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Anesth Analg 2008; 106:17-23
© 2008 International Anesthesia Research Society
doi: 10.1213/01.ane.0000289527.70545.ed
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CARDIOVASCULAR ANESTHESIOLOGY

Preconditioning by Isoflurane Retains Its Protection Against Ischemia-Reperfusion Injury in Postinfarct Remodeled Rat Hearts

Eliana Lucchinetti, PhD*, Marina Jamnicki, MD*, Gregor Fischer, DVM{dagger}, and Michael Zaugg, MD*

From the *Institute of Anesthesiology, University Hospital Zurich; and {dagger}Institute of Laboratory Animal Science, University of Zurich, Zurich, Switzerland.

Address correspondence to Michael Zaugg, MD, Institute of Anesthesiology, E-HOF, University Hospital Zurich, and Zurich Center for Integrative Human Physiology ZIHP, University of Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland. Address e-mail to michael.zaugg{at}usz.ch.

Abstract

BACKGROUND: Postinfarct remodeling in the heart may affect protective signaling. We tested whether isoflurane preconditioning retains its protection in postinfarct remodeled hearts.

METHODS: Myocardial remodeling was induced by ligation of the left anterior descending coronary artery in male Wistar rats. Six weeks later, diseased hearts were mounted on a Langendorff apparatus and exposed to 40 min of ischemia followed by 90 min of reperfusion. Isoflurane preconditioning was induced with 1.5 MAC (2.1 vol%) isoflurane for 15 min. Infarct size was determined using 1% triphenyltetrazolium chloride staining and corroborated with measurements of lactate dehydrogenase (LDH) release into the perfusate. In some experiments, the protein kinase B and mitochondrial ATP-dependent potassium channel inhibitors LY294002 (10 µM) or 5-hydroxydecanoate (100 µM), respectively, were concomitantly added with isoflurane. Cardiac function was recorded.

RESULTS: Six weeks after permanent coronary artery ligation, infarct rats exhibited a markedly increased heart weight/body weight index (5.41 ± 0.64 vs 3.60 ± 0.59 g/kg, P < 0.0001) confirming remodeling with compensatory hypertrophy. Isoflurane preconditioning decreased LDH release and reduced infarct size from 32% ± 6% to 2% ± 2% (P < 0.0001). Concomitant administration of LY294002 or 5-hydroxydecanoate with isoflurane completely abolished this protection. Functional assessment also showed significant protection from postischemic stunning by isoflurane preconditioning in remodeled hearts, which was lost in the presence of both blockers.

CONCLUSIONS: Myocardial preconditioning with isoflurane retains its protection against ischemia/reperfusion injury in postinfarct remodeled rat hearts via similar signaling pathways, as previously reported in healthy hearts.

Remodeling is a maladaptive process occurring after acute myocardial infarction that is accompanied by profound alterations in cellular composition, shape, and function of the heart.1,2 Ventricular dilation and compensatory hypertrophy of the residual intact myocardium are typical features of this process, which may place the heart at increased risk for further damage.3 Many patients with clinically relevant cardiovascular disease exhibit marked ventricular remodeling, which has a poor prognosis and decreases long-term survival.4,5 Unfortunately, one of the most powerful endogenous protective mechanisms of the heart, termed "ischemic preconditioning," has been reported to be impaired or completely abolished in postinfarct remodeled myocardium.6 Conversely, protective interventions during the early reperfusion phase seem less impaired by myocardial remodeling.7,8 Although there is convincing evidence of the efficacy of anesthetic preconditioning (APreC) in a variety of animal models using healthy hearts,9 no data are available on whether volatile anesthetics retain their infarct size-limiting effects in chronically remodeled diseased myocardium. This question is of particular clinical importance, because many elderly patients undergoing major cardiac and noncardiac surgery have preexisting cardiac disease with concomitant ventricular remodeling.

