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

Kusuoka, Hideo; Porterfield, James K.; Weisman, Harlan F.; Weisfeldt, Myron L.; Marbán, Eduardo

doi:10.1172/jci112906

Cited by 415 publications

(134 citation statements)

References 42 publications

Supporting

Mentioning

127

Contrasting

Unclassified

Order By: Relevance

“…The significantly greater increase in intracellular [Ca 2ϩ ] in CK-deficient hearts at the end of the ischemic period, however, has a significant impact on the subsequent reperfusion injury, known to be mediated by the transient Ca 2ϩ overload within the first minutes of reperfusion (12). During the course of reperfusion, systolic and diastolic LV performance remained significantly impaired in both groups of hearts despite lower resting [Ca 2ϩ ] during reperfusion.…”

Section: Discussionmentioning

confidence: 93%

Creatine kinase-deficient hearts exhibit increased susceptibility to ischemia-reperfusion injury and impaired calcium homeostasis

Spindler¹,

Meyer²,

Strömer³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Creatine kinase-deficient hearts exhibit increased susceptibility to ischemia-reperfusion injury and impaired calcium homeostasis. Am J Physiol Heart Circ Physiol 287: H1039 -H1045, 2004. First published April 22, 2004 10.1152/ajpheart.01016.2003.-The creatine kinase (CK) system is involved in the rapid transport of high-energy phosphates from the mitochondria to the sites of maximal energy requirements such as myofibrils and sarcolemmal ion pumps. Hearts of mice with a combined knockout of cytosolic M-CK and mitochondrial CK (M/Mito-CK Ϫ/Ϫ ) show unchanged basal left ventricular (LV) performance but reduced myocardial high-energy phosphate concentrations. Moreover, skeletal muscle from M/Mito-CK Ϫ/Ϫ mice demonstrates altered Ca 2ϩ homeostasis. Our hypothesis was that in CK-deficient hearts, a cardiac phenotype can be unmasked during acute stress conditions and that susceptibility to ischemia-reperfusion injury is increased because of altered Ca 2ϩ homeostasis. We simultaneously studied LV performance and myocardial Ca 2ϩ metabolism in isolated, perfused hearts of M/Mito-CK Ϫ/Ϫ (n ϭ 6) and wild-type (WT, n ϭ 8) mice during baseline, 20 min of no-flow ischemia, and recovery. Whereas LV performance was not different during baseline conditions, LV contracture during ischemia developed significantly earlier (408 Ϯ 72 vs. 678 Ϯ 54 s) and to a greater extent (50 Ϯ 2 vs. 36 Ϯ 3 mmHg) in M/Mito-CK Ϫ/Ϫ mice. During reperfusion, recovery of diastolic function was impaired (LV end-diastolic pressure: 22 Ϯ 3 vs. 10 Ϯ 2 mmHg), whereas recovery of systolic performance was delayed, in M/Mito-CK Ϫ/Ϫ mice. In parallel, Ca 2ϩ transients were similar during baseline conditions; however, M/Mito-CK Ϫ/Ϫ mice showed a greater increase in diastolic Ca 2ϩ concentration ([Ca 2ϩ ]) during ischemia (237 Ϯ 54% vs. 167 Ϯ 25% of basal [Ca 2ϩ ]) compared with WT mice. In conclusion, CK-deficient hearts show an increased susceptibility of LV performance and Ca 2ϩ homeostasis to ischemic injury, associated with a blunted postischemic recovery. This demonstrates a key function of an intact CK system for maintenance of Ca 2ϩ homeostasis and LV mechanics under metabolic stress conditions. aequorin bioluminescence; transgenic mouse THE CREATINE KINASE (CK) system comprises a family of mitochondrial (Mito-CK) and cytosolic (MM-, MB-, and BB-CK) isoenzymes that are critically involved in intracellular energy homeostasis. The primary role of CK is to catalyze the reversible transfer of a high-energy phosphoryl group between ATP and phosphocreatine (PCr; PCr ϩ ADP ϩ H ϩ 7 ATP ϩ creatine). The functional and physical coupling of certain members of the CK isoenzyme family to the sites of energy production and utilization has underscored the integrated properties of this important enzyme system in excitable tissue, particularly in muscle cells (26). MM-CK, for example, is present in membrane vesicles of the sarcoplasmic reticulum (SR) isolated from skeletal muscle (15), suggesting that an efficient and fast energy replenishing system is necessary for op...

show abstract

Section: Discussionmentioning

confidence: 93%

Creatine kinase-deficient hearts exhibit increased susceptibility to ischemia-reperfusion injury and impaired calcium homeostasis

Spindler¹,

Meyer²,

Strömer³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…First, when isolated ferret hearts subjected to 15 minutes of global normothermic ischemia are reperfused with solutions containing low concentrations of calcium, the postischemic contractile abnormalities are significantly attenuated. 27 The results of this experiment, in which no intervention is applied during ischemia, indicate that calcium entry upon reperfusion is an important mechanism of myocardial stunning. A decrease in the severity of stunning is also observed in hearts pretreated with ryanodine, an inhibitor of cellular calcium overload.29 Second, exposure of isolated ferret hearts to a transient calcium overload in the absence of ischemia produces mechanical and metabolic abnormalities similar to myocardial stunning.…”

Section: Decreased Sensitivity Of Myofilaments To Calciummentioning

confidence: 83%

Mechanism of myocardial "stunning".

1990

View full text Add to dashboard Cite

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.

show abstract

“…Myocardial stunning probably arises from the additive effects of a reperfusion-induced pathology (identified, as least in part, by the fraction [dark shading] of the contractile deficit, which can be restored through the use of an antioxidant intervention given transiently at the time of reperfusion) and a second component (light shading), which incorporates the ischemic pathology from which the heart is slowly recovering, together with any additional reperfusion-induced component that is not amenable to the chosen intervention. 14,17,28,60 ( Fig 1A). Indirect evidence indicates that Ca 2ϩ overload also contributes to postischemic dysfunction after regional ischemia in vivo, 63 but direct demonstration of this concept is still lacking.…”

Section: ؉mentioning

confidence: 95%

“…Studies in models of stunning after global ischemia in vitro 14,15 and in ventricular trabeculae isolated from these models 61 have concluded that the alteration responsible for the contractile dysfunction consists of a decrease both in the maximal Ca 2ϩ -activated force and the sensitivity of myofilaments to Ca 2ϩ . A decrease in Ca 2ϩ sensitivity of myofilaments has not been observed consistently in all models of global ischemia in vitro, however.…”

Section: ؉mentioning

confidence: 99%