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Basalay MV, Downey JM, Davidson SM, Yellon DM. The Infarct-Limiting Effect of Remote Ischemic Conditioning in Rats Is Not Affected by Aspirin. Cardiovasc Drugs Ther 2025; 39:691-695. [PMID: 38117423 PMCID: PMC12116765 DOI: 10.1007/s10557-023-07541-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/12/2023] [Indexed: 12/21/2023]
Abstract
PURPOSE Remote ischemic conditioning (RIC) has been shown to be a powerful cardioprotective therapy in animal models. However, a protective effect in patients presenting with acute myocardial infarction has failed to be confirmed. A recent pre-clinical study reported that aspirin which is routinely given to patients undergoing reperfusion therapy blocked the infarct-limiting effect of ischemic postconditioning. The present study was designed to test whether aspirin could also be blocking the infarct-limiting effect of RIC. METHODS This was investigated in vivo using male Sprague Dawley rats (n = 5 to 6 per group) subjected to either 30 min of regional myocardial ischemia, followed by 120-min reperfusion, or additionally to a RIC protocol initiated after 20-min myocardial ischemia. The RIC protocol included four cycles of 5-min hind limb ischemia interspersed with 5-min reperfusion. Intravenous aspirin (30 mg/kg) or vehicle (saline) was administered after 15-min myocardial ischemia. RESULTS RIC significantly reduced infarct size (IS) normalized to the area at risk, by 47%. Aspirin administration did not affect IS nor did it attenuate the infarct-limiting effect of RIC. CONCLUSION Aspirin administration in the setting of myocardial infarction is not likely to interfere with the cardioprotective effect of RIC.
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Affiliation(s)
- M V Basalay
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - James M Downey
- Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL, 36688, USA
| | - S M Davidson
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - D M Yellon
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.
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Keim C, Wiedenmann L, Schubert T, Rothe M, Dobre BC, Kaess BM, Ehrlich JR, Boehmer AA. Remote Ischemic Preconditioning for Electrical Cardioversion of Atrial Fibrillation-the Prospective Randomized PRECON-AF Study. CJC Open 2025; 7:571-578. [PMID: 40433224 PMCID: PMC12105482 DOI: 10.1016/j.cjco.2025.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 03/05/2025] [Indexed: 05/29/2025] Open
Abstract
Background Electrical cardioversion (ECV) is highly effective in restoring sinus rhythm in patients with atrial fibrillation (AF), but it does not influence long-term rhythm control. Remote ischemic preconditioning (RIPC) has demonstrated various cardioprotective effects. Combining ECV with RIPC could provide a promising approach to minimizing AF recurrences after successful ECV. Methods This prospective, randomized, single-blinded, single-centre study investigated the impact of RIPC on early AF recurrence following successful ECV (defined as sinus rhythm ≥ 30 seconds). Patients were randomized in a 1:1 ratio to receive either RIPC or sham preconditioning before ECV. RIPC was performed in a standardized manner, with 3 cycles of 5-minute forearm ischemia followed by 5 minutes of reperfusion. The primary efficacy endpoint was AF recurrence after 30 days. Safety endpoints included death, stroke, and procedure-related complications. Secondary endpoints were acute ECV success, mean energy, and number of shocks required to restore sinus rhythm. Results A total of 240 patients were enrolled. Of these, 214 (89%) had successful ECV. At follow-up, the RIPC group did not show a lower AF recurrence rate, compared to that in the sham group (39% vs 36%, P = 0.63), and no effect of RIPC on cardioversion parameters was seen. One stroke occurred in the RIPC group. The study was terminated before the number of prespecified follow-up visits was reached, due to determination of futility. Conclusions RIPC did not impact the short-term rhythm-control or cardioversion procedure in patients with AF undergoing ECV. Clinical Trial Registration NCT05342220.
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Affiliation(s)
- Christoph Keim
- Department of Cardiology, St. Josefs-Hospital Wiesbaden, Wiesbaden, Germany
| | - Lilli Wiedenmann
- Department of Cardiology, St. Josefs-Hospital Wiesbaden, Wiesbaden, Germany
| | - Tim Schubert
- Department of Cardiology, St. Josefs-Hospital Wiesbaden, Wiesbaden, Germany
- Department of Pediatric Cardiology and Congenital Heart Disease, Heidelberg University Hospital, Heidelberg, Germany
| | - Moritz Rothe
- Department of Cardiology, St. Josefs-Hospital Wiesbaden, Wiesbaden, Germany
| | - Bianca C. Dobre
- Department of Cardiology, St. Josefs-Hospital Wiesbaden, Wiesbaden, Germany
| | - Bernhard M. Kaess
- Department of Cardiology, St. Josefs-Hospital Wiesbaden, Wiesbaden, Germany
| | - Joachim R. Ehrlich
- Department of Cardiology, St. Josefs-Hospital Wiesbaden, Wiesbaden, Germany
| | - Andreas A. Boehmer
- Department of Cardiology, St. Josefs-Hospital Wiesbaden, Wiesbaden, Germany
- Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
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Pearce L, Galán-Arriola C, Bell RM, Carr RD, Cunningham J, Davidson SM, Ghosh AK, Giesz S, Golforoush P, Gourine AV, Hermann DM, Heusch G, Ibanez B, Kalkhoran SB, Lecour S, Lukhna K, Ntsekhe M, Sack MN, Unwin RJ, Vilahur G, Walker JM, Yellon DM. Inter-organ communication: pathways and targets to cardioprotection and neuro-protection. A report from the 12th Hatter Cardiovascular Institute workshop. Basic Res Cardiol 2025; 120:287-299. [PMID: 39681732 PMCID: PMC11976342 DOI: 10.1007/s00395-024-01094-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 12/04/2024] [Accepted: 12/04/2024] [Indexed: 12/18/2024]
Abstract
A long-standing aim in the setting of various pathologies including acute myocardial infarction, chronic kidney disease (CKD), and ischaemic stroke, has been to identify successful approaches to augment cellular and organ protection. Although the continual evolution and refinement of ideas over the past few decades has allowed the field to progress, we are yet to realise successful clinical translation of this concept. The 12th Hatter Cardiovascular Workshop identified a number of important points and key questions for future research relating to cardio- and neuro-protection and interorgan communication. Specific topics that were discussed include the 'cardio-metabolic-renal' axis of organ protection, the parasympathetic signalling hypothesis, the role of the coronary microvasculature in myocardial infarction, the RISK pathway of cardioprotection, extracellular vesicles and the way forward, the future for clinical studies of remote ischaemic conditioning, and new experimental models for cardio-oncology investigations.
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Affiliation(s)
- L Pearce
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - C Galán-Arriola
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - R M Bell
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - R D Carr
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
- School of Biomedical Sciences, Ulster University, Coleraine, UK
| | - J Cunningham
- Centre for Nephrology, University College London, London, UK
| | - S M Davidson
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - A K Ghosh
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - S Giesz
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - P Golforoush
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - A V Gourine
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, UK
| | - D M Hermann
- Chair of Vascular Neurology, Dementia and Ageing Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - G Heusch
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany
| | - B Ibanez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
- IIS-Fundación Jiménez Díaz Hospital, Madrid, Spain
| | - S Beikoghli Kalkhoran
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - S Lecour
- University of Cape Town, Cape Town, South Africa
| | - K Lukhna
- University of Cape Town, Cape Town, South Africa
| | - M Ntsekhe
- University of Cape Town, Cape Town, South Africa
| | - M N Sack
- Laboratory of Mitochondrial Biology and Metabolism, NHLBI, National Institutes of Health, Bethesda, MD, USA
| | - R J Unwin
- Centre for Nephrology, University College London, London, UK
| | - G Vilahur
- Institut de Recerca Sant Pau, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, CIBERCV, Barcelona, Spain
| | - J M Walker
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - D M Yellon
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.
