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Ann Thorac Surg 1998;65:439-443
© 1998 The Society of Thoracic Surgeons
in a Crystalloid-Perfused Model of Cardiac Ischemia-Reperfusion Injury
Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado, USA
Accepted for publication August 8, 1997.
Dr Meldrum, Division of Cardiothoracic Surgery, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Box C-306, Denver, CO 80262.
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Abstract |
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(TNF-)–producing organ. Recent basic experimental and clinical evidence suggests that TNF- is an important mediator of myocardial injury during acute myocardial infarction, chronic heart failure, cardiac allograft rejection, and cardiopulmonary bypass operations. Although it is known that the myocardium itself is capable of producing TNF- in response to endotoxin, it is unknown whether there is an increase in myocardial tissue TNF- levels after ischemia-reperfusion injury. We hypothesized that ischemia-reperfusion induces the production of TNF- by the heart.
Methods. To avoid blood-borne TNF- as a potentially confounding variable, we examined myocardial TNF- production in a crystalloid-perfused model of cardiac ischemia-reperfusion injury. Isolated rat hearts were perfused with crystalloid solution and subjected to ischemia-reperfusion. Postischemic myocardial TNF- was measured using an enzyme-linked immunosorbent assay and correlated with developed pressure, coronary flow, end-diastolic pressure, and creatine kinase loss (assay of activity in coronary effluent).
Results. Ischemia-reperfusion induced a marked increase in myocardial TNF- that was associated with decreased myocardial contractility and coronary flow and with increased end-diastolic pressure and postischemic creatine kinase loss.
Conclusions. The heart produces TNF- in response to ischemia-reperfusion. Ischemia-induced TNF- production may contribute to postischemic myocardial stunning, necrosis, or both. Strategies designed to limit ischemia-induced myocardial TNF- production may have therapeutic utility in the settings of planned myocardial ischemic events.
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Introduction |
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(TNF-) is a proinflammatory cytokine that has been implicated in the pathogenesis of septic, traumatic, and hypovolemic shock-associated cardiac dysfunction, as well as with cardiovascular diseases such as acute myocardial infarction, chronic heart failure, atherosclerosis, viral myocarditis, and cardiac allograft rejection [1] [2] [3] [4] [5] [6] [7]. The heart contains resident macrophages [8] and is a rich source of TNF- [3] [4] [5] [8] [9] [10]. Unexpectedly, cardiac myocytes themselves also produce TNF- [8]. In fact, the myocardium produces as much TNF- per gram of tissue (in response to endotoxin) as does either the liver or the spleen, both of which possess large macrophage populations and are major sources of TNF- [8]. Kapadia and co-workers [8] demonstrated that myocardial TNF- production is distributed evenly between cardiac myocytes and cardiac macrophages. Thus, local myocardial TNF- may be an important source of TNF- affecting myocardial function.
Although increased myocardial TNF- has been demonstrated after exposure to endotoxin [8], it remains unknown whether myocardial TNF- is increased in a bloodless (crystalloid)-perfused model of cardiac ischemia-reperfusion injury. The reperfusion of ischemic myocardium imposes an oxidant burden that directly injures myocardium [11]; however, oxidation products also activate oxidant-sensitive enzymes (eg, P38 mitogen-activated protein kinase and nuclear factor kappa B) involved in the initiation of TNF- production [12] [13]. We hypothesized that ischemia-reperfusion induces an increase in myocardial TNF-. To control for a potential hematologic contribution to myocardial TNF- levels, ischemia-reperfusion experiments were conducted in the isolated, crystalloid-perfused rat heart.
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Material and Methods |
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Experimental Design and Groups
Each ischemia-reperfusion experiment lasted a total of 80 minutes, beginning with a mandatory equilibration period. Stability control hearts underwent 80 minutes of oxygenated perfusion without any periods of ischemia to ensure preparation stability. Injury control hearts were perfused for 8 minutes (equilibration) and then received a 2-minute infusion of vehicle, followed by a standard ischemia-reperfusion insult (20 minutes of global ischemia at 37°C and 40 minutes of reperfusion). Cardiac functional parameters were recorded continuously.
Ischemia-Reperfusion of the Isolated Rat Heart: Developed Pressure, End-Diastolic Pressure, Coronary Flow, and Heart Rate Measurements
The isolated, crystalloid-perfused rat heart model was used as described previously [11] [14]. In brief, after anesthesia induction (sodium pentobarbital, 60 mg/kg intraperitoneally) and heparinization (heparin-sodium, 500 U intraperitoneally), hearts were excised into 4°C Krebs-Henseleit solution and perfused with oxygenated buffer within 45 seconds. Hearts were perfused retrogradely in the isolated, isovolumetric Langendorff mode (70 mm Hg) with modified Krebs-Henseleit solution (in mmol/L: glucose, 5.5; Ca2+, 1.2; KCl, 4.7; and NaHCO3, 25.0, and saturated with 92.5% O2/7.5% CO2 to achieve an oxygen tension of 440 to 460 mm Hg, a carbon dioxide tension of 39 to 41 mm Hg, and a pH of 7.39 to 7.41 (ABL-4 blood gas analyzer; Radiometer, Copenhagen, Denmark).
