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Department of Cardiothoracic Surgery, The Carlyle Fraser Heart Center/Crawford Long Hospital, Emory University School of Medicine, Atlanta, Georgia 30308-2225
Submitted 9 December 2002 ; accepted in final form 27 March 2003
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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absorbance·min–1·g
tissue–1) in the area at risk myocardium was
comparably reduced in Post-con (10.8 ± 5.5, P < 0.05) and
Pre-con (13.4 ± 3.4, P < 0.05) versus controls (47.4
± 15.3). Basal endothelial function measured by PMN adherence to
postischemic LAD endothelium (PMNs/mm2) was comparably attenuated
by Post-con and Pre-con (15 ± 0.6 and 12 ± 0.6, P <
0.05) versus controls (37 ± 1.5), consistent with reduced expression of
P-selectin on coronary vascular endothelium in Post-con and Pre-con.
Endothelial function assessed by the maximal vasodilator response of
postischemic LAD to acetylcholine was significantly greater in Post-con (104
± 6%, P < 0.05) and Pre-con (109 ± 5%, P
< 0.05) versus controls (71 ± 8%). Plasma malondialdehyde
(µM/ml), a product of lipid peroxidation, was significantly less at 1 h of
reperfusion in Post-con (2.2 ± 0.2, P < 0.05) versus
controls (3.2 ± 0.3) associated with a decrease in superoxide levels
revealed by dihydroethidium staining in the myocardial area at risk. These
data suggest that Post-con is as effective as Pre-con in reducing infarct size
and preserving endothelial function. Post-con may be clinically applicable in
coronary interventions, coronary artery bypass surgery, organ transplantation,
and peripheral revascularization where reperfusion injury is expressed.
infarct size; neutrophils
In 1986, Murry et al. (21) first introduced the concept of ischemic preconditioning in which repetitive brief periods of ischemia protected the myocardium from a subsequent longer ischemic insult. Preconditioning succeeded in significantly reducing infarct size at a time when other pharmacological strategies were inconsistent in their effect. Preconditioning has been reported to reduce infarct size (21), preserve vascular endothelial function (8, 28), decrease polymorponuclear neutrophil (PMN) accumulation (22), and reduce apoptosis (22). Although preconditioning has been clinically successful in attenuating the physiological effects of serial balloon inflations during percutaneous transluminal coronary angioplasty (9, 29), its use as a clinical cardioprotective strategy to attenuate the pathophysiological consequences (i.e., arrhythmias and infarction) of ischemia-reperfusion injury is limited by the inability to predict the onset of ischemia. However, the implementation of cardioprotective therapy at the time of reperfusion is clinically feasible because the onset of reperfusion is more predictable and is under the clinician's control.
It has been previously reported that reperfusion injury can be significantly reduced by modifying the conditions and the composition of the initial reperfusate (1, 2, 5). Relevant to the modification of the conditions (hydrodynamics or flow rate) of reperfusion, we have reported that gradual restoration of coronary blood flow (CBF) during the first 30 min of reperfusion following a period of coronary occlusion reduced infarct size and postischemic myocardial blood flow defects (26, 34). In the present study, we used an open-chest canine model of left anterior descending artery (LAD) occlusion and reperfusion to test the hypothesis that three cycles of 30-s reperfusion followed by 30-s reocclusion during the initial moments of reperfusion (i.e., postconditioning) would attenuate reperfusion-induced myocardial injury. This strategy was compared with conventional preconditioning. We found that infarct size, tissue edema, and postischemic coronary artery endothelial dysfunction in the area at risk (AR) myocardium were reduced with postconditioning to the same extent as with preconditioning.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Heartworm-free adult dogs of either sex weighing 25–35 kg were initially premedicated with an intramuscular injection of morphine sulfate (4 mg/kg) followed by continuous inhalation of isoflurane (0.5–2%) after endotracheal intubation. Dogs were ventilated with a volume-cycled respirator using oxygen-enriched room air. The left femoral artery was cannulated with a polyethylene catheter for blood sampling. The chest was opened by a left lateral thoracotomy, and the heart was suspended in a pericardial cradle. Millar catheter-tipped pressure transducers were inserted into the aorta via the internal mammary artery and into the left ventricle through an apical incision, respectively. A pair of 5-MHz ultrasonic crystals was implanted in the anterior midmyocardium and connected to a sonomicrometer (model 120, Triton Technology; San Diego, CA) to measure regional contractile function. A Doppler flow probe was placed on the proximal LAD coronary artery and connected to a pulsed Doppler flowmeter (Triton Technology) for the measurement of instantaneous CBF. A catheter was inserted into the left atrium for injection of colored microspheres to measure regional myocardial blood flow. A 2-0 silk suture was passed below the first diagonal branch of the LAD distal to the flow probe to occlude the LAD. All dogs were then systemically heparinized with 300 U/kg heparin sodium before the start of the experiment.
Experimental protocol. All animals were randomly assigned to one of three groups (Fig. 1): 1) control (n = 10), the LAD was reversibly occluded for 60 min followed by 3 h of reperfusion; 2) preconditioning (n = 9), the LAD was occluded for 5 min followed by 10 min of reperfusion before the 60 min of prolonged occlusion; 3) postconditioning (n = 10), after 60 min of LAD occlusion, reperfusion was initiated for 30 s followed by 30 s of reocclusion, repeated for three cycles (3 min total intervention). Reperfusion was continued for a total of 3 h in all experiments.
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Steady-state baseline hemodynamic measurements were acquired in duplicate, and a blood sample was withdrawn to measure plasma creatine kinase (CK) activity and malondialdehyde (MDA) level. The LAD was reversibly occluded by gently pulling up on the snare to produce a zone of regional ischemia in the anterior free wall of the left ventricle. After 60 min of LAD occlusion, colored microspheres were injected to quantify collateral blood flow in the area at risk, and lidocaine (2 mg/kg) was administered intravenously just before release of the ligature. The ligature was then loosened, and the ischemic myocardium was reperfused for 3 h. Data were again collected at 15 min and 3 h of reperfusion. At the end of reperfusion, the heart was excised to evaluate infarct size, tissue edema, myocardial blood flow, tissue myeloperoxidase activity, and superoxide level in the AR. To determine postischemic coronary artery endothelial vasoreactivity and PMN adherence to coronary endothelium, a 1.0-cm long segment of LAD and left circumflex coronary arteries (LCX) was harvested and placed in cold physiological buffer.
Hemodynamics and regional contractile function. Hemodynamic data were acquired during a 12-s period of respiratory apnea by using an analog-to-digital converter and acquisition software (Spectrum, Wake Forest University). Heart rate (HR), mean aortic pressure (MAP), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), the maximum and minimum first derivative of LVSP (+dP/dtmax and –dP/dt), LAD CBF, end-diastolic segmental length, end-systolic segmental length, percent segmental shortening, and segment work in ischemic zone were determined as described previously (39). Hemodynamic and cardiodynamic data were collected at baseline, at 60 min of ischemia, and after 15 min, 1, 2, and 3 h of reperfusion.
