Abstract
RationaleDeterioration of ventricular fibrillation (VF) into asystole or severe bradycardia (electrical failure) heralds a fatal outcome of cardiac arrest. The role of metabolism in the timing of electrical failure remains unknown.ObjectiveTo determine metabolic factors of early electrical failure in an Ex-vivo canine model of cardiac arrest (VF+global ischemia).Methods and ResultsMetabolomic screening was performed in left ventricular biopsies collected before and after 0.3, 2, 5, 10 and 20 min of VF and global ischemia. Electrical activity was monitored via plunge needle electrodes and pseudo-ECG. Four out of nine hearts exhibited electrical failure at 10.1±0.9 min (early-asys), while 5/9 hearts maintained VF for at least 19.7 min (late-asys). As compared to late-asys, early-asys hearts had more ADP, less phosphocreatine, and higher levels of lactate at some time points during VF/ischemia (all comparisons p<0.05). Pre-ischemic samples from late-asys hearts contained ∼25 times more inorganic pyrophosphate (PPi) than early-asys hearts. A mechanistic role of PPi in cardioprotection was then tested by monitoring mitochondrial membrane potential (ΔΨ) during 20 min of simulated-demand ischemia using potentiometric probe TMRM in rabbit adult ventricular myocytes incubated with PPi versus control group. Untreated myocytes experienced significant loss of ΔΨ while in the PPi-treated myocytes ΔΨ was relatively maintained throughout 20 min of simulated-demand ischemia as compared to control (p<0.05).ConclusionsHigh tissue level of PPi may prevent ΔΨm loss and electrical failure at the early phase of ischemic stress. The link between the two protective effects may involve decreased rates of mitochondrial ATP hydrolysis and lactate accumulation.
Highlights
In the setting of out-of-hospital sudden cardiac arrest (OHSCA), asystole is ‘‘non-shockable’’ rhythm associated with a very poor survival to hospital discharge [1]
We propose a mechanism whereby the contribution of PPi in the common pool of high-energy phosphates prevents excessive stimulation of anaerobic glycolysis, lactate accumulation, and early electrical failure during long-duration VF (LDVF)
After that VF rate (VFR) rapidly decreased in control-early-asys reaching 1.460.9 Hz at 5 min and approaching zero at 10 min (0.2460.19 Hz)
Summary
In the setting of out-of-hospital sudden cardiac arrest (OHSCA), asystole is ‘‘non-shockable’’ rhythm associated with a very poor survival to hospital discharge [1]. While the rhythm preceding asystole in the setting of OHSCA usually cannot be determined, it is likely that VF is the predominant cause of hemodynamic failure in the majority of sudden cardiac deaths [3]. Blockade of the ATP-sensitive K+ current (IK-ATP) fully prevented asystole within this time frame [4], suggesting that activation of IK-ATP is an important factor in the ultimate electrical failure of the heart. We hypothesized that the apparently random nature of asystole in our model of LDVF may be determined by inter-subject differences in metabolic factors upstream of IK-ATP activation
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