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J Thorac Cardiovasc Surg 1998;116:485-489
© 1998 Mosby, Inc.
Cardiopulmonary Support and Physiology |
Supported by the Heart and Stroke Foundation of Canada (grant T2683).V.R., F.M., and G.C. are Research Fellows of the HSFC. R.D.W. is a CareerInvestigator of the HSFO. R.K.L. is a Research Scholar of the HSFO.
Received for publication Dec. 4, 1997. Revisions requested Jan. 20, 1998; revisions received March 5, 1998. Accepted for publication April 15, 1998. Address for reprints: Richard D. Weisel, MD, EN 14-215, The TorontoHospital, 200 Elizabeth St., Toronto, Ontario M5G 2C4, Canada
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Abstract |
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Introduction |
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1 In a previous canine model ofcardioplegic arrest and reperfusion, cardiac metabolism was evaluated withlactate infusions labeled with radioactive carbon (14C). 2 After cardioplegic arrest, there was14C-lactate extraction by the heart despite a net myocardial lactaterelease. This suggests that exogenous administration of lactate can altermyocardial substrate preference during cardioplegic arrest. However, the balancebetween lactate production and lactate oxidation appears to favor anaerobicmetabolism. In addition, the detection of myocardial lactate release grosslyunderestimates the true amount of anaerobic glycolysis because lactate producedby ischemic regions of the heart may be extracted by normally functioningmyocardium. The extent of anaerobic lactate production correlated with depressedpostoperative left ventricular function. Improving the transition from anaerobiclactate release to aerobic lactate oxidation during reperfusion may improve thetolerance to ischemia and enhance left ventricular function.
In 1965, Sodi-Pollaris and colleagues 3demonstrated a beneficial effect of an insulin solution on theelectrocardiographic abnormalities in patients with acute myocardial infarction.Since that initial report, several investigators 4-6have attempted to use glucose and insulin solutions to improve myocardialtolerance to ischemia. Unlike acute myocardial infarction, cardioplegic arrestduring a cardiac operation provides a unique clinical situation in whichmyocardial ischemia can be anticipated and metabolic interventions introduced toimprove cellular susceptibility to ischemia. An early study by Hearse andcolleagues 6 demonstrated adetrimental effect of exogenous glucose infusions during ischemic cardiacarrest. However, only a single cardioplegic infusion was administered, and thedeleterious effects were attributed to an accumulation of metabolic end-productssuch as lactate and acid. Using a similar isolated, rat heart model, Doherty andcolleagues 4 demonstrated abenefit of high doses of glucose and insulin by providing intermittent perfusionwith hypothermic crystalloid cardioplegia. This model effectively "washedout" the end products of glycolysis and prevented the cellular acidosis.The controversy regarding the effects of glycolytic stimulation during ischemiacontinues. 7,8 We hypothesized that glycolyticstimulation during a "low flow" cardioplegic arrest condition mayhave a beneficial effect on cardiomyocyte survival. Specifically, we believethat stimulation of mitochondrial pyruvate dehydrogenase (PDH) will allow anearlier recovery of aerobic metabolism after ischemia and improve cellularsurvival.
Kobayashi and Neely 9demonstrated that the activity of mitochondrial PDH was inhibited during thefirst 2 minutes of reperfusion after ischemia and remained depressed for as long45 minutes. Stimulation of PDH after ischemia may lead to an improved transitionfrom anaerobic to aerobic metabolism. Weiss and Hiltbrand 10 demonstrated that ATP produced fromoxidative phosphorylation was preferentially used for contractile function.Thus, enhanced myocardial metabolic recovery after ischemia may increase theratio of aerobic to glycolytic ATP production and result in improved functionalrecovery. Insulin has been shown to stimulate mitochondrial PDH in adipocytesand hepatocytes. 11,13 We hypothesized that insulinwould stimulate PDH in cardiomyocytes before ischemia and prevent the inhibitionof PDH activity after ischemia.
This study used quiescent human ventricular cardiomyocytes to evaluatethe effect of insulin on the cellular response to simulated ischemia andreperfusion. The quiescent nature of these cardiomyocytes simulates cardioplegicarrest. In addition, the isolated cell culture model removes the possibleconfounding effects of other cell types and organ systems. The effects ofcirculating free fatty acids 14on myocardial substrate use are also absent in our model. Thus, this modelpermits an extensive metabolic evaluation of isolated human cardiomyocytessubjected to simulated low-flow cardioplegic arrest and reperfusion.
