A Novel Mechanism for Myocardial Stunning Involving Impaired Ca
            <sup>2+</sup>
            Handling

Kim, Song Jung; Kudej, Raymond K.; Yatani, Atsuko; Kim, Young Kwon; Takagi, Gen; Honda, Ritsu; Colantonio, David; Eyk, Jennifer E. Van; Vatner, Dorothy E.; Rasmusson, Randall L.; Vatner, Stephen F.

doi:10.1161/hh2101.098547

Cited by 90 publications

(63 citation statements)

References 39 publications

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“…Several recent studies have addressed the possible species variation after stunning versus other stimuli that produce TnI degradation. Lack of TnI degradation in swine 27,28 and dog 29 has been observed, similar to the lack on TnI degradation in the rabbit in our model. In addition, a dissociation between TnI proteolysis and stunning has been reported for rat myocardium, 30 and in a recent preliminary presentation by van Eyck and colleagues, 31 it was shown that TnI degradation was not essential for myocardial stunning in the dog.…”

Section: Hydroxyl Radical Exposure and Myofilament Responsivenesssupporting

confidence: 89%

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange

Zeitz

Maass²,

Nguyen³

et al. 2002

Circulation Research

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Abstract-Hydroxyl radicals (OH) are involved in the development of reperfusion injury and myocardial failure. In the acute phase of the OH-mediated diastolic dysfunction, increased intracellular Ca 2ϩ levels and alterations of myofilaments may play a role, but the relative contribution of these systems to myocardial dysfunction is unknown. Intact contracting cardiac trabeculae from rabbits were exposed to OH, resulting in an increase in diastolic force (F dia ) by 540%. Skinned fiber experiments revealed that OH-exposed preparations were sensitized for Ca 2ϩ (EC 50 : 3.27Ϯ0.24ϫ10Ϫ6 versus 2.69Ϯ0.15ϫ10 Ϫ6 mol/L; PϽ0.05), whereas maximal force development was unaltered. Western blots showed a proteolytic degradation of troponin T (TnT) with intact troponin I (TnI). Blocking of calpain I by MDL-28.170 inhibited both TnT-proteolysis and Ca 2ϩ sensitization, but failed to prevent the acute diastolic dysfunction in the intact preparation. The OH-induced diastolic dysfunction was similar in preparations with intact (540Ϯ93%) and pharmacologically blocked sarcoplasmic reticulum (539Ϯ77%), and was also similar in presence of the L-type Ca 2ϩ -channel antagonist verapamil. In sharp contrast, inhibition of the reverse-mode sodium-calcium exchange by KB-R7943 preserved diastolic function completely. Additional experiments were performed in rat myocardium; the rise in diastolic force was comparable to rabbit myocardium, but Ca 2ϩ sensitivity was unchanged and maximal force development was reduced. This was associated with a degradation of TnI, but not TnT. Electron microscopic analysis revealed that OH did not cause irreversible membrane damage. We conclude that OH-induced acute diastolic dysfunction is caused by Ca 2ϩ influx via reverse mode of the sodium-calcium exchanger. Degradation of troponins appears to be species-dependent but does not contribute to the acute diastolic dysfunction.

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Section: Hydroxyl Radical Exposure and Myofilament Responsivenesssupporting

confidence: 89%

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange

Zeitz

Maass²,

Nguyen³

et al. 2002

Circulation Research

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“…Thomas et al (19) reported that adult pigs with clinical evidence of stunning after either 10 min of total ischemia or 60 min of partial ischemia had no increase in TnI , but TnI(1-193) did become apparent after 1-2 h of ischemia. Similarly Kim and colleagues (20), also using adult pigs, failed to demonstrate evidence of TnI degradation in a model of stunning using 90 min of coronary stenosis followed by 60 min of reperfusion. Myocardial dysfunction in this model was attributed to alterations in calcium handling and phospholamban phosphorylation.…”

Section: Discussionmentioning

confidence: 91%

Glucocorticoids Preserve Calpastatin and Troponin I during Cardiopulmonary Bypass in Immature Pigs

