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CARDIOVASCULAR
Division of Cardiovascular Diseases and Hypertension, Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey (G.K., A.M., I.K.); Molecular and Cellular Cardiology Program, Veterans Administration New York Harbor Healthcare System, New York, New York (Y.Y., M.B.); State University of New York Downstate Medical Center, Brooklyn, New York; and New York University School of Medicine, New York, New York (M.B.)
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Abstract |
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and 
, during I/R. In conclusion, our results suggest a protective role of intracellular zinc in myocardial recovery from oxidative stress imposed by I/R. The data support the potential clinical use of zinc ionophores in the settings of acute redox stress in the heart.
). The existence of regulatory mechanisms is evidenced by the large gradients of Zn2+, free or loosely bound to proteins, so-called labile zinc, between the intracellular and extracellular milieu (nanomolar versus micromolar concentrations, respectively). Recent discoveries have revealed that the amount of intracellular free zinc is tightly controlled at the level of uptake, intracellular sequestration, redistribution, storage, and elimination, consequently creating a narrow window of optimal zinc concentration in the cells. The molecular players in zinc homeostasis have been identified. For example, membrane transport of zinc ions is mediated by zinc transporters encoded by two solute-linked carrier gene families, ZnT (SLC30), zinc extruders, and Zip (SLC39), zinc importers (Palmiter and Findley, 1995; Eide, 2004; Liuzzi and Cousins, 2004; Palmiter and Huang, 2004). Zinc storage sites, such as metallothioneins (MTs) (Fabisiak et al., 2002), mitochondria (Bossy-Wetzel et al., 2004), and zinc-rich vesicles "zincosomes" (Failla and Cousins, 1978) participate in sequestration of zinc ions as a way of cell protection from Zn2+ overload and provide zinc ions to structural and catalytic proteins under conditions of cellular zinc deficiency (Feng et al., 2005).
The central position of zinc in the redox signaling network is based on its unique chemical nature. Being itself redox inert, zinc creates a redox active environment when it binds to sulfur ligand (Maret, 2004). The chemical flexibility of transition metals allows zinc to impose conformational changes on the proteins it binds to, the required step in initiation of activation process of many signaling molecules (Clegg et al., 2005). The most important property of zinc-sulfur ligand interaction is the release of zinc under an oxidative environment (Barbirz et al., 2000). Protein kinase C (PKC) is one of the examples of redox-sensitive signaling molecules (Konishi et al., 1997; Imam et al., 2001). We have previously demonstrated that oxidative stress triggers zinc release from PKC (Korichneva et al., 2002). In addition, we showed that Zn2+ release from PKC is also triggered by a classic lipid activator, phorbol 12-myristate 13-acetate (PMA), pointing out convergence of the two signaling pathways. Cysteine-rich zinc binding regulatory domains were determined as sources of free zinc. These highly conserved structures are able to serve as "redox zinc switches," sensing the concentrations of both zinc and oxidants.
The ability of PKC to regulate many cardiovascular functions is supported by the facts that many cardiovasotropic growth factors target PKC (Feener et al., 1995; Xia et al., 199). Cardiac myocytes express multiple PKC isozymes, 
, 
1/2, , , and 
, which participate in the response of muscle cells to extracellular stimuli, modulate contractile properties, and promote cell growth and survival (Disatnik et al., 1994). The two novel PKC isoforms, and , are particularly important in myocardial responses to ischemia/reperfusion (I/R). The reports that PKC is activated by I/R, and PKC is involved in ischemic preconditioning, link PKC function to redox control in vivo (Kawamura et al., 1998; Chen et al., 1999; Baines et al., 2003; Inagaki et al., 2003). Oxidative stress imposed on cardiac tissue under I/R conditions would probably trigger changes of the redox status and zinc content of PKC, as well as that of other cellular redox-sensitive proteins, thereby affecting myocardial zinc homeostasis as a whole. Although an understanding of the redox signaling mechanisms is of particular importance in the heart, very limited data exist regarding myocardial zinc distribution and metabolism. Studies by Powell et al. (1994) documented the protective effects of zinc ions in myocardial recovery from I/R. The authors used zinc-bis-histidinate to improve membrane permeability of the cation. Addition at preischemia conferred myocardial protection, whereas treatment starting at reperfusion worsened postischemic damage, thus limiting clinical applications of the drug. The protective effect was attributed to changes in redox metabolism, namely to decrease in ·OH formation and copper reactivity.