- University of Cape Town, Cape Town, South Africa.
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Xia L, Yang Q, Jiang L, Zheng Y, Chen L, Lin S, Reinhardt JD, Lu X. Effect of perioperative remote ischemic conditioning on myocardial injury in patients with unstable angina undergoing percutaneous coronary intervention: protocol of a multicenter, randomized, double-blind clinical trial. Trials 2025; 26:63. [PMID: 39984971 PMCID: PMC11844111 DOI: 10.1186/s13063-025-08744-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 01/27/2025] [Indexed: 02/23/2025] Open
Abstract
BACKGROUND Cardiovascular disease is a leading cause of death, with ischemic heart disease being a significant contributor. While percutaneous coronary intervention (PCI) effectively reduces mortality in myocardial infarction patients, its efficacy for unstable angina (UA) patients is controversial. Complications associated with PCI further limit application in UA. RIC is hypothesized to be an effective co-intervention that reduces PCI-related complications and may potentially enhance the efficacy of the PCI procedure itself. METHODS This is a pragmatic, prospective, dual-center, double-blind, randomized controlled clinical trial assessing the effect of remote ischemic conditioning (RIC) during percutaneous coronary intervention (PCI) on injury in unstable angina patients aged ≥ 18 years undergoing coronary angiography. Participants will be randomized to receive either RIC or Sham RIC, in addition to standard pharmacotherapy. Primary outcome includes periprocedural myocardial injury measured by hs-cTnT levels, while secondary outcomes encompass major adverse cardiovascular events, coronary artery lesions Gensini Score, arrhythmia, angina incidence, SAQ scores, ECG changes, and cardiac function assessed by two-dimensional echocardiography. The trial aims to recruit 574 participants and is scheduled to be initiated on 15 January 2024. We will conduct the primary statistical analysis using the intention-to-treat principle. Results from the trial will be presented as comparative summary statistics following the Consolidated Standards of Reporting Trials (CONSORT) guidelines. TRIAL REGISTRATION ChiCTR2400079855, 15 January 2024.
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Affiliation(s)
- Lingfeng Xia
- Department of Rehabilitation Medicine, the First Affiliated Hospital of Nanjing Medical University, No.300 Guangzhou Road, Nanjing, 210029, China
| | - Qingyan Yang
- Department of Rehabilitation Medicine, the First Affiliated Hospital of Nanjing Medical University, No.300 Guangzhou Road, Nanjing, 210029, China
| | - Lingjun Jiang
- Department of Sports and Rehabilitation Medicine, Ulm University Hospital, Ulm, Germany
- Department of Molecular and Cellular Sports Medicine, German Sport University Cologne, Cologne, Germany
| | - Yu Zheng
- Department of Rehabilitation Medicine, the First Affiliated Hospital of Nanjing Medical University, No.300 Guangzhou Road, Nanjing, 210029, China
| | - Leilei Chen
- Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, No.300 Guangzhou Road, Nanjing, 210029, China.
| | - Song Lin
- Department of Cardiology, the Affiliated Nanjing First Hospital of Nanjing Medical University, No. 68 Changle Road, Nanjing, 210008, China.
| | - Jan D Reinhardt
- Institute for Disaster Management and Reconstruction of Sichuan University and Hongkong Polytechnic University, No. 122 Huanghezhong Road First Section, Chengdu, 610207, China.
- Swiss Paraplegic Research, Nottwil, 6207, Switzerland.
- Department of Health Sciences and Medicine, University of Lucerne, Lucerne, 6000, Switzerland.
| | - Xiao Lu
- Department of Rehabilitation Medicine, the First Affiliated Hospital of Nanjing Medical University, No.300 Guangzhou Road, Nanjing, 210029, China.
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Erkens R, Duse DA, Brum A, Chadt A, Becher S, Siragusa M, Quast C, Müssig J, Roden M, Cortese-Krott M, Ibáñez B, Lammert E, Fleming I, Jung C, Al-Hasani H, Heusch G, Kelm M. Inhibition of proline-rich tyrosine kinase 2 restores cardioprotection by remote ischaemic preconditioning in type 2 diabetes. Br J Pharmacol 2024; 181:4174-4194. [PMID: 38956895 DOI: 10.1111/bph.16483] [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: 12/14/2023] [Revised: 04/26/2024] [Accepted: 05/24/2024] [Indexed: 07/04/2024] Open
Abstract
BACKGROUND AND PURPOSE Remote ischaemic preconditioning (rIPC) for cardioprotection is severely impaired in diabetes, and therapeutic options to restore it are lacking. The vascular endothelium plays a key role in rIPC. Given that the activity of endothelial nitric oxide synthase (eNOS) is inhibited by proline-rich tyrosine kinase 2 (Pyk2), we hypothesized that pharmacological Pyk2 inhibition could restore eNOS activity and thus restore remote cardioprotection in diabetes. EXPERIMENTAL APPROACH New Zealand obese (NZO) mice that demonstrated key features of diabetes were studied. The consequence of Pyk2 inhibition on endothelial function, rIPC and infarct size after myocardial infarction were evaluated. The impact of plasma from mice and humans with or without diabetes was assessed in isolated buffer perfused murine hearts and aortic rings. KEY RESULTS Plasma from nondiabetic mice and humans, both subjected to rIPC, caused remote tissue protection. Similar to diabetic humans, NZO mice demonstrated endothelial dysfunction. NZO mice had reduced circulating nitrite levels, elevated arterial blood pressure and a larger infarct size after ischaemia and reperfusion than BL6 mice. Pyk2 increased the phosphorylation of eNOS at its inhibitory site (Tyr656), limiting its activity in diabetes. The cardioprotective effects of rIPC were abolished in diabetic NZO mice. Pharmacological Pyk2 inhibition restored endothelial function and rescued cardioprotective effects of rIPC. CONCLUSION AND IMPLICATIONS Endothelial function and remote tissue protection are impaired in diabetes. Pyk2 is a novel target for treating endothelial dysfunction and restoring cardioprotection through rIPC in diabetes.