Determination of area at risk and infarct size. After the heart was harvested, the LAD was religated in the original position, and diluted Unisperse blue dye was injected into the aortic root under 80-mmHg perfusion pressure to stain the nonischemic region blue and thereby outline the AR. After excision of the coronary vessels under cold buffer, the left ventricle was cut into transverse slices. The AR was separated from the nonischemic zone and incubated in a 1% solution of triphenyltetrazolium chloride (TTC) at 37°C to differentiate the area of necrosis from the nonnecrotic AR. The AR was expressed as a percentage of the left ventricular mass (AR/LV), and the area of necrosis, as a percentage of the AR (AN/AR), and they were calculated by tissue weight as reported previously (39).
Regional myocardial blood flow. Regional myocardial blood flow (expressed as ml·min–1·g tissue–1) in the ischemic subepicardium and subendocardium was determined by colored microspheres (Triton Technology) at baseline, at the end of ischemia, and at 15 min and 3 h of reperfusion using the reference sampling method as previously described (39).
Determination of CK and MDA from plasma. Arterial blood samples were withdrawn at baseline, at the end of ischemia, and at 1, 2, and 3 h of reperfusion for measuring CK (Sigma Diagnostic, St. Louis, MO) and MDA (Lipid Peroxidation Assay, Calbiochem), an index of lipid peroxidation reflecting oxygen free radicals. All samples were centrifuged, and the plasma was drawn off. The extracted supernatants after reaction of plasma with tested reagents in CK and MDA detection kits were analyzed spectrophotometrically (SPECTRAmax, Molecular Devices; Sunnyvale, CA) at 340-nm and 586-nm absorbance, respectively. CK activity was expressed as units per gram protein, and MDA values were given as micromoles per milliliter of plasma.
Edema from AR myocardium. Tissue samples (0.3 g) were taken from subepicardial and subendocardial regions of the AR, quickly blotted of surface moisture and blood, and weighed. The samples were desiccated in an 80°C oven for 24 h and reweighed. The percent tissue edema was calculated as 100·[1 – (dry weight/wet weight)].
PMN isolation and adherence to coronary artery endothelium. After induction of anesthesia, arterial blood was withdrawn from the femoral artery. PMN isolation and adherence to ischemic-reperfused coronary artery segments were performed as described previously (40). Briefly, the LAD and LCX segments were cut into 3-mm segments, carefully opened, and placed in round cell culture dishes. Fluorescently labeled and unstimulated PMNs (4 x 105 cells/ml) were added to the culture dishes containing oxygenated Krebs-Henseleit buffer at 37°C and allowed to incubate with coronary artery segments for 20 min. After coincubation, the segments were removed, rinsed of nonadherent PMNs, and placed on glass slides. The number of PMNs adhering to the endothelial surface in six separate microscopic fields was counted under epifluorescent microscopy.
Coronary artery endothelial function. Vasoreactivity in postischemic epicardial macrovessels was studied as described previously (40). Briefly, LAD and LCX coronary artery segments were cut into 3-mm segments and hung in organ chambers containing oxygenated Krebs-Henseleit buffer at 37°C. After 60 min of stabilization, the coronary artery rings were preconstricted with the thromboxane A2 mimetic U-46619. Endothelial function was assessed by quantifying the vasorelaxation responses to incremental concentrations of endothelium-dependent vasodilator acetylcholine, whereas smooth muscle function was assessed with incremental concentrations of the endothelium-independent vasodilator sodium nitroprusside. Vascular responses were monitored using a videographics program (Spectrum; Winston-Salem, NC).
Tissue myeloperoxidase activity. After we determined infarct size,
tissue samples from the nonischemic and AR zones were saved for analysis of
myeloperoxidase (MPO) activity, an enzyme used as a marker of neutrophil
accumulation. The samples were frozen and stored at –70°C until
assayed. The samples were homogenized in hexadecyltrimethyl ammonium bromide
and dissolved in potassium phosphate. After centrifugation, supernatants were
collected and mixed with o-dianisidine dihydrochloride and hydrogen
peroxide in phosphate buffer. The activity of MPO was measured
spectrophotometrically at 460 nm absorbance (abs) (SPECTRAmax, expressed as
abs·min–1·g
tissue–1)
(39).
P-selectin expression on vascular endothelium. Transmural tissue samples from nonischemic and ischemic myocardium were processed for immunohistochemistry as reported previously (39). Briefly, the tissue blocks were embedded in optimal cutting temperature (OCT, Miles Laboratories) compound after fixation in paraformaldehyde, frozen in liquid nitrogen, and stored at –70°C. Cryosections of the tissue (7 µm) were cut using a Hacker-Bright cryostat, thaw-mounted on Fisher-Plus (Fisher Scientific) slides and stored at –70°C with desiccant until use. After being fixed in acetone and air dried, the tissue sections were initially blocked with gelatin in PBS to inhibit nonspecific binding. The sections were then incubated with polyclonal rabbit anti-human CD 62P (P-selectin, BD PharMingen) for 1–2 h at a concentration of 1 µg/ml. The slides were then washed in PBS and incubated with a 1:500 dilution of biotinylated goat anti-rabbit IgG (Vector Laboratories). The sections were stained using the ABC-Alkalin Phosphatase (AK) and substrated with AK substrate kit (Vector Laboratories). The slides were then counterstained with hematoxylin and dehydrated in graded dilutions of alcohol. Controls for immunohistochemical single or double labeling were made by either eliminating the primary antibody or incubating the tissue with a nonimmune IgG.
In situ detection of superoxide. Dihydroethidium (DHE, Molecular Probes) staining for superoxide was carried out as described previously (20). Briefly, transmural tissue samples from nonischemic and ischemic myocardium were harvested, placed in cold saline, and embedded in OCT for cryosectioning. The tissue sections (20 µm) were cut using a Hacker-Bright cryostat, thaw-mounted on Fisher-Plus (Fisher Scientific) slides and stained with 10 µM DHE at 37°C for 30 min. The image of ethidium staining was obtained by using an imaging system (Image-Pro Plus, Media Cybemetics; Silver Spring, MD) with a 585-nm long-pass filter. Generation of superoxide by tissue was demonstrated by red fluorescent labeling.