In the present study, we therefore sought to determine whether isoflurane preconditioning is effective in postinfarct remodeled hearts and, if so, whether two of the previously reported signaling elements in anesthetic protection, namely the phosphatidyl inositol-3 kinase (PI3K)-protein kinase B pathway10 and the mitochondrial ATP-dependent potassium channel (KATP channel),11 would be functional in diseased hearts. We hypothesized that isoflurane preconditioning would retain its protection against ischemia/reperfusion injury despite the presence of extensive ventricular remodeling.

METHODS

Experimental protocols used in this investigation were approved by the Animal Care and Use Committee of the University of Zurich, and all procedures conformed to the Guiding Principles in the Care and Use of Animals of the American Physiological Society and were in accordance with the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (NIH publication 85–23, revised 1996).

Infarct Model and Myocardial Remodeling
Surgery was performed in 200 g male Wistar rats (8–9 wk old) kept in a 12-h light-dark cycle fed commercial rat chow and water ad libitum. Permanent ligation of the left anterior descending coronary artery was done in tracheally intubated animals under isoflurane anesthesia, as previously described.12 The heart was accessed via the fourth intercostal space, exteriorized and the pericardium was opened. The left anterior descending coronary artery was ligated between the left atrium and the pulmonary outflow tract using a 6.0 silk suture. Success of coronary occlusion was confirmed by typical color changes of the dependent myocardium and ST-segment changes in the electrocardiogram. After replacing the heart into the mediastinal cavity, the air was drained and the chest was quickly closed. All animals received enrofloxacin (10 mg/kg body weight) subcutaneously as antibiotic prophylaxis. All animals were labeled by implanting a subcutaneous microchip. At the end of the surgery, the animals received subcutaneous buprenorphine (0.02 mg/kg body weight) for postoperative analgesia. Sham-operated animals underwent the same procedure except that the suture was passed under the coronary artery without ligation. Using the described technique, infarct size reaches approximately 30% of the left ventricular mass, and induces macroscopic, microscopic, and biochemical alterations in the heart characteristic of ventricular remodeling 6 wk after infarction, as previously described in detail.7,8

Isolated Perfused Rat Heart Preparation
Six weeks after permanent coronary artery ligation, the rats were heparinized (500 U i.p.) and 20 min later decapitated without prior anesthesia. The hearts were quickly removed and perfused in a Langendorff apparatus with Krebs-Henseleit buffer (in mmol/L, Na+ 155, K+ 5.6, Cl– 138, Ca2+ 2.1, PO43– 1.2, HCO3– 25, Mg2+ 0.56, glucose 11) gassed with 95% O2/5% CO2 (pH 7.4, temperature 37°C). Perfusion pressure was set to 80 mm Hg. A water-filled balloon was inserted into the left ventricle and inflated to set an end-diastolic pressure of 10 mm Hg during the initial equilibration. The distal end of the catheter was connected to a performance analyzer (Plugsys Modular System, Hugo Sachs, March-Hugstetten, Germany) by means of a pressure transducer. Perfusion pressure, epicardial electrocardiogram, and coronary flow (Transit Time Flowmeter Type 700, Hugo Sachs, March-Hugstetten, Germany) were recorded and processed on a PC using the software IsoHeart (Hugo-Sachs, March-Hugstetten, Germany), as previously reported.13

