Persistence of myocardial injury following brief periods of coronary occlusion

Weiner, Jerold M.; Apstein, Carl S.; Arthur, John H.; Hood, William B.

doi:10.1016/0002-9149(74)90972-2

Cited by 25 publications

(28 citation statements)

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“…[8][9][10][11][12][13][14] This is the classic model of myocardial stunning, the one in which the phenomenon was originally described,9 and the one most commonly used in experimental investigations.…”

Section: Classification Of Myocardial Stunningmentioning

confidence: 99%

Mechanism of myocardial "stunning".

1990

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Among the numerous mechanisms proposed for myocardial stunning, three appear to be more plausible: 1) generation of oxygen radicals, 2) calcium overload, and 3) excitation-contraction uncoupling. First, the evidence for a pathogenetic role of oxygen-derived free radicals in myocardial stunning is overwhelming. In the setting of a single 15-minute coronary occlusion, mitigation of stunning by antioxidants has been reproducibly observed by several independent laboratories. Similar protection has been recently demonstrated in the conscious animal, that is, in the most physiological experimental preparation available. Furthermore, generation of free radicals in the stunned myocardium has been directly demonstrated by spin trapping techniques, and attenuation of free radical generation has been repeatedly shown to result in attenuation of contractile dysfunction. Numerous observations suggest that oxyradicals also contribute to stunning in other settings: after global ischemia in vitro, after global ischemia during cardioplegic arrest in vivo, and after multiple brief episodes of regional ischemia in vivo. Compelling evidence indicates that the critical free radical damage occurs in the initial moments of reflow, so that myocardial stunning can be viewed as a sublethal form of oxyradical-mediated "reperfusion injury." Second, there is also considerable evidence that a transient calcium overload during early reperfusion contributes to postischemic dysfunction in vitro; however, the importance of this mechanism in vivo remains to be defined. Third, inadequate release of calcium by the sarcoplasmic reticulum, with consequent excitation-contraction uncoupling, may occur after multiple brief episodes of regional ischemia, but its role in other forms of postischemic dysfunction has not been explored. It is probable that multiple mechanisms contribute to the pathogenesis of myocardial stunning. The three hypotheses outlined above are not mutually exclusive and in fact may represent different steps of the same pathophysiological cascade. Thus, generation of oxyradicals may cause sarcoplasmic reticulum dysfunction, and both of these processes may lead to calcium overload, which in turn could exacerbate the damage initiated by oxygen species. The concepts discussed in this review should provide not only a conceptual framework for further investigation of the pathophysiology of reversible ischemia-reperfusion injury but also a rationale for developing clinically applicable interventions designed to prevent postischemic ventricular dysfunction.

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Section: Classification Of Myocardial Stunningmentioning

confidence: 99%

Mechanism of myocardial "stunning".

1990

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“…This issue is important because, if the injury ceases after the first few ischemic episodes, then myocardial stunning would be a self-limiting process; on the other hand, if each subsequent ischemic episode continues to inflict additional injury, then the possibility exists that myocardium subjected to recurrent bouts of ischemia may become chronically stunned. Previous investigations have yielded conflicting results, with some (6-10, [14][15][16][17][18][19][20][21][22] but not all (23)(24)(25) studies reporting a cumulative effect. Even the studies that have observed a cumulative effect, however, have uniformly concluded that the decrement in function resulting from each subsequent occlusion becomes smaller with the number of repetitions and that after the first three to five occlusions, subsequent occlusions have little or no effect on postischemic dysfunction (6)(7)(8)(9)(10)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

“…One problem with the interpretation of these studies (6)(7)(8)(9)(10)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) is that the presence or absence of a cumulative effect was judged solely from the nadir of function attained immediately or shortly after each ischemia-reperfusion cycle. To our knowledge, no previous study has systematically analyzed the effect of recurrent ischemic episodes on the duration and time course of postischemic abnormalities.…”

Section: Introductionmentioning

confidence: 99%

“…emic insults may not exacerbate the mechanical dysfunction attained immediately or shortly after each reperfusion, they may increase the overall magnitude of postischemic dysfunction, i.e., the severity of the dysfunction present after the early period of reflow and/or the total duration of the dysfunction. Elucidation of this issue would require a different approach from that used in previous studies (6)(7)(8)(9)(10)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25); namely, different numbers of ischemic episodes would have to be produced in different groups of animals and integrated measurements of postischemic dysfunction would have to be compared.…”

Section: Introductionmentioning

confidence: 99%

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Recurrent ischemia in the canine heart causes recurrent bursts of free radical production that have a cumulative effect on contractile function. A pathophysiological basis for chronic myocardial "stunning".