Statistical analysis. A one-way ANOVA followed by Duncan's post-hoc test was used to analyze group differences in a single data such as PMN adherence, infarct size, and CK activity data. Hemodynamic data and other time-dependent determinations were analyzed by repeated measures analysis of variance followed by post-hoc analysis with Student-Newman-Keuls multiple comparisons. Dose-response curves of agonist-induced vascular relaxation were calculated as a percentage of the decrease of U-46619-induced isometric force. A P < 0.05 was considered significant. Results are reported as means ± SE.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Hemodynamics and regional contractile function. Hemodynamics and regional contractile function during the experiments are summarized in Table 1. In all three groups, HR increased during ischemia; however, these increases were not significant compared with their respective baseline value. HR was only significantly increased at some time points during reperfusion in control and preconditioning groups. During and after 15 min of reperfusion, LVSP in the control and preconditioning groups was significantly less compared with the respective baseline values but showed no significant group-related differences throughout the procedure. There were nonsignificant trends in the changes in LVEDP, +dP/dt, and –dP/dt compared with the respective baseline value during the experiment in the three groups. During coronary occlusion, all the groups exhibited a rightward shift in the pressure-length relationship and a significant decline in segmental shortening and segment shortening (Table 1). Wall motion remained dyskinetic or severely hypokinetic throughout the entire reperfusion period in all three groups with no group differences.
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Area at risk and infarct size. The AR was comparable among the three groups, averaging between 25 and 31% (Fig. 2). Infarct size in the postconditioning group was 44% less than that in the control group (Fig. 2). Similarly, infarct size in preconditioning was 40% less than that in the control group (P < 0.05). There was no statistical difference in infarct size between the preconditioning and postconditioning groups.
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Regional myocardial blood flow in area at risk. Regional myocardial blood flow in the nonischemic myocardium remained unchanged during the experiment (Table 2). LAD occlusion reduced regional myocardial blood flow in the ischemic subepicardium and subendocardium to the same extent in all three groups. Transmural blood flow (in ml·min–1·g–1) in the AR at the end of ischemia was comparable among all three groups, averaging 0.06 ± 0.01 in the control, 0.07 ± 0.01 in the preconditioning, and 0.09 ± 0.02 in the postconditioning groups. Release of the coronary artery snare resulted in a significant increase in regional myocardial blood flow in the AR subepicardium and subendocardium in the control group at 15 min of reperfusion relative to values during ischemia. The reactive hyperemic response in the subepicardial region of the AR at 15 min reperfusion was significantly reduced in both preconditioning and postconditioning groups. There was a similar marked hyperemic response in LAD CBF measured by the flow probe in the control group at the start of reperfusion that was significantly blunted in the postconditioning group. There were no group differences in regional myocardial blood flow in the subepicardium at 3 h of reperfusion. In addition, there were no group differences in the AR subendocardial blood flow at 15 min and 3 h of reperfusion.
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To exclude the possibility that the smaller infarct size in the preconditioning and postconditioning groups was due to higher collateral blood flow during coronary occlusion, transmural AR myocardial blood flow was plotted against the size of infarction as covariate. As shown in Fig. 3, there was an inverse relationship between infarct size and collateral blood flow. However, at any given value for collateral blood flow, the infarct size in the preconditioning and postconditioning groups was smaller than that in the control group. Therefore, the reduction in infarct size in these two intervention groups was not determined by changes in collateral blood flow during coronary occlusion.
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Plasma CK activity during ischemia and reperfusion. CK activity was used to confirm infarct size quantified by TTC staining. Coronary occlusion only slightly increased CK values, with no group differences. However, CK activity was significantly increased during reperfusion relative to ischemia, reaching a final value of 16 ± 3 IU/g protein at 3 h of reperfusion in the control group. Preconditioning and postconditioning were associated with significantly lower CK activity at 3 h of reperfusion, with values averaging 7 ± 1 and 8 ± 1 IU/g protein, respectively. Group differences in CK activity were consistent with those observed for infarct size.
Tissue edema in ischemic myocardium. Ischemia and reperfusion significantly increased tissue edema in the AR myocardium compared with the nonischemic myocardium in the control group (Fig. 4). Tissue edema in the ischemic subendocardial region in the preconditioning and postconditioning groups was significantly higher than that in the nonischemic myocardium. However, tissue edema in these two groups was significantly less compared with the respective region in the control group. There was no significant difference between preconditioning and postconditioning in tissue edema in any regions.
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Tissue MPO activity in AR myocardium. MPO activity
(abs·min–1·g
tissue–1) in the nonischemic tissue was low and
comparable among the three groups. Ischemia-reperfusion significantly
increased MPO activity in the AR in the control group (47 ± 15)
compared with that in the nonischemic tissue (3 ± 1). However, MPO
activity in the AR myocardium was significantly reduced in the preconditioning
(13 ± 3) and postconditioning (11 ± 6) groups relative to the
control group.
PMN adherence to postischemic endothelium. PMN adherence to postischemic coronary artery endothelium is a marker of endothelial dysfunction linked to attenuated basal release of nitric oxide (19). There was no difference among groups in PMN adherence to the LCX coronary artery segments. In the control group, there was a significantly augmented PMN adherence (in mm2 endothelium) to the LAD coronary artery segments at 3 h of reperfusion (37 ± 2) compared with adherence to the LCX (13 ± 0.8). PMN adherence to the ischemic-reperfused LAD was significantly reduced in both postconditioning and preconditioning groups (12 ± 0.6 and 15 ± 0.6) with no difference between groups. PMN adherence to LAD in the preconditioning and postconditioning groups was comparable to that in the nonischemic LCX.
Postischemic vasorelaxation. Endothelial function in isolated coronary arteries was assessed by relaxation responses to incremental concentrations of the vasodilators in postischemic vessels. Figure 5 shows vasodilator response to acetylcholine in the isolated postischemic coronary artery rings from LCX and LAD. The concentration-response curve of the LAD in the control group was shifted downward and to the right relative to those of the LCX, i.e., relaxation responses were less than those in the LCX. Both preconditioning and postconditioning reversed this blunted relaxation response to acetylcholine to the same extent. There were no significant differences in the responses to nitroprusside in the LAD and LCX in the three groups (data not shown).
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P-selectin expression in vascular endothelium. P-selectin is expressed on the surface of activated endothelium. Immunohistochemical staining of the endothelial surface of vessels in tissue sections obtained from nonischemic and AR myocardium is shown in Fig. 6. There was no detectable immunoreactivity to P-selectin on the endothelial surface of vessels in nonischemic myocardium (Fig. 6A). After 3 h of reperfusion, the immunoreactivity to P-selectin was markedly increased along the endothelial surface of vessels in the AR myocardium in the control group (Fig. 6B). However, less P-selectin immunoreactivity was observed in sections from AR myocardium from both preconditioning and postconditioning groups (Fig. 6, C and D).
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Plasma MDA levels during ischemia and reperfusion. Appearance of MDA-reactive products in plasma has been used as an indictor of lipid peroxidation. Coronary occlusion was associated with slightly increased MDA values with no group difference compared with baseline values (Fig. 7). However, in the blood samples withdrawn at 1 h of reperfusion in the control group, the concentration of MDA-reactive products was significantly increased relative to coronary occlusion, and higher values was maintained until the end of reperfusion. However, in the blood samples withdrawn at this time point in the postconditioning group, MDA-reactive products were significantly lower than that in the control group. No group difference was detected at end of reperfusion.