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Affiliation(s)
- Ralf Erkens
- Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
| | - Dragos Andrei Duse
- Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
| | - Amanda Brum
- Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
| | - Alexandra Chadt
- Institute for Clinical Biochemistry and Pathobiochemistry, Deutsches Diabetes Zentrum at Heinrich Heine University of Duesseldorf, Duesseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Partner Duesseldorf, Neuherberg, Germany
| | - Stefanie Becher
- Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
| | - Mauro Siragusa
- Center for Molecular Medicine, Institute for Vascular Signalling, Goethe University Frankfurt, Frankfurt, Germany
- German Centre for Cardiovascular Research, Partner site RhineMain, Frankfurt, Germany
| | - Christine Quast
- Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
| | - Johanna Müssig
- Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
| | - Michael Roden
- German Center for Diabetes Research (DZD e.V.), Partner Duesseldorf, Neuherberg, Germany
- Department of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University and University Hospital Duesseldorf, Duesseldorf, Germany
- Institute for Clinical Diabetology, Deutsches Diabetes Zentrum at Heinrich Heine University of Duesseldorf, Duesseldorf, Germany
| | - Miriam Cortese-Krott
- Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
- CARID Cardiovascular Research Institute Duesseldorf, Duesseldorf, Germany
| | - Borja Ibáñez
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Eckhard Lammert
- German Center for Diabetes Research (DZD e.V.), Partner Duesseldorf, Neuherberg, Germany
- Institute of Metabolic Physiology, Heinrich-Heine University, Duesseldorf, Germany
| | - Ingrid Fleming
- Center for Molecular Medicine, Institute for Vascular Signalling, Goethe University Frankfurt, Frankfurt, Germany
- German Centre for Cardiovascular Research, Partner site RhineMain, Frankfurt, Germany
| | - Christian Jung
- Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
| | - Hadi Al-Hasani
- Institute for Clinical Biochemistry and Pathobiochemistry, Deutsches Diabetes Zentrum at Heinrich Heine University of Duesseldorf, Duesseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Partner Duesseldorf, Neuherberg, Germany
| | - Gerd Heusch
- Institute for Pathophysiology, West German Heart and Vascular Center, University School of Medicine Essen, Essen, Germany
| | - Malte Kelm
- Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
- CARID Cardiovascular Research Institute Duesseldorf, Duesseldorf, Germany
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Lieder HR, Paket U, Skyschally A, Rink AD, Baars T, Neuhäuser M, Kleinbongard P, Heusch G. Vago-splenic signal transduction of cardioprotection in humans. Eur Heart J 2024; 45:3164-3177. [PMID: 38842545 DOI: 10.1093/eurheartj/ehae250] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 03/13/2024] [Accepted: 04/08/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND AND AIMS The spleen serves as an important relay organ that releases cardioprotective factor(s) upon vagal activation during remote ischaemic conditioning (RIC) in rats and pigs. The translation of these findings to humans was attempted. METHODS Remote ischaemic conditioning or electrical auricular tragus stimulation (ATS) were performed in 10 healthy young volunteers, 10 volunteers with splenectomy, and 20 matched controls. Venous blood samples were taken before and after RIC/ATS or placebo, and a plasma dialysate was infused into isolated perfused rat hearts subjected to global ischaemia/reperfusion. RESULTS Neither left nor right RIC or ATS altered heart rate and heart rate variability in the study cohorts. With the plasma dialysate prepared before RIC or ATS, respectively, infarct size (% ventricular mass) in the recipient rat heart was 36 ± 6% (left RIC), 34 ± 3% (right RIC) or 31 ± 5% (left ATS), 35 ± 5% (right ATS), and decreased with the plasma dialysate from healthy volunteers after RIC or ATS to 20 ± 4% (left RIC), 23 ± 6% (right RIC) or to 19 ± 4% (left ATS), 26 ± 9% (right ATS); infarct size was still reduced with plasma dialysate 4 days after ATS and 9 days after RIC. In a subgroup of six healthy volunteers, such infarct size reduction was abrogated by intravenous atropine. Infarct size reduction by RIC or ATS was also abrogated in 10 volunteers with splenectomy, but not in their 20 matched controls. CONCLUSIONS In humans, vagal innervation and the spleen as a relay organ are decisive for the cardioprotective signal transduction of RIC and ATS.
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Affiliation(s)
- Helmut Raphael Lieder
- Institute for Pathophysiology, West German Heart and Vascular Centre, University of Essen Medical School, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Umut Paket
- Institute for Pathophysiology, West German Heart and Vascular Centre, University of Essen Medical School, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Andreas Skyschally
- Institute for Pathophysiology, West German Heart and Vascular Centre, University of Essen Medical School, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Andreas D Rink
- Department of General, Visceral and Transplant Surgery, University of Essen Medical School, University of Duisburg-Essen, Essen, Germany
| | - Theodor Baars
- Private Practice of General and Internal Medicine, Kölner Straße 68, Essen, Germany
| | - Markus Neuhäuser
- Department of Mathematics and Technology, Koblenz University of Applied Sciences, Rhein-Ahr-Campus, Remagen, Germany
| | - Petra Kleinbongard
- Institute for Pathophysiology, West German Heart and Vascular Centre, University of Essen Medical School, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Gerd Heusch
- Institute for Pathophysiology, West German Heart and Vascular Centre, University of Essen Medical School, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
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Bin EP, Zaobornyj T, Garces M, D'Annunzio V, Buchholz B, Marchini T, Evelson P, Gelpi RJ, Donato M. Remote ischemic preconditioning prevents sarcolemmal-associated proteolysis by MMP-2 inhibition. Mol Cell Biochem 2024; 479:2351-2363. [PMID: 37728809 DOI: 10.1007/s11010-023-04849-2] [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: 12/01/2022] [Accepted: 09/02/2023] [Indexed: 09/21/2023]
Abstract
The death of myocytes occurs through different pathways, but the rupture of the plasma membrane is the key point in the transition from reversible to irreversible injury. In the myocytes, three major groups of structural proteins that link the extracellular and intracellular milieus and confer structural stability to the cell membrane: the dystrophin-associated protein complex, the vinculin-integrin link, and the spectrin-based submembranous cytoskeleton. The objective was to determine if remote ischemic preconditioning (rIPC) preserves membrane-associated cytoskeletal proteins (dystrophin and β-dystroglycan) through the inhibition of metalloproteinase type 2 (MMP-2) activity. A second objective was to describe some of the intracellular signals of the rIPC, that modify mitochondrial function at the early reperfusion. Isolated rat hearts were subjected to 30 min of global ischemia and 120 min of reperfusion (I/R). rIPC was performed by 3 cycles of ischemia/reperfusion in the lower limb (rIPC). rIPC significantly decreased the infarct size, induced Akt/GSK-3 β phosphorylation and inhibition of the MPTP opening. rIPC improved mitochondrial function, increasing membrane potential, ATP production and respiratory control. I/R increased ONOO- production, which activates MMP-2. This enzyme degrades β-dystroglycan and dystrophin and collaborates to sarcolemmal disruption. rIPC attenuates the breakdown of β-dystroglycan and dystrophin through the inhibition of MMP-2 activity. Furthermore, we confirm that rIPC activates different intracellular pathway that involves the an Akt/Gsk3β and MPTP pore with preservation of mitochondrial function.
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Affiliation(s)
- Eliana P Bin
- Universidad de Buenos Aires, Facultad de Ciencias Médicas, Instituto de Fisiopatología Cardiovascular, 950 J. E. Uriburu, 2nd floor, C1114AAD, Buenos Aires, Argentina
- Universidad de Buenos Aires - CONICET, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Buenos Aires, Argentina
| | - Tamara Zaobornyj
- Universidad de Buenos Aires - CONICET, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Buenos Aires, Argentina
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Físico-Química, Buenos Aires, Argentina
| | - Mariana Garces
- Universidad de Buenos Aires - CONICET, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Buenos Aires, Argentina
| | - Verónica D'Annunzio
- Universidad de Buenos Aires, Facultad de Ciencias Médicas, Instituto de Fisiopatología Cardiovascular, 950 J. E. Uriburu, 2nd floor, C1114AAD, Buenos Aires, Argentina
- Universidad de Buenos Aires - CONICET, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Buenos Aires, Argentina
| | - Bruno Buchholz
- Universidad de Buenos Aires, Facultad de Ciencias Médicas, Instituto de Fisiopatología Cardiovascular, 950 J. E. Uriburu, 2nd floor, C1114AAD, Buenos Aires, Argentina
- Universidad de Buenos Aires - CONICET, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Buenos Aires, Argentina
| | - Timoteo Marchini
- Universidad de Buenos Aires - CONICET, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Buenos Aires, Argentina
| | - Pablo Evelson
- Universidad de Buenos Aires - CONICET, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Buenos Aires, Argentina
| | - Ricardo J Gelpi
- Universidad de Buenos Aires, Facultad de Ciencias Médicas, Instituto de Fisiopatología Cardiovascular, 950 J. E. Uriburu, 2nd floor, C1114AAD, Buenos Aires, Argentina
- Universidad de Buenos Aires - CONICET, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Buenos Aires, Argentina
| | - Martín Donato
- Universidad de Buenos Aires, Facultad de Ciencias Médicas, Instituto de Fisiopatología Cardiovascular, 950 J. E. Uriburu, 2nd floor, C1114AAD, Buenos Aires, Argentina.
- Universidad de Buenos Aires - CONICET, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Buenos Aires, Argentina.
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Yan Y, Zhao C, Niu J, Yan P, Li J, Wang D, Li G. Rationale and Design of the IMPROVE Trial: A Multicenter, Randomized, Controlled, Open-label, Blinded-endpoint Trial Assessing the Efficacy of Remote Ischemic Conditioning in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting. Adv Ther 2024; 41:3003-3012. [PMID: 38616242 DOI: 10.1007/s12325-024-02836-7] [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: 12/02/2023] [Accepted: 03/07/2024] [Indexed: 04/16/2024]
Abstract
INTRODUCTION Despite the appearance of off-pump coronary artery bypass grafting (CABG), ischemia-reperfusion injury (IRI) in the perioperative period still arouses concerns of clinicians. Remote ischemic conditioning (RIC) is the process of repeated ischemia and reperfusion in the peripheral vessels, which is proven to reduce IRI in vital organs. However, the effect of RIC in patients undergoing off-pump CABG is still unclear. METHODS This IMPROVE trial is a national, multicenter, randomized, controlled, open-label, blinded-endpoint clinical trial designed to assess whether RIC intervention can improve short-term prognosis of patients undergoing off-pump CABG. It plans to enroll 648 patients who will be randomly assigned into a RIC group or control group. Patients in the RIC group will receive four cycles of 5 min of pressurization (about 200 mmHg) and 5 min of rest in the 3 days before and 7 days after the surgery. PLANNED OUTCOMES The primary outcome is the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) within the 3-month follow-up. MACCE is defined as all-cause death, myocardial infarction, stroke, and coronary revascularization surgery. CLINICAL TRIAL REGISTRATION NCT06141525 (ClinicalTrials.gov).
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Affiliation(s)
- Yang Yan
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Changying Zhao
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jialan Niu
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Pengyun Yan
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jing Li
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Cardiovascular Surgery, People's Hospital of Qinghai Province, Xining, China
| | - Duolao Wang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Clinical Sciences, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK
- Department of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Guoliang Li
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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Braczko F, Fischl SR, Reinders J, Lieder HR, Kleinbongard P. Activation of the nonneuronal cholinergic cardiac system by hypoxic preconditioning protects isolated adult cardiomyocytes from hypoxia/reoxygenation injury. Am J Physiol Heart Circ Physiol 2024; 327:H70-H79. [PMID: 38700468 PMCID: PMC11380960 DOI: 10.1152/ajpheart.00211.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 04/26/2024] [Accepted: 04/29/2024] [Indexed: 05/05/2024]
Abstract
Activation of the vagus nerve mediates cardioprotection and attenuates myocardial ischemia/reperfusion (I/R) injury. In response to vagal activation, acetylcholine (ACh) is released from the intracardiac nervous system (ICNS) and activates intracellular cardioprotective signaling cascades. Recently, however, a nonneuronal cholinergic cardiac system (NNCCS) in cardiomyocytes has been described as an additional source of ACh. To investigate whether the NNCCS mediates cardioprotection in the absence of vagal and ICNS activation, we used a reductionist approach of isolated adult rat ventricular cardiomyocytes without neuronal cells, using hypoxic preconditioning (HPC) as a protective stimulus. Adult rat ventricular cardiomyocytes were isolated, the absence of neuronal cells was confirmed, and HPC was induced by 10/20 min hypoxia/reoxygenation (H/R) before subjection to 30/5 min H/R to simulate I/R injury. Cardiomyocyte viability was assessed by trypan blue staining at baseline and after HPC+H/R or H/R. Intra- and extracellular ACh was quantified using liquid chromatography-coupled mass spectrometry at baseline, after HPC, after hypoxia, and after reoxygenation, respectively. In a subset of experiments, muscarinic and nicotinic ACh receptor (m- and nAChR) antagonists were added during HPC or during H/R. Cardiomyocyte viability at baseline (69 ± 4%) was reduced by H/R (10 ± 3%). With HPC, cardiomyocyte viability was preserved after H/R (25 ± 6%). Intra- and extracellular ACh increased during hypoxia; HPC further increased both intra- and extracellular ACh (from 0.9 ± 0.7 to 1.5 ± 1.0 nmol/mg; from 0.7 ± 0.6 to 1.1 ± 0.7 nmol/mg, respectively). The addition of mAChR and nAChR antagonists during HPC had no impact on HPC's protection; however, protection was abrogated when antagonists were added during H/R (cardiomyocyte viability after H/R: 23 ± 5%; 13 ± 4%). In conclusion, activation of the NNCCS is involved in cardiomyocyte protection; HPC increases intra- and extracellular ACh during H/R, and m- and nAChRs are causally involved in HPC's cardiomyocyte protection during H/R. The interplay between upstream ICNS activation and NNCCS activation in myocardial cholinergic metabolism and cardioprotection needs to be investigated in future studies.NEW & NOTEWORTHY The intracardiac nervous system is considered to be involved in ischemic conditioning's cardioprotection through the release of acetylcholine (ACh). However, we demonstrate that hypoxic preconditioning (HPC) protects from hypoxia/reoxygenation injury and increases intra- and extracellular ACh during hypoxia in isolated adult ventricular rat cardiomyocytes. HPC's protection involves cardiomyocyte muscarinic and nicotinic ACh receptor activation. Thus, besides the intracardiac nervous system, a nonneuronal cholinergic cardiac system may also be causally involved in cardiomyocyte protection by ischemic conditioning.
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Affiliation(s)
- Felix Braczko
- Institute for Pathophysiology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany
| | - Sara Romina Fischl
- Institute for Pathophysiology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany
| | - Jörg Reinders
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany
| | - Helmut Raphael Lieder
- Institute for Pathophysiology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany
| | - Petra Kleinbongard
- Institute for Pathophysiology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany
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Huang LY, Zhang YD, Liu YN, Liang ZY, Chen J, Wang B, Yin QL, Wang PP, Wang W, Qi SH. Remote Ischemic Postconditioning-Mediated Neuroprotection against Stroke by Promoting Ketone Body-Induced Ferroptosis Inhibition. ACS Chem Neurosci 2024; 15:2223-2232. [PMID: 38634698 DOI: 10.1021/acschemneuro.4c00014] [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] [Indexed: 04/19/2024] Open
Abstract
Neuronal death resulting from ischemic stroke is the primary cause of adult mortality and disability, and effective neuroprotective agents for poststroke intervention are still lacking. Remote ischemic postconditioning (RIPostC) has demonstrated significant protective effects against ischemia in various organs; however, the specific mechanisms are not fully understood. This study investigated the potential neuroprotective mechanisms of RIPostC in the context of ischemic stroke. Using a rat model of middle cerebral artery occlusion, we found that RIPostC mitigated neurological damage, improved movement in the open-field test, and protected against neuronal apoptosis. In terms of energy metabolism, RIPostC enhanced ATP levels, suppressed lactate content, and increased the production of ketone bodies (KBs). In the ferroptosis assay, RIPostC protected against lipoperoxidation, reversed the reduction of glutathione peroxidase 4 (GPX4), and mitigated the excessive expression of long-chain acyl-CoA synthetase family member 4 (ACSL4). In oxygen-glucose deprivation/reoxygenation-treated HT22 cells, KBs maintained GPX4 levels, suppressed ACSL4 expression, and preserved the mitochondrial cristae number. However, the effect of KBs on the expression of GPX4, ACSL4, and the number of mitochondrial cristae was blocked by erastin. Moreover, both RIPostC and KBs reduced total iron and ferrous ion content by repressing iron transporters both in vitro and in vivo. In conclusion, KBs-induced mitigation of ferroptosis could represent a new therapeutic mechanism for RIPostC in treating stroke.