The present study investigated alterations in labile zinc in rat hearts subjected to I/R and attempted to improve myocardial recovery by maintaining intracellular zinc content using the zinc ionophore pyrithione. PKC isoforms, and , were assessed as possible zinc targets and as important regulators of cardiac function under the conditions of I/R. The protective role of postischemic intracellular zinc supplementation in myocardial recovery from ischemic stress was demonstrated, suggesting the potential of development of treatments based on zinc ionophores during acute redox stress in the heart.
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Materials and Methods |
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Chemicals and Reagents. N-(6-Methoxy)-8-quinolyl-toluenesulfonamide (TSQ) was obtained from Molecular Probes/Invitrogen Labeling and Detection (Eugene, OR). Optimal cutting temperature (OCT) embedding medium for frozen tissue specimens was from Sakura Finetek U.S.A., Inc. (Torrance, CA). Cell-TAK cell and tissue adhesive was purchased from BD Bioscience (Franklin Lakes, NJ). Urethane, heparin ammonium salt, N,N,N',N'-tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN), 1-hydroxypyridine-2-thione zinc salt (mercaptopyridine N-oxide zinc salt pyrithione), and Cell-TAK cell and tissue adhesive were from BD Bioscience, and PMA was from Sigma Co. (St. Louis, MO).
Experimental Groups. Animals were assigned into experimental groups (six animals in each group) as follows: group 0 hearts were perfused for 1.5 h without I/R; group 1 did not receive any treatment before the I/R experiment and no treatment during heart perfusion and was used as a control; group 2 had no treatment prior I/R, but the perfused hearts were supplemented with zinc pyrithione at reperfusion; and groups 3, 4, and 5 were treated the same as group 2 except that membrane impermeable ZnCl2 was used in place of zinc pyrithione in group 3, the Zn2+ chelator TPEN and zinc pyrithione in group 4, and PMA and zinc pyrithione in group 5. Animals in group 6 received zinc pyrithione in their diet for 1 week (35 mg/kg body weight), and the hearts from these animals had no subsequent treatment during I/R.
Ischemia/Reperfusion of Adult Rat Hearts. Rats were anesthetized with 1.6 to 2.2 g/kg urethane and 500 IU/kg heparin, administered i.p. The hearts were rapidly excised, cannulated, and perfused retrogradely with the Langendorff method with modified Krebs-Henseleit buffer containing 117 mM NaCl, 4.7 mM KCl, 2.7 mM CaCl2, 1.2 mM MgSO4, 1.2 mM KH2PO4, 21 mM NaHCO3, 11 mM glucose, 2.0 pyruvate, and 0.2 mM EDTA, pH 7.4. The perfusion fluid was equilibrated with 95% O2/5% CO2 at 37°C. A latex balloon was inserted in the left ventricle and inflated to produce an end diastolic pressure of 8 to 12 mm Hg, and this volume was unchanged for the rest of the experiment. Coronary perfusion pressure was monitored at the point of cannulation of the aorta and adjusted to 60 to 70 mm Hg. The contractile and hemodynamic functions of the heart were continuously monitored with a computer-based data acquisition system (PowerLab; ADInstruments Inc., Colorado Springs, CO). All the hearts were subjected to a 30-min stabilization period, 15 or 30 min of global ischemia, followed by 30-min reperfusion. Hearts, which demonstrated contractile or other abnormalities during stabilization period, were discarded.
Preparation of Tissue Sections. At the end of perfusion, the hearts were quickly frozen in OCT using standard protocol to preserve tissue elements (Sheehan and Hrapchak, 1980). Cryosections of 45 µm were obtained at –14°C using a cryomicrotome and placed onto a dish with a glass bottom covered with Cell-TAK cell and tissue adhesive for confocal measurements. Control experiments revealed that OCT and isopentane did not alter subsequent loading of the tissues with fluorescent probes, nor did these procedures affect tissue response to stimuli, PMA, or H2O2.
