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Jaramillo-Torres MJ, Limpert RH, Butak WJ, Cohen KE, Whitaker-Hilbig AA, Durand MJ, Freed JK, SenthilKumar G. Promoting Resiliency to Stress in the Vascular Endothelium. Basic Clin Pharmacol Toxicol 2025; 136:e70001. [PMID: 39936288 DOI: 10.1111/bcpt.70001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/20/2024] [Accepted: 01/14/2025] [Indexed: 02/13/2025]
Abstract
By 2050, roughly 60% of the population will have cardiovascular disease. While a substantial amount of data has been generated over the last few decades that has aided in our understanding of cardiovascular disease pathology, less is known about how to increase resiliency to cardiovascular risk factors that individuals are exposed to on a daily basis. The vascular endothelium is considered the first line of defence against circulating noxious stimuli and, when dysfunctional, is an early risk factor for the development of cardiovascular disease. A vast amount of data has been generated demonstrating how external stress impairs the vascular endothelium; however, there is a paucity of knowledge regarding how to amplify protective pathways and ward off stress and the development of disease, which is the focus of this review. Targeting known protective endothelial pathways may be feasible to increase resiliency to vascular stress. Leveraging stress to boost defence mechanisms within the vascular endothelium is also proposed and may help identify novel therapeutic targets to protect individuals from the stress of everyday life.
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Affiliation(s)
- Maria J Jaramillo-Torres
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Rachel H Limpert
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - William J Butak
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Katie E Cohen
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Alicen A Whitaker-Hilbig
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Department of Physical Medicine and Rehabilitation, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Matthew J Durand
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Department of Physical Medicine and Rehabilitation, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Julie K Freed
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Gopika SenthilKumar
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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Norregaard LB, Rytter N, Christoffersen LC, Gliemann L, Hansen CS, Lawrence M, Evans PA, Kruuse C, Hellsten Y. Ischemic Preconditioning Negatively Affects Thrombogenic Clotting Profile in Cerebral Small Vessel Occlusion Stroke Patients. J Clin Med Res 2025; 17:97-105. [PMID: 39981339 PMCID: PMC11835555 DOI: 10.14740/jocmr6086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 01/13/2025] [Indexed: 02/22/2025] Open
Abstract
Background The study evaluated the effect of an acute and a 2-week daily repetitive ischemic preconditioning (IPC) on conduit artery vascular function and thrombogenic clotting profile, in patients with a recent ischemic stroke. Methods Fourteen patients, aged 71 ± 8 years, with a cerebral small vessel occlusion stroke were included in a randomized, controlled, open-label cross-over study. Treatment consisted of 2 weeks of daily IPC, four 5-min rounds of upper-arm occlusion, interspersed by 5 min rest periods. Control was without treatment. Brachial artery flow-mediated dilation (FMD) was determined at baseline and after the control and treatment periods. Before and after each period, the patients underwent an acute bout of IPC. Blood samples were obtained for thrombogenic clotting profile at baseline and after the acute IPC bout, both before and after the control and treatment periods. Results The period of daily IPC increased brachial artery diameter but did not influence FMD. Acutely, IPC was found to induce an increase in fractal dimension, indicating a denser clot microstructure, and a reduction in plasma levels of plasminogen activator inhibitor 1 (PAI-1). There was no effect of daily IPC on the basal thrombogenic clotting profile, or on the change in clotting profile induced by acute IPC. Conclusions Collectively, the data show that acute IPC leads to a prothrombotic clotting profile, despite antiplatelet therapy. Moreover, 2 weeks of daily treatment with IPC does not influence conduit artery vascular function or thrombogenicity in stroke patients.
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Affiliation(s)
- Line Boel Norregaard
- Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
- These authors contributed equally to the work
| | - Nicolai Rytter
- Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
- These authors contributed equally to the work
| | - Laura Cathrine Christoffersen
- Neurovascular Research Unit, Department of Neurology, Copenhagen University Hospital-Herlev Gentofte, Copenhagen, Denmark
| | - Lasse Gliemann
- Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | | | - Matthew Lawrence
- Welsh Centre for Emergency Medicine Research, Morriston Hospital, SBU Health Board, Swansea, UK
| | - Philip Adrian Evans
- Welsh Centre for Emergency Medicine Research, Morriston Hospital, SBU Health Board, Swansea, UK
- Swansea University Medical School, Swansea, UK
| | - Christina Kruuse
- Neurovascular Research Unit, Department of Neurology, Copenhagen University Hospital-Herlev Gentofte, Copenhagen, Denmark
| | - Ylva Hellsten
- Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
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Robertson NJ, Pang R, Hausenloy DJ. Remote ischaemic post conditioning in NE: A feasible and simple paradigm for self-protection in the brain? Pediatr Res 2025:10.1038/s41390-025-03806-7. [PMID: 39837989 DOI: 10.1038/s41390-025-03806-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 12/12/2024] [Indexed: 01/23/2025]
Affiliation(s)
- Nicola J Robertson
- Institute for Women's Health, University College London, London, UK.
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
| | - Raymand Pang
- Institute for Women's Health, University College London, London, UK
| | - Derek J Hausenloy
- The Hatter Cardiovascular Institute, University College London, London, UK
- National Heart Research Institute Singapore, National Heart Centre, Singapore, Singapore
- Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
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Rachunek-Medved K, Krauß S, Daigeler A, Adams C, Eckert F, Ganser K, Gonzalez-Menendez I, Quintanilla-Martinez L, Kolbenschlag J. Acute remote ischemic conditioning enhances (CD3+)- but not (FoxP3+)-T-cell invasion in the tumor center and increases IL 17 and TNF-alpha expression in a murine melanoma model. Front Immunol 2024; 15:1501885. [PMID: 39650654 PMCID: PMC11621216 DOI: 10.3389/fimmu.2024.1501885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 10/29/2024] [Indexed: 12/11/2024] Open
Abstract
Introduction Hypoxia can drive tumor progression, suppress anti-tumor immunity, and reduce the effectiveness of radiotherapy and chemotherapy. This study aimed to assess the impact of remote ischemic conditioning (RIC) on tumor oxygenation (sO2) and the anti-tumor immune response. Material and methods Fourteen B16-Ova tumor-bearing C57BL/6N mice received six 5-minute RIC cycles, while another fourteen underwent anesthesia only. Pimonidazole was administered 1.5 hours before sacrifice. Blood flow, sO2, and hemoglobin levels were measured in the non-ischemic hind limb and tumor. Tumor hypoxia was assessed using pimonidazole and CA IX immunohistochemistry, and T cell infiltration by CD3 and FoxP3 staining. Serum levels of 23 cytokines were analyzed using a multiplex immunoassay. Results Isoflurane anesthesia caused a slight intraindividual increase in blood flow (p = 0.07) and sO2 (p = 0.06) of the hind limb and a sole increase in tumor sO2 (p = 0.035), whereas RIC improved sO2 of the tumor in relation to the hind limb (p=0.03). The median of the tumor oxygen saturation reached 51.4% in the control group and 62.7% in the RIC group (p = 0.09), exhibiting a slight tendency towards better oxygenation in the RIC group. Pimonidazole (p=0.24) and CA IX hypoxia score (p=0.48) did not reveal statistically significant differences between the two groups. In RIC-treated tumors, the number of CD3 (p=0.006), but not FoxP3- positive cells (p = 0.84), in the tumor core was significantly higher compared to the control group. In the RIC group, the mean fluorescence intensity (MFI) of IL-17 was significantly higher (p=0.035), and TNF-α was trend-wise higher (p=0.063) compared to the control group. Conclusion Both isoflurane anesthesia and RIC have an impact on microcirculation. The application of RIC counteracted some of the effects of isoflurane, primarily in healthy tissue, and led to a significant improvement in relative tumor tissue oxygenation compared to the non-ischemic hind limb. RIC selectively enhanced immune infiltration within the tumor center, probably by previously activated tumor infiltrating T cells, while having no significant impact on T-regulatory cells. RIC appears to impact the cytokine profile, as indicated by elevated MFIs of TNF-α and IL-17.
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Affiliation(s)
- Katarzyna Rachunek-Medved
- Department of Hand, Plastic, Reconstructive and Burn Surgery, BG Trauma Center, Eberhard Karls University of Tuebingen, Tuebingen, Germany
| | - Sabrina Krauß
- Department of Hand, Plastic, Reconstructive and Burn Surgery, BG Trauma Center, Eberhard Karls University of Tuebingen, Tuebingen, Germany
| | - Adrien Daigeler
- Department of Hand, Plastic, Reconstructive and Burn Surgery, BG Trauma Center, Eberhard Karls University of Tuebingen, Tuebingen, Germany
| | - Constantin Adams
- Department of Paediatrics, University Hospital Tuebingen, Tuebingen, Germany
| | - Franziska Eckert
- Department of Radiation Oncology, University of Tuebingen, Tuebingen, Germany
| | - Katrin Ganser
- Department of Radiation Oncology, University of Tuebingen, Tuebingen, Germany
| | - Irene Gonzalez-Menendez
- Institute of Pathology and Neuropathology, Comprehensive Cancer Center, University Hospital Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Tuebingen, Germany
| | - Leticia Quintanilla-Martinez
- Institute of Pathology and Neuropathology, Comprehensive Cancer Center, University Hospital Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Tuebingen, Germany
| | - Jonas Kolbenschlag
- Department of Hand, Plastic, Reconstructive and Burn Surgery, BG Trauma Center, Eberhard Karls University of Tuebingen, Tuebingen, Germany
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Lo E, Cizmeci MN, Wilson D, Ly LG, El-Shahed A, Offringa M, Pierro A, Kalish BT. Remote ischemic post-conditioning for neonatal encephalopathy: a safety and feasibility trial. Pediatr Res 2024:10.1038/s41390-024-03625-2. [PMID: 39396091 DOI: 10.1038/s41390-024-03625-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/10/2024] [Accepted: 09/19/2024] [Indexed: 10/14/2024]
Abstract
BACKGROUND Despite implementation of therapeutic hypothermia (TH) for infants with neonatal encephalopathy (NE), a significant proportion of infants suffer neurodevelopmental impairment (NDI). Remote ischemic conditioning (RIC) is a proposed neuroprotective maneuver that has been studied in adults with brain injury, but it has not been previously investigated in infants with NE. METHODS We performed a prospective, randomized, safety and dose escalation study in 32 neonates with NE. Four cohorts of consecutive patients were randomized to RIC therapy, including four cycles of limb ischemia and reperfusion on progressive days of TH, or sham. Clinical, biochemical, and safety outcomes were monitored in both groups. RESULTS All patients received the designated RIC therapy without interruption or delay. RIC was not associated with increased pain, vascular, cutaneous, muscular, or neural safety events. There was no difference in the incidence of seizures, brain injury, or mortality between the two groups with the escalation of RIC dose and frequency. CONCLUSIONS We found that RIC is a safe and feasible adjunctive therapy for neonates with NE undergoing TH. IMPACT This pilot study establishes critical safety and feasibility data that are necessary for the design of future studies to investigate the potential efficacy of RIC to reduce NDI. IMPACT Remote ischemic conditioning (RIC) is a possible neuroprotective intervention in infants with hypoxic-ischemic encephalopathy (HIE). RIC can be administered concurrently with therapeutic hypothermia without any notable adverse events. Future studies will need to address potential efficacy of RIC to improve neurodevelopmental outcomes, as well as consider the ideal temporal window and dose for RIC in this patient population.
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Affiliation(s)
- Emily Lo
- Division of Neonatology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, M5G 1X8, Canada
| | - Mehmet N Cizmeci
- Division of Neonatology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, M5G 1X8, Canada
| | - Diane Wilson
- Division of Neonatology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, M5G 1X8, Canada
| | - Linh G Ly
- Division of Neonatology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, M5G 1X8, Canada
| | - Amr El-Shahed
- Division of Neonatology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, M5G 1X8, Canada
| | - Martin Offringa
- Child Health Evaluative Sciences, SickKids Research Institute, 686 Bay Street, Toronto, ON, M5G 1L7, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, M5S 1A1, Canada
| | - Agostino Pierro
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
- Translational Medicine, SickKids Research Institute, 686 Bay Street, Toronto, ON, M5G 1L7, Canada
- Division of General and Thoracic Surgery, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1×8, Canada
| | - Brian T Kalish
- Division of Neonatology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, M5G 1X8, Canada.
- Department of Molecular Genetics, University of Toronto, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.
- Program in Neuroscience and Mental Health, SickKids Research Institute, 686 Bay Street, Toronto, ON, M5G 1L7, Canada.
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Zhao M, Wang J, Liu G, Li S, Ding Y, Ji X, Zhao W. Multi-Target and Multi-Phase Adjunctive Cerebral Protection for Acute Ischemic Stroke in the Reperfusion Era. Biomolecules 2024; 14:1181. [PMID: 39334947 PMCID: PMC11429592 DOI: 10.3390/biom14091181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 08/25/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Stroke remains the leading cause of death and disability in some countries, predominantly attributed to acute ischemic stroke (AIS). While intravenous thrombolysis and endovascular thrombectomy are widely acknowledged as effective treatments for AIS, boasting a high recanalization rate, there is a significant discrepancy between the success of revascularization and the mediocre clinical outcomes observed among patients with AIS. It is now increasingly understood that the implementation of effective cerebral protection strategies, serving as adjunctive treatments to reperfusion, can potentially improve the outcomes of AIS patients following recanalization therapy. Herein, we reviewed several promising cerebral protective methods that have the potential to slow down infarct growth and protect ischemic penumbra. We dissect the underlying reasons for the mismatch between high recanalization rates and moderate prognosis and introduce a novel concept of "multi-target and multi-phase adjunctive cerebral protection" to guide our search for neuroprotective agents that can be administered alongside recanalization therapy.
