Suppression of Superoxide-Hydrogen Peroxide Production at Site IQ of Mitochondrial Complex I Attenuates Myocardial Stunning and Improves Postcardiac Arrest Outcomes
| Autor: | Yong-Hu Fang, Stephen L. Archer, Gökhan M. Mutlu, Lin Piao, Robert B. Hamanaka, Willard W. Sharp, Cameron Dezfulian |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_specialty
Resuscitation medicine.medical_treatment Critical Care and Intensive Care Medicine cardiopulmonary resuscitation Mice Random Allocation 03 medical and health sciences Online Laboratory Investigations 0302 clinical medicine Superoxides Internal medicine Animals Medicine Cardiopulmonary resuscitation reactive oxygen species Myocardial Stunning chemistry.chemical_classification Reactive oxygen species Myocardial stunning Electron Transport Complex I business.industry Cardiogenic shock 030208 emergency & critical care medicine Sudden cardiac arrest Hydrogen Peroxide medicine.disease oxygen consumption Heart Arrest Mitochondria 3. Good health Mice Inbred C57BL 030228 respiratory system chemistry Mitochondrial permeability transition pore Shock (circulatory) ComputingMethodologies_DOCUMENTANDTEXTPROCESSING Cardiology Female medicine.symptom business metabolism |
| Zdroj: | Critical Care Medicine |
| ISSN: | 0090-3493 |
| Popis: | Supplemental Digital Content is available in the text. Objectives: Cardiogenic shock following cardiopulmonary resuscitation for sudden cardiac arrest is common, occurring even in the absence of acute coronary artery occlusion, and contributes to high rates of postcardiopulmonary resuscitation mortality. The pathophysiology of this shock is unclear, and effective therapies for improving clinical outcomes are lacking. Design: Laboratory investigation. Setting: University laboratory. Subjects: C57BL/6 adult female mice. Interventions: Anesthetized and ventilated adult female C57BL/6 wild-type mice underwent a 4, 8, 12, or 16-minute potassium chloride-induced cardiac arrest followed by 90 seconds of cardiopulmonary resuscitation. Mice were then blindly randomized to a single IV injection of vehicle (phosphate-buffered saline) or suppressor of site IQ electron leak, an inhibitor of superoxide production by complex I of the mitochondrial electron transport chain. Suppressor of site IQ electron leak and vehicle were administered during cardiopulmonary resuscitation. Measurements and Main Results: Using a murine model of asystolic cardiac arrest, we discovered that duration of cardiac arrest prior to cardiopulmonary resuscitation determined postresuscitation success rates, degree of neurologic injury, and severity of myocardial dysfunction. Post-cardiopulmonary resuscitation cardiac dysfunction was not associated with myocardial necrosis, apoptosis, inflammation, or mitochondrial permeability transition pore opening. Furthermore, left ventricular function recovered within 72 hours of cardiopulmonary resuscitation, indicative of myocardial stunning. Postcardiopulmonary resuscitation, the myocardium exhibited increased reactive oxygen species and evidence of mitochondrial injury, specifically reperfusion-induced reactive oxygen species generation at electron transport chain complex I. Suppressor of site IQ electron leak, which inhibits complex I-dependent reactive oxygen species generation by suppression of site IQ electron leak, decreased myocardial reactive oxygen species generation and improved postcardiopulmonary resuscitation myocardial function, neurologic outcomes, and survival. Conclusions: The severity of cardiogenic shock following asystolic cardiac arrest is dependent on the length of cardiac arrest prior to cardiopulmonary resuscitation and is mediated by myocardial stunning resulting from mitochondrial electron transport chain complex I dysfunction. A novel pharmacologic agent targeting this mechanism, suppressor of site IQ electron leak, represents a potential, practical therapy for improving sudden cardiac arrest resuscitation outcomes. |
| Databáze: | OpenAIRE |
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