Labile Zn2+ Imaging by Confocal Microscopy. Fluorescent imaging of intracellular Zn2+ was performed with selective high-affinity Zn2+-sensitive probe TSQ, as described previously (Frederickson et al., 2000; Korichneva et al., 2002). Thawed tissue sections were loaded with 5 µM TSQ for 20 min, washed intensively, and moved to the stage of confocal laser scanning microscope. Images were acquired with a Zeiss/LSM510 system (Carl Zeiss Microimaging Inc., Thornwood, NY) equipped with the Enterprise UV laser (Coherent Inc., Santa Clara, CA). The 351-nm line was used for the excitation of TSQ, and fluorescence between 420 and 480 nm was captured. To minimize the UV damage, laser intensity was kept at 5%. Fluorescence intensity was recorded on-line for several minutes to obtain the background steady-state fluorescence value, and after the addition of activator, the acquisition of images continued for 30 min to reach saturation. The PKC activator, PMA (50 nM), was used to assess Zn2+ release potential, as described previously (Korichneva et al., 2002). To ascertain the specificity of TSQ for Zn2+ and to address the factor of probe concentration and environment, the specific zinc chelator TPEN was used in competition experiments. Addition of PMA and TPEN to the tissue samples was performed directly on the microscope stage. Morphometric analysis was performed using the MetaMorph image analysis software.
Isolation and Treatment of Adult Rat Ventricular Myocytes and Cell Lysates. Isolated adult rat ventricular myocytes were prepared as described previously (Puceat et al., 1995). Hearts from anesthetized animals were quickly removed and perfused in a nominal Ca-free medium for 5 min and then with 1.2 mg/ml collagenase added with 30 µM CaCl2. The cells were incubated for 15 min at 37°C. Meanwhile, Ca2+ concentration of the incubation medium was increased gradually up to 1 mM. The preparation provided at least 6 x 106 rod-shaped cells. Cells were kept until used at 37°C in HEPES-buffered medium adjusted to pH 7.4 and containing 117 mM NaCl, 5.7 mM KCl, 4.4 mM NaHCO3, 1.5 mM KH2PO4, 1.7 mM MgCl2, 1 mM CaCl2, 21 mM HEPES, 11 mM glucose, 10 mM creatine, 20 mM taurine, and 0.5% bovine serum albumin. The cells were treated at indicated time intervals with PMA (50 nM) to initiate PKC activation followed by down-regulation in the presence or in the absence of TPEN (10 µM), pelleted, and resuspended in a 50 mM glycerophosphate buffer adjusted to pH 7.4 and supplemented with 1 mM EGTA, 1% Triton X-100, 1 mM phenylmethylsulfonyl fluoride, 10 µg/ml leupeptin, and 100 µM E64. The lysate was incubated at 4°C for 15 min and centrifuged at 15,000g for 15 min. Electrophoresis and Western blotting analysis were carried out as described previously (Korichneva and Hammerling, 1999).
Preparation of Whole-Heart Lysates and Western Blotting Analysis. At the end of each experiment, the hearts were cut into small pieces, extensively washed, and homogenized in a Tris-HCl buffer, pH 7.5, containing 50 mM Tris, 2 mM EDTA, 10 mM EGTA, 5 mM dithiothreitol, 250 mM sucrose, 1% Triton X-100, 1 mM phenylmethylsulfonyl fluoride, 10 µg/ml leupeptin, and 100 µM E64. The homogenates were centrifuged for 15 min at 15,000g to discard the myofilaments. Electrophoresis and Western blotting analysis were carried out as above.
Statistical Analysis. Data are presented as means ± S.D. The number of experiments (n) indicates the number of hearts used. The parameters obtained from experimental hearts were compared with the ones for control hearts, and the differences were determined with unpaired Student's t test. The results were considered significant at the p < 0.05 level.