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15,16 In brief, 20 mg biopsies wereobtained from the right ventricle of patients undergoing corrective repair oftetralogy of Fallot. The myocardial biopsies were washed in phosphate-bufferedsaline solution without calcium (phosphate-buffered saline solution [PBS]: NaCl136.9 mmol/L, KCl 2.7 mmol/L, Na2HPO4 8.1 mmol/L, KH2PO41.5 mmol/L). After removing connective tissue, the myocytes were separated withenzymatic digestion with a mixture of 0.2% trypsin (Difco Laboratories,Detroit, Mich.) and 0.1% collagenase (Worthington Biochemical Corp.,Freehold, N.J.). The isolated cells were cultured at 37 C in 5% carbondioxide and 95% air in Iscove's modified Dulbecco's medium (GIBCOlaboratories, Grand Island, N.Y.) containing 10% fetal bovine serum, 100U/mL penicillin, 100 µg/mL streptomycin, and 0.1 mmol/L ß-mercaptoethanol.Purification was achieved with the dilution cloning technique. Enzymaticallyisolated cells were seeded at a low density (50 to 100 cells per 9-cm diameterculture dish). At this low density, individual cardiomyocytes can bedistinguished morphologically by their rectangular shape and large size (40 x80 µm) from contaminating cells such as fibroblasts and endothelial cells.Culture purity greater than 95% was demonstrated in passage 3 with afluorescent monoclonal antibody staining for human ventricular myosin heavychain (Rougier Bio-Tech Ltd., Montreal, Quebec, Canada). Cells passaged 2 to 7times with a time from primary culture of less than 60 days were used for thisstudy.
Experimental protocols
The cardiomyocytes were studied in PBS with magnesium and calcium (MgCl20.49 mmol/L, CaCl2 0.69 mmol/L). Our in vitro technique to simulateischemia and reperfusion has been previously described in detail. 17,18Cells were stabilized for 30 minutes in 10 mL of normoxic (PO2= 150 mm Hg) PBS with varying concentrations of insulin and glucose.Cardioplegic ischemia was simulated by placing the cells into a sealed Plexiglaschamber flushed with 100% nitrogen and exposing the cells to a low volume(1.5 mL) of deoxygenated PBS. Deoxygenated PBS was prepared by degassingnormoxic PBS with 95% nitrogen and 5% carbon dioxide until themeasured PO2 reached 0 mm Hg.Reperfusion was accomplished by exposure to 10 mL of normoxic PBS for 30minutes. A small sample of deoxygenated PBS (2 mL) was placed into a center dishin the chamber to monitor temperature and to confirm the absence of oxygen atthe end of the ischemic period. The temperature was maintained at 37° Cthroughout the experiment. The osmolality of the degassed PBS solutions wasmaintained between 280 and 320 mOsm/L with sodium chloride or water as required.
Assessment of cellular injury
Cellular injury was assessed with non-confluent plates of cardiomyocytes(approximately 337,000 cells per 9 cm diameter culture dish) cultured for 4 to 5days after the last passage. After the intervention of interest, cell plateswere incubated with 0.4% trypan blue dye (Sigma Chemical Company, St.Louis, Mo.) dissolved in normal saline solution and assessed for injury under aninverted light microscope (Nikon Canada Instrument Inc., Mississauga, Ontario)at x200 magnification. Injured cells were unable to exclude the largemolecular weight dye and stained blue. The number of blue-stained cells wascounted from 5 standard locations on each plate and expressed as a percentage ofthe total number of cells. All counts were performed by a single observer whowas blinded to the intervention.
After a dose-response analysis for both glucose and insulin, we chose tocompare 4 groups. A physiologic glucose concentration of 5 mmol/L was comparedwith a glucose concentration of 100 mmol/L. The latter concentrationapproximates the glucose concentration in the cardioplegic solution currentlyused at our institution. The effects of 10 IU/L of insulin was then evaluated atboth levels of glucose: group 1, 5 mmol/L glucose; group 2, 5 mmol/L glucose and10 IU/L insulin; group 3, 100 mmol/L glucose; group 4, 100 mmol/L glucose and 10IU/L insulin.
Biochemical measurements
The activity of PDH was measured after each intervention of interest withthe modifications described by Robinson and colleagues 19 of the method of Sheu andcolleagues. 20 Cell extractswere aliquoted into separate Eppendorf tubes containing PBS. After incubationfor 10 minutes, cells were treated with a buffer containing 25 mmol/L sodiumfluoride and snap frozen in liquid nitrogen. Cell extracts were then reactedwith a 14C-pyruvate containing buffer in an open Eppendorf insertand placed in sealed containers containing benzothonium hydroxide to trap 14CO2.The reaction was stopped with 10% trichloroacetic acid, and 14CO2collected for 1 hour. After the 14CO2 collection, thecell inserts were removed and scintillation fluid was added to the exposedbenzothonium hydroxide. The collected 14CO2 was thencounted in a ß-counter. PDH activity was calculated after correction forprotein content and expressed as nanomoles of pyruvate oxidized per milligram ofprotein per minute.
Confluent cultures of cardiomyocytes (approximately 600,000 cells perculture dish) cultured for 5 to 10 days from the last passage were used forbiochemical analysis. After being removed from the culture dish, thecardiomyocytes and the extracellular fluid recovered from each intervention wereanalyzed for lactate by an enzymatic method (Stat-Pack rapid lactate test kit;Behring Diagnostics, La Jolla, Calif.).
In a separate series of experiments, extracellular lactate and pyruvatewere measured in the supernatant of each plate. Supernatants were collected andtreated with a measured volume of 6% perchloric acid to inhibit enzymaticdegradation. Lactate concentrations were determined as described earlier.Pyruvate concentrations were determined using a lactate dehydrogenase coupledreaction. 19 The concentrationof hydrogen ion in the extracellular fluid was determined by measuring the pHvalue with a blood gas analyzer (1312 Blood Gas Manager; InstrumentationLaboratory, Milano, Italy).
Confluent plates of cardiomyocytes were used to determine cellularadenine nucleotide contents after the intervention of interest. The specimenswere flash frozen in liquid nitrogen and then freeze-dried. Specimens wereanalyzed by high-performance liquid chromatography to determine the myocardialconcentrations of adenosine triphosphate (ATP), adenosine diphosphate (ADP) andadenosine monophosphate (AMP). We also measured the metabolites adenosine,inosine, hypoxanthine and xanthine. Total adenine nucleotides were determined asthe sum of ATP, ADP and AMP. Total degradation products were calculated as thesum of adenosine, inosine, hypoxanthine, and xanthine. Energy charge representsthe usable high-energy phosphate pool and was calculated as: energy charge =(ATP + 0.5 ADP)/(ATP + ADP + AMP). The DNA in the cell extracts was recovered in5% perchloric acid and quantitated with a spectrophotometric,diphenylamine color reaction with calf thymus DNA as the standard. 1 Intracellular and extracellularlactate and adenine nucleotide values were then corrected for DNA content fromeach plate. 18
Non-ischemic control cardiomyocytes were subjected to similar protocolswith equivalent volumes of normoxic PBS (PO2= 150 mm Hg) for equal time periods as their ischemic counterparts.Baseline biochemical measurements were made after removing the culture media andwashing the cells with normoxic PBS. In a separate series of experimentsdesigned to eliminate the effects of glucose, cells were exposed to 5 or 100mmol/L of mannitol with or without insulin.
Statistical analysis
The SAS Statistical Package (SAS Institute, Cary, N.C.) was used foranalysis of all data. Data are expressed as the mean ± standarderror with 8 plates per group, unless otherwise specified. Biochemical endpoints are expressed as a percentage of the value obtained from non-ischemiccontrol plates exposed to an equivalent volume of normoxic PBS for theequivalent period of time. Analysis of variance (ANOVA) was used tosimultaneously compare groups at different time periods. When statisticallysignificant differences were found, they were specified by the Duncan's multiplerange test.
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Results |
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A glucose dose-response curve (Fig. 1) demonstrated higher cell injurywith increasing glucose concentration (by 2-way ANOVA, glucose effect F =6.48, P < .0001).The addition of 10 IU/L of insulin ateach glucose concentration reduced cellular injury (insulin effect F =24.26, P < .0001). There was nointeractive effect between glucose concentration and insulin treatment(glucose-insulin effect F = 2.05, P =.08). Significant differences between insulin- and non-insulin–treatedgroups were found at 50 and 100 mmol/L glucose.
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Fig. 4 (bottom panel) displays totalcellular lactate. Insulin treatment lowered total cellular lactate duringstabilization, ischemia, and reperfusion. Similarly, extracellular pyruvateconcentrations were lower in the insulin-treated cells. The lactate/pyruvateratios were higher in the cells exposed to high concentrations of glucose. TableI displays the lactate, pyruvate, PDH, and pH measurements after eachintervention.
