In Vivo Post–Cardiac Arrest Myocardial Dysfunction Is Supported by Ca ²⁺ /Calmodulin-Dependent Protein Kinase II–Mediated Calcium Long-Term Potentiation and Mitigated by Alda-1, an Agonist of Aldehyde Dehydrogenase Type 2

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 Ca2+ induced Ca2+ 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 Ca2+/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 Ca2+ 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.

Targeting mitochondrial dysfunction and oxidative stress in heart failure: Challenges and opportunities

“…Using an in vitro model of atherosclerosis, Alda-1 was effective in reducing 4-HNE-protein adducts, ER stress and apoptosis in smooth muscle cells [169]. In addition, activation of ALDH2 by Alda-1 reduced ROS and reactive aldehydes levels, mitigated calcium overload and dramatically improved resuscitation survival in an in vivo model of post-myocardial arrest dysfunction [170]. These studies established a critical connection between ALDH2 activity, cardiac function and heart failure.…”

Phenotyping Cardiac Arrest: Bench and Bedside Characterization of Brain and Heart Injury Based on Etiology

“…(37) The hypothesis that VF increased cardiac injury explaining these adverse effects is intriguing though speculative. Myocardial dysfunction after CA has been attributed to calcium overload,(38) which parallels classic findings in myocardial infarction. (39) This mechanism may explain why Vaagenes found that lidoflazine therapy, a calcium antagonist, improved outcomes after VF-CA but not A-CA and free radical scavengers improved outcomes after A-CA not VF-CA.…”

Microarray Analysis of Differentially Expressed Profiles of Circular RNAs in a Mouse Model of Intestinal Ischemia/Reperfusion Injury with and Without Ischemic Postconditioning

“…However, some mRNAs that acted as the linear alternative transcript of those circRNAs were found to participate in various cellular processes associated with I/R injury. For instance, Calm3 is the linear transcript of circRNA_41204 (one of the top 5 decreased circRNAs in intestinal I/R) and it encodes calmodulin (CaM), a ubiquitous Ca 2+ -binding protein that regulates a vast array of Ca 2+ -sensitive biological events, which play important roles in the pathogenesis of I/R injury [28,29]. Wdfy1 is the linear transcript of circRNA_18944 (one of the top 5 decreased circRNAs in iPoC), and its protein product was found to recruit the signaling adaptor protein TRIF to Toll-like receptors (TLRs) 3 and 4, thereby mediating the activation of NF-κB and induction of inflammatory cytokines [30].…”