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Affiliation(s)
- Lin-Yan Huang
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R China
| | - Yi-de Zhang
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R China
- Xuzhou Central Hospital, Xuzhou 221000, P.R China
| | - Yi-Ning Liu
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R China
| | - Zhi-Yan Liang
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R China
| | - Jie Chen
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R China
| | - Bin Wang
- Department of Laboratory Medicine, the Affiliated Hospital of Xuzhou Medical University, No.99 Huaihai West Road, Xuzhou 221000, P.R China
| | - Qi-Long Yin
- Department of Laboratory Medicine, the Affiliated Hospital of Xuzhou Medical University, No.99 Huaihai West Road, Xuzhou 221000, P.R China
- Pharmacology College, Xuzhou Medical University, Xuzhou 221004, P.R China
| | - Pei-Pei Wang
- Pharmacology College, Xuzhou Medical University, Xuzhou 221004, P.R China
| | - Wan Wang
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R China
| | - Su-Hua Qi
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R China
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11
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Keevil H, Phillips BE, England TJ. Remote ischemic conditioning for stroke: A critical systematic review. Int J Stroke 2024; 19:271-279. [PMID: 37466245 PMCID: PMC10903142 DOI: 10.1177/17474930231191082] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 07/10/2023] [Indexed: 07/20/2023]
Abstract
Remote ischemic conditioning (RIC) is the application of brief periods of ischemia to an organ or tissue with the aim of inducing protection from ischemia in a distant organ. It was first developed as a cardioprotective strategy but has been increasingly investigated as a neuroprotective intervention. The mechanisms by which RIC achieves neuroprotection are incompletely understood. Preclinical studies focus on the hypothesis that RIC can protect the brain from ischemia reperfusion (IR) injury following the restoration of blood flow after occlusion of a large cerebral artery. However, increasingly, a role of chronic RIC (CRIC) is being investigated as a means of promoting recovery following an ischemic insult to the brain. The recent publication of two large, randomized control trials has provided promise that RIC could improve functional outcomes after acute ischemic stroke, and that there may be a role for CRIC in the prevention of recurrent stroke. Although less developed, there is also proof-of-concept to suggest that RIC may be used to reduce vasospasm after subarachnoid hemorrhage or improve cognitive outcomes in vascular dementia. As a cheap, well-tolerated and almost universally applicable intervention, the motivation for investigating possible benefit of RIC in patients with cerebrovascular disease is great. In this review, we shall review the current evidence for RIC as applied to cerebrovascular disease.
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Affiliation(s)
- Harry Keevil
- Stroke Trials Unit, Division of Mental Health and Clinical Neuroscience, University of Nottingham, Nottingham, UK
- Medical Research Council Versus Arthritis Centre for Musculoskeletal Ageing Research, and NIHR Nottingham Biomedical Research Centre, Division of Injury, Recovery & Inflammation Sciences, University of Nottingham, Nottingham, UK
| | - Bethan E Phillips
- Medical Research Council Versus Arthritis Centre for Musculoskeletal Ageing Research, and NIHR Nottingham Biomedical Research Centre, Division of Injury, Recovery & Inflammation Sciences, University of Nottingham, Nottingham, UK
| | - Timothy J England
- Stroke Trials Unit, Division of Mental Health and Clinical Neuroscience, University of Nottingham, Nottingham, UK
- Department of Stroke, University Hospitals of Derby and Burton, Derby, UK
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12
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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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Ravingerova T, Adameova A, Lonek L, Farkasova V, Ferko M, Andelova N, Kura B, Slezak J, Galatou E, Lazou A, Zohdi V, Dhalla NS. Is Intrinsic Cardioprotection a Laboratory Phenomenon or a Clinically Relevant Tool to Salvage the Failing Heart? Int J Mol Sci 2023; 24:16497. [PMID: 38003687 PMCID: PMC10671596 DOI: 10.3390/ijms242216497] [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: 10/24/2023] [Revised: 11/13/2023] [Accepted: 11/13/2023] [Indexed: 11/26/2023] Open
Abstract
Cardiovascular diseases, especially ischemic heart disease, as a leading cause of heart failure (HF) and mortality, will not reduce over the coming decades despite the progress in pharmacotherapy, interventional cardiology, and surgery. Although patients surviving acute myocardial infarction live longer, alteration of heart function will later lead to HF. Its rising incidence represents a danger, especially among the elderly, with data showing more unfavorable results among females than among males. Experiments revealed an infarct-sparing effect of ischemic "preconditioning" (IPC) as the most robust form of innate cardioprotection based on the heart's adaptation to moderate stress, increasing its resistance to severe insults. However, translation to clinical practice is limited by technical requirements and limited time. Novel forms of adaptive interventions, such as "remote" IPC, have already been applied in patients, albeit with different effectiveness. Cardiac ischemic tolerance can also be increased by other noninvasive approaches, such as adaptation to hypoxia- or exercise-induced preconditioning. Although their molecular mechanisms are not yet fully understood, some noninvasive modalities appear to be promising novel strategies for fighting HF through targeting its numerous mechanisms. In this review, we will discuss the molecular mechanisms of heart injury and repair, as well as interventions that have potential to be used in the treatment of patients.
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Affiliation(s)
- Tanya Ravingerova
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, 9 Dubravska cesta, 841 04 Bratislava, Slovakia; (A.A.); (L.L.); (V.F.); (M.F.); (N.A.); (B.K.); (J.S.)
| | - Adriana Adameova
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, 9 Dubravska cesta, 841 04 Bratislava, Slovakia; (A.A.); (L.L.); (V.F.); (M.F.); (N.A.); (B.K.); (J.S.)
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, 10 Odbojárov St., 832 32 Bratislava, Slovakia
| | - Lubomir Lonek
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, 9 Dubravska cesta, 841 04 Bratislava, Slovakia; (A.A.); (L.L.); (V.F.); (M.F.); (N.A.); (B.K.); (J.S.)
| | - Veronika Farkasova
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, 9 Dubravska cesta, 841 04 Bratislava, Slovakia; (A.A.); (L.L.); (V.F.); (M.F.); (N.A.); (B.K.); (J.S.)
| | - Miroslav Ferko
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, 9 Dubravska cesta, 841 04 Bratislava, Slovakia; (A.A.); (L.L.); (V.F.); (M.F.); (N.A.); (B.K.); (J.S.)
| | - Natalia Andelova
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, 9 Dubravska cesta, 841 04 Bratislava, Slovakia; (A.A.); (L.L.); (V.F.); (M.F.); (N.A.); (B.K.); (J.S.)
| | - Branislav Kura
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, 9 Dubravska cesta, 841 04 Bratislava, Slovakia; (A.A.); (L.L.); (V.F.); (M.F.); (N.A.); (B.K.); (J.S.)
| | - Jan Slezak
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, 9 Dubravska cesta, 841 04 Bratislava, Slovakia; (A.A.); (L.L.); (V.F.); (M.F.); (N.A.); (B.K.); (J.S.)
| | - Eleftheria Galatou
- School of Biology, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece; (E.G.); (A.L.)
- Department of Life and Health Sciences, University of Nicosia, 2417 Nicosia, Cyprus
| | - Antigone Lazou
- School of Biology, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece; (E.G.); (A.L.)
| | - Vladislava Zohdi
- Department of Anatomy, Faculty of Medicine, Comenius University in Bratislava, 24 Špitalska, 813 72 Bratislava, Slovakia;
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, 19 Innovation Walk, Clayton, VIC 3800, Australia
| | - Naranjan S. Dhalla
- Institute of Cardiovascular Sciences St. Boniface Hospital Albrechtsen Research Centre, 351 Tache Avenue, Winnipeg, MB R2H 2A6, Canada;
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Liang H, Ye R, Zhang X, Ye H, Ouyang W, Cai S, Wei L. Autonomic function may mediate the neuroprotection of remote ischemic postconditioning in stroke: A randomized controlled trial. J Stroke Cerebrovasc Dis 2023; 32:107198. [PMID: 37329785 DOI: 10.1016/j.jstrokecerebrovasdis.2023.107198] [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: 01/26/2023] [Revised: 05/18/2023] [Accepted: 05/20/2023] [Indexed: 06/19/2023] Open
Abstract
OBJECTIVES To evaluate the effect of remote ischemic postconditioning (RIPostC) on the prognosis of acute ischemic stroke(AIS) patients and investigate the mediating role of autonomic function in the neuroprotection of RIPostC. MATERIALS AND METHODS 132 AIS patients were randomized into two groups. Patients received four cycles of 5-min inflation to a pressure of 200 mmHg(i.e., RIPostC) or patients' diastolic BP(i.e., shame), followed by 5 min of deflation on healthy upper limbs once a day for 30 days. The main outcome was neurological outcome including the National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), and Barthel index(BI). The second outcome measure was autonomic function measured by heart rate variability(HRV). RESULTS Compared with the baseline, the post-intervention NIHSS score was significantly reduced in both groups (P<0.001). NIHSS score was significantly lower in the control group than intervention group at day 7.[RIPostC:3(1,5) versus shame:2(1,4); P=0.030]. mRS scored lower in the intervention group compared with the control group at day 90 follow-up(RIPostC:0.5±2.0 versus shame:1.0±2.0;P=0.016). The goodness-of-fit test revealed a significant difference between the generalized estimating equation model of mRS and BI scores of uncontrolled-HRV and controlled-HRV(P<0.05, both). The results of bootstrap revealed a complete mediation effect of HRV between group on mRS[indirect effect: -0.267 (LLCI = -0.549, ULCI = -0.048), the direct effect: -0.443 (LLCI = -0.831, ULCI = 0.118)]. CONCLUSION This is the first human-based study providing evidence for a mediation role of autonomic function between RIpostC and prognosis in AIS patients. It indicated that RIPostC could improve the neurological outcome of AIS patients. Autonomic function may play a mediating role in this association. TRIAL REGISTRATION The clinical trials registration number for this study is NCT02777099 (ClinicalTrials.gov Identifier).
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Affiliation(s)
- Hao Liang
- Department of Neurology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China
| | - Richun Ye
- Department of Neurology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China
| | - Xiaopei Zhang
- Department of Neurology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China
| | - Huanwen Ye
- Department of Cardiac Function, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China
| | - Wenwei Ouyang
- Key Unit of Methodology in Clinical Research, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China
| | - Shuang Cai
- Tongde Hospital of Zhejiang Province, Zhejiang, China
| | - Lin Wei
- Department of Neurology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China.
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Truter N, Malan L, Essop MF. Glial cell activity in cardiovascular diseases and risk of acute myocardial infarction. Am J Physiol Heart Circ Physiol 2023; 324:H373-H390. [PMID: 36662577 DOI: 10.1152/ajpheart.00332.2022] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Growing evidence indicates that the pathophysiological link between the brain and heart underlies cardiovascular diseases, specifically acute myocardial infarction (AMI). Astrocytes are the most abundant glial cells in the central nervous system and provide support/protection for neurons. Astrocytes and peripheral glial cells are emerging as key modulators of the brain-heart axis in AMI, by affecting sympathetic nervous system activity (centrally and peripherally). This review, therefore, aimed to gain an improved understanding of glial cell activity and AMI risk. This includes discussions on the potential role of contributing factors in AMI risk, i.e., autonomic nervous system dysfunction, glial-neurotrophic and ischemic risk markers [glial cell line-derived neurotrophic factor (GDNF), astrocytic S100 calcium-binding protein B (S100B), silent myocardial ischemia, and cardiac troponin T (cTnT)]. Consideration of glial cell activity and related contributing factors in certain brain-heart disorders, namely, blood-brain barrier dysfunction, myocardial ischemia, and chronic psychological stress, may improve our understanding regarding the pathological role that glial dysfunction can play in the development/onset of AMI. Here, findings demonstrated perturbations in glial cell activity and contributing factors (especially sympathetic activity). Moreover, emerging AMI risk included sympathovagal imbalance, low GDNF levels reflecting prothrombic risk, hypertension, and increased ischemia due to perfusion deficits (indicated by S100B and cTnT levels). Such perturbations impacted blood-barrier function and perfusion that were exacerbated during psychological stress. Thus, greater insights and consideration regarding such biomarkers may help drive future studies investigating brain-heart axis pathologies to gain a deeper understanding of astrocytic glial cell contributions and unlock potential novel therapies for AMI.
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Affiliation(s)
- Nina Truter
- Centre for Cardio-metabolic Research in Africa, Department of Physiological Sciences, Stellenbosch University, Cape Town, South Africa
| | - Leoné Malan
- Technology Transfer and Innovation-Support Office, North-West University, Potchefstroom, South Africa
| | - M Faadiel Essop
- Centre for Cardio-metabolic Research in Africa, Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
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Dang Y, Hua W, Zhang X, Sun H, Zhang Y, Yu B, Wang S, Zhang M, Kong Z, Pan D, Chen Y, Li S, Yuan L, Reinhardt JD, Lu X, Zheng Y. Anti-angiogenic effect of exo-LncRNA TUG1 in myocardial infarction and modulation by remote ischemic conditioning. Basic Res Cardiol 2023; 118:1. [PMID: 36635484 DOI: 10.1007/s00395-022-00975-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 01/13/2023]
Abstract
The successful use of exosomes in therapy after myocardial infarction depends on an improved understanding of their role in cardiac signaling and regulation. Here, we report that exosomes circulating after myocardial infarction (MI) carry LncRNA TUG1 which downregulates angiogenesis by disablement of the HIF-1α/VEGF-α axis and that this effect can be counterbalanced by remote ischemic conditioning (RIC). Rats with MI induced through left coronary artery ligation without (MI model) and with reperfusion (ischemia/reperfusion I/R model) were randomized to RIC, or MI (I/R) or sham-operated (SO) control. Data from one cohort study and one randomized-controlled trial of humans with MI were also utilized, the former involving patients who had not received percutaneous coronary intervention (PCI) and the latter patients with PCI. Exosome concentrations did not differ between intervention groups (RIC vs. control) in rats (MI and I/R model) as well as humans (with and without PCI). However, MI and I/R exosomes attenuated HIF-1α, VEGF-α, and endothelial function. LncRNA TUG1 was increased in MI and I/R exosomes, but decreased in SO and RIC exosomes. HIF-1α expression was downregulated with MI and I/R exosomes but increased with RIC exosomes. Exosome inhibition suppressed HIF-1α upregulation through RIC exosomes. VEGF-α was identified as HIF-1α-regulated target gene. Knockdown of HIF-1α decreased VEGF-α, endothelial cell capability, and tube formation. Overexpression of HIF-1α exerted opposite effects. Transfection and co-transfection of 293 T cells with exosome-inhibitor GW4869 and HIF-1α inhibitor si-HIF-1α confirmed the exosomal-LncRNA TUG1/HIF-1α/VEGF-α pathway. LncRNA TUG1 is a potential therapeutic target after MI with or without reperfusion through PCI.