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Affiliation(s)
- Min Zhao
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Jing Wang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Guiyou Liu
- Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China
| | - Sijie Li
- Department of Emergency, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Yuchuan Ding
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Xunming Ji
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Wenbo Zhao
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
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Badimon L, Kiss A, Podesser BK. Spleen in action for cardioprotection. Eur Heart J 2024; 45:3178-3180. [PMID: 39016156 DOI: 10.1093/eurheartj/ehae420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/18/2024] Open
Affiliation(s)
- Lina Badimon
- Research Institute-Hospital de la Santa Creu i Sant Pau, IR-Sant Pau, CiberCV, Av. S. Antoni M. Claret, 167, 08025 Barcelona, Spain
| | - Attila Kiss
- Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research and Translational Surgery, Medical University of Vienna, Vienna, Austria
| | - Bruno K Podesser
- Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research and Translational Surgery, Medical University of Vienna, Vienna, Austria
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Weavers H. Biological resilience in health and disease. Dis Model Mech 2024; 17:dmm050799. [PMID: 39051470 PMCID: PMC11552498 DOI: 10.1242/dmm.050799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/27/2024] Open
Abstract
All living organisms - from single-celled prokaryotes through to invertebrates and humans - are frequently exposed to numerous challenges during their lifetime, which could damage their molecular and cellular contents and threaten their survival. Nevertheless, these diverse organisms are, on the whole, remarkably resilient to potential threats. Recent years have seen rapid advances in our mechanistic understanding of this emerging phenomenon of biological resilience, which enables cells, tissues and whole organisms to bounce back from challenges or stress. In this At a Glance article, I discuss current knowledge on the diverse molecular mechanisms driving biological resilience across scales, with particular focus on its dynamic and adaptive nature. I highlight emerging evidence that loss of biological resilience could underly numerous pathologies, including age-related frailty and degenerative disease. Finally, I present the multi-disciplinary experimental approaches that are helping to unravel the causal mechanisms of resilience and how this emerging knowledge could be harnessed therapeutically in the clinic.
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Affiliation(s)
- Helen Weavers
- School of Biochemistry, Faculty of Life Sciences, Biomedical Sciences, University of Bristol, Bristol BS8 1TD, UK
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9
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Barrère-Lemaire S, Vincent A, Jorgensen C, Piot C, Nargeot J, Djouad F. Mesenchymal stromal cells for improvement of cardiac function following acute myocardial infarction: a matter of timing. Physiol Rev 2024; 104:659-725. [PMID: 37589393 DOI: 10.1152/physrev.00009.2023] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 07/05/2023] [Accepted: 08/16/2023] [Indexed: 08/18/2023] Open
Abstract
Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.
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Affiliation(s)
- Stéphanie Barrère-Lemaire
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Anne Vincent
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Christian Jorgensen
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | - Christophe Piot
- Département de Cardiologie Interventionnelle, Clinique du Millénaire, Montpellier, France
| | - Joël Nargeot
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Farida Djouad
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
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10
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Bartlett E, Morse SC, Morse D, Goodson L, Adams KN, Nichol G. Randomized feasibility trial of remote ischemic conditioning to enhance resuscitation (RICE). Resuscitation 2024; 195:110003. [PMID: 37839518 DOI: 10.1016/j.resuscitation.2023.110003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/29/2023] [Accepted: 10/02/2023] [Indexed: 10/17/2023]
Abstract
RATIONALE Restoration of blood flow after out-of-hospital cardiac arrest (OHCA) is associated with inflammation that causes cellular injury. The extent of this reperfusion injury (RI) is associated with the duration of ischemia and adequacy of resuscitation. Remote ischemic conditioning (RIC) consists of repeated application of non-lethal ischemia then reperfusion to a limb distal to the heart by inflating a blood pressure (BP) cuff. Trials in animal models in cardiac arrest and in humans with acute infarction show RIC reduces RI. OBJECTIVE We sought to demonstrate the feasibility and safety of RIC in patients resuscitated from OHCA and transported to hospital. METHODS This study was conducted under exception from informed consent (EFIC) for emergency research. Eligible subjects were randomized with masked allocation to control (standard care) versus intervention (standard care and RIC). Included were adults with non-traumatic OHCA. The primary outcome was attrition, the proportion of patients enrolled and not on allocated therapy for the study duration. Key secondary outcomes were survival to discharge, neurologic status at discharge, hospital-free survival, and adverse events. Results were summarized descriptively as recommended for pilot studies. RESULTS N = 30 patients were enrolled (n = 14 control, n = 16 intervention). Mean age of enrolled patients was 52.5 ± 16.2 years. Eight (27%) were female gender and 7 (23%) had a shockable first recorded rhythm. 100% of enrolled patients completed their allocated study intervention (i.e., 0% attrition). The RIC group had 7 (44%) survival to discharge and median Rankin score of 6 (IQR 1, 6) at discharge as compared to the standard care group which had 6 (43%) survival to discharge and median Rankin score of 6 (IQR 1.5, 6) at discharge. A single patient (6%) in the intervention group had transient occlusion of their upper extremity intravenous line, which immediately resolved on repositioning of the blood pressure cuff. CONCLUSION Application of RIC to patients resuscitated from CA and transported to an ED is feasible and safe. An adequately powered trial is required to assess whether RIC is effective at decreasing morbidity and mortality after CA.
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Affiliation(s)
- Emily Bartlett
- Department of Emergency Medicine, University of Washington, Seattle, WA, United States
| | - Sophie C Morse
- University of Washington School of Medicine, University of Washington, Seattle, WA, United States; University of Washington-Harborview Center for Prehospital Emergency Care, Departments of Medicine and Emergency Medicine, University of Washington, Seattle, WA, United States
| | - Dana Morse
- University of Washington-Harborview Center for Prehospital Emergency Care, Departments of Medicine and Emergency Medicine, University of Washington, Seattle, WA, United States
| | - Lucy Goodson
- Department of Emergency Medicine, University of Washington, Seattle, WA, United States
| | - Karen N Adams
- University of Washington-Harborview Center for Prehospital Emergency Care, Departments of Medicine and Emergency Medicine, University of Washington, Seattle, WA, United States
| | - Graham Nichol
- University of Washington-Harborview Center for Prehospital Emergency Care, Departments of Medicine and Emergency Medicine, University of Washington, Seattle, WA, United States.
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11
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Yang H, Hu Z, Gao X, Su J, Jiang H, Yang S, Zhang Q, Ni W, Gu Y. Safety and efficacy of remote ischemic conditioning in adult moyamoya disease patients undergoing revascularization surgery: a pilot study. Front Neurol 2023; 14:1200534. [PMID: 37576009 PMCID: PMC10419176 DOI: 10.3389/fneur.2023.1200534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 07/10/2023] [Indexed: 08/15/2023] Open
Abstract
Background and purpose Revascularization surgery for patients with moyamoya disease (MMD) is very complicated and has a high rate of postoperative complications. This pilot study aimed to prove the safety and efficacy of remote ischemic conditioning (RIC) in adult MMD patients undergoing revascularization surgery. Methods A total of 44 patients with MMD were enrolled in this single-center, open-label, prospective, parallel randomized study, including 22 patients assigned to the sham group and 22 patients assigned to the RIC group. The primary outcome was the incidence of major neurologic complications during the perioperative period. Secondary outcomes were the modified Rankin Scale (mRS) score at discharge, at 90 days post-operation, and at 1 year after the operation. The outcome of safety was the incidence of adverse events associated with RIC. Blood samples were obtained to monitor the serum concentrations of cytokines (VEGF, IL-6). Results No subjects experienced adverse events during RIC intervention, and all patients could tolerate the RIC intervention in the perioperative period. The incidence of major neurologic complications was significantly lower in the RIC group compared with the control group (18.2% vs. 54.5%, P = 0.027). The mRS score at discharge in the RIC group was also lower than the control group (0.86 ± 0.99 vs. 1.18 ± 1.22, P = 0.035). In addition, the serum IL-6 level increased significantly at 7 days after bypass surgery in the control group and the serum level of VEGF at 7 days post-operation in the RIC group. Conclusion In conclusion, our study demonstrated the neuroprotective effect of RIC by reducing perioperative complications and improving cerebral blood flow in adult MMD patients undergoing revascularization surgery. Thus, RIC seems to be a potential treatment method for MMD. Clinical trial registration ClinicalTrials.gov, identifier: NCT05860946.
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Affiliation(s)
- Heng Yang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
- Neurosurgical Institute, Fudan University, Shanghai, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Neurosurgery, Huashan Hospital North, Fudan University, Shanghai, China
| | - Zhenzhen Hu
- Department of Nursing, Huashan Hospital North, Fudan University, Shanghai, China
| | - Xinjie Gao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
- Neurosurgical Institute, Fudan University, Shanghai, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Neurosurgery, Huashan Hospital North, Fudan University, Shanghai, China
| | - Jiabin Su
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
- Neurosurgical Institute, Fudan University, Shanghai, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hanqiang Jiang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
- Neurosurgical Institute, Fudan University, Shanghai, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shaoxuan Yang
- Department of Neurosurgery, Huashan Hospital North, Fudan University, Shanghai, China
| | - Qing Zhang
- Department of Nursing, Huashan Hospital North, Fudan University, Shanghai, China
| | - Wei Ni
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
- Neurosurgical Institute, Fudan University, Shanghai, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Neurosurgery, Huashan Hospital North, Fudan University, Shanghai, China
| | - Yuxiang Gu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
- Neurosurgical Institute, Fudan University, Shanghai, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Neurosurgery, Huashan Hospital North, Fudan University, Shanghai, China
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12
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Ganji N, Biouss G, Sabbatini S, Li B, Lee C, Pierro A. Remote ischemic conditioning in necrotizing enterocolitis. Semin Pediatr Surg 2023; 32:151312. [PMID: 37295298 DOI: 10.1016/j.sempedsurg.2023.151312] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Necrotizing enterocolitis (NEC) is a devastating intestinal inflammatory disorder, most prevalent in premature infants, and associated with a high mortality rate that has remained unchanged in the past two decades. NEC is characterized by inflammation, ischemia, and impaired microcirculation in the intestine. Preclinical studies by our group have led to the discovery of remote ischemic conditioning (RIC) as a promising non-invasive intervention in protecting the intestine against ischemia-induced damage during early-stage NEC. RIC involves the administration of brief reversible cycles of ischemia and reperfusion in a limb (similar to taking standard blood pressure measurement) which activate endogenous protective signaling pathways that are conveyed to distant organs such as the intestine. RIC targets the intestinal microcirculation and by improving blood flow to the intestine, reduces the intestinal damage of experimental NEC and prolongs survival. A recent Phase I safety study by our group demonstrated that RIC was safe in preterm infants with NEC. A phase II feasibility randomized controlled trial involving 12 centers in 6 countries is currently underway, to investigate the feasibility of RIC as a treatment for early-stage NEC in preterm neonates. This review provides a brief background on RIC as a therapeutic strategy and summarizes the progression of RIC as a treatment for NEC from preclinical investigation to clinical evaluation.
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Affiliation(s)
- Niloofar Ganji
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - George Biouss
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - Stella Sabbatini
- Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - Bo Li
- Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - Carol Lee
- Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - Agostino Pierro
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada; Division of General and Thoracic Surgery, The Hospital for Sick Children, University of Toronto, 1526-555 University Ave, Toronto, ON M5G 1×8, Canada.
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13
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Naraiah Mukkala A, Petrut R, Goldfarb R, Leigh Beroncal E, Ho Leung C, Khan Z, Ailenberg M, Jerkic M, Andreazza AC, Rhind SG, Jeschke MG, Kapus A, Rotstein OD. Augmented Parkin-dependent mitophagy underlies the hepatoprotective effect of remote ischemic conditioning used prior to hemorrhagic shock. Mitochondrion 2023; 70:20-30. [PMID: 36906251 DOI: 10.1016/j.mito.2023.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 02/04/2023] [Accepted: 03/05/2023] [Indexed: 03/11/2023]
Abstract
BACKGROUND AND AIMS Hemorrhagic shock-resuscitation (HSR) following trauma contributes to organ dysfunction by causing ischemia-reperfusion injury (IRI). We previously showed that 'remote ischemic preconditioning' (RIPC) exerted multi-organ protection from IRI. Maintenance of mitochondrial quality by clearance of dysfunctional mitochondria via mitophagy is vital in restoring organ integrity. We hypothesized that parkin-dependent mitophagy played a role in RIPC-induced hepatoprotection following HSR. METHODS The hepatoprotective effect of RIPC in a murine model of HSR-IRI was investigated in wild type and parkin-/- animals. Mice were subjected to HSR ± RIPC and blood and organs were collected, followed by cytokine ELISAs, histology, qPCR, Western blots, and transmission electron microscopy. RESULTS HSR increased hepatocellular injury, as measured by plasma ALT and liver necrosis, while antecedent RIPC prevented this injury; in parkin-/- mice, RIPC failed to exert hepatoprotection. The ability of RIPC to lessen HSR-induced rises in plasma IL-6 and TNFα, was lost in parkin-/- mice. While RIPC alone did not induce mitophagy, the application of RIPC prior to HSR caused a synergistic increase in mitophagy, this increase was not observed in parkin-/- mice. RIPC induced shifts in mitochondrial morphology favoring mitophagy in WT but not in parkin-/- animals. CONCLUSIONS RIPC was hepatoprotective in WT mice following HSR but not in parkin-/- mice. Loss of protection in parkin-/- mice corresponded with the failure of RIPC plus HSR to upregulate the mitophagic process. Improving mitochondrial quality by modulating mitophagy, may prove to be an attractive therapeutic target in disease processes caused by IRI.
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Affiliation(s)
- Avinash Naraiah Mukkala
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Raluca Petrut
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada
| | - Rachel Goldfarb
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada
| | | | - Chung Ho Leung
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Zahra Khan
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Menachem Ailenberg
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada
| | - Mirjana Jerkic
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada
| | - Ana C Andreazza
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada
| | - Shawn G Rhind
- Defence Research and Development Canada, Department of National Defense, Government of Canada, Toronto, Canada
| | - Marc G Jeschke
- Hamilton Health Sciences Centre and McMaster University, Hamilton, Canada
| | - Andras Kapus
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; Department of Surgery, University of Toronto, Toronto, Canada; Department of Biochemistry, University of Toronto, Toronto, Canada
| | - Ori D Rotstein
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; Department of Surgery, University of Toronto, Toronto, Canada.
