Therapy to reduce free radicals during early reperfusion does not limit the size of myocardial infarcts caused by 90 minutes of ischemia in dogs.

Richard, Vincent; Murry, Charles E.; Jennings, Robert B.; Reimer, Keith A.

doi:10.1161/01.cir.78.2.473

Cited by 111 publications

(44 citation statements)

References 28 publications

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“…15 The regression lines between infarct size and collateral blood flow obtained in these two studies were superimposable with similar scatter. These observations suggest that 1) the methods of estimating infarct size in the present study were reliable and 2) most, if not all, of the myocyte death that is observed after 90 minutes of ischemia and 4 days of reperfusion has already occurred by the end of the first hour of reperfusion.…”

Section: Myocardial Blood Flowmentioning

confidence: 56%

“…Conversely, in a similar study, also of reperfusion after 90 minutes of ischemia, but in which no critical stenosis was used, we found no effect of SOD and catalase on infarct size. 15 The difference in the mode of reperfusion is a possible reason for these discrepant results. A critical stenosis could exacerbate reperfusion injury, for example, by slowing blood velocity, increasing PMN adhesion to endothelium, and thereby increasing free radical production.…”

mentioning

confidence: 99%

“…A critical stenosis could exacerbate reperfusion injury, for example, by slowing blood velocity, increasing PMN adhesion to endothelium, and thereby increasing free radical production. 15 If so, a critical stenosis could increase the proportion of an infarct attributable to free radical-mediated cell death, and thereby, potentially preventable by anti-free radical therapy. Alternatively, it is possible that reactive hyperemia increases PMN or free radical-induced reperfusion injury to such an extent that it overcomes the potential beneficial effects of an anti-free radical therapy.…”

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confidence: 99%

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Effect of a critical coronary stenosis on myocardial neutrophil accumulation during ischemia and early reperfusion in dogs.

et al. 1989

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In many experimental models of ischemia and reperfusion, reperfusion is performed abruptly, allowing full reactive hyperemia to occur. In the clinical setting, however, reperfusion after thrombolysis is often limited by residual stenosis. Some experimental models attempt to mimic this situation with a "critical stenosis" (defined as a coronary constriction sufficient to abolish reactive hyperemia without altering baseline flow). The purpose of this study was to determine whether preventing reactive hyperemia during the initial phase of reperfusion would modify the transmural distribution of myocardial blood flow or the myocardial accumulation of polymorphonuclear leukocytes (PMNs). The left circumflex artery was occluded for 90 minutes and then reperfused for 60 minutes in anesthetized, open-chest dogs. Autologous PMNs were isolated, labeled with`lIn, and reinjected 1 hour before coronary occlusion.`251-labeled albumin was injected simultaneously to correct for "'in associated with plasma proteins and to permit calculation of the number of PMNs in the inner, middle, and outer thirds of nonischemic and ischemic-reperfused tissue. The presence of a critical stenosis abolished reactive hyperemia during the first 5 minutes of reperfusion, but did not substantially affect blood flow measured after 55 minutes of reperfusion. In both groups, there was a significant accumulation of PMNs in all layers of the ischemic-reperfused bed compared with the nonischemic bed, and the magnitude of this PMN accumulation was not altered by the presence of a critical stenosis. Moreover, infarct size, estimated by triphenyl tetrazolium chloride (TTC) loss after 60 minutes of reperfusion, was not affected by the presence of a critical stenosis. Thus, the presence of a critical stenosis abolished the hyperemic blood flow after reperfusion but did not influence the early PMN response to ischemia and reperfusion or the early loss of TTC staining. (Circulation 1989;80:1805-1815 T he severity and duration of an ischemic interval are the major determinants of whether cardiac myocytes will recover or undergo necrosis after reperfusion. It has been postulated in recent years, however, that the fate of some myocytes may be determined, in part, by events One potentially important variable aspect of reperfusion is the distal arterial pressure and consequent rate of flow through the microvasculature during the initial phase of reperfusion. In many experimental models, coronary occlusion is followed by an abrupt, complete reopening of the artery, permitting a marked hyperemic flow through the ischemically dilated microvasculature. In clinical circumstances, however, reperfusion is usually achieved more slowly (e.g., by thrombolytic therapy), and reactive hyperemia may be limited by the residual stenosis caused by underlying atherosclerotic plaque.4 Some investigators mimic this situation in their experimental models of ischemia and reperfusion by imposing a persistent partial constriction on the occluded and reopened artery.3 This "critical steno...

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Section: Myocardial Blood Flowmentioning

confidence: 56%

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confidence: 99%

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confidence: 99%

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Effect of a critical coronary stenosis on myocardial neutrophil accumulation during ischemia and early reperfusion in dogs.

et al. 1989

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“…Other investigators found similar beneficial effects of antioxidant interventions in experimental models of myocardial infarction. However, there is a significant number of studies describing a failure of antioxidants to prevent injury, or demonstrating an early protective effect, that waned with increased duration of reperfusion [63,64]. Transgenic mice that overexpress copper, zinc superoxide dismutase (SOD1) exhibited significant protection from postischemic injury [65].…”

Section: Generation Of Reactive Oxygen Species (Ros) and The Post-infmentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

572

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Myocardial infarction is the most common cause of cardiac injury and results in acute loss of a large number of myocardial cells. Because the heart has negligible regenerative capacity, cardiomyocyte death triggers a reparative response that ultimately results in formation of a scar and is associated with dilative remodeling of the ventricle. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Toll Like Receptor-mediated pathways, the complement cascade and reactive oxygen generation induce Nuclear Factor (NF)-κB activation and upregulate chemokine and cytokine synthesis in the infarcted heart. Chemokines stimulate the chemotactic recruitment of inflammatory leukocytes into the infarct, while cytokines promote adhesive interactions between leukocytes and endothelial cells, resulting in transmigration of inflammatory cells into the site of injury. Monocyte subsets play distinct roles in phagocytosis of dead cardiomyocytes and in granulation tissue formation through the release of growth factors. Clearance of dead cells and matrix debris may be essential for resolution of inflammation and transition into the reparative phase. Transforming Growth Factor (TGF)-β plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. Myofibroblast proliferation and angiogenesis result in formation of highly vascularized granulation tissue. As the healing infarct matures, fibroblasts become apoptotic and a collagen-based matrix is formed, while many infarct neovessels acquire a muscular coat and uncoated vessels regress. Timely resolution of the inflammatory infiltrate and spatial containment of the inflammatory and reparative response into the infarcted area are essential for optimal infarct healing. Targeting inflammatory pathways following infarction may reduce cardiomyocyte injury and attenuate adverse remodeling. In addition, understanding the role of the immune system in cardiac repair is necessary in order to design optimal strategies for cardiac regeneration.

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“…Explosive myocardial swelling, calcium overload, and release of toxic oxygen-derived free radicals are the mechanisms most frequently implicated in the genesis of reperfusion-induced extension of necrosis.1-4 The conclusion that free radicals extend necrosis is based on reports of marked reductions in infarct size by free radical scavengers administered just before or during reperfusion.5-18 However, other investigators, using the same agents in the same mode, were unable to demonstrate a reduction in infarct size. [19][20][21][22][23][24][25][26][27][28][29][30] The role of explosive myocardial swelling and calcium overload is also controversial because many consider these changes to be the consequences rather than the causes of myocardial necrosis. 31,32 The controversy concerning the mechanisms and treatments of reperfusion-induced extension of necrosis is compounded by the fact that there is no See p 1070 direct and unequivocal evidence that reperfusion does extend necrosis.…”

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Does reperfusion extend necrosis? A study in a single territory of myocardial ischemia--half reperfused and half not reperfused.

et al. 1990

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The purpose of this study was to confirm or disprove the existence of reperfusion-induced extension of necrosis. To avoid the effect of the variability of collateral circulation when groups of dogs are compared, we compared the effect of reperfusion and nonreperfusion on myocardial necrosis in a single ischemic territory, half of which was reperfused and half of which was not. The left anterior descending coronary artery (LAD) territory between its last diagonal branch and the apex was studied because it was found to have uniform collateral blood flow. In 20 dogs, the LAD was occluded for 90-240 minutes to produce necrosis of different degrees of transmurality. Before release of this occlusion, the LAD was occluded distally halfway to the apex to keep the distal half nonreperfused. After 5 minutes of proximal reperfusion, Monastral blue dye was injected into the left atrium for demarcation of the reperfused region, and the heart was arrested, excised, cut parallel to the LAD, and placed into triphenyl tetrazolium chloride (T1C) solution for delineation of the region of necrosis. The validity of TTC staining under the conditions of this study was confirmed by light and electron microscopy. The transmurality of necrosis, measured within 1 or 0.5 cm on either side of the boundary, ranged from 30o to 88o of wail thickness and was not different in the reperfused compared with the nonreperfused region (paired t test). Reperfusion did not advance the epicardial edge ofnecrosis compared with the nonreperfused region. In conclusion, at 5 minutes after reperfusion, comparson of necrosis in the reperfused and nonreperfused halves of a single ischemic territory could not demonstrate an extension of necrosis by reperfusion.

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Therapy to reduce free radicals during early reperfusion does not limit the size of myocardial infarcts caused by 90 minutes of ischemia in dogs.

Cited by 111 publications

References 28 publications

Effect of a critical coronary stenosis on myocardial neutrophil accumulation during ischemia and early reperfusion in dogs.

Effect of a critical coronary stenosis on myocardial neutrophil accumulation during ischemia and early reperfusion in dogs.

The immune system and cardiac repair

Does reperfusion extend necrosis? A study in a single territory of myocardial ischemia--half reperfused and half not reperfused.

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