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). The areas with vesicular zinc localized mainly to the zones of damaged cells, suggesting that zinc concentration had been elevated in these zones and sequestrated by zincosomes (Fig. 1B). The distribution of labile zinc in the I/R tissues supplemented with zinc pyrithione was similar to the control samples (Fig. 1C).
Comparison of the labile zinc levels in the tissue sections showed that overall fluorescence intensity was significantly lower in I/R-stressed hearts but not in those supplemented with zinc pyrithione (Fig. 1D). The latter tissues displayed the highest level of basal zinc. Treatment of the samples on the stage of the microscope with PMA significantly increased TSQ fluorescence of tissue sections obtained from the control hearts (90% increase) but not from the ones after I/R with or without zinc pyrithione (11 and 14% increase, respectively). The kinetic of Zn2+ release triggered by PMA in control hearts was similar to what we have previously reported (Korichneva et al., 2002); specifically, TSQ staining reached saturation within 10 min. Thus, our data suggest that heart tissue becomes zinc-depleted after I/R and that the capacity to liberate labile zinc by a classical trigger PMA is significantly diminished.
Myocardial Protection from I/R-Induced Damage by Intracellular Zinc. To examine whether replenishment of intracellular zinc improves heart function during reperfusion after a period of ischemia, we analyzed the recovery of hemodynamic parameters, left ventricular developed pressure (LVDP), heart rate (HR), maximal time rate of change of pressure (dP/dT), and rate pressure product (RPP) (LVDP x HR) as an index of cardiac performance and heart rate, as well as the incidence of arrhythmias in isolated adult rat hearts subjected to both reversible (15 min) and irreversible (30 min) global ischemia followed by 30 min of reperfusion. The baseline LVDP of 101.37 ± 10.98 mm Hg recovered by 83.83% by the end of reperfusion after 15 min of global ischemia (Table 1). Zinc ionophore, pyrithione (10–5 M) applied at the time of reperfusion improved myocardial recovery up to 100%, at the same time reducing incidence of arrhythmias more than 2-fold, particularly obvious at late stages of reperfusion. The results summarizing the incidence of ventricular fibrillation (VF) and ventricular tachycardia (VT) are shown in Table 2. The zinc pyrithione effect was enhanced when the ischemia period was extended up to 30 min, yielding the improvement of LVDP recovery from 15.58% (experimental group 1) to 74.95% (experimental group 2) and diminishing VF (but not VT) 8-fold. The examples of the original recordings from these experiments are shown in Fig. 2A. The dose response of zinc pyrithione treatment was biphasic with the increase of protection at the concentrations up to 10 µM followed by a sharp decrease most likely due to Zn2+ toxicity. The recovery was attenuated by 10–5 M TPEN (experimental group 4). A significant finding was that zinc pyrithione in the diet (experimental group 6) could substitute for zinc pyrithione supplementation into the reperfusion buffer, showing similar recovery of LVDP (Fig. 3). Improved recovery was not observed with nonpermeable ZnCl2 (experimental group 3). We found that the effect of intracellular zinc supplementation on myocardial recovery depended on the activation status of PKC. The addition of the PKC trigger, PMA (50 nM, experimental group 5), after ischemia prior to zinc pyrithione, accelerated the recovery that was not sustained (Fig. 3).
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PKC Involvement in Zinc-Mediated Cardioprotection. Because the two PKC isoforms, and , are among possible zinc controlled targets, we examined their alterations by Western blot analysis of the proteins prepared from rat hearts at the end of physiological experiments. Experimental groups 0 to 2 were compared. Although there were no visible changes in PKC levels after 15 min of ischemia followed by reperfusion, the results shown in Fig. 4A clearly demonstrate that PKC level is diminished after 30 min of ischemia. Zinc pyrithione addition at reperfusion prevents PKC reduction. Thus, prolonged stress leads to significant change in this important signaling kinase.
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activation during reperfusion has been linked to augmentation of myocardial injury (Inagaki et al., 2003). Upon proteolytic cleavage to 56- and 40-kDa fragments PKC can initiate aberrant signal transduction pathway leading to apoptosis (Chou et al., 2004). We determined that myocardial I/R is associated with PKC cleavage shifting the ratio in the levels of the 78-versus 56- and 40-kDa PKC bands toward lower molecular mass. The cleavage was diminished by supplementation of perfusion buffer with zinc pyrithione (Fig. 4B).
