Metabolic Determinants of Electrical Failure in Ex-Vivo Canine Model of Cardiac Arrest: Evidence for the Protective Role of Inorganic Pyrophosphate

Academic Article

Abstract

  • Rationale: Deterioration 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. Objective: To determine metabolic factors of early electrical failure in an Ex-vivo canine model of cardiac arrest (VF+global ischemia). Methods and Results: Metabolomic 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). Conclusions: High 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. © 2013 Shibayama et al.
  • Authors

    Digital Object Identifier (doi)

    Pubmed Id

  • 25220657
  • Author List

  • Shibayama J; Taylor TG; Venable PW; Rhodes NL; Gil RB; Warren M; Wende AR; Abel ED; Cox J; Spitzer KW
  • Volume

  • 8
  • Issue

  • 3