Preclinical Evaluation of Triiodothyronine Nanoparticles As a Novel Therapeutic Intervention for Resuscitation from Cardiac Arrest

Overview

Journal Resuscitation

Specialty Emergency Medicine

Date 2023 Feb 22

PMID 36806653

Authors

Brian R Weil

Shannon E Allen

Thomas Barbaccia

Kimberly Wong

Abigail M Beaver

Elizabeth A Slabinski

Jeffrey G Mellott

Peter C Taylor Dickinson

Shaker A Mousa

Affiliations

Soon will be listed here.

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.

References

Liu Y, Yeh C, Lin K . Molecular Functions of Thyroid Hormone Signaling in Regulation of Cancer Progression and Anti-Apoptosis. Int J Mol Sci. 2019; 20(20). PMC: 6834155. DOI: 10.3390/ijms20204986. View

Davis P, Leonard J, Lin H, Leinung M, Mousa S . Molecular Basis of Nongenomic Actions of Thyroid Hormone. Vitam Horm. 2018; 106:67-96. DOI: 10.1016/bs.vh.2017.06.001. View

Ristagno G, Sun S, Tang W, Castillo C, Weil M . Effects of epinephrine and vasopressin on cerebral microcirculatory flows during and after cardiopulmonary resuscitation. Crit Care Med. 2007; 35(9):2145-9. DOI: 10.1097/01.ccm.0000280427.76175.d2. View

Lin H, Davis F, Luidens M, Mousa S, Cao J, Zhou M . Molecular basis for certain neuroprotective effects of thyroid hormone. Front Mol Neurosci. 2011; 4:29. PMC: 3193027. DOI: 10.3389/fnmol.2011.00029. View

Becker L, Aufderheide T, Graham R . Strategies to Improve Survival From Cardiac Arrest: A Report From the Institute of Medicine. JAMA. 2015; 314(3):223-4. DOI: 10.1001/jama.2015.8454. View

Rea T, Kudenchuk P, Sayre M, Doll A, Eisenberg M . Out of hospital cardiac arrest: Past, present, and future. Resuscitation. 2021; 165:101-109. DOI: 10.1016/j.resuscitation.2021.06.010. View

Zwemer C, Whitesall S, Nachreiner R, Mayor G, DAlecy L . 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(3):271-80. DOI: 10.1016/s0300-9572(96)01040-4. View

Wortsman J, Premachandra B, Chopra I, Murphy J . Hypothyroxinemia in cardiac arrest. Arch Intern Med. 1987; 147(2):245-8. View

Davis P, Ashur-Fabian O, Incerpi S, Mousa S . Editorial: Non Genomic Actions of Thyroid Hormones in Cancer. Front Endocrinol (Lausanne). 2019; 10:847. PMC: 6905132. DOI: 10.3389/fendo.2019.00847. View

10.

Whitesall S, Mayor G, Nachreiner R, Zwemer C, DAlecy L . Acute administration of T3 or rT3 failed to improve outcome following resuscitation from cardiac arrest in dogs. Resuscitation. 1996; 33(1):53-62. DOI: 10.1016/s0300-9572(96)00985-9. View

11.

Navab E, Esmaeili M, Poorkhorshidi N, Salimi R, Khazaei A, Moghimbeigi A . Predictors of Out of Hospital Cardiac Arrest Outcomes in Pre-Hospital Settings; a Retrospective Cross-sectional Study. Arch Acad Emerg Med. 2019; 7(1):36. PMC: 6732204. View

12.

McCarthy J, Carr B, Sasson C, Bobrow B, Callaway C, Neumar R . Out-of-Hospital Cardiac Arrest Resuscitation Systems of Care: A Scientific Statement From the American Heart Association. Circulation. 2018; 137(21):e645-e660. DOI: 10.1161/CIR.0000000000000557. View

13.

Jung J, Rice J, Bord S . Rethinking the role of epinephrine in cardiac arrest: the PARAMEDIC2 trial. Ann Transl Med. 2019; 6(Suppl 2):S129. PMC: 6330609. DOI: 10.21037/atm.2018.12.31. View

14.

Davis P, Mousa S, Lin H . Nongenomic Actions of Thyroid Hormone: The Integrin Component. Physiol Rev. 2020; 101(1):319-352. DOI: 10.1152/physrev.00038.2019. View

15.

Gough C, Nolan J . The role of adrenaline in cardiopulmonary resuscitation. Crit Care. 2018; 22(1):139. PMC: 5975505. DOI: 10.1186/s13054-018-2058-1. View

16.

Perkins G, Ji C, Deakin C, Quinn T, Nolan J, Scomparin C . A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2018; 379(8):711-721. DOI: 10.1056/NEJMoa1806842. View

17.

Benjamin E, Muntner P, Alonso A, Bittencourt M, Callaway C, Carson A . Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation. 2019; 139(10):e56-e528. DOI: 10.1161/CIR.0000000000000659. View

18.

Karakus O, Darwish N, Sudha T, Salaheldin T, Fujioka K, Taylor Dickinson P . Development of Triiodothyronine Polymeric Nanoparticles for Targeted Delivery in the Cardioprotection against Ischemic Insult. Biomedicines. 2021; 9(11). PMC: 8615924. DOI: 10.3390/biomedicines9111713. View

19.

Facktor M, Mayor G, Nachreiner R, DAlecy L . Thyroid hormone loss and replacement during resuscitation from cardiac arrest in dogs. Resuscitation. 1993; 26(2):141-62. DOI: 10.1016/0300-9572(93)90174-o. View

20.

Angelos M, Butke R, Panchal A, Torres C, Blumberg A, Schneider J . Cardiovascular response to epinephrine varies with increasing duration of cardiac arrest. Resuscitation. 2008; 77(1):101-10. DOI: 10.1016/j.resuscitation.2007.10.017. View