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DHE staining in the AR myocardium. DHE reacts with superoxide anions to form ethidium bromide, which in turn intercalates with DNA to provide nuclear fluorescence as a marker of superoxide anion generation. As shown in Fig. 8, the intensity of DHE staining in ischemic-reperfused myocardium was markedly enhanced in vascular endothelial cells and in myocytes in the control group compared with staining intensity in the nonischemic myocardium. However, the intensity of fluorescent staining in the postconditioning group was markedly reduced in the ischemic myocardium to a comparable level in the nonischemic myocardium.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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In the present study, we present evidence that repetitive cycles of briefly interrupted reperfusion applied at the onset of coronary reflow (i.e., postconditioning) significantly reduces infarct size. This reduction in infarct size was corroborated by a similar decrease in plasma CK activity and attenuation in tissue edema. The comparable collateral blood flow during ischemia among the three groups suggests that the protective effect of postconditioning on infarct size was not due to differences in coronary collateral blood flow. In addition, postconditioning reduced neutrophil accumulation in the AR myocardium and preserved postischemic coronary artery endothelial function assessed by vasodilatory responses to acetylcholine and adherence of unactivated neutrophils to the endothelial surface. However, neither postconditioning nor preconditioning improved regional contractile function. Postconditioning was associated with a significant decrease in MDA-reactive products of lipid peroxidation and with less intensity of DHE staining of endothelium and myocytes in the AR myocardium. These observations suggest a reduction in the generation of reactive oxygen species and less oxidant-mediated injury by postconditioning. The protection achieved with postconditioning was equivalent to the benefits gained by ischemic preconditioning in all physiological end points studied. Therefore, strategically modifying early reperfusion events provides powerful cardioprotection by reducing reperfusion injury comparable to a pretreatment strategy such as preconditioning. However, because preconditioning triggers cardioprotective pathways before ischemia while postconditioning alters events after ischemia, the mechanisms and the timing of those mechanisms are likely quite different between the two maneuvers.
Generation of abundant oxygen free radicals during early reperfusion has been implicated as a major player in the pathogenesis of tissue injury. The burst of oxygen-derived free radicals occurs within the first minute and peaks at 4 to 7 min after reperfusion; increased free radical generation is still detectable during later periods of reperfusion (4). Superoxide anions have been implicated in lipid peroxidation of biological membranes, triggering adhesion molecule expression on endothelium, and subsequent initiation of neutrophil and endothelial cell interactions (10, 25). Both in vivo and in vitro studies have shown that oxygen free radicals are potent stimuli for the rapid upregulation of P-selectin and ICAM-1 on endothelium as well as initiation of acute inflammation and subsequent recruitment of neutrophils in ischemic myocardium (3, 10, 11). Our observations are consistent with this oxygen-mediated process. However, the source of oxidants [i.e., PMNs, endothelium via NAD(P)H oxidase, or myocytes] have not yet been elucidated. In addition, it is not clear whether postconditioning blocks a single pathway or etiology of endothelial dysfunction (i.e., endothelial superoxide generation), or multiple signals (i.e., endothelial oxidants, PMN oxidants, and proteasas, etc.). Further studies are needed to clarify the source and the species of free radicals attenuated by postconditioning and the major pathways of endothelial dysfunction that are interdicted by this cardioprotective maneuver.
The brief repetitively interrupted reperfusion with postconditioning applied during the onset of reperfusion was associated with lower levels of MDA-reactive products and DHE-staining intensity, suggesting attenuated lipid peroxidation and reduced generation of superoxide anions in the AR myocardium. Postconditioning may have limited delivery of oxygen substrate and thereby directly attenuated the generation of oxygen-derived free radicals. In turn, the reduced generation of oxygen free radicals may have reduced endothelial activation (P-selectin expression) and dysfunction (PMN adherence and vasorelaxation responses) and potentially the pathogenesis of infarction. We did not measure MDA-reactive products or DHE fluorescence in the preconditioning group; however, previous studies have shown that ischemic preconditioning has been associated with reduced generation of oxygen free radicals and attenuated oxidant-related injury to endothelium and myocytes (31, 36). In vitro studies using isolated cardiomyocytes and endothelial cells have reported that the generation of superoxide radicals and cytokines at reoxygenation was significantly attenuated by hypoxic preconditioning (31, 36). These authors suggest that a transient low-level stimulation of oxygen radical generation by preconditioning may act as a signal that awakens an antiinflammatory-type "cardiomyocyte and endothelial preconditioning," which then reduces responsiveness of these cells to inflammatory mediators.
In addition to potentially attenuating oxidant injury, postconditioning may have favorably altered mechanical events during reperfusion independent of altering oxidant-mediated injury. For example, the increase in perpendicular and shear stresses caused by abruptly elevated blood pressure in the reperfused vessels has been reported to induce tissue injury and edema by physically overstretching vascular endothelium and increasing fluid extravasation in the parenchyma (12). As has been reported, an abrupt increase in blood pressure in canine coronary arteries selectively reduced endothelium-dependent vascular relaxation, resulting in enhanced vascular responses to vasoconstrictor agents (7). In previous studies from our laboratory and that of others (26, 34), the gradual restoration of perfusion pressure during early reperfusion was associated with a reduction in microvascular injury, infarct size, and tissue edema. Postconditioning may have modulated these hydrodynamic forces during early reperfusion and thereby attenuated edema and endothelial injury. However, there are notable differences in the protection afforded by postconditioning compared with gradually restoring perfusion. Gradually, reperfusion was associated with increased neutrophil accumulation, whereas in contrast postconditioning was associated with a decrease in neutrophil accumulation in the AR. In addition, there was significant preservation in maximal endothelium-dependent vascular relaxation with postconditioning, which was not observed with gradual reperfusion (26). The differences in neutrophil accumulation and postischemic endothelial function between gradual reperfusion and postconditioning suggest that different mechanisms are, in part, involved.
Regional contractile dysfunction is a consequence of both reversible and irreversible injury after ischemiareperfusion. Short periods (<15 min) of coronary artery occlusion cause contractile dysfunction in the absence of infarction; this recovery of myocardial stunning takes at least 6 h (16). However, contractile dysfunction in irreversibly damaged (infarcted) myocardium persists, and recovery may require days or months (6, 16, 38). In the present study, contractile dysfunction was observed in the AR of untreated hearts, as has been abundantly reported previously (17, 34, 38). Although pre- and postconditioning reduced infarct size significantly, they did not improve postischemic function in the AR. The ultrasonic crystals were placed in the subendocardial region of the AR, which was infarcted to some extent in both groups. Acute recovery of function would not be expected regardless of the mechanism involved in myocardial salvage, unless the overlying noninfarcted myocardium could acutely compensate for the contractile failure of the underlying subendocardial (infarcted) tissue. However, few studies have reported functional recovery even in the presence of persistent albeit diminished infarction (27, 30).