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Discussion |
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14C-labeled fatty acidoxidation was inhibited for as long as 60 minutes after cardioplegic arrest. 22 In addition, during reperfusionthere is a delay in the recovery of normal aerobic glucose metabolism. Severalclinical trials at our institution demonstrate persistent lactate release duringreperfusion, which suggests continued anaerobic glycolysis. 1,23,24 Because net myocardial lactaterelease is an underestimate of total lactate production, due to a low level ofcontinuous myocardial lactate extraction, we believe that cardioplegic arrestresults in a significant impairment of normal aerobic metabolism. Improving thetransition from anaerobic to aerobic metabolism after cardioplegic arrest shouldimprove tolerance to ischemia and enhance the recovery of ventricular function.
Several investigators have attempted to stimulate glucose oxidationduring reperfusion to improve myocardial functional recovery. 25-27These authors used dichloroacetate to stimulate PDH activity that resulted in animprovement in glucose oxidation and myocardial functional recovery afterischemia. However, Mazer and colleagues 28found that dichloroacetate did not improve systolic function in the in vivoporcine heart, despite an increase in glucose oxidation. Therefore alternativemethods of PDH stimulation may prove to be superior to dichloroacetate inenhancing myocardial functional recovery after ischemia.
Insulin has been shown to stimulate PDH activity in adipocytes, 12 hepatocytes, 11 and cardiomyocytes. 13 The mechanism by which insulinstimulates PDH remains controversial. The PDH complex is regulated by a PDHphosphatase and a PDH kinase. Phosphorylation of the complex by PDH kinaserenders it inactive, although dephosphorylation by the phosphatase returns thecomplex to its active form. Lilley and colleagues 13 found that insulin in bovine heartmitochondria preferentially stimulates the PDH phosphatase. In contrast,dichloroacetate causes PDH stimulation by inhibiting the PDH kinase.
The ability of pre-ischemic insulin exposure to stimulate post-ischemicPDH activity in human myocardial tissue has not previously been demonstrated.This study examined the clinically relevant effects of pre-ischemic exposure toinsulin in the presence of physiologic or hyperglycemic concentrations ofglucose. Insulin was found to stimulate PDH activity before ischemia andpartially prevented the inhibition of PDH activity during reperfusion. Inaddition, insulin treatment reduced extracellular lactate release and improvedthe preservation of ATP. The beneficial metabolic effects of insulin were foundto protect against cellular injury after simulated ischemia and reperfusion.
Cell culture model
The cardiomyocytes used in these studies have been extensively evaluatedin previous reports. 15,18 These cardiomyocytes retain manycharacteristics of freshly isolated cells but have distinct differences. Thesecells become quiescent after enzymatic digestion and passaging. Otherinvestigators 29 who havesuccessfully cultured adult cardiomyocytes have reported that the cells losetheir ability to contract. Despite an abundant supply of mitochondria andcontractile proteins, the sarcomeres become disrupted during division and do notreestablish their characteristic functional format. However, the metabolicresponse of these cells after ischemia is similar to our intraoperative findingsduring cardiac operations. 1,22-24 Therefore we believe that thesecells provide a unique opportunity to evaluate the cellular response to ischemiaand reperfusion and the effects of metabolic interventions such as insulin.
Simulated ischemia and reperfusion
We are able to produce a deoxygenated PBS solution with a measured PO2 of 0 mm Hg. 17 Exposing cells to 90 minutes ofischemia resulted in significant cellular injury as assessed by trypan blueexclusion. Reducing the volume of the solution over the cells from 10 mL to 1.5mL and exposure to an anoxic atmosphere resulted in an accumulation of theproducts of ischemic metabolism and a marked reduction in the extracellular pH.Therefore this model is similar to the effects of global ischemia on the heart.Unfortunately, the volume overlying the cells remains greater than the solutionto which the cells are exposed during global ischemia and may actually representa form of low-flow ischemia, analagous to limited cardioplegic perfusion.
We believe that our model represents low-flow ischemia rather thanhypoxia because of the volume differences. When the cells are exposed to 90minutes of hypoxia with 10 mL of deoxygenated PBS, the biochemical abnormalitiesare much less severe and cellular injury is only 25% to 30%,compared with approximately 45% with 1.5 mL of anoxic PBS. 30 Therefore the volume changes overthe culture dishes result in a greater ischemic insult than occurs with simplehypoxia and reoxygenation. There was an increase in PDH activity after anincrease in PBS volume to 10 mL in the control plates. This increase in PDHactivity in the control plates was due to a decrease in the extracellularlactate concentration and a sharp fall in the lactate/pyruvate ratio causinginhibition of the PDH kinase. Similarly, stabilization in PBS with 5 mmol/L ofglucose resulted in an inhibition of PDH activity, compared with cells recovereddirectly from culture media. This inhibition was associated by a rise in thelactate/pyruvate ratio. However, PDH activity was higher in cells exposed tohigh glucose or insulin.
