Experimental paper|Articles in Press, 109735

Preclinical evaluation of triiodothyronine nanoparticles as a novel therapeutic intervention for resuscitation from cardiac arrest



      Given emerging evidence of rapid non-genomic cytoprotective effects of triiodothyronine (T3), we evaluated the resuscitative efficacy of two nanoparticle formulations of T3 (T3np) designed to prolong cell membrane receptor-mediated signaling.


      Swine (n = 40) were randomized to intravenous vehicle (empty np), EPI (0.015 mg/kg), T3np (0.125 mg/kg), or T3np loaded with phosphocreatine (T3np + PCr; 0.125 mg/kg) during CPR following 7-min cardiac arrest (n = 10/group). Hemodynamics and biomarkers of heart (cardiac troponin I; cTnI) and brain (neuron-specific enolase; NSE) injury were assessed for up to 4-hours post-ROSC, at which time the heart and brain were collected for post-mortem analysis.


      Compared with vehicle (4/10), the rate of ROSC was higher in swine receiving T3np (10/10; p < 0.01), T3np + PCr (8/10; p = 0.08) or EPI (10/10; p < 0.01) during CPR. Although time to ROSC and survival duration were comparable between groups, EPI was associated with a ∼2-fold higher post-ROSC concentration of cTnI vs T3np and T3np + PCr and the early post-ROSC rise in NSE and neuronal injury were attenuated in T3np-treated vs EPI-treated animals. Analysis of hippocampal ultrastructure revealed deterioration of mitochondrial integrity, reduced active zone length, and increased axonal vacuolization in EPI-treated animals vs controls. However, the frequency of these abnormalities was diminished in animals resuscitated with T3np.


      T3np achieved a ROSC rate and post-ROSC survival that was superior to vehicle and comparable to EPI. The attenuation of selected biomarkers of cardiac and neurologic injury at individual early post-ROSC timepoints in T3np-treated vs EPI-treated animals suggests that T3np administration during CPR may lead to more favorable outcomes in cardiac arrest.



      ANOVA (analysis of variance), CPP (coronary perfusion pressure), CPR (cardiopulmonary resuscitation), cTnI (cardiac troponin I), EPI (epinephrine), LDH (lactate dehydrogenase), LV (left ventricular), NSE (neuron-specific enolase), PCr (phosphocreatine), PEA (pulseless electrical activity), PLGA (polylactic acid-co-glycolic acid), ROSC (return of spontaneous circulation), T3 (triiodothyronine), T3np (triiodothyronine nanoparticles), TEM (transmission electron microscopy), VF (ventricular fibrillation)
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