In conclusion, although experimental studies demonstrate that ischemic and pharmacological preconditioning attenuate ischemia-reperfusion injury, these interventions have to be applied before the prolonged "index" ischemia. In the clinical setting, however, pretreatment is rarely an option. The results of the present study show that salvage of the coronary endothelium and cardiomyocyte can be achieved when the heart is postconditioned by cycles of briefly interrupted perfusion during the early moments of reflow. The degree of myocardial salvage with postconditioning was comparable to that observed with preconditioning, although the intervention is applied at opposite ends of the index ischemia. The observations from the present study provide compelling evidence demonstrating a new mechanism of myocardial protection from reperfusion injury specifically, which is in contradistinction to the mechanism of ischemic preconditioning. Future studies are necessary to determine the optimal algorithm of perfusion-occlusion sequences, as well as other mechanisms involved in postconditioning. It is possible that postconditioning may delay the washout of endogenous anti-inflammatory autacoids such as adenosine (37) and maintain cellular high-energy phosphate stores in ischemic myocardium (24).
The postconditioning procedure is very simple, and therefore, may be clinically applicable. For example, cycles of briefly interrupted reperfusion could be achieved during percutaneous transluminal coronary angioplasty by using rapid reiterative balloon inflation and deflation or by using controllable intracoronary flow devices such as delivery pumps and appropriately sized catheters. This procedure can also be applied after completion of vascular grafts in surgical revascularization, as a final procedure before removal of the aortic cross-clamp in on-pump cardiac surgery, upon removal of the target vessel ligature during off-pump coronary artery bypass graft surgery, or during organ transplantation.
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DISCLOSURES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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B and AP-1 and upregulation of ICAM-1 in reperfused
canine heart. Am J Physiol Heart Circ Physiol
282: H1778–H1786,
2002.
. FASEB J 14:
555–564, 2000.This article has been cited by other articles:
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  L. Lacerda, S. Somers, L. H. Opie, and S. Lecour Ischaemic postconditioning protects against reperfusion injury via the SAFE pathway Cardiovasc Res, November 1, 2009; 84(2): 201 - 208. [Abstract] [Full Text] [PDF]
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G. Heusch No RISK, no ... cardioprotection? A critical perspective Cardiovasc Res, November 1, 2009; 84(2): 173 - 175. [Full Text] [PDF]
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|
|
 |
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 C. Leconte, E. Tixier, T. Freret, J. Toutain, R. Saulnier, M. Boulouard, S. Roussel, P. Schumann-Bard, and M. Bernaudin Delayed Hypoxic Postconditioning Protects Against Cerebral Ischemia in the Mouse Stroke, October 1, 2009; 40(10): 3349 - 3355. [Abstract] [Full Text] [PDF]
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G. Heusch and R. Schulz Neglect of the coronary circulation: some critical remarks on problems in the translation of cardioprotection Cardiovasc Res, October 1, 2009; 84(1): 11 - 14. [Full Text] [PDF]
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 |
|
 H. Zhao, Y. Wang, Y. Wu, X. Li, G. Yang, X. Ma, R. Zhao, and H. Liu Hyperlipidemia does not prevent the cardioprotection by postconditioning against myocardial ischemia/reperfusion injury and the involvement of hypoxia inducible factor-1{alpha} upregulation Acta Biochim Biophys Sin, September 1, 2009; 41(9): 745 - 753. [Abstract] [Full Text] [PDF]
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J. Musiolik, P. van Caster, A. Skyschally, K. Boengler, P. Gres, R. Schulz, and G. Heusch Reduction of infarct size by gentle reperfusion without activation of reperfusion injury salvage kinases in pigs Cardiovasc Res, August 25, 2009; (2009) cvp271v2. [Abstract] [Full Text] [PDF]
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|
 D. C. Fernandez, M. P. Bordone, M. S. Chianelli, and R. E. Rosenstein Retinal Neuroprotection against Ischemia-Reperfusion Damage Induced by Postconditioning Invest. Ophthalmol. Vis. Sci., August 1, 2009; 50(8): 3922 - 3930. [Abstract] [Full Text] [PDF]
|
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K. Boengler, R. Schulz, and G. Heusch Loss of cardioprotection with ageing Cardiovasc Res, July 15, 2009; 83(2): 247 - 261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Hausenloy and D. M. Yellon Cardioprotective growth factors Cardiovasc Res, July 15, 2009; 83(2): 179 - 194. [Abstract] [Full Text] [PDF]
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A. Granfeldt, D. J. Lefer, and J. Vinten-Johansen Protective ischaemia in patients: preconditioning and postconditioning Cardiovasc Res, July 15, 2009; 83(2): 234 - 246. [Abstract] [Full Text] [PDF]
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D. B. Zorov, M. Juhaszova, Y. Yaniv, H. B. Nuss, S. Wang, and S. J. Sollott Regulation and pharmacology of the mitochondrial permeability transition pore Cardiovasc Res, July 15, 2009; 83(2): 213 - 225. [Abstract] [Full Text] [PDF]
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 I. Szwarc, G. Mourad, and A. Argiles Post-conditioning to reduce renal ischaemia/reperfusion injury Nephrol. Dial. Transplant., July 1, 2009; 24(7): 2288 - 2289. [Full Text] [PDF]
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 T. Krieg, Y. Liu, T. Rutz, C. Methner, X.-M. Yang, T. Dost, S. B. Felix, J.-P. Stasch, M. V. Cohen, and J. M. Downey BAY 58-2667, a nitric oxide-independent guanylyl cyclase activator, pharmacologically post-conditions rabbit and rat hearts Eur. Heart J., July 1, 2009; 30(13): 1607 - 1613. [Abstract] [Full Text] [PDF]
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 J. Frassdorf, S. De Hert, and W. Schlack Anaesthesia and myocardial ischaemia/reperfusion injury Br. J. Anaesth., July 1, 2009; 103(1): 89 - 98. [Abstract] [Full Text] [PDF]
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 G. J. Gross, K. M. Gauthier, J. Moore, W. B. Campbell, J. R. Falck, and K. Nithipatikom Evidence for role of epoxyeicosatrienoic acids in mediating ischemic preconditioning and postconditioning in dog Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H47 - H52. [Abstract] [Full Text] [PDF]
