered saline (G-PBS) was prepared daily in distilled water and contained in mM: NaCl 136.9, KCl 2.68, Na2HPO4 8.10, KH2PO4 1.53, MgCl2 x 6H2O 0.5, CaCl2 x 2H2O 0.9, glucose 5.55 (pH 7.45). The MTT solution was prepared by dissolving 0.5 mg of MTT in 1 mL of G-PBS. The 5HD was dissolved in G-PBS to a final concentration of 0.1 mmol/L in the experimental setting. The insulin was diluted to the working concentration with G-PBS.

Isolated human atrial trabeculae
The investigation conforms to the principles outlined in the Helsinki Declaration. Approval to conduct the study was obtained from the Institutional Ethics Committee on Human Research (January 17, 2001) and informed consent was obtained from each patient.

The use of isolated human atrial sections to simulate ischemia and reoxygenation was adopted from studies by Ghosh and associates [13]. Right atrial appendages were obtained from 54 patients undergoing elective cardiac surgery before initiation of cardiopulmonary bypass (Table 1). The specimens were placed in test tubes containing oxygenated heparinized blood and immediately transferred to the laboratory. The specimens were rinsed with G-PBS and trabeculae were gently separated longitudinally.


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  		Table 1. Patient Demographics

 
Simulated ischemia and reoxygenation
Basically the atrial sections were exposed to 30 minutes of aerobic equilibration (O2, 37°C), 90 minutes of ischemia (N2, 37°C), and 90 minutes of reoxygenation (O2, 37°C).

Atrial sections (5 to 10 mg each) were placed in containers with 20 mL G-PBS and incubated 30 minutes for equilibration at 37°C in a cell culture incubator. After aerobic equilibration the sections were rinsed in phosphate buffered saline without glucose (PBS) and subjected to ischemia and reoxygenation while the aerobic control sections were left in the incubator in G-PBS for the entire experiment. Ischemia (37°C) was simulated by placing the sections (2 sections per 35-mm culture plate) in a sealed Plexiglas chamber [14]. The chamber was vigorously flushed with 100% N2 for 5 minutes in order to replace the oxygen with N2. En route to the chamber the gas passes two traps: trap 1 contains 1% Na2SO3; trap 2 contains water. A 2-mL syringe flushed with N2 was filled with ischemic PBS (without glucose, bubbled for 1 hour with N2). Each well was quickly filled with 0.4 mL of ischemic PBS and corked. The flow of N2 was attenuated to aproximately 1 bubble per second at the exit trap and the ischemia was maintained for 90 minutes.

At the end of 90 minutes of simulated ischemia, the slices were subjected to 90 minutes reoxygenation in G-PBS at 37°C in a 100% oxygenated environment

Drug administration
Cyclosporin A (0.2 µmol/L) [6, 15] was applied to the sections during the 30 minutes of preischemic equilibration. Cyclosporin A was omitted from the simulated ischemic and reoxygenation PBS. Insulin (5 mU/mL) was applied during the preischemic equilibration, or during the reoxygenation, or during both periods. The 5HD (0.1 mmol/L), a KATP blocker, was applied during the 30-minute preischemic period in order to inhibit the protective effect of CSA [15].

Assessment of tissue injury and viability
At the end of each experimental protocol, tissue viability was determined by MTT staining—reduction of 3-[4,5 dimethylthiazol-2yl]-2.5 diphenyltetrazolium bromide to blue formazan by mitochondrial dehydrogenases. The intensity of MTT staining in the myocardial sections is correlated with the viability of the tissue [13].

The MTT was present for the entire period of the reoxygenation—two atrial sections were incubated in 1 mL G-PBS containing MTT (0.5 mg/mL) at 37°C for 90 minutes. The sections were then transferred to a small test tube containing 3 mL of saline, which was shaken for 1 minute to remove excess dye. The sections were wiped on gauze cloth and transferred to 1.5 mL plastic test tubes and frozen overnight. Extraction of the Formazan dye into 1 mL of DMSO was done with vigorous shaking for 1 hour at 37°C. The colored supernatant was measured spectrophotometrically at 500 nm. The sections were dried in a 90°C oven for 24 hours and the results were expressed as optical density per mg dry weight of myocardial tissue. Tissue viability was expressed as the ratio between the ischemia and reoxygenation optical density to that of its aerobic controls normalized to dry weight of myocardial tissue

Statistical analysis
Results are expressed as mean ± SEM. Statistical significance of differences between groups was carried out using analysis of variance (ANOVA) and Tukey posthoc test. Statistical differences of p less than 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Effect of cyclosporin A on viability of human right atrial slices
Human right atrial slices exposed to simulated ischemia and reoxygenation benefit from cyclosporin A treatment. The viability of the slices from untreated controls was 30.45% ± 2.5% versus 52.65% ± 4.4% in the CSA treated slices (p < 0.001; Fig 1a). Subgroup analysis revealed attenuated effect of CSA on atrial slices collected from patients that were treated with oral glibenclamide (KATP blocker) preoperatively (36% ± 5% for untreated controls versus 42.1% ± 5.4% for CSA, p > 0.05; Fig 1, b).