A pulmonary arteriotomy and left atrial resection were performed before the insertion of a water-filled latex balloon through the left atrium into the left ventricle. This balloon then was adjusted to a left ventricular end-diastolic pressure of 6 mm Hg during the initial equilibration. This preload volume was held constant during the entire experiment to allow continuous recording of the ventricular pressure during ischemia-reperfusion. Pacing wires were fixed to the right atrium and pulmonary outflow tract and hearts were paced at approximately 6 Hz (355 beats/min) to compare functional measurements using a standardized heart rate.
Measured indices of myocardial function were left ventricular developed pressure, end-diastolic pressure, and coronary flow. Data were recorded continuously using a computerized MacLab 8 preamplifier/digitizer (AD Instruments Inc, Milford, MA) and an Apple Quadra 800 computer (Apple Computer Inc, Cupertino, CA). Paced hearts that did not produce 105 ± 25 mm Hg of left ventricular developed pressure at 6 mm Hg of end-diastolic pressure were discarded. A three-way stopcock above the aortic root was used to create global ischemia, during which the heart was placed in a 37°C degassed organ bath. Coronary flow was measured by collecting pulmonary artery effluent. After reperfusion, the left ventricular myocardium was excised and added to 10 vol of cold isotonic homogenization buffer (50 mM of imidazole acetate, 10 mg of acetate, 4 mM of KH2PO4, 2 mM of ethylenediamine tetraacetic acid, 50 µM of N-acetylcysteine as an antioxidant, and 12.5 µM of sulfur in 0.8% ethanol to inhibit adenylate cyclase; pH 7.6). Samples were homogenized in a vertishear tissue homogenizer (with parallel blades 0.5 cm apart) at half maximal speed for 20 seconds (10 equally spaced bursts) and then centrifuged at 2,000 x g for 15 minutes. The supernatant total protein concentration was quantitated using the Lowry assay and then the samples were stored at -70°C until they were used in the TNF- assays.
Myocardial Tumor Necrosis Factor-
Myocardial homogenate TNF- content was determined by an enzyme-linked immunosorbent assay (Genzyme, Cambridge, MA). The assay was performed by adding 100 mL of each sample (equal protein and tested in duplicate) to wells in a 96-well plate of a commercially available enzyme-linked immunosorbent assay kit. The antibodies used in this assay are not influenced by either the type 1 or the type 2 TNF- receptor, and they have a lower limit of detectability (50 pg/mL). The TNF- enzyme-linked immunosorbent assay was performed according to the manufacturer’s instructions. The final results were expressed as picograms of TNF- per gram.
Coronary Effluent Creatine Kinase Activity
Coronary effluent (1 mL) was collected during equilibration and at 10, 20, 30, and 40 minutes of reperfusion and then was frozen at -70°C until it was assayed. All assays were performed within 2 weeks of effluent collection. The assay was performed with Sigma diagnostic kit no. 47-UV (Sigma Chemical Co) on an automated spectrophotometer (Centrifichem 500 discrete auto-analyzer; Union Carbide) in cuvettes maintained at 30°C. Samples and reagents were maintained at 4°C before assay. Solutions were prepared in distilled, deionized water (resistivity, >18 molecular weight). Results are presented as units per liter of creatine kinase activity.
Presentation of Data and Statistical Analysis
All reported values are mean plus or minus standard error of the mean (n = 4 to 6 per group). Differences at the 95% confidence level were considered to be statistically significant. Data were compared at the corresponding time points between groups using one-way analysis of variance with the post hoc Bonferroni/Dunn test (StatView 4.0; Abacus Concepts, Berkeley, CA).
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Results |
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levels before and after myocardial ischemia-reperfusion are shown in Fig 1. Ischemia-reperfusion resulted in a marked increase (from 332 ± 39 to 857 ± 92 pg/g) in myocardial TNF- (p < 0.05).
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Comment |
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levels in an isolated, crystalloid-perfused model of myocardial ischemia-reperfusion injury, and that increased myocardial TNF- levels are associated with postischemic myocardial dysfunction. The results of this study suggest that cardiac myocytes and cardiac resident macrophages are an important source of TNF- that affects myocardial function, because ischemia and reperfusion provoked myocardial TNF- production even in the absence of blood circulation. Indeed, this may have important clinical implications for preservation of the myocardium during and after ischemia. Heart transplant operations, cardiac bypass operations, and coronary angioplasty are three clinical scenarios in which myocardial ischemia-reperfusion is obligatory. Tumor necrosis factor- recently has been appreciated as an important mediator of myocardial ischemic damage [3] [9] [15] [16]. The present model allows the study of these mechanisms in the laboratory, as well as the opportunity to test potential therapeutic strategies.
