title: In Vivo Post-Cardiac Arrest Myocardial Dysfunction Is Supported by Ca2+/Calmodulin-Dependent Protein Kinase II-Mediated Calcium Long-Term Potentiation and Mitigated by Alda-1, an Agonist of Aldehyde Dehydrogenase Type 2.
abstract: Survival after sudden cardiac arrest is limited by postarrest myocardial dysfunction, but understanding of this phenomenon is constrained by a 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.
  
  
  
  We developed rodent models of in vivo postarrest myocardial dysfunction using extracorporeal membrane oxygenation resuscitation followed by invasive hemodynamics measurement. In postarrest isolated cardiomyocytes, we assessed mechanical load and Ca(2) (+)-induced Ca(2+) release (CICR) simultaneously using the microcarbon fiber technique and observed reduced function and myofilament calcium sensitivity. We used a novel fiberoptic catheter imaging system and a genetically encoded calcium sensor, GCaMP6f, to image CICR in vivo.
  
  
  
  We found potentiation of CICR in isolated cells from this extracorporeal membrane oxygenation model and 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 after arrest was mediated by the activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Increased phosphorylation of CaMKII, phospholamban, and ryanodine receptor 2 was detected in the postarrest period. Exogenous adrenergic activation in vivo recapitulated Ca(2+) potentiation but was associated with lesser CaMKII activation. Because oxidative stress and aldehydic adduct formation were high after 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 postarrest outcome in vivo.
  
  
  
  Cardiac arrest and reperfusion lead to CaMKII activation and calcium long-term potentiation, which support cardiomyocyte contractility in the face of impaired postarrest myofilament calcium sensitivity. Alda-1 mitigates these effects, normalizes calcium cycling, and improves outcome.
authors: Division of Cardiology, Arrhythmia Section, Palo Alto Medical Foundation, Burlingame, CA.
authors: Christopher
authors: C
authors: Woods
authors: Division of Cardiovascular Medicine, Stanford University, Stanford, CA.
authors: Ching
authors: C
authors: Shang
authors: Department of Cardiothoracic Surgery, Papworth Hospital, Cambridge, UK.
authors: Fouad
authors: F
authors: Taghavi
authors: Division of Cardiology, Columbia University, New York, NY.
authors: Peter
authors: P
authors: Downey
authors: Division of Cardiology, Columbia University, New York, NY.
authors: Adrian
authors: A
authors: Zalewski
authors: Division of Cardiovascular Medicine, Stanford University, Stanford, CA.
authors: Gabriel R
authors: GR
authors: Rubio
authors: Division of Cardiovascular Medicine, Stanford University, Stanford, CA.
authors: Jing
authors: J
authors: Liu
authors: Division of Cardiovascular Medicine, Stanford University, Stanford, CA.
authors: Julian R
authors: JR
authors: Homburger
authors: Division of Cardiovascular Medicine, Stanford University, Stanford, CA.
authors: Zachary
authors: Z
authors: Grunwald
authors: Division of Cardiology, Columbia University, New York, NY.
authors: Wei
authors: W
authors: Qi
authors: Qatar Institute of Cardiovascular Center, London, UK.
authors: Christian
authors: C
authors: Bollensdorff
authors: Division of Cardiovascular Medicine, Stanford University, Stanford, CA.
authors: Porama
authors: P
authors: Thanaporn
authors: Department of Cardiothoracic Surgery, Papworth Hospital, Cambridge, UK.
authors: Ayyaz
authors: A
authors: Ali
authors: Department of Cardiothoracic Surgery, Stanford University, London, UK.
authors: Kirk
authors: K
authors: Riemer
authors: National Heart and Lung Institute, Imperial College, London, UK.
authors: Peter
authors: P
authors: Kohl
authors: Department of Chemical and Systems Biology, Stanford University, CA.
authors: Daria
authors: D
authors: Mochly-Rosen
authors: Division of Cardiology, UCSF School of Medicine, San Francisco, CA.
authors: Edward
authors: E
authors: Gerstenfeld
authors: Department of Cardiothoracic Surgery, Papworth Hospital, Cambridge, UK.
authors: Stephen
authors: S
authors: Large
authors: Division of Cardiology, Columbia University, New York, NY.
authors: Ziad
authors: Z
authors: Ali
authors: Division of Cardiovascular Medicine, Stanford University, Stanford, CA.
authors: Euan
authors: E
authors: Ashley
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D009202:Cardiomyopathies / Q000188:drug therapy / Q000378:metabolism; D006323:Heart Arrest / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D001549:Benzamides; D052117:Benzodioxoles; D002135:Calcium-Binding Proteins; C531525:N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; D000444:Aldehyde Dehydrogenase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: calcium-calmodulin-dependent protein kinase type 2; extracorporeal membrane oxygenation; heart arrest; oxidative stress