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BackgroundWe aim to develop a rat model of veno-arterial extracorporeal membrane oxygenation (VA-ECMO).MethodsVA-ECMO was established in twelve Male Sprague-Dawley rats (250-350 g) through cannulation of the right jugular vein for venous drainage and the right femoral artery for arterial reinfusion. Arterial blood pressure was measured using a conductance catheter through cannulation of the left carotid artery. Heart rate was monitored by electrocardiography and arterial blood gas parameters with a blood gas analyzer. The VA-ECMO circuit was tested by subjecting the rats to hypoxic cardiac arrest with resuscitation using VA-ECMO. Both load-dependent and load-independent measures of myocardial contractility were measured using pressure-volume loop analysis to confirm restoration of myocardial function post-resuscitation.ResultsFollowing hypoxic cardiac arrest VA-ECMO provided sufficient oxygenation to support the circulation. The haemodynamic and blood gas parameters were maintained at transition and during ECMO. All animals were resuscitated, regained cardiac function and were able to be weaned off ECMO post-resuscitation.ConclusionWe have established a safe, high-throughput, economical, functioning rat model of VA-ECMO.

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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.