To determine whether zinc depletion plays a role in PKC changes, we performed the in vitro studies using the zinc chelator TPEN. To initiate PKC activation followed by down-regulation, cells were treated with PMA (50 nM). After 8 h of PMA treatment, PKC level decreased by nearly 30% (Fig. 4C). The protein was barely detected after 16 h of PMA incubation. In the presence of TPEN, PKC degradation was markedly accelerated, reaching 30% decrease at 4 h of PMA incubation with subsequent elimination of the protein.
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There is growing evidence that many proteins are regulated by a redox environment through reversible oxidation of their cysteine residues (Jakob et al., 2000). More refined redox zinc switches are in addition controlled by zinc availability (Maret, 2004; Korichneva, 2006). The underlying chemical changes of protein redox zinc switches seem to be among the very first responses to oxidative stress. Liberated zinc therefore would serve as a reliable indicator of the redox status of cellular proteins. Increase in free zinc has been observed in the cells treated by nitric oxide (Chang et al., 2004) or hydrogen peroxide (Korichneva, 2005).
Fluorescent probes designed to determine free zinc differ in their chemical properties and physical characteristics and provide different advantages depending on the experimental goals. The TSQ probe that features high sensitivity and selectivity for Zn2+ (Frederickson et al., 2000; Korichneva et al., 2002) was used as the Zn2+ reporter in this work. The specific requirement for such a reporter is the value of its affinity for Zn2+, which is related to the potential to withdraw zinc ions from the numerous protein-binding sites. In other words, the probe should be sensitive enough to detect changes in intracellular Zn2+ concentration without competing with high-affinity protein binding sites. The submicromolar affinity of TSQ for Zn2+ meets these criteria exactly. The use of TSQ to determine PMA-triggered zinc release has been validated. We have reported previously that the probe does not bind to PKC upon stimulation of the cells with PMA (Korichneva et al., 2002). Likewise, we excluded the possible influence of PMA triggered alkalinization as a cause of TSQ fluorescence increase because the probe is known to be pH-independent (Frederickson et al., 2000). Fluorescent signal quenching by the selective Zn2+ chelator TPEN provides a "zero" point for calculations of Zn2+ increase and indicates specificity. TSQ histofluorescence has been used in a number of tissues to ascertain the distribution of free zinc (Nitzan et al., 2004).
The areas of elevated labile zinc within the cells in myocardial cryosection include myofilaments, intercalated disks, and sarcomeres. The function of zinc ions in these zones is unknown. Possibly, increased TSQ fluorescence due to increased labile zinc is connected to localization of signaling modules in myocytes. Several PKC isoforms as well as their binding copartners, receptors for activated C kinase, have been shown to localize to the area of Z discs (Pyle and Solaro, 2004). Stress-induced change in sarcomeric pattern of Zn2+ staining may be related to destabilization of cytoskeletal elements similarly to those shown by us earlier on the model of anhydroretinol-induced apoptosis (Korichneva and Hammerling, 1999).
It is well known that PKC and PKC have different functions in cardiac ischemia/reperfusion (Kawamura et al., 1998; Chen et al., 1999; Baines et al., 2003; Inagaki et al., 2003). However, they both are redox-sensitive, and both are subjected to degradation at prolonged ischemia (30 min). The degradation was not that obvious at shorter ischemic period (15 min), which is known as a reversible ischemia. Correspondingly, the effect of zinc ionophore on myocardial recovery was not that pronounced at 15-min ischemia, as compared with 30-min ischemia. Although it seems obvious that preservation of PKC as an antiapoptotic PKC isoform should confer myocardial protection, the results obtained for PKC might be viewed as controversial. This isoform is activated at reperfusion, and its inhibition significantly diminishes the infarct zone (Inagaki et al., 2003). However, the timing of this inhibition seems to be important because this isoform can also mediate preconditioning (Hirotani and Sadoshima, 2005). Nonetheless, PKC is subject to processing to truncated catalytically active forms that mediate an aberrant signaling pathway leading to apoptosis (Chou et al., 2004), and our results demonstrated that zinc pyrithione treatment shifts the ratio of the truncated versus full-length PKC toward full-length protein, possibly explaining the protective role of intracellular zinc supplementation.