Although considerable information exists concerning the mechanisms by which lipopolysaccharide induces TNF- production, little is known about the mechanisms of ischemia-induced myocardial TNF- production [17]. Reperfusion of the ischemic myocardium imposes an oxidant burden in which the reduction product of molecular oxygen, hydrogen peroxide, contributes to myocardial injury [11]. Hydrogen peroxide activates P38 mitogen-activated protein kinase, which may contribute to ischemia-induced TNF- production [12] [13]. Oxidant stress activates nuclear factor kappa B [18], the transcription factor for TNF- production, which may play a role in the sequence of ischemia-induced TNF- production in the heart. This, however, remains to be determined.
Tumor necrosis factor- induces hemodynamic alterations, including decreased ejection fraction and reduced myocardial contractile efficiency, biventricular dilatation, decreased systemic vascular resistance, and hypotension. Tumor necrosis factor- has been demonstrated to depress myocardial function in an ex vivo, crystalloid-superfused papillary muscle preparation [16]. Although TNF has been known to mediate lipopolysaccharide-induced myocardial depression, ischemia-provoked myocardial TNF- production has been reported only recently. Ischemia-induced myocardial TNF- production may prove to be more common clinically than sepsis-induced myocardial TNF- production by an order of magnitude.
The mechanisms by which TNF- causes myocardial dysfunction include calcium dyshomeostasis, direct cytotoxicity, oxidant stress, disruption of excitation-contraction coupling, myocyte apoptosis, and induction of other cardiac depressants. The biphasic nature of TNF-–induced myocardial depression suggests that TNF- induces negative inotropic effects by at least two different mechanisms [1] [19]. The early phase of TNF-–induced functional depression occurs within minutes and the delayed phase appears to require hours [1]. Tumor necrosis factor-–induced nitric oxide production has been demonstrated to mediate this depression [16]; however, TNF- may not induce high levels of nitric oxide rapidly enough to account for the early phase [1].
Sphingolipid metabolites are stress-induced second messengers that participate in intracellular signal transduction after TNF- binding to the TNF- receptor type 1 (molecular weight, 55 kd). Two important characteristics of sphingolipid metabolites led to the hypothesis [1] that sphingosine mediates TNF-–induced myocardial contractile dysfunction: (1) it is produced rapidly by cardiac myocytes (through sphingomyelin degeneration) after TNF- triggering of the TNF- receptor type 1 [20], and (2) sphingosine decreases calcium transients by blocking the ryanodine receptor, which mediates calcium-induced calcium release from the sarcoplasmic reticulum [21]. Oral and co-workers [1] reported that myocardial sphingosine production occurred within minutes of TNF- administration and correlated temporally with myocardial dysfunction. Blockade of sphingosine production abolished TNF-–induced contractile dysfunction. Sphingosine administration replicated TNF-–induced contractile depression in a dose-dependent fashion. Tumor necrosis factor- also may induce contractile dysfunction by the induction of apoptosis. Tumor necrosis factor- induces apoptosis in many cell types, including the myocardium [22]. Krown and colleagues [23] demonstrated that TNF- induced cardiac myocyte apoptosis by a sphingosine-dependent mechanism.
The overwhelming evidence strongly suggests that TNF- participates in myocardial ischemia-reperfusion injury and cardiac allograft rejection [1] [2] [3] [6] [7]. Thus, strategies designed to decrease myocardial TNF- production may be of therapeutic value. The model used in this study may provide an opportunity to test anti–TNF- therapeutic strategies against cardiac ischemia-reperfusion in the laboratory. However, this study should be interpreted with several important caveats.
First, the ex vivo myocardial perfusion model used did not replicate precisely the in vivo situation. Although we have used this model successfully to answer questions concerning myocardial physiology and pathophysiology in the past [24] [25] [26] [27] [28] [29] [30], it does not reflect in vivo conditions in many ways. Because this heart model is perfused with crystalloid and not blood, aspects of blood that are either protective (ie, antioxidants) or injurious (ie, neutrophils, blood-derived cytokines) do not contribute. Indeed, this model was chosen to more accurately determine myocardial TNF- production (versus accumulation from blood).
Second, we have not linked myocardial TNF- production with ischemia-reperfusion injury. Specific TNF- blockade would answer that question more effectively. However, TNF- binding proteins may not work in this model because TNF- likely works in a paracrine fashion; that is, because perfusate is not recirculated, TNF- entering the coronary circulation never reenters the heart. Thus, TNF- binding proteins, which presumably would remain intravascular, may not influence interstitial or membrane-bound TNF-. This study was not designed to determine the portion of injury mediated by TNF-, but rather to determine whether ischemia-reperfusion, in the absence of blood, is a sufficient stimulus to induce an increase in myocardial TNF- [31].
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Acknowledgments |
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References |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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in the adult mammalian cardiac myocyte. J Biol Chem 1997;272:4836-4842. and the failing human heart. Clin Cardiol 1995;18:S20-S27.
and tumor necrosis factor receptors in the failing human heart. Circulation 1996;93:704-711. in the adult mammalian cardiac myocyte. J Clin Invest 1993;92:2303-2312.
gene and protein expression in adult feline myocardium after endotoxin administration. J Clin Invest 1995;96:1042-1052.
1-adrenoceptor mediated, protein synthesis independent mechanism. Am J Physiol 1997;272:R718-R725.
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