Insulin's effect on PDH activity
We found that insulin treatment resulted in a stimulation of PDHactivity. Similar findings have been reported by several authors in variousorgan systems. 11-13 Kobayashi and Neely 9 found that PDH activity was inhibitedafter ischemia within 2 minutes of reperfusion. We found that PDH activity wasinhibited at the end of ischemia. Our technique of measuring PDH involvesapproximately 10 minutes of incubation in PBS. Thus, our measurement of PDHactivity after ischemia may correlate with 10 minutes of reperfusion inKobayashi and Neely's model. In addition, Kobayashi and Neely demonstrated a 55%inhibition of PDH activity during reperfusion. The magnitude of PDH inhibitionin our model was much less severe (20% to 45% at end of ischemia).Cells treated with high glucose displayed better preservation of PDH activityafter ischemia. High extracellular glucose concentrations may increaseintracellular diacylglycerol levels with a resultant stimulation of proteinkinase C. Benelli and colleagues 11found that protein kinase C mediated insulin's ability to stimulate PDH activityin cultured hepatocytes. After 30 minutes of reperfusion, PDH activities werestill depressed compared with control, non-ischemic values; however, thehigh-glucose– and insulin-exposed cells displayed a better recovery of PDHactivity. Because our experimental protocol involved only a 30-minute exposureto insulin, we do not feel that insulin's stimulatory effect involves anincrease in protein synthesis. Rather, insulin exposure results in an increasedactivity of native PDH.
Insulin's effect on intermediate metabolites
Insulin-treated cells produced less lactate and pyruvate than non-insulin–treatedcells. After ischemia, intracellular lactate accumulation was significantlyhigher in the 100 mmol/L glucose group. Insulin reduced intracellular lactate tolevels similar to that in groups with 5 mmol/L of glucose. However, lactateextraction was higher after reperfusion in cells exposed to 100 mmol/L glucoseand insulin. Both intracellular and extracellular lactate concentrations weresignificantly higher in all groups during reperfusion, compared with thenon-ischemic controls. This persistent anaerobic glycolysis has been observed inpatients who are undergoing cardiac operation. 1,22-24
Insulin's effect on adenine nucleotides
Insulin treatment resulted in a better preservation of intracellular ATPand total adenine nucleotides after ischemia and reperfusion. This may be due tothe higher activity of PDH during reperfusion. Higher PDH activity improves theefficiency of ATP production by stimulating oxidative metabolism. However, bothATP and total adenine nucleotide levels remained well below control values. Theimprovement in high-energy phosphates may simply be due to higher preischemicvalues. However, preischemic ATP levels were higher in the 100 mmol/L glucosegroup than in the 100 mmol/L glucose and insulin group, yet ATP levels werebetter preserved in the latter group.
The ratio of oxidatively derived ATP to ATP derived from glycolysis maybe higher in the insulin-treated group. We did not directly measure oxidativephosphorylation in these studies. Weiss and Hiltbrand 10 described a functionalcompartmentation of energy production in isolated rabbit hearts. They reportedthat aerobically derived ATP was preferentially used for contractile functionwhereas ATP derived from anaerobic glycolysis was used preferentially to supportsarcolemmal function. We are unable to measure contractile function in thismodel. Demonstration of an improved transition from anaerobic to aerobicmetabolism with an evaluation of the effect on contractile function will requirefurther investigation.
Significance
We have demonstrated that preischemic exposure to insulin improvescellular tolerance to simulated ischemia and reperfusion in isolated humanventricular cardiomyocytes. We believe that this is the first report todemonstrate that in isolated human myocardial tissue:
The results of these investigations suggest that insulintreatment can enhance human myocardial PDH activity, improve the transition fromanaerobic to aerobic metabolism, and result in improved cellular survival afterischemia and reperfusion. These findings may prove important in clinicalsituations of controlled ischemia, such as cardioplegic arrest during cardiacoperations. Although we have performed an extensive evaluation of the metabolicresponse to ischemia, the results require confirmation in a whole organ model.
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