Experimental Protocols, Analysis of Functional Variables and Determination of Infarct Size
Spontaneously beating hearts were equilibrated for 10 min. The following protocols were used (Fig. 1). APreC was induced by isoflurane administered for 15 min at 2.1 vol% (1.5 MAC in rats at 37°C). Isoflurane was washed out for 10 min before the 40 min of test ischemia followed by 90 min of reperfusion. The buffer solution was equilibrated with isoflurane using an Isotec 3 vaporizer (Datex-Ohmeda, Tewksbury, MA). Isoflurane concentrations were measured in the buffer solution using a gas chromatograph (Perkin-Elmer, Norwalk, CT) and reached 0.51 ± 0.07 mM. In some experiments, the PI3K-protein kinase B inhibitor LY294002 at 10 µM (Alexis, Lausen, Switzerland) and the mitochondrial KATP channel blocker 5-hydroxydecanoate at 100 µM (Sigma, St. Louis, MO) were co-administered with isoflurane. LY294002 was dissolved in dimethyl sulfoxide at a final concentration <0.1%. Hearts exposed to ischemia/reperfusion alone served as ischemic control (ISCH). For each experimental group, five hearts were prepared and cardiac function was continuously recorded. At the conclusion of the experiments, the hearts were frozen at –20°C for 2 h and subsequently sliced into five 2 mm cross-sections. The sections were incubated at 37°C for 30 min in 1% 2,3,5-triphenyltetrazolium chloride in 0.1 M phosphate buffer adjusted to a pH of 7.4. Slices were fixed in 10% formaldehyde and digitally photographed. Planimetric analysis was performed on a PC using ImageJ 1.33 software.14 Infarct sizes were calculated by dividing the freshly necrotic area (salmon pink) of the left ventricle by the area at risk, as previously described.7 The chronic infarct (bright white) was subtracted from the total left ventricular slice area to obtain the area at risk. Thus, areas infarcted in vivo by permanent coronary artery ligation (chronic infarct) were excluded from infarct size analysis. As an additional marker of myocardial injury, lactate dehydrogenase (LDH) release from necrotic tissue was determined from collected perfusate using the Roche/Hitachi 917 (sensitivity 6 U/L, intra-assay and inter-assay coefficients of variance <1%, Hitachi Corp. Tokyo, Japan). In separate experiments, conventional histological staining with Masson’s trichrome was performed after perfusing the heart with 4% paraformaldehyde and embedding it in paraffin.


Figure 14
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  		Figure 1. Schematic of groups and protocols. CTRL: time-matched perfusion of remodeled hearts. ISCH = remodeled hearts exposed to ischemia/reperfusion alone; APreC = anesthetic preconditioning with isoflurane at 1.5 MAC (2.1 vol%) for 15 min with subsequent 10 min of washout before 40 min of ischemia; APreC + HD = administration of 100 µM 5-hydroxydecanoate, a specific blocker of the mitochondrial KATP channel during isoflurane preconditioning; APreC + LY = administration of 10 µM LY294002, a specific blocker of the PI3-kinase-protein kinase B pathway, dissolved in dimethyl sulfoxide (<0.1%) during isoflurane preconditioning; ISCH + HD = administration of 100 µM 5-hydroxydecanoate for 15 min followed by 10 min of washout; ISCH + LY = administration of 10 µM LY294002 dissolved in dimethyl sulfoxide (DMSO) for 15 min followed by 10 min of washout; ISCH + DMSO = administration of DMSO for 15 min followed by 10 min of washout. n = 5 in each group.

 

Statistical Analysis
Using a similar protocol in healthy hearts, we previously observed a reduction in infarct size from 36% ± 1% to 7% ± 1% of the area at risk.15 Thus, five hearts in each group was considered sufficient. Data are presented as mean ± sd. Repeated-measures analysis of variance was used to evaluate differences in functional recovery over time among groups. Unpaired t-test was used to compare groups at identical time points, and paired t-tests to compare within groups over time (SigmaStat v 2.0; SPSS Science, Chicago, IL). Post hoc Bonferroni test for multiple comparisons was used. For all other data, one-way analysis of variance with post hoc Tukey test was used for multiple comparisons. P < 0.05 was considered significant. SigmaStat (version 2.0; SPSS Science, Chicago, IL) was used for analysis.

RESULTS

Myocardial Remodeling After Permanent Coronary Artery Ligation
In 41 rats, ligation of the left anterior descending coronary artery was performed without complications. One chronically remodeled infarct heart was used for histological assessment. The remaining 40 animals were used for Langendorff perfusion protocols. Before each experiment, body weight and heart weight were quickly determined to see whether remodeling-associated hypertrophy was present in the heart used for experimentation. In all infarct rats, heart weight/body weight index was more than five indicating successful remodeling with compensatory hypertrophy (Table 1). Remodeled hearts had a spherical shape as opposed to healthy ellipsoid-shaped hearts (Fig. 2). Furthermore, the hearts showed reduced left ventricular developed pressure at baseline conditions on the Langendorff apparatus after equilibration.