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14
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Muñoz-Gómez E, Mollà-Casanova S, Sempere-Rubio N, Serra-Añó P, Aguilar-Rodríguez M, Alonso-Aubin DA, Chulvi-Medrano I, Inglés M. Potential Benefits of a Single Session of Remote Ischemic Preconditioning and Walking in Sedentary Older Adults: A Pilot Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:3515. [PMID: 36834210 PMCID: PMC9966602 DOI: 10.3390/ijerph20043515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 02/10/2023] [Accepted: 02/15/2023] [Indexed: 06/18/2023]
Abstract
Ischemic preconditioning (IPC) has shown positive effects in endurance-type sports among healthy young individuals; however, its effects in endurance-type exercises in older adults have not been explored. We aimed to examine the acute effects of a single session of IPC prior to an endurance-type exercise on cardiovascular- and physical-function-related parameters in sedentary older adults. A pilot study with a time-series design was carried out. Nine participants were enrolled consecutively in the following intervention groups: (i) SHAM (sham IPC + walking) and (ii) IPC (IPC + walking) groups. The main outcomes were resting systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR), peripheral oxygen saturation (SpO2), maximum isometric voluntary contraction (MIVC), endurance performance, and perceived fatigue. After the intervention, the IPC group showed a significant reduction in SBP, whereas SpO2 decreased in the SHAM group. The IPC group maintained quadriceps MIVC levels, whereas these levels dropped in the SHAM group. No changes in DBP, resting HR, endurance, or fatigue in any group were observed. These findings are of interest for the promotion of cardiovascular and physical health in older people.
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Affiliation(s)
- Elena Muñoz-Gómez
- Research Unit in Clinical Biomechanics (UBIC), Department of Physiotherapy, Faculty of Physiotherapy, University of Valencia, 46010 Valencia, Spain
| | - Sara Mollà-Casanova
- Research Unit in Clinical Biomechanics (UBIC), Department of Physiotherapy, Faculty of Physiotherapy, University of Valencia, 46010 Valencia, Spain
| | - Núria Sempere-Rubio
- Research Unit in Clinical Biomechanics (UBIC), Department of Physiotherapy, Faculty of Physiotherapy, University of Valencia, 46010 Valencia, Spain
| | - Pilar Serra-Añó
- Research Unit in Clinical Biomechanics (UBIC), Department of Physiotherapy, Faculty of Physiotherapy, University of Valencia, 46010 Valencia, Spain
| | - Marta Aguilar-Rodríguez
- Research Unit in Clinical Biomechanics (UBIC), Department of Physiotherapy, Faculty of Physiotherapy, University of Valencia, 46010 Valencia, Spain
| | - Diego A. Alonso-Aubin
- Strength Training and Neuromuscular Performance Research Group (STreNgthP), Faculty of Health, Camilo José Cela University, 28692 Madrid, Spain
| | - Iván Chulvi-Medrano
- UIRFIDE Research Group, Physical Education and Sport Department, University of Valencia, 46010 Valencia, Spain
| | - Marta Inglés
- Research Unit in Clinical Biomechanics (UBIC), Department of Physiotherapy, Faculty of Physiotherapy, University of Valencia, 46010 Valencia, Spain
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15
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Seeley AD, Caldwell AR, Cahalin LP, Ahn S, Perry AC, Arwari B, Jacobs KA. Seven days of ischemic preconditioning augments hypoxic exercise ventilation and muscle oxygenation in recreationally trained males. Am J Physiol Regul Integr Comp Physiol 2022; 323:R457-R466. [PMID: 35968897 PMCID: PMC9529270 DOI: 10.1152/ajpregu.00335.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 08/09/2022] [Accepted: 08/10/2022] [Indexed: 11/22/2022]
Abstract
This investigation sought to assess whether single or repeated bouts of ischemic preconditioning (IPC) could improve oxyhemoglobin saturation ([Formula: see text]) and/or attenuate reductions in muscle tissue saturation index (TSI) during submaximal hypoxic exercise. Fifteen healthy young men completed submaximal graded exercise under four experimental conditions: 1) normoxia (NORM), 2) hypoxia (HYP) [oxygen fraction of inspired air ([Formula: see text]) = 0.14, ∼3,200 m], 3) hypoxia preceded by a single session of IPC (IPC1-HYP), and 4) hypoxia preceded by seven sessions of IPC, one a day for 7 consecutive days (IPC7-HYP). IPC7-HYP heightened minute ventilation (V̇e) at 80% HYP peak cycling power output (Wpeak) (+10.47 ± 3.35 L·min-1, P = 0.006), compared with HYP, as a function of increased breathing frequency. Both IPC1-HYP (+0.17 ± 0.04 L·min-1, P < 0.001) and IPC7-HYP (+0.16 ± 0.04 L·min-1, P < 0.001) elicited greater oxygen consumption (V̇o2) across exercise intensities compared with NORM, whereas V̇o2 was unchanged with HYP alone. [Formula: see text] was unchanged by either IPC condition at any exercise intensity, yet the reduction of muscle TSI during resting hypoxic exposure was attenuated by IPC7-HYP (+9.9 ± 3.6%, P = 0.040) compared with HYP, likely as a function of reduced local oxygen extraction. Considering all exercise intensities, IPC7-HYP attenuated reductions of TSI with HYP (+6.4 ± 1.8%, P = 0.001). Seven days of IPC heightens ventilation, posing a threat to ventilatory efficiency, during high-intensity submaximal hypoxic exercise and attenuates reductions in hypoxic resting and exercise muscle oxygenation in healthy young men. A single session of IPC may be capable of modulating hypoxic ventilation; however, our present population was unable to demonstrate this with certainty.
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Affiliation(s)
- Afton D Seeley
- Department of Kinesiology and Sport Sciences, School of Education and Human Development, University of Miami, Coral Gables, Florida
- Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts
- Oak Ridge Institute of Science and Education, Oak Ridge, Tennessee
| | - Aaron R Caldwell
- Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts
- Oak Ridge Institute of Science and Education, Oak Ridge, Tennessee
| | - Lawrence P Cahalin
- Department of Physical Therapy, University of Miami Miller School of Medicine, Coral Gables, Florida
| | - Soyeon Ahn
- Department of Educational and Psychological Studies, School of Education and Human Development, University of Miami, Coral Gables, Florida
| | - Arlette C Perry
- Department of Kinesiology and Sport Sciences, School of Education and Human Development, University of Miami, Coral Gables, Florida
| | - Brian Arwari
- Department of Kinesiology and Sport Sciences, School of Education and Human Development, University of Miami, Coral Gables, Florida
| | - Kevin A Jacobs
- Department of Kinesiology and Sport Sciences, School of Education and Human Development, University of Miami, Coral Gables, Florida
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16
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Ischemic limb preconditioning-induced anti-arrhythmic effect in reperfusion-induced myocardial injury: is it mediated by the RISK or SAFE pathway? Pflugers Arch 2022; 474:979-991. [PMID: 35695933 DOI: 10.1007/s00424-022-02716-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 06/04/2022] [Indexed: 02/05/2023]
Abstract
The mechanism for limb ischemic precondition (RLIPC)-induced suppression of reperfusion arrhythmia remains unknown. The purpose of this study was to examine the roles of the pro-survival reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways in this RLIPC-mediated antiarrhythmic activity. Male Sprague Dawley rats were assigned to sham-operated, control, or RLIPC groups. All rats except for the sham rats had 5 min of left main coronary artery occlusion with another 20 min of reperfusion. RLIPC was initiated by four cycles of limb ischemia (5 min) and reperfusion (5 min) on the bilateral femoral arteries. Hearts in every group were taken for protein phosphorylation analysis. RLIPC ameliorated reperfusion-induced arrhythmogenesis and reduced the incidence of sudden cardiac death during the entire 20-min reperfusion period (66.7% of control rats had SCD vs. only 16.7% of RLIPC-treated rats). RLIPC enhances ventricular ERK1/2 phosphorylation after reperfusion. RLIPC-induced antiarrhythmic action and ERK1/2 phosphorylation are abolished in the presence of the ERK1/2 inhibitor U0126. Limb ischemic preconditioning protects the heart against myocardial reperfusion injury-induced lethal arrhythmia. These beneficial effects may involve the activation of ERK1/2 in the RISK signaling pathway.
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17
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Remote ischemic conditioning causes CD4 T cells shift towards reduced cell-mediated inflammation. Pediatr Surg Int 2022; 38:657-664. [PMID: 35244771 DOI: 10.1007/s00383-022-05093-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/02/2022] [Indexed: 12/20/2022]
Abstract
PURPOSE Necrotizing enterocolitis (NEC) is a gastrointestinal disease in neonates that is associated with immune-mediated intestinal inflammation. Remote ischemic conditioning (RIC) applied to a limb has been shown to be protective against experimental NEC. In this study, we explore the immune cell-mediated response involved in NEC and the immunomodulatory effects of RIC in an experimental mouse model of the disease. METHODS NEC was induced in C57BL/6 mice (ethical approval #58119) pups on postnatal day5 (p5) using gavage hyperosmolar formula, lipopolysaccharide, and hypoxia. RIC consisted of 4 cycles of 5 min ischemia followed by 5 min reperfusion of the right hindlimb during NEC induction on p6 and p8. Breastfed mice were used as control. The mice were sacrificed on p9, with ileal tissue evaluated for inflammatory cytokines and by characterization of T-cell populations. RESULTS NEC mice had increased number of CD4+ cells indicating an accumulation of T-cells in the mesenchyme of the NEC ileum. Compared to control, NEC pups had upregulated expression pro-inflammatory cytokines (GATA3, IFNγ, IL1β, IL6, IL17, IL22, and TNFα) and reduced anti-inflammatory cytokine (TGFβ). In NEC, there was also a shift in the balance of Treg/Th17 cells towards Th17. Compared to NEC alone, RIC during the course of NEC resulted in reduction of pro-inflammatory cytokines (GATA3, IFNγ, IL1β, IL6, IL17, IL22, and TNFα), increase in anti-inflammatory cytokine TGFβ and concomitant shift back of Th17 cells towards Treg cells. CONCLUSION In experimental NEC, remote ischemic conditioning reduces the production of pro-inflammatory markers and increases the production of anti-inflammatory markers. In addition, during NEC, RIC reverses the imbalance of Treg/Th17 providing support for its effect on cell-mediated inflammation. RIC is a non-invasive physical maneuver that can have a significant beneficial effect in reducing the inflammation seen in NEC.
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Wu YK, Harel NY, Wecht JM, Bloom OE. Effects of Remote Ischemic Conditioning on Hand Engagement in individuals with Spinal cord Injury (RICHES): protocol for a pilot crossover study. F1000Res 2022; 10:464. [PMID: 35342620 PMCID: PMC8924555 DOI: 10.12688/f1000research.52670.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/06/2022] [Indexed: 11/20/2022] Open
Abstract
Background: Most spinal cord injuries (SCI) are not full transections, indicating that residual nerve circuits are retained. Rehabilitation interventions have been shown to beneficially reorganize motor pathways in the brain, corticospinal tract, and at the spinal level. However, rehabilitation training require a large number of repetitions, and intervention effects may be absent or show transient retention. Therefore, the need remains for an effective approach to synergistically improve the amount and duration of neuroplasticity in combination with other interventions. Remote ischemic conditioning (RIC) demonstrates several potential advantages as a candidate for such an approach. Therefore, we propose a protocol to investigate RIC coupled with physical training to promote neuroplasticity in hand muscles. Methods: This will be a prospective randomized-order crossover trial to be performed in eight able-bodied participants and eight participants with chronic cervical SCI. Patients will participate in two experimental sessions consisting of either active or sham RIC preceding a bout of pinch movement exercise. Serial evaluations will be conducted at baseline, after RIC, immediately after pinch exercise, and follow up 15-minutes later. The primary outcome is the change in corticospinal excitability (primarily measured by the motor evoked potential of abductor pollicis brevis muscle). Secondary outcomes will include maximal volitional pinch force, and inflammatory biomarkers. To ensure safety, we will monitor tolerability and hemodynamic responses during RIC. Discussion: This protocol will be the first to test RIC in people with cervical SCI and to investigate whether RIC alters corticospinal excitability. By sharing the details of our protocol, we hope other interested researchers will seek to investigate similar approaches – depending on overlap with the current study and mutual sharing of participant-level data, this could increase the sample size, power, and generalizability of the analysis and results. Trial registration: ClinicalTrial.gov, ID: NCT03851302; Date of registration: February 22, 2019
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Affiliation(s)
- Yu-Kuang Wu
- Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York, NY, 10003, USA
- Bronx Veterans Medical Research Foundation, Bronx, NY, 10468, USA
| | - Noam Y. Harel
- Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York, NY, 10003, USA
- Bronx Veterans Medical Research Foundation, Bronx, NY, 10468, USA
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10003, USA
| | - Jill M. Wecht
- Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York, NY, 10003, USA
- Bronx Veterans Medical Research Foundation, Bronx, NY, 10468, USA
| | - Ona E. Bloom
- Bronx Veterans Medical Research Foundation, Bronx, NY, 10468, USA
- The Feinstein Institute for Medical Research, Manhasset, NY, 11030, USA
- The Zucker School of Medicine at Hofstra Northwell, Hempstead, NY, 11549, USA
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Feige K, Torregroza C, Gude M, Maddison P, Stroethoff M, Roth S, Lurati Buse G, Hollmann MW, Huhn R. Cardioprotective Properties of Humoral Factors Released after Remote Ischemic Preconditioning in CABG Patients with Propofol-Free Anesthesia-A Translational Approach from Bedside to Bench. J Clin Med 2022; 11:jcm11051450. [PMID: 35268540 PMCID: PMC8910912 DOI: 10.3390/jcm11051450] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 02/27/2022] [Accepted: 03/04/2022] [Indexed: 12/11/2022] Open
Abstract
The cardioprotective effect of remote ischemic preconditioning (RIPC) is well detectable in experimental studies but not in clinical trials. Propofol, a commonly used sedative, is discussed to negatively influence the release of humoral factors after RIPC. Further, results from experimental and clinical trials suggest various comorbidities interact with inducible cardioprotective properties of RIPC. In the present study, we went back from bedside to bench to investigate, in male patients undergoing CABG surgery, whether (1) humoral factors are released after RIPC during propofol-free anesthesia and/or (2) DM interacts with plasma factor release. Blood samples were taken from male patients with and without DM undergoing CABG surgery before (control) and after RIPC (RIPC). To investigate the release of cardioprotective humoral factors into the plasma, isolated perfused hearts of young rats (n = 5 per group) were used as a bioassay. The hearts were perfused with patients’ plasma without (Con) and with RIPC (RIPC) for 10 min (1% of coronary flow) before global ischemia and reperfusion. In additional groups, the plasma of patients with DM was administered (Con DM, RIPC DM). Infarct size was determined by TTC staining. Propofol-free RIPC plasma of male patients without DM showed an infarct size of 59 ± 5% compared to 61 ± 13% with Con plasma (p = 0.973). Infarct sizes from patients with DM showed similar results (RIPC DM: 55 ± 3% vs. Con DM: 56 ± 4%; p = 0.995). The release of humoral factors into the blood after RIPC in patients receiving propofol-free anesthesia undergoing CABG surgery did not show any cardioprotective properties independent of a pre-existing diabetes mellitus.
