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In vivo post-cardiac arrest myocardial dysfunction is supported by camkii-mediated calcium long-term potentiation and mitigated by Alda-1, an agonist of aldehyde dehydrogenase type 2
- Publication Year :
- 2016
- Publisher :
- American Heart Association, 2016.
-
Abstract
- BACKGROUND: -Survival after sudden cardiac arrest is limited by post-arrest myocardial dysfunction but understanding of this phenomenon is constrained by lack of data from a physiological model of disease. In this study, we established an in vivo model of cardiac arrest and resuscitation, characterized the biology of the associated myocardial dysfunction, and tested novel therapeutic strategies. METHODS: -We developed rodent models of in vivo post-arrest myocardial dysfunction using extra-corporeal membrane oxygenation (ECMO) resuscitation followed by invasive hemodynamics measurement. In post-arrest isolated cardiomyocytes, we assessed mechanical load and Ca(2+) induced Ca(2+) release (CICR) simultaneously using the micro-carbon-fiber technique and observed reduced function and myofilament calcium sensitivity. We used a novel-designed fiber optic catheter imaging system, and a genetically encoded calcium sensor GCaMP6f, to image CICR in vivo RESULTS: -We found potentiation of CICR in isolated cells from this ECMO model and also in cells isolated from an ischemia-reperfusion Langendorff model perfused with oxygenated blood from an arrested animal, but not when reperfused in saline. We established that CICR potentiation begins in vivo The augmented CICR observed post-arrest was mediated by the activation of Ca(2+)/calmodulin kinase II (CaMKII). Increased phosphorylation of CaMKII, phospholamban and ryanodine receptor 2 (RyR2) was detected in the post-arrest period. Exogenous adrenergic activation in vivo recapitulated Ca(2+) potentiation but was associated with lesser CaMKII activation. Since oxidative stress and aldehydic adduct formation were high post arrest, we tested a small molecule activator of aldehyde dehydrogenase type 2, Alda-1, which reduced oxidative stress, restored calcium and CaMKII homeostasis, and improved cardiac function and post-arrest outcome in vivo CONCLUSIONS: -Cardiac arrest and reperfusion lead to CaMKII activation and calcium long-term potentiation which support cardiomyocyte contractility in the face of impaired post-ischemic myofilament calcium sensitivity. Alda-1 mitigates these effects, normalizes calcium cycling and improves outcome.
- Subjects :
- CAMKII
Science & Technology
Cardiac & Cardiovascular Systems
PHOSPHOLAMBAN PHOSPHORYLATION
ELECTRICAL STORM
1103 Clinical Sciences
calcium-calmodulin-dependent protein kinase type 2
extracorporeal membrane oxygenation
ISCHEMIA/REPERFUSION INJURY
SARCOPLASMIC-RETICULUM
1102 Cardiovascular Medicine And Haematology
INHIBITION PROTECTS
CA2+
Peripheral Vascular Disease
Cardiovascular System & Hematology
1117 Public Health And Health Services
AMERICAN-HEART-ASSOCIATION
PRESSURE-OVERLOAD
cardiovascular system
Cardiovascular System & Cardiology
oxidative stress
SIGNALING PATHWAY
Life Sciences & Biomedicine
heart arrest
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.od......1032..9795d1effc86c75e7dacb7548276c1d2