Bolli¹,

Zughaib²,

Li³

et al. 1995

J. Clin. Invest.

118

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Open-chest dogs (total number used, 117) underwent 10 5-min coronary occlusions (0) interspersed with 10 min of reperfusion (R). When systolic thickening fraction was measured 9 min after each R, the first O-R cycle was found to cause the largest decrement, with only a slight additional loss during the next four cycles and no further loss during the last five cycles (group IV), suggesting that the first few episodes of ischemia preconditioned the myocardium against the stunning induced by the last five episodes. However, different results were obtained when the total deficit of wall thickening during the final 4-h R interval was measured. The total deficit was similar after one and three 5-min o (groups V and VI, respectively), indicating that the first ischemic episode did precondition against the next two episodes; however, it was 2.5-fold greater after 10 0 (group IV) than after 3, indicating that the first 3 episodes failed to precondition against the next 7. Thus, at some point between the 4th and 10th 0, the preconditioning effect was lost and recurrent ischemic episodes started to have a cumulative effect. Measurements of free radicals with a-phenyl N-tert-butyl nitrone (PBN) demonstrated a burst of free radical generation immediately after the 1st, 5th, and 10th R (group VIII). The total cumulative release of PBN adducts during the initial 5 min of reflow was 58% less after the 5th R than after the 1st (P < 0.05) but did not differ significantly between the 1st and 10th R. When administered throughout the 10 O-R cycles, the -OH scavenger mercaptopropionyl glycine significantly enhanced the recovery of function (group I) and markedly suppressed the formation of free radicals (group VII). However, the beneficial effects of mercaptopropionyl glycine were completely, or largely, lost if the drug was discontinued after the first five (group II) or eight (group III) O-R cycles, respectively, implying that (a) the oxidative stress associated with the last five, or even two, cycles was sufficient to cause severe postischemic dysfunction, and (b) the cumulative injury caused by repetitive ischemic episodes is mediated by recurrent oxidative stress. This study provides direct in vivo evidence that oxygen radicals play an important role in the pathogenesis of myocardial stunning after repetitive ischemia, and implicates -OH as a primary culprit. Taken together, the data indicate that recurrent brief ischemic episodes result in recurrent bouts of oxyradical-mediated injury that have a cumulative effect on contractility, a situation that could lead to protracted or even chronic myocardial stunning. (J. Clin.

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“…Reperfusion after myocardial ischemia of brief duration does not induce necrosis, but results in prolonged contractile dysfunction (1)(2)(3). This phenomenon, which has come to be known as myocardial stunning (4), is manifested clinically in the sluggish recovery of pump function after coronary revascularization after briefperiods ofischemia (3).…”

Section: Introductionmentioning

confidence: 99%

Pathophysiology and pathogenesis of stunned myocardium. Depressed Ca2+ activation of contraction as a consequence of reperfusion-induced cellular calcium overload in ferret hearts.

Porterfield²,

et al. 1987

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Contractile dysfunction in stunned myocardium could result from a decrease in the intracellular free [Ca2+1 transient during each beat, a decrease in maximal Ca2+-activated force, or a shift in myofilament Ca2+ sensitivity. We measured developed pressure (DP) at several [Cal6 (0.5-7.5 mM) in isovolumic Langendoriperfused ferret hearts at 370C after 15 min of global ischemia (stunned group, n = 13) or in a nomnschemic control group (a = 6). At all ICal6, DP was depressed in the stunned group (P < 0.001). Maximal Ca2+-activated pressure (MCAP), measured from tetani after exposure to ryanodine, was decreased after stunning (P < 0.05). Normalization of the DP-ICa]o relationship by corresponding MCAP (Cao sensitivity) revealed a shift to higher ICalb in stunned hearts. To test whether cellular Ca overload initiates stunning, we reperfused with low-[Cai6 solution (0.1-0.5 mM; n = 8). DP and MCAP in the low-[Cajo group were comparable to control (P > 0.05), and higher than in the stunned group (P < 0.05). Myocardial IATP] observed by phosphorus NMR failed to correlate with functional recovery. In conclusion, contractile dysfunction in stunned myocardium is due to a decline in maximal force, and a shift in Cao sensitivity (which may reflect either decreased myofilament Ca2+ sensitivity or a decrease in the [Ca2+j transient). Our results also indicate that calcium entry upon reperfusion plays a major role in the pathogenesis of myocardial stunning.

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Persistence of myocardial injury following brief periods of coronary occlusion

Cited by 25 publications

References 0 publications

Mechanism of myocardial "stunning".

Mechanism of myocardial "stunning".

Recurrent ischemia in the canine heart causes recurrent bursts of free radical production that have a cumulative effect on contractile function. A pathophysiological basis for chronic myocardial "stunning".

Pathophysiology and pathogenesis of stunned myocardium. Depressed Ca2+ activation of contraction as a consequence of reperfusion-induced cellular calcium overload in ferret hearts.

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