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  		Table 1. Characteristics of Remodeled Hearts used for Langendorff Experiments

 

Figure 24
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  		Figure 2. Histochemistry of a representative sham-operated (Panel A) and remodeled (Panel B) heart 6 wk after permanent ligation of the left anterior descending coronary artery. Masson’s trichrome staining, 3 µm sections: chronic infarct scar stains blue whereas myocardium stains red. Black arrow head shows compensatory hypertrophy, white arrow head infarct scar.

 

Isoflurane Preconditioning Effectively Reduces Infarct Size in Remodeled Hearts
Isoflurane preconditioning at 1.5 MAC for 15 min followed by 10 min of washout markedly reduced infarct size in remodeled hearts from 32% ± 6% to 2% ± 2% (P < 0.0001, Fig. 3). Concomitant administration of LY294002 or 5-hydroxydecanoate completely abolished the protection (LY294002: 31% ± 6%; 5-hydroxydecanoate: 30% ± 6%). Dimethyl sulfoxide or blockers alone did not affect infarct size. Because infarct size determination may be complicated by the scar formation after permanent coronary artery ligation, LDH release into the perfusate was also determined as an additional surrogate marker of myocardial injury. The results of these experiments closely paralleled infarct size measurements obtained with triphenyltetrazolium chloride staining (Fig. 3).


Figure 34
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  		Figure 3. Myocardial injury after ischemia/reperfusion in remodeled hearts. Panel A: percent infarct size of the left ventricular area at risk, as measured by tripheyltetrazolium chloride staining after 90 min of reperfusion. Panel B: release of lactate dehydrogenase (LDH in U/g*h), a surrogate marker of myocardial damage. Panel C: cross-sections of representative hearts after 2,3,5-tripheyltetrazolium chloride staining. Note that the white chronic infarct (fibrosis) was clearly distinguished from fresh salmon pink infarct regions. ISCH = ischemic control; APreC = anesthetic preconditioning with isoflurane; APreC + HD = isoflurane preconditioning with 5-hydroxydecanoate; APreC + LY = isoflurane preconditioning with LY294002; ISCH + HD = 5-hydroxydecanoate alone followed by ischemia/reperfusion; ISCH + LY = LY294002 alone followed by ischemia/reperfusion; ISCH + DMSO = DMSO (<0.1%) alone followed by ischemia/reperfusion. *P < 0.0001 vs ISCH. n = 5 in each group.

 

Cardiac Function Is Markedly Improved After Isoflurane Preconditioning in Postinfarct Hearts
Time-matched infarct hearts served as control and were hemodynamically stable over the study period. Ischemia/reperfusion markedly reduced all functional variables and coronary flow (Table 2). In contrast, hearts protected with isoflurane preconditioning exhibited significantly better postischemic functional recovery and higher coronary flow than unprotected hearts. Isoflurane protection was completely lost in the presence of the specific blockers for the PI3K-protein kinase B pathway LY294002 and for the mitochondrial KATP channel 5-hydroxydecanoate.


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  		Table 2. Hemodynamic Parameters

 

DISCUSSION

Our results show that isoflurane preconditioning retains its protection against ischemia/reperfusion injury in postinfarct remodeled hearts. Infarct size reduction, as determined with triphenyltetrazolium chloride staining, was corroborated by measuring the release of the necrosis marker LDH into the coronary effluent. In addition to the marked infarct size reduction, isoflurane preconditioning also improved functional recovery and decreased postischemic myocardial stunning. Our findings further suggest that the pro-survival pathway PI3K-protein kinase B and protection mediated by opening of the mitochondrial KATP channels are functional, despite the presence of severe structural changes in the heart after infarction. We have recently demonstrated that protection by isoflurane7 and ischemic8 postconditioning is preserved in postinfarct remodeled myocardium. Although pre- and postconditioning share many signaling steps,7,16–18 marked differences in postischemic transcriptional changes were reported,15 and it could not be taken for granted that the two anti-ischemic strategies located on opposite sides of ischemia would elicit similar protection in remodeled hearts. Thus, our findings add valuable new information.