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 M. Juhaszova, D. B. Zorov, Y. Yaniv, H. B. Nuss, S. Wang, and S. J. Sollott Role of Glycogen Synthase Kinase-3{beta} in Cardioprotection Circ. Res., June 5, 2009; 104(11): 1240 - 1252. [Abstract] [Full Text] [PDF]
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 V. Venugopal, A. Ludman, D. M. Yellon, and D. J. Hausenloy 'Conditioning' the heart during surgery Eur. J. Cardiothorac. Surg., June 1, 2009; 35(6): 977 - 987. [Abstract] [Full Text] [PDF]
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 N. Couvreur, R. Tissier, S. Pons, M. Chenoune, X. Waintraub, A. Berdeaux, and B. Ghaleh The Ceiling Effect of Pharmacological Postconditioning with the Phytoestrogen Genistein Is Reversed by the GSK3{beta} Inhibitor SB 216763 [3-(2,4-Dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione] through Mitochondrial ATP-Dependent Potassium Channel Opening J. Pharmacol. Exp. Ther., June 1, 2009; 329(3): 1134 - 1141. [Abstract] [Full Text] [PDF]
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J. N. Peart and J. P. Headrick Clinical cardioprotection and the value of conditioning responses Am J Physiol Heart Circ Physiol, June 1, 2009; 296(6): H1705 - H1720. [Abstract] [Full Text] [PDF]
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 M. Carlsson, J. F.A. Ubachs, E. Hedstrom, E. Heiberg, S. Jovinge, and H. Arheden Myocardium at risk after acute infarction in humans on cardiac magnetic resonance quantitative assessment during follow-up and validation with single-photon emission computed tomography. J. Am. Coll. Cardiol. Img., May 1, 2009; 2(5): 569 - 576. [Abstract] [Full Text] [PDF]
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 Y. Murozono, N. Takahashi, T. Shinohara, T. Ooie, Y. Teshima, M. Hara, T. Saikawa, and H. Yoshimatsu Hyperthermia-Induced Cardioprotection Is Potentiated by Ischemic Postconditioning in Rats Experimental Biology and Medicine, May 1, 2009; 234(5): 573 - 581. [Abstract] [Full Text] [PDF]
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J. S. Karliner Sphingosine kinase regulation and cardioprotection Cardiovasc Res, May 1, 2009; 82(2): 184 - 192. [Abstract] [Full Text] [PDF]
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C. Pavoine and F. Pecker Sphingomyelinases: their regulation and roles in cardiovascular pathophysiology Cardiovasc Res, May 1, 2009; 82(2): 175 - 183. [Abstract] [Full Text] [PDF]
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 J. Huffmyer and J. Raphael Physiology and Pharmacology of Myocardial Preconditioning and Postconditioning Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2009; 13(1): 5 - 18. [Abstract] [PDF]
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I. Hecht, J. Rong, A. L. F. Sampaio, C. Hermesh, C. Rutledge, R. Shemesh, A. Toporik, M. Beiman, L. Dassa, H. Niv, et al. A Novel Peptide Agonist of Formyl-Peptide Receptor-Like 1 (ALX) Displays Anti-Inflammatory and Cardioprotective Effects J. Pharmacol. Exp. Ther., February 1, 2009; 328(2): 426 - 434. [Abstract] [Full Text] [PDF]
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A. Skyschally, P. van Caster, K. Boengler, P. Gres, J. Musiolik, D. Schilawa, R. Schulz, and G. Heusch Ischemic Postconditioning in Pigs: No Causal Role for RISK Activation Circ. Res., January 2, 2009; 104(1): 15 - 18. [Abstract] [Full Text] [PDF]
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 R. G. Katare, M. Ando, Y. Kakinuma, M. Arikawa, T. Handa, F. Yamasaki, and T. Sato Vagal nerve stimulation prevents reperfusion injury through inhibition of opening of mitochondrial permeability transition pore independent of the bradycardiac effect. J. Thorac. Cardiovasc. Surg., January 1, 2009; 137(1): 223 - 231. [Abstract] [Full Text] [PDF]
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 B. Li, R. Chen, R. Huang, and W. Luo Clinical benefit of cardiac ischemic postconditioning in corrections of tetralogy of Fallot Interactive CardioVascular and Thoracic Surgery, January 1, 2009; 8(1): 17 - 21. [Abstract] [Full Text] [PDF]
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 H. Ishii, T. Amano, T. Matsubara, and T. Murohara Pharmacological Intervention for Prevention of Left Ventricular Remodeling and Improving Prognosis in Myocardial Infarction Circulation, December 16, 2008; 118(25): 2710 - 2718. [Full Text] [PDF]
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G. Heusch, K. Boengler, and R. Schulz Cardioprotection: Nitric Oxide, Protein Kinases, and Mitochondria Circulation, November 4, 2008; 118(19): 1915 - 1919. [Full Text] [PDF]
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O. Bouhidel, S. Pons, R. Souktani, R. Zini, A. Berdeaux, and B. Ghaleh Myocardial ischemic postconditioning against ischemia-reperfusion is impaired in ob/ob mice Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1580 - H1586. [Abstract] [Full Text] [PDF]
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J. Feng, M. Zhu, M. C. Schaub, P. Gehrig, B. Roschitzki, E. Lucchinetti, and M. Zaugg Phosphoproteome analysis of isoflurane-protected heart mitochondria: phosphorylation of adenine nucleotide translocator-1 on Tyr194 regulates mitochondrial function Cardiovasc Res, October 1, 2008; 80(1): 20 - 29. [Abstract] [Full Text] [PDF]
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L. Xi, A. Das, Z.-Q. Zhao, V. F. Merino, M. Bader, and R. C. Kukreja Loss of Myocardial Ischemic Postconditioning in Adenosine A1 and Bradykinin B2 Receptors Gene Knockout Mice Circulation, September 30, 2008; 118(14_suppl_1): S32 - S37. [Abstract] [Full Text] [PDF]
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 P. S. Pagel, J. G. Krolikowski, P. F. Pratt Jr, Y. H. Shim, J. Amour, D. C. Warltier, and D. Weihrauch The Mechanism of Helium-Induced Preconditioning: A Direct Role for Nitric Oxide in Rabbits Anesth. Analg., September 1, 2008; 107(3): 762 - 768. [Abstract] [Full Text] [PDF]
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Q. C. Yong, S. W. Lee, C. S. Foo, K. L. Neo, X. Chen, and J.-S. Bian Endogenous hydrogen sulphide mediates the cardioprotection induced by ischemic postconditioning Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1330 - H1340. [Abstract] [Full Text] [PDF]
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 S. E. McAllister, H. Ashrafpour, N. Cahoon, N. Huang, M. A. Moses, P. C. Neligan, C. R. Forrest, J. E. Lipa, and C. Y. Pang Postconditioning for salvage of ischemic skeletal muscle from reperfusion injury: efficacy and mechanism Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2008; 295(2): R681 - R689. [Abstract] [Full Text] [PDF]
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Y. Nishino, I. G. Webb, S. M. Davidson, A. I. Ahmed, J. E. Clark, S. Jacquet, A. M. Shah, T. Miura, D. M. Yellon, M. Avkiran, et al. Glycogen Synthase Kinase-3 Inactivation Is Not Required for Ischemic Preconditioning or Postconditioning in the Mouse Circ. Res., August 1, 2008; 103(3): 307 - 314. [Abstract] [Full Text] [PDF]