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Affiliation(s)
- Katharina Feige
- Department of Anesthesiology, University Hospital Duesseldorf, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany; (K.F.); (M.G.); (P.M.); (M.S.); (S.R.); (G.L.B.); (R.H.)
| | - Carolin Torregroza
- Department of Anesthesiology, University Hospital Duesseldorf, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany; (K.F.); (M.G.); (P.M.); (M.S.); (S.R.); (G.L.B.); (R.H.)
- Correspondence:
| | - Milena Gude
- Department of Anesthesiology, University Hospital Duesseldorf, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany; (K.F.); (M.G.); (P.M.); (M.S.); (S.R.); (G.L.B.); (R.H.)
| | - Patrick Maddison
- Department of Anesthesiology, University Hospital Duesseldorf, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany; (K.F.); (M.G.); (P.M.); (M.S.); (S.R.); (G.L.B.); (R.H.)
| | - Martin Stroethoff
- Department of Anesthesiology, University Hospital Duesseldorf, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany; (K.F.); (M.G.); (P.M.); (M.S.); (S.R.); (G.L.B.); (R.H.)
| | - Sebastian Roth
- Department of Anesthesiology, University Hospital Duesseldorf, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany; (K.F.); (M.G.); (P.M.); (M.S.); (S.R.); (G.L.B.); (R.H.)
| | - Giovanna Lurati Buse
- Department of Anesthesiology, University Hospital Duesseldorf, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany; (K.F.); (M.G.); (P.M.); (M.S.); (S.R.); (G.L.B.); (R.H.)
| | - Markus W. Hollmann
- Department of Anesthesiology, Amsterdam University Medical Center (AUMC), Meiberdreef 9, 1105 AZ Amsterdam, The Netherlands;
| | - Ragnar Huhn
- Department of Anesthesiology, University Hospital Duesseldorf, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany; (K.F.); (M.G.); (P.M.); (M.S.); (S.R.); (G.L.B.); (R.H.)
- Department of Anesthesiology, Kerckhoff-Clinic GmbH, Benekestr. 2-8, 61231 Bad Nauheim, Germany
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Ma X, Ji C. Remote Ischemic Conditioning: A Potential Treatment for Chronic Cerebral Hypoperfusion. Eur Neurol 2022; 85:253-259. [PMID: 35104816 DOI: 10.1159/000521803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 12/19/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND Chronic cerebral hypoperfusion (CCH) is a clinical syndrome, which is characterized by significantly decreased cerebral blood flow (CBF). CCH is a common consequence of cerebrovascular and cardiovascular diseases and the elderly. CCH results in a series of pathological damages, increasing cell death, autophagy dysfunction, amyloid β (Aβ) peptide accumulation, blood-brain barrier (BBB) disruption, and endothelial damage, which are found in CCH models. In addition, CCH is a prominent risk factor of cognitive impairment, such as vascular dementia, and CCH contributes to the occurrence and development of Alzheimer's disease. Therefore, the treatment of patients with CCH is of great value. It has been confirmed that remote ischemic conditioning (RIC) is a safe, promising treatment for acute and chronic cerebrovascular diseases. RIC significantly increases CBF in both CCH models and patients, inhibits neuronal apoptosis, reduces Aβ deposition, protects BBB integrity and endothelial function, alleviates neuroinflammation, improves cognitive impairment, and exerts neuroprotection. SUMMARY With the development of animal models, the pathophysiological mechanisms of CCH and RIC are increasingly revealed. Key Messages: We discuss the mechanisms related to hypoperfusion in the brain and explore the potential treatment of RIC for CCH to promote its transformation and application in humans.
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Affiliation(s)
- Xiao Ma
- Department of General Practice Medicine, Dalian Municipal Central Hospital, Dalian, China
| | - Chenhua Ji
- Department of General Practice Medicine, Dalian Municipal Central Hospital, Dalian, China
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21
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Synergetic protective effect of remote ischemic preconditioning and prolyl 4‑hydroxylase inhibition in ischemic cardiac injury. Mol Med Rep 2022; 25:80. [PMID: 35029283 PMCID: PMC8778658 DOI: 10.3892/mmr.2022.12596] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 06/21/2021] [Indexed: 12/11/2022] Open
Abstract
It has been reported that hypoxia-inducible factor 1α (HIF-1α) serves a key role in the protective effect of remote ischemic preconditioning (RIP) in ischemia/reperfusion (I/R)-induced cardiac injury. Moreover, inhibition of prolyl 4-hydroxylase (PHD), an enzyme responsible for HIF-1α degradation, prevents I/R-induced cardiac injury. However, whether their protective effects are synergetic remains to be elucidated. The present study aimed to investigate the protective effect of RIP, PHD inhibition using dimethyloxalylglycine (DMOG) and their combination on I/R-induced cardiac injury. Rabbits were randomly divided into seven groups: i) Sham; ii) I/R; iii) lung RIP + I/R; iv) thigh RIP + I/R; v) DMOG + I/R; vi) DMOG + lung RIP + I/R; and vii) DMOG + thigh RIP + I/R. I/R models were established via 30 min left coronary artery occlusion and 3 h reperfusion. For lung/thigh RIP, rabbits received left pulmonary artery (or left limb) ischemia for 25 min and followed by release for 5 min. Some rabbits were administered 20 mg/kg DMOG. The results demonstrated that both lung/thigh RIP and DMOG significantly decreased myocardial infarct size, creatine kinase activity and myocardial apoptosis in I/R rabbits. Furthermore, the combination of RIP and PHD inhibition exerted synergetic protective effects on these aforementioned changes. The mechanistic study indicated that both treatments increased mRNA and protein expression levels of HIF-1α and its downstream regulators, including vascular endothelial growth factor (VEGF), AKT and endothelial nitric oxide synthase (eNOS). In conclusion, the present study demonstrated that RIP and PHD inhibition exerted synergetic protective effects on cardiac injury via activation of HIF-1α and the downstream VEGF/AKT-eNOS signaling pathway.
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22
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Intracellular Signaling. Stroke 2022. [DOI: 10.1016/b978-0-323-69424-7.00006-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Abbasi-Habashi S, Jickling GC, Winship IR. Immune Modulation as a Key Mechanism for the Protective Effects of Remote Ischemic Conditioning After Stroke. Front Neurol 2021; 12:746486. [PMID: 34956045 PMCID: PMC8695500 DOI: 10.3389/fneur.2021.746486] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 11/09/2021] [Indexed: 12/12/2022] Open
Abstract
Remote ischemic conditioning (RIC), which involves a series of short cycles of ischemia in an organ remote to the brain (typically the limbs), has been shown to protect the ischemic penumbra after stroke and reduce ischemia/reperfusion (IR) injury. Although the exact mechanism by which this protective signal is transferred from the remote site to the brain remains unclear, preclinical studies suggest that the mechanisms of RIC involve a combination of circulating humoral factors and neuronal signals. An improved understanding of these mechanisms will facilitate translation to more effective treatment strategies in clinical settings. In this review, we will discuss potential protective mechanisms in the brain and cerebral vasculature associated with RIC. We will discuss a putative role of the immune system and circulating mediators of inflammation in these protective processes, including the expression of pro-and anti-inflammatory genes in peripheral immune cells that may influence the outcome. We will also review the potential role of extracellular vesicles (EVs), biological vectors capable of delivering cell-specific cargo such as proteins and miRNAs to cells, in modulating the protective effects of RIC in the brain and vasculature.
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Affiliation(s)
- Sima Abbasi-Habashi
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
| | - Glen C Jickling
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
- Division of Neurology, Faculty of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Ian R Winship
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
- Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
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Jankovic A, Zakic T, Milicic M, Unic-Stojanovic D, Kalezic A, Korac A, Jovic M, Korac B. Effects of Remote Ischaemic Preconditioning on the Internal Thoracic Artery Nitric Oxide Synthase Isoforms in Patients Undergoing Coronary Artery Bypass Grafting. Antioxidants (Basel) 2021; 10:antiox10121910. [PMID: 34943013 PMCID: PMC8750270 DOI: 10.3390/antiox10121910] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/25/2021] [Accepted: 11/26/2021] [Indexed: 01/03/2023] Open
Abstract
Remote ischaemic preconditioning (RIPC) is a medical procedure that consists of repeated brief periods of transient ischaemia and reperfusion of distant organs (limbs) with the ability to provide internal organ protection from ischaemia. Even though RIPC has been successfully applied in patients with myocardial infarction during coronary revascularization (surgery/percutaneous angioplasty), the underlying molecular mechanisms are yet to be clarified. Thus, our study aimed to determine the role of nitric oxide synthase (NOS) isoforms in RIPC-induced protection (3 × 5 min of forearm ischaemia with 5 min of reperfusion) of arterial graft in patients undergoing urgent coronary artery bypass grafting (CABG). We examined RIPC effects on specific expression and immunolocalization of three NOS isoforms — endothelial (eNOS), inducible (iNOS) and neuronal (nNOS) in patients’ internal thoracic artery (ITA) used as a graft. We found that the application of RIPC protocol leads to an increased protein expression of eNOS, which was further confirmed with strong eNOS immunopositivity, especially in the endothelium and smooth muscle cells of ITA. The same analysis of two other NOS isoforms, iNOS and nNOS, showed no significant differences between patients undergoing CABG with or without RIPC. Our results demonstrate RIPC-induced upregulation of eNOS in human ITA, pointing to its significance in achieving protective phenotype on a systemic level with important implications for graft patency.
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Affiliation(s)
- Aleksandra Jankovic
- Department of Physiology, Institute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia; (A.J.); (T.Z.); (A.K.)
| | - Tamara Zakic
- Department of Physiology, Institute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia; (A.J.); (T.Z.); (A.K.)
| | - Miroslav Milicic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (M.M.); (D.U.-S.)
- Dedinje Cardiovascular Institute, 11000 Belgrade, Serbia;
| | - Dragana Unic-Stojanovic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (M.M.); (D.U.-S.)
- Dedinje Cardiovascular Institute, 11000 Belgrade, Serbia;
| | - Andjelika Kalezic
- Department of Physiology, Institute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia; (A.J.); (T.Z.); (A.K.)
| | - Aleksandra Korac
- Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia;
| | - Miomir Jovic
- Dedinje Cardiovascular Institute, 11000 Belgrade, Serbia;
| | - Bato Korac
- Department of Physiology, Institute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia; (A.J.); (T.Z.); (A.K.)
- Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia;
- Correspondence: ; Tel.: +381-11-2078-307
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Pignataro G. Emerging Role of microRNAs in Stroke Protection Elicited by Remote Postconditioning. Front Neurol 2021; 12:748709. [PMID: 34744984 PMCID: PMC8567963 DOI: 10.3389/fneur.2021.748709] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 09/16/2021] [Indexed: 12/27/2022] Open
Abstract
Remote ischemic conditioning (RIC) represents an innovative and attractive neuroprotective approach in brain ischemia. The purpose of this intervention is to activate endogenous tolerance mechanisms by inflicting a subliminal ischemia injury to the limbs, or to another “remote” region, leading to a protective systemic response against ischemic brain injury. Among the multiple candidates that have been proposed as putative mediators of the protective effect generated by the subthreshold peripheral ischemic insult, it has been hypothesized that microRNAs may play a vital role in the infarct-sparing effect of RIC. The effect of miRNAs can be exploited at different levels: (1) as transducers of protective messages to the brain or (2) as effectors of brain protection. The purpose of the present review is to summarize the most recent evidence supporting the involvement of microRNAs in brain protection elicited by remote conditioning, highlighting potential and pitfalls in their exploitation as diagnostic and therapeutic tools. The understanding of these processes could help provide light on the molecular pathways involved in brain protection for the future development of miRNA-based theranostic agents in stroke.
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Affiliation(s)
- Giuseppe Pignataro
- Division of Pharmacology, Department of Neuroscience, School of Medicine, "Federico II" University of Naples, Naples, Italy
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26
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Filaretova L, Komkova O, Sudalina M, Yarushkina N. Non-Invasive Remote Ischemic Preconditioning May Protect the Gastric Mucosa Against Ischemia-Reperfusion-Induced Injury Through Involvement of Glucocorticoids. Front Pharmacol 2021; 12:682643. [PMID: 34744702 PMCID: PMC8563572 DOI: 10.3389/fphar.2021.682643] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 09/30/2021] [Indexed: 11/29/2022] Open
Abstract
Remote ischemic preconditioning (RIPC) is one of the most effective approaches to attenuate tissue injury caused by severe ischemia-reperfusion (I/R). Experimental studies have demonstrated that RIPC is capable of producing a protective effect not only on heart, but also on brain, lungs, kidneys, liver, intestine, and stomach. We previously demonstrated that glucocorticoids participate in protective effect of local gastric ischemic preconditioning against I/R-induced gastric injury. In the present study we investigated whether RIPC may protect the gastric mucosa against I/R-induced injury through involvement of glucocorticoids. Anesthetized fasted Sprague Dawley male rats were exposed to prolonged gastric I/R (30 min occlusion of celiac artery followed by 3 h of reperfusion) alone or with preliminary brief RIPC (10 min non-invasive occlusion of right hind limb blood flow followed by reperfusion for 30 min). First, we investigated the effect of RIPC on I/R-induced injury by itself. Then to study the role of glucocorticoids similar experiments were carried out: 1) in rats pretreated with the inhibitor of glucocorticoid synthesis, metyrapone (30 mg/kg, i.p), and in control animals; 2) in adrenalectomized rats without or with corticosterone replacement (4 mg/kg, s.c.) and in sham-operated animals; 3) in rats pretreated with glucocorticoid receptor antagonist RU-38486 (20 mg/kg, s.c.) and in control animals. I/R induced corticosterone rise and resulted in the gastric erosion formation. RIPC significantly reduced the erosion area in control animals. Metyrapone injected shortly before RIPC caused a decrease in plasma corticosterone levels and prevented the gastroprotective effect of RIPC and, moreover, further aggravated the deleterious effect of I/R. Adrenalectomy performed 1 week before experiment created long-lasting corticosterone deficiency and had no effect on the gastroprotective effect of RIPC. Nevertheless, corticosterone replacement which mimics the corticosterone rise, similar to RIPS, significantly reduced erosion areas of gastric mucosa in adrenalectomized rats supporting the role of glucocorticoids in gastroprotection. RU-38486, which occupied glucocorticoid receptors, similar to metyrapone prevented the gastroprotective effect of RIPC and, moreover, further aggravated the deleterious effect of I/R. The results of the present study demonstrate for the first time that RIPC may protect the gastric mucosa against I/R-induced injury through involvement of glucocorticoids.