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Affiliation(s)
- Yini Dang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Division of Gastroenterological Rehabilitation, Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wenjie Hua
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, China
| | - Xintong Zhang
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, China
| | - Hao Sun
- Department of Emergency Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yingjie Zhang
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, China
| | - Binbin Yu
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, China
| | - Shengrui Wang
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, China
| | - Min Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Division of Gastroenterological Rehabilitation, Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zihao Kong
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Division of Gastroenterological Rehabilitation, Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dijia Pan
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, China
| | - Ying Chen
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, China
| | - Shurui Li
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, China
| | - Liang Yuan
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jan D Reinhardt
- Institute for Disaster Management and Reconstruction, Sichuan University, No. 122 Huanghezhong Road First Section, Chengdu, 610207, China. .,Swiss Paraplegic Research, Nottwil, Switzerland. .,Department of Health Sciences and Medicine, University of Lucerne, Lucerne, Switzerland.
| | - Xiao Lu
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, China.
| | - Yu Zheng
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, China.
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17
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Bell RM, Basalay M, Bøtker HE, Beikoghli Kalkhoran S, Carr RD, Cunningham J, Davidson SM, England TJ, Giesz S, Ghosh AK, Golforoush P, Gourine AV, Hausenloy DJ, Heusch G, Ibanez B, Kleinbongard P, Lecour S, Lukhna K, Ntsekhe M, Ovize M, Salama AD, Vilahur G, Walker JM, Yellon DM. Remote ischaemic conditioning: defining critical criteria for success-report from the 11th Hatter Cardiovascular Workshop. Basic Res Cardiol 2022; 117:39. [PMID: 35970954 PMCID: PMC9377667 DOI: 10.1007/s00395-022-00947-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/03/2022] [Accepted: 08/03/2022] [Indexed: 01/31/2023]
Abstract
The Hatter Cardiovascular Institute biennial workshop, originally scheduled for April 2020 but postponed for 2 years due to the Covid pandemic, was organised to debate and discuss the future of Remote Ischaemic Conditioning (RIC). This evolved from the large multicentre CONDI-2-ERIC-PPCI outcome study which demonstrated no additional benefit when using RIC in the setting of ST-elevation myocardial infarction (STEMI). The workshop discussed how conditioning has led to a significant and fundamental understanding of the mechanisms preventing cell death following ischaemia and reperfusion, and the key target cyto-protective pathways recruited by protective interventions, such as RIC. However, the obvious need to translate this protection to the clinical setting has not materialised largely due to the disconnect between preclinical and clinical studies. Discussion points included how to adapt preclinical animal studies to mirror the patient presenting with an acute myocardial infarction, as well as how to refine patient selection in clinical studies to account for co-morbidities and ongoing therapy. These latter scenarios can modify cytoprotective signalling and need to be taken into account to allow for a more robust outcome when powered appropriately. The workshop also discussed the potential for RIC in other disease settings including ischaemic stroke, cardio-oncology and COVID-19. The workshop, therefore, put forward specific classifications which could help identify so-called responders vs. non-responders in both the preclinical and clinical settings.
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Affiliation(s)
- R M Bell
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - M Basalay
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - H E Bøtker
- Aarhus University Hospital and Aarhus University, Aarhus, Denmark
| | - S Beikoghli Kalkhoran
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - R D Carr
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | | | - S M Davidson
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - T J England
- Stroke, Division of Mental Health and Clinical Neurosciences, School of Medicine, University of Nottingham, Nottingham, UK
| | - S Giesz
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - A K Ghosh
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - P Golforoush
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - A V Gourine
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, UK
| | - D J Hausenloy
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
- CVMD, Duke-NUS, Singapore, Singapore
- National Heart Research Institute Singapore, National Heart Centre, Singapore, Singapore
- Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taichung City, Taiwan
| | - G Heusch
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Duisburg-Essen, Duisburg, Germany
| | - B Ibanez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), IIS-Fundación Jiménez Díaz University Hospital & CIBERCV, Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
- IIS-Fundación Jiménez Díaz Hospital, Madrid, Spain
| | - P Kleinbongard
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Duisburg-Essen, Duisburg, Germany
| | - S Lecour
- University of Cape Town, Cape Town, South Africa
| | - K Lukhna
- University of Cape Town, Cape Town, South Africa
| | - M Ntsekhe
- University of Cape Town, Cape Town, South Africa
| | - M Ovize
- INSERM U1060, CarMeN Laboratory, Université de Lyon, Groupement Hospitalier Est, Bâtiment B13, F-69500, Bron, France
| | | | - G Vilahur
- Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, CIBERCV, Barcelona, Spain
| | - J M Walker
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - D M Yellon
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.
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18
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SOGORSKI ALEXANDER, DOSTIBEGIAN MARYNA, LEHNHARDT MARCUS, WALLNER CHRISTOPH, WAGNER JOHANNESM, DADRAS MEHRAN, GLINSKI MAXIVON, KOLBENSCHLAG JONAS, BEHR BJÖRN. Postoperative Remote Ischemic Conditioning (RIC) significantly improves entire flap microcirculation beyond 4 hours. J Plast Reconstr Aesthet Surg 2022; 75:4003-4012. [DOI: 10.1016/j.bjps.2022.08.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 05/28/2022] [Accepted: 08/17/2022] [Indexed: 11/25/2022]
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19
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Cardioprotective Effects of Physical Activity: Focus on Ischemia and Reperfusion. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2022. [DOI: 10.2478/sjecr-2022-0025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Abstract
This review aimed to revisit the old and introduce some of the new various cardioprotective effects of physical exercise, focusing on ischemia-reperfusion injury. A wealth of data shows that regular physical exercise is necessary to prevent cardiovascular diseases. In the last few years, a number of new training regimes, usually modified variations of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) protocols, have been rising in popularity among people of all ages. Since exercising is not limited to only healthy people, our study emphasized the benefits of HIIT and MICT in preventing or mitigating cardiac ischemia-reperfusion injury. Different kinds of research are being performed, studying the various positive and side effects of these training regimes, all in hopes of finding the most optimal ones. So far, all of them have shown that exercising to any extent, even for a short period of time, is beneficial in one way or another, and outweighs the possible risks it might have. We also revisited some of the known molecular mechanisms responsible for many of the effects of physical exercise and introduced some new findings related to them. Lastly, we summarized and compared the benefits of different HIIT and MICT protocols to narrow down the search for the most efficient training method.
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20
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Lang JA, Kim J. Remote ischaemic preconditioning - translating cardiovascular benefits to humans. J Physiol 2022; 600:3053-3067. [PMID: 35596644 PMCID: PMC9327506 DOI: 10.1113/jp282568] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 05/17/2022] [Indexed: 11/26/2022] Open
Abstract
Remote ischaemic preconditioning (RIPC), induced by intermittent periods of limb ischaemia and reperfusion, confers cardiac and vascular protection from subsequent ischaemia–reperfusion (IR) injury. Early animal studies reliably demonstrate that RIPC attenuated infarct size and preserved cardiac tissue. However, translating these adaptations to clinical practice in humans has been challenging. Large clinical studies have found inconsistent results with respect to RIPC eliciting IR injury protection or improving clinical outcomes. Follow‐up studies have implicated several factors that potentially affect the efficacy of RIPC in humans such as age, fitness, frequency, disease state and interactions with medications. Thus, realizing the clinical potential for RIPC may require a human experimental model where confounding factors are more effectively controlled and underlying mechanisms can be further elucidated. In this review, we highlight recent experimental findings in the peripheral circulation that have added valuable insight on the mechanisms and clinical benefit of RIPC in humans. Central to this discussion is the critical role of timing (i.e. immediate vs. delayed effects following a single bout of RIPC) and the frequency of RIPC. Limited evidence in humans has demonstrated that repeated bouts of RIPC over several days uniquely improves vascular function beyond that observed with a single bout alone. Since changes in resistance vessel and microvascular function often precede symptoms and diagnosis of cardiovascular disease, repeated bouts of RIPC may be promising as a preclinical intervention to prevent or delay cardiovascular disease progression.
