Uncertainty exists regarding whether cyclophilin D (CypD), a mitochondrial matrix
protein that plays a key role in ischemia-reperfusion injury, can be a pharmacological
target for improving outcomes after cardiac arrest (CA), especially when therapeutic
hypothermia is used. Using CypD knockout mice (CypD−/−), we investigated the effects of loss of CypD on short-term and medium-term outcomes
after CA. CypD−/− mice or their wild-type (WT) littermates underwent either 5 minute CA followed by
resuscitation with and/or without hypothermia at 33°C–34°C (targeted temperature reached
within minutes after resuscitation), or a sham procedure. Brain and cardiac injury
were assessed using echocardiography, neurological scores, MRI and biomarkers. Seven
day survival was compared using Kaplan-Meier estimates. The rate of restoration of
spontaneous circulation was significantly higher in CypD−/− mice (with shorter cardiac massage duration) than in WT mice (P < 0.05). Loss of CypD significantly attenuated CA-induced release of troponin and
S100ß protein, and limited myocardial dysfunction at 150 minutes after CA. Loss of
CypD combined with hypothermia led to the best neurological and MRI scores at 24 hours
and highest survival rates at 7 days compared to other groups (P < 0.05). In animals successfully resuscitated, loss of CypD had no benefits on day
7 survival while hypothermia was highly protective. Pharmacological inhibition of
CypD with cyclosporine A combined with hypothermia provided similar day 7 survival
than loss of CypD combined with hypothermia. CypD is a viable target to improve success
of cardiopulmonary resuscitation but its inhibition is unlikely to improve long-term
outcomes, unless therapeutic hypothermia is associated.
Abbreviations:
ADC (Apparent diffusion coefficient), CI (Confidence intervals), CPR (Cardio-pulmonary resuscitation), CsA (Cyclosporine A), CypD (Cyclophilin D), DWI (Diffusion-weighted images), EtCO2 (End-tidal carbon dioxide concentration), FiO2 (Inspired fraction of oxygen), HR (Hazard ratio), LV (Left ventricle), MRI (Brain magnetic resonance imaging), PTP (Permeability transition pore), ROSC (Restoration of spontaneous circulation), SSF (Surface shortening fraction), WT (Wild-type)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Translational ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Variation in survival after out-of-hospital cardiac arrest Between emergency medical services agencies.JAMA Cardiol. 2018; 3: 989-999https://doi.org/10.1001/jamacardio.2018.3037
- Post–cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council.Circulation. 2008; 118: 2452-2483https://doi.org/10.1161/CIRCULATIONAHA.108.190652
- Pharmacological approach for neuroprotection after cardiac arrest - a narrative review of current therapies and future neuroprotective cocktail.Front Med. 2021; 8636651https://doi.org/10.3389/fmed.2021.636651
- Part 3: Adult basic and advanced life support: 2020 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care.Circulation. 2020; 142: S366-S368https://doi.org/10.1161/CIR.0000000000000916
- Targeting the mitochondrial permeability transition pore for neuroprotection in a piglet model of neonatal hypoxic-ischemic encephalopathy.J Neurosci Res. 2021; 99: 1550-1564https://doi.org/10.1002/jnr.24821
- Ubiquitous protective effects of cyclosporine A in preventing cardiac arrest-induced multiple organ failure.J Appl Physiol. 2014; 117: 930-936https://doi.org/10.1152/japplphysiol.00495.2014
- Postconditioning: from the bench to bedside.J Cardiovasc Pharmacol Ther. 2011; 16: 117-130https://doi.org/10.1177/1074248410383174
- Inhibition of mitochondrial permeability transition to prevent the post-cardiac arrest syndrome: a pre-clinical study.Eur Heart J. 2011; 32: 226-235https://doi.org/10.1093/eurheartj/ehq112
- Post-cardiac arrest myocardial dysfunction is improved with cyclosporine treatment at onset of resuscitation but not in the reperfusion phase.Resuscitation. 2011; 82: S41-S47https://doi.org/10.1016/s0300-9572(11)70150-2
- Therapeutic hypothermia after cardiac arrest: involvement of the RISK pathway in mitochondrial PTP-mediated neuroprotection.Shock. 2019; 52: 224-229https://doi.org/10.1097/SHK.0000000000001234
- Fast therapeutic hypothermia prevents post-cardiac arrest syndrome through cyclophilin D-mediated mitochondrial permeability transition inhibition.Basic Res Cardiol. 2017; 112: 35https://doi.org/10.1007/s00395-017-0624-3
- Evaluation of cyclosporine A as a cardio- and neuroprotective agent after cardiopulmonary resuscitation in a rat model.Shock. 2015; 43: 576-581https://doi.org/10.1097/shk.0000000000000357