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  		Fig 1. Protection of human right atrial sections with cyclosporin A (CSA). The atrial sections were exposed to 30 minutes of aerobic equilibration, 90 minutes of simulated ischemia (37°C), and 90 minutes of reoxygenation (untreated control and CSA treated groups). The CSA (0.2 µmol/L) was administered during the preischemic equilibration. Postischemic viability was measured by MTT (3-[4.5 dimethylthiazol 2-yl]-2,5-diphenyltetrazolium bromide). (a) The group includes all the patients (n = 20) mean ± SEM. *p less than 0.001 versus the untreated control group (without CSA). (b) Subgroup analysis of the effect of presurgery oral glybenclamide on the CSA protective effect. Left: atrial slices from patients orally treated with glybenclamide (n = 8). Right: atrial slices from patients nontreated with glybenclamide (n = 12). *p less than 0.001 versus the untreated control group (without CSA).

 
In the light of the above results we assumed that KATP channels might have a major contribution to the effect elicited by CSA treatment. Atrial slices obtained from a different group of patients without history of diabetes and glibenclamide treatment were used to test this assumption. Figure 2 indicates that 5HD, a specific KATP channel blocker [9], abolishes the protective effect of CSA (32.6% ± 4.4% for the CSA plus 5HD treated versus 67.4% ± 8% for the CSA treated only group, p < 0.001).



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  		Fig 2. Inhibition of the protective effect of cyclosporin A (CSA) in human right atrial sections. The experimental protocol was the same as in Figure 1; however, atrial slices obtained from a different group of patients without history of diabetes and glibenclamide treatment were used. The KATP channel inhibitor, 5-hydroxydecanoate (5HD, 0.1 mmol/L), was added during the preischemic equilibration (n = 6). *p less than 0.001.

 
Effect of insulin on viability of human right atrial slices
The effect of insulin (5 mU/mL) administered at different stages of the experimental protocol is exhibited in Figure 3a. The results demonstrate that maximal protection can be obtained when insulin is administered throughout the entire experiment (68.9% ± 9.3% viability versus 33.2% ± 6.9% in the untreated controls, p < 0.001). The protective effect of insulin was less significant when added only during preischemic incubation or reoxygenation period (viability of 45.3% ± 7.1%, p > 0.05, and 47.9% ± 8.3%, p < 0.05 respectively; Fig 3a). Unlike the results with CSA the beneficial effect of insulin on the viability of the slices is independent of prior use of glibenclamide by the patients (43.2% ± 9% for untreated controls versus 77.2% ± 10.2% for the insulin treated slices, p < 0.05; Fig 3b).



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  		Fig 3. Protection of human right atrial sections with insulin. Experimental protocol of simulated ischemia and reoxygenation as described for Figure 1. (a) Insulin (5 mU/mL) was added during preischemia or reoxygenation or both. *p less than 0.001 versus untreated control. #p less than 0.01. ##p less than 0.001 versus insulin preischemia plus reoxygenation. {wedge}p less than 0.05 versus untreated control. (b) Subgroup analysis of the effect of presurgery oral glybenclamide on the insulin (added during preischemia and reoxygenation) protective effect in left atrial slices (n = 5). *p less than 0.05 versus the untreated control group.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
The present study has demonstrated the possibility of protecting human myocardium from simulated ischemic injury by CSA or insulin. Cyclosporin A was efficient when added during the preischemic period in part of the cohort; right atrial specimens obtained from noninsulin-dependent diabetes patients treated with glibenclamide did not respond well to CSA in vitro treatment. Insulin protected effectively slices exposed to simulated ischemia and reoxygenation from all the patients. Our study demonstrates that KATP channels are involved in the CSA protection process since 5HD, a specific KATP channel blocker, abolished the protection obtained by CSA.

The fact that glibenclamide inhibits preconditioning of the in vitro system is already known [16]. Involvement of KATP in preconditioning was suggested [17] after studies in the canine heart. These authors demonstrated that KATP blockers, glibenclamide and 5HD, blocked the protection induced by preconditioning and also revealed that aprikalim, a KATP opener, mimicked preconditioning cardioprotection by reducing infarct size. It was demonstrated that the KATP opener diazoxide was about 1,000-fold more effective in opening mitochondrial KATP (mitoKATP) than sarcolemmal KATP and that its cardioprotective potency in rat hearts correlated with its effectiveness on mitochondrial rather than sarcolemmal channels [18].

