Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Keywords
Abbreviations:
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)To read this article in full you will need to make a payment
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References
- Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association.Circulation. 2019; 139: e56-e528
- Strategies to Improve Survival From Cardiac Arrest: A Report From the Institute of Medicine.JAMA. 2015; 314: 223-224
- Out of hospital cardiac arrest: Past, present, and future.Resuscitation. 2021; 165: 101-109
- Rethinking the role of epinephrine in cardiac arrest: the PARAMEDIC2 trial.Ann Transl Med. 2018; 6: S129-S
- The role of adrenaline in cardiopulmonary resuscitation.Critical Care. 2018; 22: 139
- A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.N Engl J Med. 2018; 379: 711-721
- Predictors of Out of Hospital Cardiac Arrest Outcomes in Pre-Hospital Settings; a Retrospective Cross-sectional Study.Arch Acad Emerg Med. 2019; 7: 36
- Out-of-Hospital Cardiac Arrest Resuscitation Systems of Care: A Scientific Statement From the American Heart Association.Circulation. 2018; 137: e645-e660
- How thyroid hormone works depends upon cell type, receptor type, and hormone analogue: implications in cancer growth.Discov Med. 2019; 27: 111-117
- Editorial: Non Genomic Actions of Thyroid Hormones in Cancer.Frontiers in endocrinology. 2019; 10: 847
- Molecular aspects of thyroid hormone actions.Endocr Rev. 2010; 31: 139-170
- Molecular Basis of Nongenomic Actions of Thyroid Hormone.Vitam Horm. 2018; 106: 67-96
- Nongenomic actions of thyroid hormone on the heart.Thyroid: Official J Am Thyroid Assoc. 2002; 12: 459-466
- Molecular functions of thyroid hormone signaling in regulation of cancer progression and anti-apoptosis.Int J Mol Sci. 2019; 20: 4986
- Tetraiodothyroacetic acid-conjugated PLGA nanoparticles: a nanomedicine approach to treat drug-resistant breast cancer.Nanomedicine (Lond). 2013; 8: 1943-1954
- Development of Triiodothyronine Polymeric Nanoparticles for Targeted Delivery in the Cardioprotection against Ischemic Insult.Biomedicines. 2021; : 9
- Abstract 133: Cardiovascular Protective Effect of Thyroxine and Nano- Thyroxine Against Ischemic Insults.Circulation. 2019; 140: A133
- Effects of epinephrine and vasopressin on cerebral microcirculatory flows during and after cardiopulmonary resuscitation.Crit Care Med. 2007; 35: 2145-2149
- Cardiovascular response to epinephrine varies with increasing duration of cardiac arrest.Resuscitation. 2008; 77: 101-110
- Hypothyroxinemia in cardiac arrest.Arch Intern Med. 1987; 147: 245-248
- Thyroid hormone loss and replacement during resuscitation from cardiac arrest in dogs.Resuscitation. 1993; 26: 141-162
- Acute administration of T3 or rT3 failed to improve outcome following resuscitation from cardiac arrest in dogs.Resuscitation. 1996; 33: 53-62
- Acute thyroid hormone administration increases systemic oxygen delivery and consumption immediately following resuscitation from cardiac arrest without changes in thyroid-stimulating hormone.Resuscitation. 1997; 33: 271-280
- Nongenomic Actions of Thyroid Hormone: The Integrin Component.Physiol Rev. 2021; 101: 319-352
- Molecular basis for certain neuroprotective effects of thyroid hormone.Front Mol Neurosci. 2011; 4: 29
Article info
Publication history
Published online: February 15, 2023
Accepted:
February 8,
2023
Received in revised form:
February 6,
2023
Received:
October 11,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Elsevier B.V. All rights reserved.