- Brain and myocardial mitochondria follow different patterns of dysfunction after cardiac arrest.Shock. 2021; 56: 857-864https://doi.org/10.1097/SHK.0000000000001793
- Effect of cyclosporine in non-shockable out-of-hospital cardiac arrest: The CYRUS randomized clinical trial.JAMA Cardiol. 2016; 1: 557-565https://doi.org/10.1001/jamacardio.2016.1701
- Cyclosporine A prevents ischemia-reperfusion-induced lymphopenia after out-of-hospital cardiac arrest: a predefined sub-study of the CYRUS trial.Resuscitation. 2019; 138: 129-131https://doi.org/10.1016/j.resuscitation.2019.02.048
- Cyclosporine A prevents cardiac arrest-induced acute respiratory failure: a post-hoc analysis of the CYRUS trial.Intensive Care Med. 2020; 46: 1281-1283https://doi.org/10.1007/s00134-020-06043-0
- Cyclosporine A: a valid candidate to treat COVID-19 patients with acute respiratory failure?.Crit Care. 2020; 24: 276https://doi.org/10.1186/s13054-020-03014-1
- Cyclosporin A and cardioprotection: from investigative tool to therapeutic agent.Br J Pharmacol. 2012; 165: 1235-1245https://doi.org/10.1111/j.1476-5381.2011.01700.x
- Pharmacology of mitochondrial permeability transition pore inhibitors.Drug Dev Res. 2019; 80: 1013-1030https://doi.org/10.1002/ddr.21593
- Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia.Proc Natl Acad Sci USA. 2005; 102: 12005-12010https://doi.org/10.1073/pnas.0505294102
- Mitochondrial permeability transition in cardiac ischemia–reperfusion: whether cyclophilin D is a viable target for cardioprotection?.Cell Mol Life Sci. 2017; 74: 2795-2813https://doi.org/10.1007/s00018-017-2502-4
- Nanoliposome containing cyclosporine A reduced neuroinflammation responses and improved neurological activities in cerebral ischemia/reperfusion in rat.Fundam Clin Pharmacol. 2017; 31: 185-193https://doi.org/10.1111/fcp.12244
- Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research.PLoS Biol. 2010; 8e1000412https://doi.org/10.1371/journal.pbio.1000412
- Endoplasmic reticulum stress contributes to heart protection induced by cyclophilin D inhibition.Basic Res Cardiol. 2013; 108: 363https://doi.org/10.1007/s00395-013-0363-z
- Involvement of cyclophilin D and calcium in isoflurane-induced preconditioning.Anesthesiology. 2015; 123: 1374-1384https://doi.org/10.1097/aln.0000000000000876
- Dose and timing of injections for effective cyclosporine A pretreatment before renal ischemia reperfusion in mice.PLoS One. 2017; 12e0182358https://doi.org/10.1371/journal.pone.0182358
- Intra-Arrest cooling improves outcomes in a murine cardiac arrest model.Circulation. 2004; 109: 2786-2791https://doi.org/10.1161/01.cir.0000131940.19833.85
- In vivo MRI assessment of permanent middle cerebral artery occlusion by electrocoagulation: pitfalls of procedure.Exp Transl Stroke Med. 2010; 2: 4https://doi.org/10.1186/2040-7378-2-4
- Evaluation of cyclosporine A in a stroke model in the immature rat brain.Exp Neurol. 2011; 230: 58-66https://doi.org/10.1016/j.expneurol.2010.06.009
- Development and evaluation of a novel mouse model of asphyxial cardiac arrest revealed severely impaired lymphopoiesis after resuscitation.J Am Heart Assoc. 2021; 10e019142https://doi.org/10.1161/JAHA.120.019142
- Ultrafast and whole-body cooling with total liquid ventilation induces favorable neurological and cardiac outcomes after cardiac arrest in rabbits.Circulation. 2011; 124: 901-911https://doi.org/10.1161/CIRCULATIONAHA.111.039388
- Cooling Uncouples differentially ROS production from respiration and Ca2+ homeostasis dynamic in brain and heart mitochondria.Cells. 2022; 11: 989https://doi.org/10.3390/cells11060989
- Minor changes in core temperature prior to cardiac arrest influence outcomes: an experimental study.J Cardiovasc Pharmacol Ther. 2015; 20: 407-413https://doi.org/10.1177/1074248414562911
- Cyclosporine for reperfusion injury after cardiac arrest: too little too Late?.JAMA Cardiol. 2016; 1: 566-567https://doi.org/10.1001/jamacardio.2016.1822
- Molar sodium lactate attenuates the severity of postcardiac arrest syndrome: a preclinical study.Crit Care Med. 2021; 50: e719https://doi.org/10.1097/CCM.0000000000005233
- Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest.N Engl J Med. 2021; 384: 2283-2294https://doi.org/10.1056/NEJMoa2100591
Article info
Publication history
Published online: June 08, 2022
Accepted:
June 3,
2022
Received in revised form:
May 31,
2022
Received:
April 14,
2022
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