et al. 2003

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Degradation of troponin I (TnI) by calpain occurs with myocardial stunning in ischemia-reperfusion injury. Glucocorticoids attenuate myocardial ischemia-reperfusion injury, but their effect on TnI degradation is unknown. A piglet model was used to test the hypotheses that cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) are associated with TnI degradation and that TnI alterations could be prevented by glucocorticoid treatment. Piglets were cooled to 18°C, subjected to 2 h of circulatory arrest, rewarmed to 37°C, and allowed to recover for 2 h. Methylprednisolone was administered 6 h before surgery (3 0 mg/kg) and at initiation of CPB (30 mg/kg). The untreated group received saline. Left ventricular tissue was collected after recovery and analyzed by Western blot for TnI, calpain, and calpastatin (the natural inhibitor of calpain). CPB/ DHCA animals had 27.4 Ϯ 0.2% of total detected TnI present in degraded form. Glucocorticoid treatment significantly decreased the percentage of degraded TnI (12.0 Ϯ 0.1%, p Ͻ 0.05). Calpain I and calpain II increased after CPB/DHCA compared with non-CPB/DHCA controls (p Ͻ 0.05), with or without glucocorticoid treatment. Calpastatin significantly decreased in untreated CPB/DHCA animals compared with non-CPB/DHCA controls (p Ͻ 0.05), but levels were preserved by glucocorticoids. Glucocorticoids were associated with preservation of maximum rate of increase of left ventricular pressure at 95 Ϯ 10% of baseline, whereas maximum rate of increase of left ventricular pressure decreased to 62 Ϯ 12% of baseline without steroids. TnI degradation occurs after CPB/DHCA in neonatal pigs. Reduction in reperfusion injury by glucocorticoids may depend partly on preservation of calpastatin activity and intact TnI. Surgery for congenital heart disease often requires CPB and periods of myocardial ischemia. A period of total circulatory arrest may also be required, particularly for complex neonatal repairs. In the first 8 to 12 h after CPB there is a transient decrease in myocardial function consistent with reperfusion injury (1). Although the exact mechanisms of CPB-related myocardial injury remain unknown, there is substantial evidence that CPB can produce a systemic inflammatory response or free radical injury (2-4). The cysteine protease calpain exists in the myocardium in two isoforms, calpain I and calpain II. Recently, it has been suggested that activation of calpain during reperfusion of ischemic myocardium may be a key event in the process of myocardial stunning (5, 6). Calcium influx that occurs when ischemic myocardium is reperfused promotes dissociation of calpain from its inhibitor, calpastatin. Activated calpain then degrades the contractile regulatory protein TnI by cleavage at the C-terminus to form the fragment . Additional systematic degradation of the amino terminus can lead to subsequent smaller degradation products. Degradation products and covalent complexes of TnI have been observed in humans with ischemic heart disease (7,8).The use of glucocorticoids ...

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“…During the compensated stage of cardiac remodeling both sarcolemmal L-type Ca 2+ channel density and I Ca,L are unchanged; however, in advanced stages of HF, these parameters are reduced to some extent in infarcted hearts (47). The SR is the major source of the activator Ca 2+ for contraction.…”

Section: Molecular Substrate For Contractile Dysfunctionmentioning

confidence: 99%

Remodeling in the ischemic heart: the stepwise progression for heart

Mill¹,

Stefanon

Santos

et al. 2011

Braz J Med Biol Res

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Coronary artery disease is the leading cause of death in the developed world and in developing countries. Acute mortality from acute myocardial infarction (MI) has decreased in the last decades. However, the incidence of heart failure (HF) in patients with healed infarcted areas is increasing. Therefore, HF prevention is a major challenge to the health system in order to reduce healthcare costs and to provide a better quality of life. Animal models of ischemia and infarction have been essential in providing precise information regarding cardiac remodeling. Several of these changes are maladaptive, and they progressively lead to ventricular dilatation and predispose to the development of arrhythmias, HF and death. These events depend on cell death due to necrosis and apoptosis and on activation of the inflammatory response soon after MI. Systemic and local neurohumoral activation has also been associated with maladaptive cardiac remodeling, predisposing to HF. In this review, we provide a timely description of the cardiovascular alterations that occur after MI at the cellular, neurohumoral and electrical level and discuss the repercussions of these alterations on electrical, mechanical and structural dysfunction of the heart. We also identify several areas where insufficient knowledge limits the adoption of better strategies to prevent HF development in chronically infarcted individuals.

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A Novel Mechanism for Myocardial Stunning Involving Impaired Ca ²⁺ Handling

Cited by 90 publications

References 39 publications

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange

Glucocorticoids Preserve Calpastatin and Troponin I during Cardiopulmonary Bypass in Immature Pigs

Remodeling in the ischemic heart: the stepwise progression for heart

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A Novel Mechanism for Myocardial Stunning Involving Impaired Ca 2+ Handling

Cited by 90 publications

References 39 publications

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na + -Ca 2+ Exchange

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na + -Ca 2+ Exchange

Glucocorticoids Preserve Calpastatin and Troponin I during Cardiopulmonary Bypass in Immature Pigs

Remodeling in the ischemic heart: the stepwise progression for heart

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Product

Resources

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A Novel Mechanism for Myocardial Stunning Involving Impaired Ca ²⁺ Handling

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange