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
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Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2016-08-31
Online Publication Date
2016-08-31
2017-03-17T10:31:41Z
Date Acceptance
2016-07-21
ISSN
0009-7322
Publisher
American Heart Association
Start Page
961
End Page
977
Journal / Book Title
Circulation
Volume
134
Copyright Statement
© 2016 American Heart Association, Inc.
Source Database
web-of-science
Sponsor
Commission of the European Communities
British Heart Foundation
Grant Number
323099
FS/12/17/29532
Subjects
Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Peripheral Vascular Disease
Cardiovascular System & Cardiology
calcium-calmodulin-dependent protein kinase type 2
extracorporeal membrane oxygenation
heart arrest
oxidative stress
AMERICAN-HEART-ASSOCIATION
ISCHEMIA/REPERFUSION INJURY
PHOSPHOLAMBAN PHOSPHORYLATION
SARCOPLASMIC-RETICULUM
INHIBITION PROTECTS
PRESSURE-OVERLOAD
SIGNALING PATHWAY
ELECTRICAL STORM
CAMKII
CA2+
Cardiovascular System & Hematology
1103 Clinical Sciences
1102 Cardiovascular Medicine And Haematology
1117 Public Health And Health Services
Publication Status
Published