Permanent ligation of the left anterior descending coronary artery is a well-established model to induce ventricular remodeling.12 Macroscopic hallmarks of the remodeling process are compensatory hypertrophy and ventricular dilation, precipitating pump failure and lethal arrhythmias. After infarction, a variety of conditions associated with pathologic cardiac workload lead to changes in cellular tissue composition, structure, and energy metabolism of the heart. At the molecular level, fetal genes are reactivated19 and protective signaling pathways were reported to be lost in various disease models associated with remodeling.20 Experiments from muscle slices of human right atrial appendices of patients with failing hearts indicate that remodeled myocardium is less amenable to protection by ischemic preconditioning,21 one of the most important innate protective strategies of the heart. Hyperglycemia and hypercholesterolemia per se promote the remodeling process and are known to inhibit ischemic preconditioning.22–24 Not surprisingly, loss of ischemic preconditioning in hearts of patients with coronary artery disease leads to reduced long-term survival.25 In a rabbit infarct model with ventricular remodeling, complete refractoriness to ischemic preconditioning stimulus, but not diazoxide, a direct mitochondrial KATP opener, was previously reported.6 Subsequent studies revealed that interruption of signal transduction between G-protein coupled receptors and protein kinase C was responsible for this refractoriness.26 Conversely, erythropoietin-mediated preconditioning was shown to be preserved in postinfarct remodeled myocardium despite the disruption of the erythropoietin receptor-PI3K-protein kinase B pathway.27 In this case, compensatory PI3K-independent activation of extracellular signal-regulated kinase upstream of the guanylyl cyclase-mitochondrial KATP channel pathway was found to rescue the protective phenotype and to restore the protection.28 In the present study, isoflurane, which indirectly (via G-protein coupled receptors and activation of pro-survival kinases) and directly affects mitochondrial KATP channels similar to diazoxide,11 effectively protected the diseased hearts.

Our findings are in accordance with a growing number of clinical studies showing reduced ischemic damage and improved perioperative cardiac function in patients undergoing coronary artery bypass graft surgery when a volatile anesthetic instead of propofol was used as the main hypnotic drug.29–33 Of note, all patients in these studies suffered from ischemic heart disease with varying degrees of ventricular remodeling, and many of them were receiving chronic anti-remodeling medication, including β-blockers and inhibitors of the renin-angiotensin system. Nonetheless, patients randomized to treatment with the volatile anesthetic showed improved functional and biochemical cardiac outcome.

In the present study, we did not directly evaluate the effects of isoflurane preconditioning on mitochondrial KATP channel activity or protein kinase B activation, as previously reported in healthy hearts.10,11 Future studies should therefore determine whether downstream targets of protein kinase B, such as endothelial nitric oxide synthase, p70S6 kinase, and glycogen synthase kinase 3β, are similarly activated in remodeled versus healthy myocardium.7

In summary, the data provided in this study show, for the first time under well-controlled experimental conditions, that protection by isoflurane preconditioning is fully preserved in postinfarct remodeled hearts.

Footnotes

Accepted for publication August 30, 2007.

Supported by the Grant #3200B0-103980/1 and 3200B0-116110/1 of the Swiss National Science Foundation, Berne, Switzerland, the Swiss University Conference, Berne, Switzerland, a Grant of the EMDO Foundation, Zurich, Switzerland, a Grant from Abbott Switzerland, Baar, Switzerland, and the 5th Frontiers in Anesthesia Research Award from the International Anesthesia Research Society, Cleveland, OH, USA.

Dr. Lucchinetti and Dr. Jamnicki equally contributed to this work.

Reprints will not be available from the author.

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press