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Affiliation(s)
- Ludmila Filaretova
- Laboratory of Experimental Endocrinology, Pavlov Institute of Physiology, Russian Academy of Sciences, St. Petersburg, Russia
| | - Olga Komkova
- Laboratory of Experimental Endocrinology, Pavlov Institute of Physiology, Russian Academy of Sciences, St. Petersburg, Russia
| | - Maria Sudalina
- Laboratory of Experimental Endocrinology, Pavlov Institute of Physiology, Russian Academy of Sciences, St. Petersburg, Russia
| | - Natalia Yarushkina
- Laboratory of Experimental Endocrinology, Pavlov Institute of Physiology, Russian Academy of Sciences, St. Petersburg, Russia
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27
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Yan Y, Gu T, Christensen SDK, Su J, Lassen TR, Hjortbak MV, Lo IJ, Venø ST, Tóth AE, Song P, Nielsen MS, Bøtker HE, Blagoev B, Drasbek KR, Kjems J. Cyclic Hypoxia Conditioning Alters the Content of Myoblast-Derived Extracellular Vesicles and Enhances Their Cell-Protective Functions. Biomedicines 2021; 9:biomedicines9091211. [PMID: 34572398 PMCID: PMC8471008 DOI: 10.3390/biomedicines9091211] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/06/2021] [Accepted: 09/08/2021] [Indexed: 11/16/2022] Open
Abstract
Remote ischemic conditioning (RIC) is a procedure that can attenuate ischemic-reperfusion injury by conducting brief cycles of ischemia and reperfusion in the arm or leg. Extracellular vesicles (EVs) circulating in the bloodstream can release their content into recipient cells to confer protective function on ischemia-reperfusion injured (IRI) organs. Skeletal muscle cells are potential candidates to release EVs as a protective signal during RIC. In this study, we used C2C12 cells as a model system and performed cyclic hypoxia-reoxygenation (HR) to mimic RIC. EVs were collected and subjected to small RNA profiling and proteomics. HR induced a distinct shift in the miRNA profile and protein content in EVs. HR EV treatment restored cell viability, dampened inflammation, and enhanced tube formation in in vitro assays. In vivo, HR EVs showed increased accumulation in the ischemic brain compared to EVs secreted from normoxic culture (N EVs) in a mouse undergoing transient middle cerebral artery occlusion (tMCAO). We conclude that HR conditioning changes the miRNA and protein profile in EVs released by C2C12 cells and enhances the protective signal in the EVs to recipient cells in vitro.
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Affiliation(s)
- Yan Yan
- Interdisciplinary Nanoscience Center, Aarhus University, 8000 Aarhus, Denmark; (Y.Y.); (J.S.); (I.L.); (P.S.)
- Omiics ApS, 8200 Aarhus, Denmark;
| | - Tingting Gu
- Center of Functionally Integrative Neuroscience, Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark; (T.G.); (K.R.D.)
| | - Stine Duelund Kaas Christensen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark; (S.D.K.C.); (B.B.)
| | - Junyi Su
- Interdisciplinary Nanoscience Center, Aarhus University, 8000 Aarhus, Denmark; (Y.Y.); (J.S.); (I.L.); (P.S.)
| | - Thomas Ravn Lassen
- Department of Cardiology, Aarhus University Hospital, Skejby, 8200 Aarhus, Denmark; (T.R.L.); (M.V.H.); (H.E.B.)
| | - Marie Vognstoft Hjortbak
- Department of Cardiology, Aarhus University Hospital, Skejby, 8200 Aarhus, Denmark; (T.R.L.); (M.V.H.); (H.E.B.)
| | - IJu Lo
- Interdisciplinary Nanoscience Center, Aarhus University, 8000 Aarhus, Denmark; (Y.Y.); (J.S.); (I.L.); (P.S.)
| | | | - Andrea Erzsebet Tóth
- Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; (A.E.T.); (M.S.N.)
| | - Ping Song
- Interdisciplinary Nanoscience Center, Aarhus University, 8000 Aarhus, Denmark; (Y.Y.); (J.S.); (I.L.); (P.S.)
| | | | - Hans Erik Bøtker
- Department of Cardiology, Aarhus University Hospital, Skejby, 8200 Aarhus, Denmark; (T.R.L.); (M.V.H.); (H.E.B.)
| | - Blagoy Blagoev
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark; (S.D.K.C.); (B.B.)
| | - Kim Ryun Drasbek
- Center of Functionally Integrative Neuroscience, Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark; (T.G.); (K.R.D.)
| | - Jørgen Kjems
- Interdisciplinary Nanoscience Center, Aarhus University, 8000 Aarhus, Denmark; (Y.Y.); (J.S.); (I.L.); (P.S.)
- Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark
- Correspondence: ; Tel.: +45-289-920-86
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Influence of Hyperglycemia and Diabetes on Cardioprotection by Humoral Factors Released after Remote Ischemic Preconditioning (RIPC). Int J Mol Sci 2021; 22:ijms22168880. [PMID: 34445586 PMCID: PMC8396298 DOI: 10.3390/ijms22168880] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/11/2021] [Accepted: 08/16/2021] [Indexed: 02/07/2023] Open
Abstract
Remote ischemic preconditioning (RIPC) protects hearts from ischemia-reperfusion (I/R) injury in experimental studies; however, clinical RIPC trials were unsatisfactory. This discrepancy could be caused by a loss of cardioprotection due to comorbidities in patients, including diabetes mellitus (DM) and hyperglycemia (HG). RIPC is discussed to confer protective properties by release of different humoral factors activating cardioprotective signaling cascades. Therefore, we investigated whether DM type 1 and/or HG (1) inhibit the release of humoral factors after RIPC and/or (2) block the cardioprotective effect directly at the myocardium. Experiments were performed on male Wistar rats. Animals in part 1 of the study were either healthy normoglycemic (NG), type 1 diabetic (DM1), or hyperglycemic (HG). RIPC was implemented by four cycles of 5 min bilateral hind-limb ischemia/reperfusion. Control (Con) animals were not treated. Blood plasma taken in vivo was further investigated in isolated rat hearts in vitro. Plasma from diseased animals (DM1 or HG) was administered onto healthy (NG) hearts for 10 min before 33 min of global ischemia and 60 min of reperfusion. Part 2 of the study was performed vice versa-plasma taken in vivo, with or without RIPC, from healthy rats was transferred to DM1 and HG hearts in vitro. Infarct size was determined by TTC staining. Part 1: RIPC plasma from NG (NG Con: 49 ± 8% vs. NG RIPC 29 ± 6%; p < 0.05) and DM1 animals (DM1 Con: 47 ± 7% vs. DM1 RIPC: 38 ± 7%; p < 0.05) reduced infarct size. Interestingly, transfer of HG plasma showed comparable infarct sizes independent of prior treatment (HG Con: 34 ± 9% vs. HG RIPC 35 ± 9%; ns). Part 2: No infarct size reduction was detectable when transferring RIPC plasma from healthy rats to DM1 (DM1 Con: 54 ± 13% vs. DM1 RIPC 53 ± 10%; ns) or HG hearts (HG Con: 60 ± 16% vs. HG RIPC 53 ± 14%; ns). These results suggest that: (1) RIPC under NG and DM1 induces the release of humoral factors with cardioprotective impact, (2) HG plasma might own cardioprotective properties, and (3) RIPC does not confer cardioprotection in DM1 and HG myocardium.
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29
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Myocardial remote ischemic preconditioning: from cell biology to clinical application. Mol Cell Biochem 2021; 476:3857-3867. [PMID: 34125317 DOI: 10.1007/s11010-021-04192-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 05/26/2021] [Indexed: 12/25/2022]
Abstract
Remote ischemic preconditioning (rIPC) is a cardioprotective phenomenon where brief periods of ischemia followed by reperfusion of one organ/tissue can confer subsequent protection against ischemia/reperfusion injury in other organs, such as the heart. It involves activation of humoral, neural or systemic communication pathways inducing different intracellular signals in the heart. The main purpose of this review is to summarize the possible mechanisms involved in the rIPC cardioprotection, and to describe recent clinical trials to establish the efficacy of these strategies in cardioprotection from lethal ischemia/reperfusion injury. In this sense, certain factors weaken the subcellular mechanisms of rIPC in patients, such as age, comorbidities, medication, and anesthetic protocol, which could explain the heterogeneity of results in some clinical trials. For these reasons, further studies, carefully designed, are necessary to develop a clearer understanding of the pathways and mechanism of early and late rIPC. An understanding of the pathways is important for translation to patients.
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Hodoodi F, Allah-Tavakoli M, Tajik F, Fatemi I, Moghadam Ahmadi A. The effect of head cooling and remote ischemic conditioning on patients with traumatic brain injury. iScience 2021; 24:102472. [PMID: 34169235 PMCID: PMC8207229 DOI: 10.1016/j.isci.2021.102472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 09/12/2020] [Accepted: 04/22/2021] [Indexed: 11/17/2022] Open
Abstract
Cerebral impairment caused by an external force to the head is known as traumatic brain injury (TBI). The aim of this study was to determine the role of local hypothermia and remote ischemic conditioning (RIC) on oxidative stress, inflammatory response after TBI, and other involved variables. The present study is a clinical trial on 84 patients with TBI who were divided into 4 groups. The head cooling for 1.5 to 6 hr was performed in the first three days after TBI. RIC intervention was performed within the golden time after TBI in the form of four 5-min cycles with full cuff and 5 min of emptying of cuff. The group receiving the head cooling technique recovered better than the group receiving the RIC technique. Generally, combination of the two interventions of head cooling and RIC techniques is more effective on the improvement of clinical status of patients than each separate technique.
The effect of the head cooling method in controlling secondary injury in patients with TBI. The effect of the RIC method in controlling secondary injury in patients with TBI. Comparison of two interventions of head cooling and RIC. Evaluation of clinical and paraclinical parameters.
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Affiliation(s)
- Fardin Hodoodi
- Department of Physiology and Pharmacology, Schoole of Medicine, Rafsanjan University of Medical Science, Rafsanjan, Iran
| | - Mohammad Allah-Tavakoli
- Department of Physiology and Pharmacology, Schoole of Medicine, Rafsanjan University of Medical Science, Rafsanjan, Iran
- Physiology-pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Farzad Tajik
- Department of Clinical Research Sciences, Department of Medicine, Rafsanjan University of Medical Science, Rafsanjan, Iran
- Department of Neurology, Department of Medicine, Rafsanjan University of Medical Science, Rafsanjan, Iran
| | - Iman Fatemi
- Research Center of Tropical and Infectious Diseases, Kerman University of Medical Sciences, Kerman, Iran
| | - Amir Moghadam Ahmadi
- Department of Neurology, Department of Medicine, Rafsanjan University of Medical Science, Rafsanjan, Iran
- Non-Communicable Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Corresponding author
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Pansani AP, Ghazale PP, Dos Santos EG, Dos Santos Borges K, Gomes KP, Lacerda IS, Castro CH, Mendes EP, Dos Santos FCA, Biancardi MF, Nejm MB, Dogini DB, Rabelo LA, Nunes-Souza V, Scorza FA, Colugnati DB. The number and periodicity of seizures induce cardiac remodeling and changes in micro-RNA expression in rats submitted to electric amygdala kindling model of epilepsy. Epilepsy Behav 2021; 116:107784. [PMID: 33548915 DOI: 10.1016/j.yebeh.2021.107784] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 01/03/2021] [Accepted: 01/03/2021] [Indexed: 12/20/2022]
Abstract
Generalized tonic-clonic seizures (GTCS) are the main risk factor for sudden unexpected death in epilepsy (SUDEP). Also, among the several mechanisms underlying SUDEP there is the cardiac dysfunction. So, we aimed to evaluate the impact of the number of seizures on heart function and morphology in rats with epilepsy. Rats were randomized into three groups: Sham (without epilepsy), 5 S, and 10 S groups, referred as rats with epilepsy with a total of 5 or 10 GTCS, respectively. Epilepsy was induced by electrical amygdala kindling. The ventricular function was analyzed by the Langendorff technique and challenged by ischemia/reperfusion protocol. Cardiac fibrosis and hypertrophy were analyzed by histology. We also analyzed cardiac metalloproteinases (MMP2 and MMP9), ERK 1/2 and phosphorylated ERK1/2 (P-ERK) by western blot; microRNA-21 and -320 by RT-PCR; and oxidative stress (TBARS, catalase activity and nitrite) by biochemical analysis. Only the 5S group presented decreased values of ventricular function at before ischemia/reperfusion (baseline): intraventricular systolic pressure, developed intraventricular pressure, positive and negative dP/dt. During ischemia/reperfusion protocol, the variation of the ventricular function did not differ among groups. Both 5S and 10S groups had increased cardiomyocyte hypertrophy and fibrosis compared to Sham, but in the 5S group, these alterations were higher than in the 10S group. The 5S group increased in microRNA-21 and decreased in microRNA-320 expression compared to Sham and the 10S group. The 10S group increased in MMP9 and decreased in P-ERK/ERK expression, and increased in nitrite content compared to both Sham and the 5S group. Therefore, seizures impair cardiac function and morphology, probably through microRNA modulation. The continuation of seizures seems to exert a preconditioning-like stimulus that fails to compensate the cardiac tissue alteration.