Activation of PKC by PMA prior reperfusion mediates post-conditioning, but in combination with the zinc ionophore, the protection is not sustained. This suggests that if one of the mechanisms by which PMA confers the protection depends on zinc release, additional supplementation of intracellular Zn2+ may result in toxicity. Thus, the combination of protective agents should be carefully considered with regard to shared molecular mechanisms.
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, are the primary examples. In case of irreversible activation similar to long-term PMA treatment or prolonged oxidative stress, the degradation pathway will be initiated. Thus, prolonged stress imposed by 30-min ischemia will lead to irreversible loss of zinc from the proteins triggering, or at least participating in, the initiation of protein degradation and cell death. Our in vitro experiments demonstrate that zinc removal by chelation accelerates down-regulation of PKC. Although several mechanisms of this down-regulation, including transcriptional regulation, may be triggered by prolonged exposure to zinc chelator and PMA, protein degradation observed at 4 h of treatment is the likely mechanism shared in both in vivo and in vitro experimental models. As a consequence, elimination of Zn2+ renders sensitivity to damaging factors. As it has been reported, oxidative treatment of C6 glioma cells resulted in 50% of total zinc exported through the plasma membrane (Haase and Beyersmann, 2002).
In the situation of zinc loss, one would suggest that zinc replenishment could compensate at least in part for the damage associated with this loss. A potential mechanism utilizing zinc donation by MTs already has been proven in the model of myocardial I/R (Jiang et al., 2000; Kang et al., 2003). Studies using a cardiac-specific MT-overexpressing transgenic mouse model have demonstrated that MT inhibits myocardial injuries triggered by oxidative stress (Kang et al., 2003). We show here that supplementation of intracellular zinc using the zinc ionophore pyrithione confers a similar effect on stressed myocardium, significantly improving the mechanical properties of the heart and diminishing the incidence of fatal ventricular arrhythmias. Zinc pyrithione supplement in the diet, which had a similar effect in our experiments, probably confers protection through MT induction. We showed that PKC isoforms are among the potential targets whose functionality is preserved by zinc, although we cannot exclude the effect of intracellular zinc supplementation on other mechanisms involved in injury following ischemia, including calcium entry by an L-type Ca channel (Turan, 2003). A better understanding of these mechanisms and of the physiological role of zinc in cellular redox control in myocardium may lead to the development of agents for zinc manipulation and promising new areas for future biomedical and pharmacological research.
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Acknowledgements |
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Footnotes |
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This study was presented in abstract form at the Third Annual Symposium of the American Heart Association Council on Basic Cardiovascular Sciences: Translation of Basic Insights into Clinical Practice, 2006 Jul 31–Aug 3; Keystone, CO [Karagulova G, Yankun Yue, Boutjdr M, Moreyra AE, and Korichneva I (2006) Intracellular Zn protects isolated rat hearts from ischemia/reperfusion injury: involvement of protein kinase C. Circ Res 99:136].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: MT, metallothionein; PKC, protein kinase C; PMA, phorbol-12myristate-13acetate; I/R, ischemia/reperfusion; TSQ, N-(6-methoxy)-8-quinolyl-toluenesulfonamide; TPEN, N,N,N',N'-tetrakis-(2-pyridylmethyl)ethylenediamine; LVDP, left ventricular developed pressure; HR, heart rate; dP/dT, maximal time rate of change of pressure; LVDP x HR, rate pressure product; VF, ventricular fibrillation; VT, ventricular tachycardia; OCT, optimal cutting temperature; RPP, rate pressure product.
Address correspondence to: Irina Korichneva, Department of Medicine, University of Medicine and Dentistry, New Jersey-Robert Wood Johnson Medical School, One Robert Wood Johnson Place, P.O. Box 19, New Brunswick, NJ 08903. E-mail: korichil{at}umdnj.edu
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