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D. J. Hausenloy and D. M. Yellon Remote ischaemic preconditioning: underlying mechanisms and clinical application Cardiovasc Res, August 1, 2008; 79(3): 377 - 386. [Abstract] [Full Text] [PDF]
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 C. Piot, P. Croisille, P. Staat, H. Thibault, G. Rioufol, N. Mewton, R. Elbelghiti, T. T. Cung, E. Bonnefoy, D. Angoulvant, et al. Effect of Cyclosporine on Reperfusion Injury in Acute Myocardial Infarction N. Engl. J. Med., July 31, 2008; 359(5): 473 - 481. [Abstract] [Full Text] [PDF]
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D. J. Hausenloy and D. M. Yellon Time to Take Myocardial Reperfusion Injury Seriously N. Engl. J. Med., July 31, 2008; 359(5): 518 - 520. [Full Text] [PDF]
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Z.-Q. Jin, J. S. Karliner, and D. A. Vessey Ischaemic postconditioning protects isolated mouse hearts against ischaemia/reperfusion injury via sphingosine kinase isoform-1 activation Cardiovasc Res, July 1, 2008; 79(1): 134 - 140. [Abstract] [Full Text] [PDF]
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 J. Dow, A. Bhandari, and R. A. Kloner Ischemic Postconditioning's Benefit on Reperfusion Ventricular Arrhythmias Is Maintained in the Senescent Heart Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2008; 13(2): 141 - 148. [Abstract] [PDF]
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L. Gomez, M. Paillard, H. Thibault, G. Derumeaux, and M. Ovize Inhibition of GSK3{beta} by Postconditioning Is Required to Prevent Opening of the Mitochondrial Permeability Transition Pore During Reperfusion Circulation, May 27, 2008; 117(21): 2761 - 2768. [Abstract] [Full Text] [PDF]
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G. Serviddio, A. D. Romano, L. Gesualdo, R. Tamborra, A. M. Di Palma, T. Rollo, E. Altomare, and G. Vendemiale Postconditioning is an effective strategy to reduce renal ischaemia/reperfusion injury Nephrol. Dial. Transplant., May 1, 2008; 23(5): 1504 - 1512. [Abstract] [Full Text] [PDF]
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R. Hinkel, C. El-Aouni, T. Olson, J. Horstkotte, S. Mayer, S. Muller;, M. Willhauck, C. Spitzweg, F.-J. Gildehaus, W. Munzing, et al. Thymosin {beta}4 Is an Essential Paracrine Factor of Embryonic Endothelial Progenitor Cell-Mediated Cardioprotection Circulation, April 29, 2008; 117(17): 2232 - 2240. [Abstract] [Full Text] [PDF]
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 E. Murphy and C. Steenbergen Mechanisms Underlying Acute Protection From Cardiac Ischemia-Reperfusion Injury Physiol Rev, April 1, 2008; 88(2): 581 - 609. [Abstract] [Full Text] [PDF]
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J.-y. Wang, J. Shen, Q. Gao, Z.-g. Ye, S.-y. Yang, H.-w. Liang, I. C. Bruce, B.-y. Luo, and Q. Xia Ischemic Postconditioning Protects Against Global Cerebral Ischemia/Reperfusion-Induced Injury in Rats Stroke, March 1, 2008; 39(3): 983 - 990. [Abstract] [Full Text] [PDF]
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W. Luo, B. Li, R. Chen, R. Huang, and G. Lin Effect of ischemic postconditioning in adult valve replacement Eur. J. Cardiothorac. Surg., February 1, 2008; 33(2): 203 - 208. [Abstract] [Full Text] [PDF]
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A. M. Deschamps, J. Zavadzkas, R. L. Murphy, C. N. Koval, J. E. McLean, L. Jeffords, S. M. Saunders, N. J. Sheats, R. E. Stroud, and F. G. Spinale Interruption of endothelin signaling modifies membrane type 1 matrix metalloproteinase activity during ischemia and reperfusion Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H875 - H883. [Abstract] [Full Text] [PDF]
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H. M. Piper, Y. Abdallah, S. Kasseckert, and K.-D. Schluter Sarcoplasmic reticulum-mitochondrial interaction in the mechanism of acute reperfusion injury Cardiovasc Res, January 15, 2008; 77(2): 234 - 236. [Full Text] [PDF]
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 T. Yue, B. Roth Z'graggen, S. Blumenthal, S. B. Neff, L. Reyes, C. Booy, M. Steurer, D. R. Spahn, T. A. Neff, E. R. Schmid, et al. Postconditioning with a volatile anaesthetic in alveolar epithelial cells in vitro Eur. Respir. J., January 1, 2008; 31(1): 118 - 125. [Abstract] [Full Text] [PDF]
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|
 R. M. Mentzer Jr, M. S. Jahania, and R. D. Lasley Myocardial Protection Card. Surg. Adult, January 1, 2008; 3(2008): 443 - 464. [Full Text]
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L. Argaud, O. Gateau-Roesch, L. Augeul, E. Couture-Lepetit, J. Loufouat, L. Gomez, D. Robert, and M. Ovize Increased mitochondrial calcium coexists with decreased reperfusion injury in postconditioned (but not preconditioned) hearts Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H386 - H391. [Abstract] [Full Text] [PDF]
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S. L. Hale, A. Mehra, J. Leeka, and R. A. Kloner Postconditioning fails to improve no reflow or alter infarct size in an open-chest rabbit model of myocardial ischemia-reperfusion Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H421 - H425. [Abstract] [Full Text] [PDF]
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 D. A. Liem, H. M. Honda, J. Zhang, D. Woo, and P. Ping Past and present course of cardioprotection against ischemia- reperfusion injury J Appl Physiol, December 1, 2007; 103(6): 2129 - 2136. [Abstract] [Full Text] [PDF]
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A. Jahangir, S. Sagar, and A. Terzic Aging and cardioprotection J Appl Physiol, December 1, 2007; 103(6): 2120 - 2128. [Abstract] [Full Text] [PDF]
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J. Vinten-Johansen, Z.-Q. Zhao, R. Jiang, A. J. Zatta, and G. P. Dobson Preconditioning and postconditioning: innate cardioprotection from ischemia-reperfusion injury J Appl Physiol, October 1, 2007; 103(4): 1441 - 1448. [Abstract] [Full Text] [PDF]
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Y.-X. Shi, Y. Chen, Y.-Z. Zhu, G.-Y. Huang, P. K. Moore, S.-H. Huang, T. Yao, and Y.-C. Zhu Chronic sodium hydrosulfide treatment decreases medial thickening of intramyocardial coronary arterioles, interstitial fibrosis, and ROS production in spontaneously hypertensive rats Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2093 - H2100. [Abstract] [Full Text] [PDF]
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R. R. Morrison, X. L. Tan, C. Ledent, S. J. Mustafa, and P. A. Hofmann Targeted deletion of A2A adenosine receptors attenuates the protective effects of myocardial postconditioning Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2523 - H2529. [Abstract] [Full Text] [PDF]