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Affiliation(s)
- Aline Priscila Pansani
- Department of Physiological Sciences, Institute of Biological Sciences, Federal University of Goiás, Goiânia, Brazil.
| | - Poliana Peres Ghazale
- Department of Neurology and Neurosurgery, Federal University of São Paulo, São Paulo, Brazil
| | - Emilly Gomes Dos Santos
- Department of Physiological Sciences, Institute of Biological Sciences, Federal University of Goiás, Goiânia, Brazil
| | - Kiscilla Dos Santos Borges
- Department of Physiological Sciences, Institute of Biological Sciences, Federal University of Goiás, Goiânia, Brazil
| | - Karina Pereira Gomes
- Department of Physiological Sciences, Institute of Biological Sciences, Federal University of Goiás, Goiânia, Brazil
| | - Ismaley Santos Lacerda
- Department of Physiological Sciences, Institute of Biological Sciences, Federal University of Goiás, Goiânia, Brazil
| | - Carlos Henrique Castro
- Department of Physiological Sciences, Institute of Biological Sciences, Federal University of Goiás, Goiânia, Brazil
| | - Elizabeth Pereira Mendes
- Department of Physiological Sciences, Institute of Biological Sciences, Federal University of Goiás, Goiânia, Brazil
| | | | | | - Mariana Bocca Nejm
- Department of Neurology and Neurosurgery, Federal University of São Paulo, São Paulo, Brazil
| | - Danyella Barbosa Dogini
- Department of Medical Genetics and Genomic Medicine, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Luiza Antas Rabelo
- Department of Physiology, Institute of Biological and Health Sciences, Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Valéria Nunes-Souza
- Department of Physiological and Pharmacology Sciences, Institute of Biological Sciences, Federal University of Pernambuco, Recife, Pernambuco, Brazil
| | - Fulvio Alexandre Scorza
- Department of Neurology and Neurosurgery, Federal University of São Paulo, São Paulo, Brazil
| | - Diego Basile Colugnati
- Department of Physiological Sciences, Institute of Biological Sciences, Federal University of Goiás, Goiânia, Brazil
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Remote ischemic conditioning avoids the development of intestinal damage after ischemia reperfusion by reducing intestinal inflammation and increasing intestinal regeneration. Pediatr Surg Int 2021; 37:333-337. [PMID: 33555396 DOI: 10.1007/s00383-020-04831-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/30/2020] [Indexed: 01/02/2023]
Abstract
AIM OF THE STUDY Midgut volvulus is a potentially life-threatening condition which is based on intestinal ischemia and reperfusion (I/R) injury. Remote ischemia conditioning (RIC) applied to a limb can protect distant organs such as heart and kidney. The aims of this study were to investigate the effect of RIC on a model of midgut volvulus and to explore its underlying mechanism of action. METHODS Six-weeks old C57BL/6 mice were studied: (a) sham (n = 4): laparotomy alone. (b) Intestinal I/R injury (n = 5): occlusion of the superior mesenteric artery (SMA) for 45 min followed by reperfusion. (c) Intestinal I/R (as in group above) with RIC immediately after reperfusion (n = 5). RIC consisted of 4 cycles of 5 min hind limb ischemia followed by 5 min reperfusion. 24-h after laparotomy, animals were euthanized, and the small intestine (same distance from cecum) was harvested. The intestine was examined for inflammatory cytokines (TNF-α and IL-6), epithelial proliferation marker Ki67 and stem cell marker Lgr5 expression. MAIN RESULTS Compared to sham, the small intestine of IR mice had more intestinal damage, increased expression of inflammatory cytokines, decreased intestinal proliferation and stem cell activity. RIC significantly counteracted all these changes. CONCLUSIONS Remote ischemia conditioning avoids intestinal damage due to I/R injury. This beneficial effect is associated with decreased intestinal inflammation and enhanced intestinal regeneration. This study implicates that RIC is a novel non-invasive intervention to reduce the intestinal damage occurring in midgut volvulus.
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[Perioperative cardioprotection - From bench to bedside : Current experimental evidence and possible reasons for the limited translation into the clinical setting]. Anaesthesist 2021; 70:401-412. [PMID: 33464375 PMCID: PMC8099823 DOI: 10.1007/s00101-020-00912-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/21/2020] [Indexed: 12/30/2022]
Abstract
Hintergrund Ziel der perioperativen Kardioprotektion ist es, die Auswirkungen eines Ischämie- und Reperfusionsschadens zu minimieren. Aus anästhesiologischer Sicht spielt dieser Aspekt insbesondere in der Herzchirurgie bei Patienten mit Einsatz der Herz-Lungen-Maschine, aber auch allgemein bei längerfristigen hypotensiven Phasen oder perioperativen ischämischen Ereignissen im nichtkardiochirurgischen Setting eine wichtige Rolle. Im Laufe der letzten Jahre konnten diverse pharmakologische sowie nichtpharmakologische Strategien der Kardioprotektion identifiziert werden. Die Ergebnisse von Studien an isoliertem Gewebe sowie von tierexperimentellen In-vivo-Studien sind vielversprechend. Eine Translation dieser kardioprotektiven Strategien in die klinische Praxis ist bislang jedoch nicht gelungen. Große klinische Studien konnten keine signifikante Verbesserung des Outcome der Patienten zeigen. Ziel der Arbeit Dieser Übersichtsartikel gibt einen Überblick über die aktuelle experimentelle Evidenz pharmakologischer und nichtpharmakologischer Kardioprotektion. Außerdem sollen mögliche Gründe für die limitierte Translation diskutiert werden. Schließlich werden Möglichkeiten aufgezeigt, wie der Schritt „from bench to bedside“ in Zukunft doch noch gelingen könnte. Material und Methoden Narrative Übersichtsarbeit. Ergebnisse und Diskussion Trotz der vielversprechenden präklinischen experimentellen Ansätze zum Thema Kardioprotektion besteht nach wie vor eine große Diskrepanz zu den Ergebnissen aus großen klinischen Studien in der perioperativen Phase. Mögliche Gründe für die limitierte Translation könnten insbesondere Komorbiditäten und Komedikationen, die Wahl des Anästhesieverfahrens, aber auch die Wahl des Studiendesigns sein. Eine sorgfältige Studienplanung mit Berücksichtigung der genannten Probleme sowie ein simultaner Einsatz mehrerer kardioprotektiver Strategien mit dem Ziel eines additiven bzw. synergistischen Effekts stellen mögliche Ansätze für die Zukunft dar.
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Vinciguerra A, Cepparulo P, Anzilotti S, Cuomo O, Valsecchi V, Amoroso S, Annunziato L, Pignataro G. Remote postconditioning ameliorates stroke damage by preventing let-7a and miR-143 up-regulation. Theranostics 2020; 10:12174-12188. [PMID: 33204336 PMCID: PMC7667695 DOI: 10.7150/thno.48135] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 09/29/2020] [Indexed: 01/03/2023] Open
Abstract
Remote limb ischemic postconditioning (RLIP) is a well-established neuroprotective strategy able to protect the brain from a previous harmful ischemic insult through a sub-lethal occlusion of the femoral artery. Neural and humoral mechanisms have been proposed as mediators required to transmit the peripheral signal from limb to brain. Moreover, different studies suggest that protection observed at brain level is associated to a general genetic reprogramming involving also microRNAs (miRNAs) intervention. Methods: Brain ischemia was induced in male rats by transient occlusion of the middle cerebral artery (tMCAO), whereas RLIP was achieved by one cycle of temporary occlusion of the ipsilateral femoral artery after tMCAO. The expression profile of 810 miRNAs was evaluated in ischemic brain samples from rats subjected either to tMCAO or to RLIP. Among all analyzed miRNAs, there were four whose expression were upregulated after stroke and returned to basal level after RLIP, thus suggesting a possible involvement in RLIP-induced neuroprotection. These selected miRNAs were intracerebroventricularly infused in rats subjected to remote ischemic postconditioning, and their effect was evaluated in terms of brain damage, neurological deficit scores and expression of putative targets. Results: Twenty-one miRNAs, whose expression was significantly affected by tMCAO and by tMCAO plus RLIP, were selected based on microarray microfluidic profiling. Our data showed that: (1) stroke induced an up-regulation of let-7a and miR-143 (2) these two miRNAs were involved in the protective effects induced by RLIP and (3) HIF1-α contributes to their protective effect. Indeed, their expression was reduced after RLIP and the exogenous intracerebroventricularly infusion of let-7a and miR-143 mimics prevented neuroprotection and HIF1-α overexpression induced by RLIP. Conclusions: Prevention of cerebral let-7a and miR-143 overexpression induced by brain ischemia emerges as new potential strategy in stroke intervention.
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RiPerC Attenuates Cerebral Ischemia Injury through Regulation of miR-98/PIK3IP1/PI3K/AKT Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:6454281. [PMID: 33082912 PMCID: PMC7559836 DOI: 10.1155/2020/6454281] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 09/11/2020] [Accepted: 09/19/2020] [Indexed: 02/06/2023]
Abstract
Background Cerebral ischemic stroke is a refractory disease which seriously endangers human health. Remote ischemic perconditioning (RiPerC) by which the sublethal ischemic stimulus is administered during the ischemic event is beneficial after an acute stroke. However, the regulatory mechanism of RiPerC that relieves cerebral ischemic injury is still not completely clear. Methods In the present study, we investigated the regulatory mechanism of RiPerC in a rat model of ischemia induced by the middle cerebral artery occlusion (MCAO). Forty-eight adult male Sprague-Dawley (SD) rats were injected intracerebroventricularly with miR-98 agomir, miR-98 antagomir, or their negative controls (agomir-NC, antagomir-NC) 2 h before MCAO or MCAO+RiPerC followed by animal behavior tests and infraction volume measurement at 24 h after MCAO. The expression of miR-98, PIK3IP1, and tight junction proteins in rat hippocampus and cerebral cortex tissues was detected by quantitative polymerase chain reaction (qPCR) and Western blot (WB). Enzyme-linked immunosorbent assay (ELISA) was used to assess the IL-1β, IL-6, and TNF-α levels in the rat serum. Results The results showed that in MCAO group, the expression of PIK3IP1 was upregulated, but decreased after RiPerC treatment. Then, we found that PIK3IP1 was a potential target of miR-98. Treatment with miR-98 agomir decreased the infraction volume, reduced brain edema, and improved neurological functions compared to control rats. But treating with miR-98 antagomir in RiPerC group, the protective effect on cerebral ischemia injury was canceled. Conclusion Our finding indicated that RiPerC inhibited the MCAO-induced expression of PIK3IP1 through upregulated miR-98, thereby reducing the apoptosis induced by PIK3IP1 through the PI3K/AKT signaling pathway, thus reducing the cerebral ischemia-reperfusion injury.
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36
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Koike Y, Li B, Ganji N, Zhu H, Miyake H, Chen Y, Lee C, Janssen Lok M, Zozaya C, Lau E, Lee D, Chusilp S, Zhang Z, Yamoto M, Wu RY, Inoue M, Uchida K, Kusunoki M, Delgado-Olguin P, Mertens L, Daneman A, Eaton S, Sherman PM, Pierro A. Remote ischemic conditioning counteracts the intestinal damage of necrotizing enterocolitis by improving intestinal microcirculation. Nat Commun 2020; 11:4950. [PMID: 33009377 PMCID: PMC7532542 DOI: 10.1038/s41467-020-18750-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 09/09/2020] [Indexed: 02/07/2023] Open
Abstract
Necrotizing enterocolitis (NEC) is a devastating disease of premature infants with high mortality rate, indicating the need for precision treatment. NEC is characterized by intestinal inflammation and ischemia, as well derangements in intestinal microcirculation. Remote ischemic conditioning (RIC) has emerged as a promising tool in protecting distant organs against ischemia-induced damage. However, the effectiveness of RIC against NEC is unknown. To address this gap, we aimed to determine the efficacy and mechanism of action of RIC in experimental NEC. NEC was induced in mouse pups between postnatal day (P) 5 and 9. RIC was applied through intermittent occlusion of hind limb blood flow. RIC, when administered in the early stages of disease progression, decreases intestinal injury and prolongs survival. The mechanism of action of RIC involves increasing intestinal perfusion through vasodilation mediated by nitric oxide and hydrogen sulfide. RIC is a viable and non-invasive treatment strategy for NEC. Necrotizing enterocolitis (NEC) is one of the most lethal gastrointestinal emergencies in neonates needing precision treatment. Here the authors show that remote ischemic conditioning is a non-invasive therapeutic method that enhances blood flow in the intestine, reduces damage, and improves NEC outcome.
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Affiliation(s)
- Yuhki Koike
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada.,Departments of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Bo Li
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Niloofar Ganji
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Haitao Zhu
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Hiromu Miyake
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Yong Chen
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Carol Lee
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Maarten Janssen Lok
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Carlos Zozaya
- Division of Neonatology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Ethan Lau
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Dorothy Lee
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Sinobol Chusilp
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Zhen Zhang
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Masaya Yamoto
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Richard Y Wu
- Cell Biology Program, Research Institute, Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, ON, Canada.,Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Mikihiro Inoue
- Departments of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Keiichi Uchida
- Departments of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Masato Kusunoki
- Departments of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Paul Delgado-Olguin
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.,Heart & Stroke Richard Lewar Centre of Excellence, Toronto, ON, Canada
| | - Luc Mertens
- The Labatt Family Heart Center, Cardiology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Alan Daneman
- Department of Diagnostic Imaging, Division of Nuclear Medicine, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Simon Eaton
- UCL Great Ormond Street Institute of Child Health, London, UK
| | - Philip M Sherman
- Cell Biology Program, Research Institute, Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, ON, Canada.,Faculty of Dentistry, University of Toronto, Toronto, ON, Canada
| | - Agostino Pierro
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada. .,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada. .,Department of Surgery, University of Toronto, Toronto, ON, Canada.