Opening of the mitoKATP channel results in the influx of potassium into the mitochondrial matrix with a subsequent dissipation of the electrical potential over the inner membrane, potentially leading to an increase in mitochondrial volume [19]. Modest changes in mitochondrial volume regulate the activity of the electron transport chain with mitochondrial "swelling" resulting in an augmentation of ATP production [6]. This may be considered an adaptive mitochondrial response to cellular stress.

Others have also shown that low concentrations of CSA protect ischemic and reperfused rat heart [6, 8, 15, 20]. Cyclosporin A protective effects were linked to the inhibition of the mitochondrial transition pore [6] by inhibition of the PP2B phosphatase, calcineurin [20]. In addition to its inhibitory effects on the mitochondrial transition pore and on calcineurin activity [20] CSA directly affects mitochondrial energy metabolism by inhibition of the respiratory chain between cytochromes b and c1 [21]. The mitoKATP channel blocker 5HD can abolish ischemic preconditioning, thereby linking the mitochondria with ischemic preconditioning. Cyclosporin A by inhibiting (partially) the oxidative chain results in decreased ATP production. The mitoKATP is strongly inhibited by high ATP. Thus agents such as CSA that slightly decrease ATP production might deinhibit this channel [15]. The present study indicates for the first time that human heart tissue can also be preconditioned with CSA.

Insulin has long been known to modulate cellular metabolism. The regulation of gene expression has been recognized as a major action of insulin [22]. Diabetes causes a decrease in transient outward potassium current in rat ventricular myocytes [23]. However myocytes from diabetic rats incubated in vitro for 5 to 9 hours with insulin resulted in normalization of the potassium current [24]. This effect on potassium channels was attributed by the authors to the effect of insulin on transcription and expression of the channel proteins, rather than changes in cellular metabolism.

The ability of insulin in our study to efficiently protect all slices including those of noninsulin-dependent diabetes patients medicated with glibenclamide and the fact that the protection is time dependent (insulin should be present during both preischemia and reperfusion) suggests that the protection involves regulation of gene expression. Insulin could control gene expression, stimulate protein synthesis, or have mitogenic properties. The contribution of these different insulin effects during reperfusion to improve postischemic myocardial function remains to be evaluated [25].

Cardiovascular complications of diabetes mellitus are among the leading causes of death. In addition to diabetic vascular complications, diabetic cardiomyopathy is an independent risk characterized by defects in cardiomyocyte function that includes impaired contractility and abnormal electrophysiological properties [26]. One cellular electrophysiological finding that has been consistently observed in experimental models of diabetes is a significant prolongation of action potential duration [24]. The latter has been attributed to net decrease of outward repolarizing K+ currents, in particular the fast transient outward current that also controls action potential duration in human ventricular myocytes [24].

Recently Ghosh and associates [27] exhibited the impossibility to precondition human myocardial slices from diabetic patients: noninsulin-dependent diabetic patients receiving KATP channel blockers, insulin-dependent diabetic patients, and patients with poor cardiac function. By using insulin we were able to achieve protection to all myocardial slices including those from diabetic patients who were treated with glibenclamide before surgery.

Our in vitro study reinforces clinical studies using glucose-insulin-potassium therapy [28] for enhanced myocardial performance after coronary bypass in diabetic patients. The glucose-insulin-potassium was begun at anesthetic induction and continued for 12 hours postoperatively. Patients treated with glucose-insulin-potassium had higher postoperative cardiac indices, lower inotrope scores, less weight gain, shorter times of ventilation support, lower prevalence of atrial fibrillation, and shorter hospital stay [28]. Taking into consideration the low cost of glucose-insulin-potassium therapy the fact that it is readily available in hospitals and easy to administer during cardiac surgery and above all that it produces protection against ischemic injury to all pathologic myocardium suggests that insulin maybe useful in the treatment of the failing myocardium.

The conclusions drawn from this study are somewhat limited since the effect of CSA and insulin were tested using atrial tissue and not ventricular tissue. Given that human ventricular myocardium is very difficult to obtain for such studies, atrial tissue is the only human myocardium readily available for research during open hear surgery.

We conclude from this study that it may be possible to offer ischemia and reoxygenation protection for human myocardium by means of drug intervention (CSA, insulin). The most important finding of our study however is that the use of insulin may have a potential protective effect on the pathologic human myocardium regardless of preoperative use of glibenclamide (KATP channel blocker). That a high percentage of patients undergoing coronary bypass surgery have noninsulin-dependent diabetes mellitus and are treated orally makes this finding even more significant.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
This study was partially supported by the Aaron Beare Foundation.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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  16. Cleveland J.C., Jr, Meldrum D.R., Cain B.S., Banerjee A., Harken A.H. Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium. Two paradoxes revisited. Circulation 1997;96:29-32.[Abstract/Free Full Text]
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