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H. Sato, R. Bolli, G. D. Rokosh, Q. Bi, S. Dai, G. Shirk, and X.-L. Tang The cardioprotection of the late phase of ischemic preconditioning is enhanced by postconditioning via a COX-2-mediated mechanism in conscious rats Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2557 - H2564. [Abstract] [Full Text] [PDF]
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S. P. Loukogeorgakis, R. Williams, A. T. Panagiotidou, S. K. Kolvekar, A. Donald, T. J. Cole, D. M. Yellon, J. E. Deanfield, and R. J. MacAllister Transient Limb Ischemia Induces Remote Preconditioning and Remote Postconditioning in Humans by a KATP Channel Dependent Mechanism Circulation, September 18, 2007; 116(12): 1386 - 1395. [Abstract] [Full Text] [PDF]
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D. M. Yellon and D. J. Hausenloy Myocardial Reperfusion Injury N. Engl. J. Med., September 13, 2007; 357(11): 1121 - 1135. [Full Text] [PDF]
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L. Gomez, H. Thibault, A. Gharib, J.-M. Dumont, G. Vuagniaux, P. Scalfaro, G. Derumeaux, and M. Ovize Inhibition of mitochondrial permeability transition improves functional recovery and reduces mortality following acute myocardial infarction in mice Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1654 - H1661. [Abstract] [Full Text] [PDF]
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 J. Taki, T. Higuchi, A. Kawashima, M. Fukuoka, D. Kayano, J. F. Tait, I. Matsunari, K. Nakajima, S. Kinuya, and H. W. Strauss Effect of Postconditioning on Myocardial 99mTc-Annexin-V Uptake: Comparison with Ischemic Preconditioning and Caspase Inhibitor Treatment J. Nucl. Med., August 1, 2007; 48(8): 1301 - 1307. [Abstract] [Full Text] [PDF]
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S. Y. Lim, S. M. Davidson, D. J. Hausenloy, and D. M. Yellon Preconditioning and postconditioning: The essential role of the mitochondrial permeability transition pore Cardiovasc Res, August 1, 2007; 75(3): 530 - 535. [Abstract] [Full Text] [PDF]
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C. Penna, D. Mancardi, R. Rastaldo, G. Losano, and P. Pagliaro Intermittent activation of bradykinin B2 receptors and mitochondrial KATP channels trigger cardiac postconditioning through redox signaling Cardiovasc Res, July 1, 2007; 75(1): 168 - 177. [Abstract] [Full Text] [PDF]
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J. Dow and R. A. Kloner Postconditioning Does Not Reduce Myocardial Infarct Size in an In Vivo Regional Ischemia Rodent Model Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2007; 12(2): 153 - 163. [Abstract] [PDF]
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 D. J Hausenloy and D. M Yellon The evolving story of "conditioning" to protect against acute myocardial ischaemia-reperfusion injury Heart, June 1, 2007; 93(6): 649 - 651. [Abstract] [Full Text] [PDF]
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W. Luo, B. Li, G. Lin, and R. Huang Postconditioning in cardiac surgery for tetralogy of Fallot J. Thorac. Cardiovasc. Surg., May 1, 2007; 133(5): 1373 - 1374. [Full Text] [PDF]
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 W. Y. Vanagt, R. N. Cornelussen, T. C. Baynham, A. Van Hunnik, Q. P. Poulina, F. Babiker, J. Spinelli, T. Delhaas, and F. W. Prinzen Pacing-Induced Dyssynchrony During Early Reperfusion Reduces Infarct Size J. Am. Coll. Cardiol., May 1, 2007; 49(17): 1813 - 1819. [Abstract] [Full Text] [PDF]
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S. M. Davidson and M. R. Duchen Endothelial Mitochondria: Contributing to Vascular Function and Disease Circ. Res., April 27, 2007; 100(8): 1128 - 1141. [Abstract] [Full Text] [PDF]
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E. Shi, X. Jiang, T. Kazui, N. Washiyama, K. Yamashita, H. Terada, and A. H. M. Bashar Controlled low-pressure perfusion at the beginning of reperfusion attenuates neurologic injury after spinal cord ischemia J. Thorac. Cardiovasc. Surg., April 1, 2007; 133(4): 942 - 948. [Abstract] [Full Text] [PDF]
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A. Lerman, D. R. Holmes, J. Herrmann, and B. J. Gersh Microcirculatory dysfunction in ST-elevation myocardial infarction: cause, consequence, or both? Eur. Heart J., April 1, 2007; 28(7): 788 - 797. [Abstract] [Full Text] [PDF]
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M. R. Schmidt, M. Smerup, I. E. Konstantinov, M. Shimizu, J. Li, M. Cheung, P. A. White, S. B. Kristiansen, K. Sorensen, V. Dzavik, et al. Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism: first demonstration of remote ischemic perconditioning Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1883 - H1890. [Abstract] [Full Text] [PDF]
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M. Fujita, H. Asanuma, A. Hirata, M. Wakeno, H. Takahama, H. Sasaki, J. Kim, S. Takashima, O. Tsukamoto, T. Minamino, et al. Prolonged transient acidosis during early reperfusion contributes to the cardioprotective effects of postconditioning Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H2004 - H2008. [Abstract] [Full Text] [PDF]
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L. Tao, E. Gao, X. Jiao, Y. Yuan, S. Li, T. A. Christopher, B. L. Lopez, W. Koch, L. Chan, B. J. Goldstein, et al. Adiponectin Cardioprotection After Myocardial Ischemia/Reperfusion Involves the Reduction of Oxidative/Nitrative Stress Circulation, March 20, 2007; 115(11): 1408 - 1416. [Abstract] [Full Text] [PDF]
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O. C. Manintveld, M. te Lintel Hekkert, E. J. van den Bos, G. M. Suurenbroek, D. H. Dekkers, P. D. Verdouw, J. M. Lamers, and D. J. Duncker Cardiac effects of postconditioning depend critically on the duration of index ischemia Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1551 - H1560. [Abstract] [Full Text] [PDF]
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P. Pacher, J. S. Beckman, and L. Liaudet Nitric Oxide and Peroxynitrite in Health and Disease Physiol Rev, January 1, 2007; 87(1): 315 - 424. [Abstract] [Full Text] [PDF]
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 Q. Chen, A. K. S. Camara, D. F. Stowe, C. L. Hoppel, and E. J. Lesnefsky Modulation of electron transport protects cardiac mitochondria and decreases myocardial injury during ischemia and reperfusion Am J Physiol Cell Physiol, January 1, 2007; 292(1): C137 - C147. [Abstract] [Full Text] [PDF]
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P < 0.01 vs. control group. Values are group means
± SE.