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ter Beek F, Jokumsen PS, Sloth BN, Stevenson AJT, Larsen RG. Ischemic Preconditioning Attenuates Rating of Perceived Exertion But Does Not Improve Maximal Oxygen Consumption or Maximal Power Output. J Strength Cond Res 2020; 36:2479-2485. [DOI: 10.1519/jsc.0000000000003625] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Mukai A, Suehiro K, Kimura A, Fujimoto Y, Funao T, Mori T, Nishikawa K. Protective effects of remote ischemic preconditioning against spinal cord ischemia-reperfusion injury in rats. J Thorac Cardiovasc Surg 2020; 163:e137-e156. [PMID: 32414598 DOI: 10.1016/j.jtcvs.2020.03.094] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 02/28/2020] [Accepted: 03/25/2020] [Indexed: 12/25/2022]
Abstract
OBJECTIVES We aimed to investigate the protective effect of remote ischemic preconditioning against spinal cord ischemia and find a clue to its mechanism by measuring glutamate concentrations in the spinal ventral horn. METHODS Male Sprague-Dawley rats were divided into 5 groups (n = 6 in each group) as follows: sham; SCI (only spinal cord ischemia); RIPC/SCI (perform remote ischemic preconditioning before spinal cord ischemia); MK-801/RIPC/SCI (administer MK-801, N-methyl-D-aspartate receptor antagonist, before remote ischemic preconditioning); and MK-801/SCI (administer MK-801 without remote ischemic preconditioning). Remote ischemic preconditioning was achieved by brief limb ischemia 80 minutes before spinal cord ischemia. MK-801 (1 mg/kg, intravenous) was administered 60 minutes before remote ischemic preconditioning. The glutamate concentration in the ventral horn was measured by microdialysis for 130 minutes after spinal cord ischemia. Immunofluorescence was also performed to evaluate the expression of N-methyl-D-aspartate receptor 2B subunit in the ventral horn 130 minutes after spinal cord ischemia. RESULTS The glutamate concentrations in the spinal cord ischemia group were significantly higher than in the sham group at all time points (P < .01). Remote ischemic preconditioning attenuated the spinal cord ischemia-induced glutamate increase. When MK-801 was preadministered before remote ischemic preconditioning, glutamate concentration was increased after spinal cord ischemia (P < .01). Immunofluorescence showed that remote ischemic preconditioning prevented the increase in the expression of N-methyl-D-aspartate receptor 2B subunit on the surface of motor neurons (P = .047). CONCLUSIONS Our results showed that remote ischemic preconditioning prevented spinal cord ischemia-induced extracellular glutamate increase in ventral horn and suppressed N-methyl-D-aspartate receptor 2B subunit expression.
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Affiliation(s)
- Akira Mukai
- Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koichi Suehiro
- Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka, Japan.
| | - Aya Kimura
- Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yohei Fujimoto
- Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Tomoharu Funao
- Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Takashi Mori
- Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kiyonobu Nishikawa
- Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka, Japan
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Athiraman U, Tempelhoff R, Karanikolas M. Effects of Hypoxic and Ischemic Clinical Conditions on the Outcomes of Acute Ischemic Stroke Patients. Indian J Crit Care Med 2020; 24:104-108. [PMID: 32205941 PMCID: PMC7075063 DOI: 10.5005/jp-journals-10071-23349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background Several studies have shown the neuroprotective role afforded by hypoxic and ischemic preconditioning in cerebrovascular disorders. There are several clinical conditions which simulate the hypoxic and ischemic conditioning in humans. The aim of this retrospective study is to identify whether the presence of any clinical scenarios mimicking the hypoxic and ischemic conditions prior to the current acute ischemic stroke (AIS) has a neuroprotective role in these patients. Materials and methods Data were collected for patients >18 years of age who underwent endovascular treatment for AIS from January 2009 to June 2015. A good outcome was defined as modified Rankin score (mRS) of 0 to 3 at discharge and a poor outcome as mRS of 4-6. A logistic regression analysis was performed to identify independent predictors of outcomes at discharge in both groups. A p value of <0.05 was considered statistically significant for all analyses. Results A total of 102 patients, aged 67 ± 16 years with median preprocedural National Institute of Health Stroke Scale (NIHSS) score 17.5 (1-36), were included. Twenty-one (21%) patients had a good outcome (mRS: 0-3) and 81 (79%) had a poor outcome (mRS: 4-6). A logistic regression analysis identified higher NIHSS score [odds ratio (OR): 1.251, confidence interval (CI): 1.11-1.40, p = 0.0002] and history of transient ischemic attack (TIA; OR: 7.881, CI: 1.05-21.01, p < 0.04) as predictors of a poor outcome at discharge. Conclusion Our data suggest that the occurrence of TIA preceding an AIS may be associated with the poor outcomes in patients with AIS, although this finding needs confirmation in larger studies. How to cite this article Athiraman U, Tempelhoff R, Karanikolas M. Effects of Hypoxic and Ischemic Clinical Conditions on the Outcomes of Acute Ischemic Stroke Patients. Indian J Crit Care Med 2020;24(2):104-108.
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Affiliation(s)
| | - Rene Tempelhoff
- Department of Anesthesiology and Neurological Surgery, Washington University, St. Louis, Missouri, USA
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Gorog DA, Farag M, Spinthakis N, Yellon DM, Bøtker HE, Kharbanda RK, Hausenloy DJ. Effect of remote ischaemic conditioning on platelet reactivity and endogenous fibrinolysis in ST-elevation myocardial infarction: a substudy of the CONDI-2/ERIC-PPCI randomized controlled trial. Cardiovasc Res 2020; 117:623-634. [PMID: 32163139 DOI: 10.1093/cvr/cvaa061] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/20/2020] [Accepted: 03/11/2020] [Indexed: 01/30/2023] Open
Abstract
AIMS Remote ischaemic conditioning (RIC) has been shown to reduce myocardial infarct size in animal models of myocardial infarction. Platelet thrombus formation is a critical determinant of outcome in ST-segment elevation myocardial infarction (STEMI). Whether the beneficial effects of RIC are related to thrombotic parameters is unclear. METHODS AND RESULTS In a substudy of the Effect of Remote Ischaemic Conditioning on clinical outcomes in STEMI patients undergoing Primary Percutaneous Coronary Intervention (ERIC-PPCI) trial, we assessed the effect of RIC on thrombotic status. Patients presenting with STEMI were randomized to immediate RIC consisting of an automated autoRIC™ cuff on the upper arm inflated to 200 mmHg for 5 min and deflated for 5 min for four cycles (n = 53) or sham (n = 47). Venous blood was tested at presentation, discharge (48 h) and 6-8 weeks, to assess platelet reactivity, coagulation, and endogenous fibrinolysis using the Global Thrombosis Test and thromboelastography. Baseline thrombotic status was similar in the two groups. At discharge, there was some evidence that the time to in vitro thrombotic occlusion under high shear stress was longer with RIC compared to sham (454 ± 105 s vs. 403 ± 105 s; mean difference 50.1 s; 95% confidence interval 93.7-6.4, P = 0.025), but this was no longer apparent at 6-8 weeks. There was no difference in clot formation or endogenous fibrinolysis between the study arms at any time point. CONCLUSION RIC may reduce platelet reactivity in the first 48 h post-STEMI. Further research is needed to delineate mechanisms through which RIC may reduce platelet reactivity, and whether it may improve outcomes in patients with persistent high on-treatment platelet reactivity.
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Affiliation(s)
- Diana A Gorog
- National Heart and Lung Institute, Faculty of Medicine, Imperial College, Dovehouse Street, London SW3 6LR, UK.,Postgraduate Medical School, University of Hertfordshire, Hertfordshire, UK.,Department of Cardiology, East and North Hertfordshire NHS Trust, Hertfordshire, UK
| | - Mohamed Farag
- Postgraduate Medical School, University of Hertfordshire, Hertfordshire, UK.,Cardiology Department, Royal Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge, UK
| | - Nikolaos Spinthakis
- Postgraduate Medical School, University of Hertfordshire, Hertfordshire, UK.,Department of Cardiology, East and North Hertfordshire NHS Trust, Hertfordshire, UK
| | - Derek M Yellon
- The Hatter Cardiovascular Institute, University College London, London, UK
| | - Hans Erik Bøtker
- Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark
| | - Rajesh K Kharbanda
- Cardiology Department, Oxford Heart Centre, Oxford University Hospitals NHS Trust, Oxford, UK.,Department of Cardiovascular Medicine, University of Oxford, Oxford, UK
| | - Derek J Hausenloy
- The Hatter Cardiovascular Institute, University College London, London, UK.,Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.,Department of Cardiology, National Heart Research Institute Singapore, National Heart Centre, Singapore, Singapore.,Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore.,Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taichung City, Taiwan.,Tecnologico de Monterrey, Centro de Biotecnologia-FEMSA, Nuevo Leon, Mexico
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The impact of acute remote ischaemic preconditioning on cerebrovascular function. Eur J Appl Physiol 2020; 120:603-612. [PMID: 31932877 PMCID: PMC7042189 DOI: 10.1007/s00421-019-04297-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 12/30/2019] [Indexed: 12/04/2022]
Abstract
Purpose Remote ischaemic preconditioning (RIPC) refers to the protection conferred to tissues and organs via brief periods of ischaemia in a remote vascular territory, including the brain. Recent studies in humans report that RIPC provides neuroprotection against recurrent (ischaemic) stroke. To better understand the ability of RIPC to improve brain health, the present study explored the potential for RIPC to acutely improve cerebrovascular function. Methods Eleven young healthy (females n = 6, age; 28.1 ± 3.7 years) and 9 older individuals (females n = 4, age 52.5 ± 6.7 years) at increased risk for stroke (cardiovascular disease risk factors) underwent assessments of cerebrovascular function, assessed by carbon dioxide (CO2) reactivity and cerebral autoregulation during normo- and hypercapnia (5% CO2) following 40 mins of bilateral arm RIPC or a sham condition. Squat-to-stand manoeuvres were performed to induce changes in blood pressure to assess cerebral autoregulation (0.10 Hz) and analysed via transfer function. Results We found no change in middle cerebral artery velocity or blood pressure across 40 mins of RIPC. Application of RIPC resulted in no change in CO2 reactivity slopes (sham vs RIPC, 1.97 ± 0.88 vs 2.06 ± 0.69 cm/s/mmHg P = 0.61) or parameters of cerebral autoregulation during normocapnia (sham vs RIPC, normalised gain%, 1.27 ± 0.25 vs 1.22 ± 0.35, P = 0.46). Conclusion This study demonstrates that a single bout of RIPC does not influence cerebrovascular function acutely in healthy individuals, or those at increased cardiovascular risk. Given the previously reported protective role of RIPC on stroke recurrence in humans, it is possible that repeated bouts of RIPC may be necessary to impart beneficial effects on cerebrovascular function.
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Durand MJ, Beckert AK, Peterson CY, Ludwig KA, Ridolfi TJ, Lauer KK, Freed JK. You Are Only as Frail as Your Arteries: Prehabilitation of Elderly Surgical Patients. CURRENT ANESTHESIOLOGY REPORTS 2019. [DOI: 10.1007/s40140-019-00357-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Abstract
Purpose of Review
To discuss the concept of prehabilitation for the elderly frail surgical patient as well as strategies to improve preoperative functional capacity and vascular function to decrease postoperative complications.
Recent Findings
Frailty is associated with poor surgical outcomes yet there is no consensus on how frailty should be measured or mitigated in the preoperative period. Prehabilitation, or improving functional capacity prior to surgery typically through exercise, has been shown to be an effective strategy to decrease preoperative frailty and improves surgical outcomes. Use of remote ischemic preconditioning (RIPC) may serve as an alternative to exercise in this fragile patient population.
Summary
Prehabilitation programs using strategies targeted at improving vascular function may decrease frailty in the preoperative period and improve surgical outcomes in the elderly population.
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43
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Weavers H, Wood W, Martin P. Injury Activates a Dynamic Cytoprotective Network to Confer Stress Resilience and Drive Repair. Curr Biol 2019; 29:3851-3862.e4. [PMID: 31668626 PMCID: PMC6868510 DOI: 10.1016/j.cub.2019.09.035] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 08/27/2019] [Accepted: 09/13/2019] [Indexed: 02/07/2023]
Abstract
In healthy individuals, injured tissues rapidly repair themselves following damage. Within a healing skin wound, recruited inflammatory cells release a multitude of bacteriocidal factors, including reactive oxygen species (ROS), to eliminate invading pathogens. Paradoxically, while these highly reactive ROS confer resistance to infection, they are also toxic to host tissues and may ultimately delay repair. Repairing tissues have therefore evolved powerful cytoprotective "resilience" machinery to protect against and tolerate this collateral damage. Here, we use in vivo time-lapse imaging and genetic manipulation in Drosophila to dissect the molecular and cellular mechanisms that drive tissue resilience to wound-induced stress. We identify a dynamic, cross-regulatory network of stress-activated cytoprotective pathways, linking calcium, JNK, Nrf2, and Gadd45, that act to both "shield" tissues from oxidative damage and promote efficient damage repair. Ectopic activation of these pathways confers stress protection to naive tissue, while their inhibition leads to marked delays in wound closure. Strikingly, the induction of cytoprotection is tightly linked to the pathways that initiate the inflammatory response, suggesting evolution of a fail-safe mechanism for tissue protection each time inflammation is triggered. A better understanding of these resilience mechanisms-their identities and precise spatiotemporal regulation-is of major clinical importance for development of therapeutic interventions for all pathologies linked to oxidative stress, including debilitating chronic non-healing wounds.
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Affiliation(s)
- Helen Weavers
- School of Biochemistry, Biomedical Sciences, University of Bristol, Bristol BS8 1TD, UK.
| | - Will Wood
- School of Cellular and Molecular Medicine, Biomedical Sciences, University of Bristol, Bristol BS8 1TD, UK; Centre for Inflammation Research, University of Edinburgh, Queens Medical Research Institute, Edinburgh EH16 4TJ, UK
| | - Paul Martin
- School of Biochemistry, Biomedical Sciences, University of Bristol, Bristol BS8 1TD, UK; School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, Bristol BS8 1TD, UK; School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
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Abstract
Following tissue injury, cells produce reactive molecules that fight off invading pathogens, but these factors might also damage the host tissue. A new study has characterized a network of defense pathways that synergize to protect cells from collateral damage and drive repair.
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Affiliation(s)
- Paul Hiebert
- Institute of Molecular Health Sciences, ETH Zurich, Switzerland.
| | - Sabine Werner
- Institute of Molecular Health Sciences, ETH Zurich, Switzerland.
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45
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Blauenfeldt RA, Hjort N, Gude MF, Behrndtz AB, Fisher M, Valentin JB, Kirkegaard H, Johnsen SP, Hess DC, Andersen G. A multicentre, randomised, sham-controlled trial on REmote iSchemic conditioning In patients with acute STroke (RESIST) - Rationale and study design. Eur Stroke J 2019; 5:94-101. [PMID: 32232175 DOI: 10.1177/2396987319884408] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 10/03/2019] [Indexed: 12/20/2022] Open
Abstract
Rationale Remote ischaemic conditioning, applied in the prehospital setting and continued in-hospital, may improve functional outcome in patients with acute ischaemic stroke and intracerebral haemorrhage. Aims To evaluate whether combined remote ischaemic per- and postconditioning can improve long-term functional outcome in acute ischaemic stroke and intracerebral haemorrhage patients. Methods and design Danish multicentre, prospective, randomised, patient-assessor blinded, sham-controlled study. Adult patients with a putative stroke identified prehospital with symptom duration <4 h, who are independent in daily activities will be randomised 1:1 to remote ischaemic conditioning or Sham-remote ischaemic conditioning. The treatment protocol will be five cycles, each consisting of 5 min with a blood pressure cuff inflation and 5 min with a deflated cuff placed on the upper extremity. The cuff pressure for remote ischaemic conditioning will be 200 mmHg-285 mmHg according to the individual systolic blood pressure and 20 mmHg sham-remote ischaemic conditioning during inflation. The study is approved as an acute study and consent is waived in the acute phase.Sample size estimation: For a 7% increased odds for a beneficial shift on the modified Rankin Scale at a significance level of 5% and power of 90%, 1000 patients with a target diagnosis of acute ischaemic stroke and intracerebral haemorrhage and a total of 1500 patients with a prehospital presumed stroke will be included.Study outcomes: The primary outcome will be the modified Rankin Scale score measured at three-month follow-up (analysed using ordinal logistic regression). ClinicalTrials.gov Identifier: NCT03481777.
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Affiliation(s)
- Rolf A Blauenfeldt
- Neurology & Danish Stroke Center, Aarhus University Hospital, Aarhus, Denmark
| | - Niels Hjort
- Neurology & Danish Stroke Center, Aarhus University Hospital, Aarhus, Denmark
| | - Martin F Gude
- Department of Research and Development, Emergency Medical Services, Central Denmark Region and Aarhus University, Aarhus, Denmark
| | - Anne B Behrndtz
- Neurology & Danish Stroke Center, Aarhus University Hospital, Aarhus, Denmark.,Department of Neurology, Regional Hospital of West Jutland, Holstebro, Denmark
| | - Marc Fisher
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Jan B Valentin
- Danish Center for Clinical Health Services Research, Department of Clinical Medicine, Aalborg University and Aalborg University Hospital, Aalborg, Denmark
| | - Hans Kirkegaard
- Department of Research and Development, Emergency Medical Services, Central Denmark Region and Aarhus University, Aarhus, Denmark
| | - Søren P Johnsen
- Danish Center for Clinical Health Services Research, Department of Clinical Medicine, Aalborg University and Aalborg University Hospital, Aalborg, Denmark
| | - David C Hess
- Department of Neurology, Medical College Georgia & Augusta University, Augusta, GA, USA
| | - Grethe Andersen
- Neurology & Danish Stroke Center, Aarhus University Hospital, Aarhus, Denmark
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46
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Liu C, Zhang C, Du H, Geng X, Zhao H. Remote ischemic preconditioning protects against ischemic stroke in streptozotocin-induced diabetic mice via anti-inflammatory response and anti-apoptosis. Brain Res 2019; 1724:146429. [PMID: 31476295 DOI: 10.1016/j.brainres.2019.146429] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 08/15/2019] [Accepted: 08/29/2019] [Indexed: 01/03/2023]
Abstract
OBJECTIVE It has been shown that remote ischemic preconditioning (RIPreC) attenuates ischemic injury after stroke in healthy rats or mice. The present study aims to examine whether RIPreC offers neuroprotection against ischemic stroke in streptozotocin-induced diabetic mice. METHODS Streptozotocin (STZ, 120 mg/kg) was intraperitoneally injected into the mice to induce type 1 diabetic model. The immune and inflammatory changes were analyzed 2 days after reperfusion by flow cytometry and multiplex cytokine assay analysis, respectively. RESULTS We found that RIPreC reduced infarct sizes and alleviated neurological impairment in diabetic mice. RIPreC decreased CD8 T cells infiltrated into the brain, and attenuated the decreases of CD8 T cells in the blood, CD4 T cells and CD8 T cells in the spleen. Results from multiplex cytokine assay showed that RIPreC treatment decreased IL-6, IL-1 beta and TNF alpha levels in the cortex, while it inhibited IL-6 level in the hippocampus and striatum, and TNF alpha level in the hippocampus. RIPreC treatment also downregulated IL-6 and IFN gamma level in the blood, which increased after cerebral ischemic injury. In addition, RIPreC reduced pro-apoptotic protein BAX expression in the ischemic brain. CONCLUSIONS Our results indicate that RIPreC attenuates cerebral injuries in streptozotocin-induced diabetic mice via anti-inflammatory response and anti-apoptosis in the ischemic brain.
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Affiliation(s)
- Cuiying Liu
- China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, China.
| | - Chencheng Zhang
- China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Huishan Du
- China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, China; Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Xiaokun Geng
- China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, China; Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China.
| | - Heng Zhao
- Department of Neurosurgery, Stanford University, Stanford, CA, USA
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Effects of ischemic conditioning on maximal voluntary plantar flexion contractions. J Electromyogr Kinesiol 2019; 48:37-43. [PMID: 31226630 DOI: 10.1016/j.jelekin.2019.06.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 06/05/2019] [Accepted: 06/11/2019] [Indexed: 01/21/2023] Open
Abstract
Intermittent blood flow restriction to local or remote vascular beds induces endogenous protection against ischemia-reperfusion injury in several tissues and organs. When applied non-invasively by placing occlusion cuffs on the limbs, this ischemic conditioning has been shown to elicit an acute ergogenic response. However, the underlying mechanisms behind this phenomenon remain unknown. Prior research suggest that ischemic conditioning may operate via improved motor discharges from the central nervous system, thus enhancing the electrochemical activation and force generation of agonist muscles. Here we show that, for healthy individuals performing maximal voluntary contractions of the plantar flexors, the acute benefit elicited by ischemic conditioning on maximal isometric ankle torque production is largely explained by parallel gains in the surface myoelectrical activity of the triceps surae. However, the magnitude of this response appears to vary between individuals. These findings indicate that enhanced levels of agonist activity contribute to the ergogenic effect of ischemic conditioning during maximal efforts, thereby enabling more direct assessments of neural output following the procedure.
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48
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Ziegler M, Wang X, Peter K. Platelets in cardiac ischaemia/reperfusion injury: a promising therapeutic target. Cardiovasc Res 2019; 115:1178-1188. [PMID: 30906948 PMCID: PMC6529900 DOI: 10.1093/cvr/cvz070] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 02/01/2019] [Accepted: 03/21/2019] [Indexed: 12/21/2022] Open
Abstract
Acute myocardial infarction (AMI) is the single leading cause of mortality and morbidity worldwide. A key component of AMI therapy is the timely reopening of occluded vessels to prevent further ischaemic damage to the myocardium. However, reperfusion of the ischaemic myocardium can itself trigger reperfusion injury causing up to 50% of the overall infarct size. In recent years, considerable research has been devoted to understanding the pathogenesis of ischaemia/reperfusion (I/R) injury and platelets have emerged as a major contributing factor. This review summarizes the role of platelets in the pathogenesis of I/R injury and highlights the potential of platelet-directed therapeutics to minimize cardiac I/R injury. Activated platelets infiltrate specifically into the ischaemic/reperfused myocardium and contribute to I/R injury by the formation of microthrombi, enhanced platelet-leucocyte aggregation, and the release of potent vasoconstrictor and pro-inflammatory molecules. This review demonstrates the benefits of platelet inhibition beyond their well-described anti-thrombotic effect and highlights the direct cardioprotective role of anti-platelet drugs. In particular, the inhibition of COX, the P2Y12 receptor and the GPIIb/IIIa receptor has demonstrated the potential to attenuate I/R injury. Moreover, targeting of drug candidates or regenerative cells to the activated platelets accumulated within the ischaemic/reperfused myocardium shows remarkable potential to protect the myocardium from I/R injury. Overall, activated platelets play a key role in the pathogenesis of I/R injury. Their direct inhibition as well as their use as epitopes for site-directed therapy is a unique and promising therapeutic approach for the prevention of I/R injury and ultimately the preservation of cardiac function.
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Affiliation(s)
- Melanie Ziegler
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Commercial Road 75, Melbourne, Australia
| | - Xiaowei Wang
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Commercial Road 75, Melbourne, Australia
| | - Karlheinz Peter
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Commercial Road 75, Melbourne, Australia
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49
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Varga G, Ghanem S, Szabo B, Nagy K, Pal N, Tanczos B, Somogyi V, Barath B, Deak A, Peto K, Nemeth N. Renal ischemia-reperfusion-induced metabolic and micro-rheological alterations and their modulation by remote organ ischemic preconditioning protocols in the rat. Clin Hemorheol Microcirc 2019; 71:225-236. [DOI: 10.3233/ch-189414] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Gabor Varga
- Department of Operative Techniques and Surgical Research, Institute of Surgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Souleiman Ghanem
- Department of Operative Techniques and Surgical Research, Institute of Surgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Balazs Szabo
- Department of Operative Techniques and Surgical Research, Institute of Surgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Kitti Nagy
- Department of Operative Techniques and Surgical Research, Institute of Surgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Noemi Pal
- Department of Operative Techniques and Surgical Research, Institute of Surgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Bence Tanczos
- Department of Operative Techniques and Surgical Research, Institute of Surgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Viktoria Somogyi
- Department of Operative Techniques and Surgical Research, Institute of Surgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Barbara Barath
- Department of Operative Techniques and Surgical Research, Institute of Surgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Adam Deak
- Department of Operative Techniques and Surgical Research, Institute of Surgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Katalin Peto
- Department of Operative Techniques and Surgical Research, Institute of Surgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Norbert Nemeth
- Department of Operative Techniques and Surgical Research, Institute of Surgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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50
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Santos RB, Silveira I, Trêpa M, Brochado B, Magalhães R, Rodrigues P, Sousa MJ, Luz A, Silveira J, Albuquerque A, Torres S, Leite-Moreira AF, Carvalho H. The impact of preinfarct angina on the incidence of acute kidney injury in patients with myocardial infarction: interaction with pre-existent chronic kidney disease. Coron Artery Dis 2019; 30:488-493. [PMID: 30741743 DOI: 10.1097/mca.0000000000000710] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
AIM Remote ischemic conditioning may reduce acute kidney injury (AKI) in patients undergoing a coronary intervention. As preinfarct angina (PIA) might act as a preconditioning stimulus in patients with ST-elevation myocardial infarction (STEMI), we aimed to study whether PIA reduces AKI in accordance to pre-existing chronic kidney disease. PATIENTS AND METHODS We conducted a retrospective study including 891 consecutive STEMI patients who underwent primary coronary intervention from January 2008 to March 2016. AKI was determined on the basis of KDIGO criteria. The impact of PIA was evaluated in three groups according to the baseline glomerular filtration rate: less than 45 ml/min/1.73 m (group 1, n = 89), 45-59 ml/min/1.73 m (group 2, n = 117), and greater than or equal to 60 ml/min/1.73 m (group 3, n = 642). Univariate and multivariate predictors for AKI were determined. RESULTS AKI developed in 13.8% of patients (n = 117) and was more prevalent in patients with worse baseline renal function (35% in group 1; 22% in group 2; and 9% in group 3, P < 0.01). The prevalence of PIA was similar across groups (28-34%, P = 0.2). Only in group 1 did patients with PIA have a significantly lower rate of AKI than patients without PIA (19 vs. 42%, P = 0.033). In multivariate analysis, the absence of PIA in group 1 patients conferred an almost three-fold risk of developing AKI (odds ratio = 2.92, P = 0.009), whereas no differences were found for the other groups. Age, total ischemic time, and intra-aortic balloon pump utilization were also related independently to AKI. CONCLUSION In our series, STEMI patients with at least stage 3B chronic kidney disease had a three-fold risk of developing AKI in the absence of PIA. These findings suggest that patients with worse renal function may be more susceptible to the renoprotective effect of myocardial ischemic preconditioning.
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Affiliation(s)
| | | | - Maria Trêpa
- Department of Cardiology, Porto Hospital Centre
| | | | - Rui Magalhães
- Unit for Multidisciplary Investigation in Biomedicine, Institute of Biomedical Sciences of 'Abel Salazar'
| | - Patrícia Rodrigues
- Department of Cardiology, Porto Hospital Centre.,Unit for Multidisciplary Investigation in Biomedicine, Institute of Biomedical Sciences of 'Abel Salazar'
| | | | - André Luz
- Department of Cardiology, Porto Hospital Centre.,Unit for Multidisciplary Investigation in Biomedicine, Institute of Biomedical Sciences of 'Abel Salazar'
| | | | | | | | - Adelino F Leite-Moreira
- Department of Surgery and Physiology, Cardiovascular Research Centre, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Henrique Carvalho
- Department of Cardiology, Porto Hospital Centre.,Unit for Multidisciplary Investigation in Biomedicine, Institute of Biomedical Sciences of 'Abel Salazar'
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