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Affiliation(s)
- James A Lang
- Department of Kinesiology, Iowa State University, Ames, IA, USA
| | - Jahyun Kim
- Department of Kinesiology, California State University Bakersfield, Bakersfield, CA, USA
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21
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Singhanat K, Apaijai N, Sumneang N, Maneechote C, Arunsak B, Chunchai T, Chattipakorn SC, Chattipakorn N. Therapeutic potential of a single-dose melatonin in the attenuation of cardiac ischemia/reperfusion injury in prediabetic obese rats. Cell Mol Life Sci 2022; 79:300. [PMID: 35588335 PMCID: PMC11072751 DOI: 10.1007/s00018-022-04330-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 04/24/2022] [Accepted: 04/27/2022] [Indexed: 01/05/2023]
Abstract
Although acute melatonin treatment effectively reduces cardiac ischemia/reperfusion (I/R) injury in lean rats by modulating melatonin receptor 2 (MT2), there is no information regarding the temporal effects of melatonin administration during cardiac I/R injury in prediabetic obese rats. Prediabetic obese rats induced by chronic consumption of a high-fat diet (HFD) were used. The rats underwent a cardiac I/R surgical procedure (30-min of ischemia, followed by 120-min of reperfusion) and were randomly assigned to receive either vehicle or melatonin treatment. In the melatonin group, rats were divided into 3 different subgroups: (1) pretreatment, (2) treatment during ischemic period, (3) treatment at the reperfusion onset. In the pretreatment subgroup either a nonspecific MT blocker (Luzindole) or specific MT2 blocker (4-PPDOT) was also given to the rats prior to melatonin treatment. Pretreatment with melatonin (10 mg/kg) effectively reduced cardiac I/R injury by reducing infarct size, arrhythmia, and LV dysfunction. Reduction in impaired mitochondrial function, mitochondrial dynamic balance, oxidative stress, defective autophagy, and apoptosis were observed in rats pretreated with melatonin. Unfortunately, the cardioprotective benefits were not observed when 10-mg/kg of melatonin was acutely administered to the rats after cardiac ischemia. Thus, we increased the dose of melatonin to 20 mg/kg, and it was administered to the rats during ischemia or at the onset of reperfusion. The results showed that 20-mg/kg of melatonin effectively reduced cardiac I/R injury to a similar extent to the 10-mg/kg pretreatment regimen. The MT2 blocker inhibited the protective effects of melatonin. Acute melatonin treatment during cardiac I/R injury exerted protective effects in prediabetic obese rats. However, a higher dose of melatonin is required when given after the onset of cardiac ischemia. These effects of melatonin were mainly mediated through activation of MT2.
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Affiliation(s)
- Kodchanan Singhanat
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Nattayaporn Apaijai
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Natticha Sumneang
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Chayodom Maneechote
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Busarin Arunsak
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Titikorn Chunchai
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Siriporn C Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
- Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
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22
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Cho YJ, Jung DE, Nam K, Bae J, Lee S, Jeon Y. Effects of transcutaneous electrical nerve stimulation on myocardial protection in patients undergoing aortic valve replacement: a randomized clinical trial. BMC Anesthesiol 2022; 22:68. [PMID: 35264104 PMCID: PMC8905743 DOI: 10.1186/s12871-022-01611-x] [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: 10/29/2021] [Accepted: 03/04/2022] [Indexed: 11/10/2022] Open
Abstract
Background Cardiopulmonary bypass-related myocardial ischemia-reperfusion injury is a major contributor to postoperative morbidity. Although transcutaneous electrical nerve stimulation (TENS) has been found to have cardioprotective effects in animal studies and healthy volunteers, its effects on cardiac surgery under cardiopulmonary bypass patients have not been evaluated. We investigated the effects of TENS on myocardial protection in patients undergoing aortic valve replacement surgery using cardiopulmonary bypass. Methods Thirty patients were randomized to receive TENS or sham in three different anesthetic states – pre-anesthesia, sevoflurane, or propofol (each n = 5). TENS was applied with a pulse width of 385 μs and a frequency of 10 Hz using two surface electrodes at the upper arm for 30 min. Sham treatment was provided without stimulation. The primary outcome was the difference in myocardial infarct size following ischemia-reperfusion injury in rat hearts perfused with pre- and post-TENS plasma dialysate obtained from the patients using Langendorff perfusion system. The cardioprotective effects of TENS were determined by assessing reduction in infarct size following treatment. Results There were no differences in myocardial infarct size between pre- and post-treatment in any group (41.4 ± 4.3% vs. 36.7 ± 5.3%, 39.8 ± 7.3% vs. 27.8 ± 12.0%, and 41.6 ± 2.2% vs. 37.8 ± 7.6%; p = 0.080, 0.152, and 0.353 in the pre-anesthesia, sevoflurane, and propofol groups, respectively). Conclusions In our study, TENS did not show a cardioprotective effect in patients undergoing aortic valve replacement surgery. Trial registration This study was registered at clinicaltrials.gov (NCT03859115, on March 1, 2019). Supplementary Information The online version contains supplementary material available at 10.1186/s12871-022-01611-x.
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Affiliation(s)
- Youn Joung Cho
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, 03080, South Korea
| | - Dhong-Eun Jung
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, 03080, South Korea
| | - Karam Nam
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, 03080, South Korea
| | - Jinyoung Bae
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, 03080, South Korea
| | - Seohee Lee
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, 03080, South Korea
| | - Yunseok Jeon
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, 03080, South Korea.
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23
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Boerger TF, Hyngstrom AS, Furlan JC, Kalsi-Ryan S, Curt A, Kwon BK, Kurpad SN, Fehlings MG, Harrop JS, Aarabi B, Rahimi-Movaghar V, Guest JD, Wilson JR, Davies BM, Kotter MRN, Koljonen PA. Developing Peri-Operative Rehabilitation in Degenerative Cervical Myelopathy [AO Spine RECODE-DCM Research Priority Number 6]: An Unexplored Opportunity? Global Spine J 2022; 12:97S-108S. [PMID: 35174735 PMCID: PMC8859699 DOI: 10.1177/21925682211050925] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
STUDY DESIGN Narrative review. OBJECTIVE Degenerative cervical myelopathy is one of the most frequent impairments of the spinal cord encountered internationally in adults. Currently, surgical decompression is the recommended treatment for people with DCM (PwCM) presenting with moderate to severe symptoms or neurological deficits. However, despite surgical intervention, not all patients make a complete recovery due to the irreversible tissue damage within the spinal cord. The objective of this review is to describe the state and gaps in the current literature on rehabilitation for PwCM and possible innovative rehabilitation strategies. METHODS Literature search. RESULTS In other neurological disorders such as stroke and acute traumatic spinal cord injury (SCI), timely and strategic rehabilitation has been shown to be indispensable for maximizing functional outcomes, and it is imperative that appropriate perioperative rehabilitative interventions accompany surgical approaches in order to enable the best outcomes. In this review, the current state of knowledge regarding rehabilitation for PwCM is described. Additionally, various therapies that have shown to improve outcomes in comparable neurological conditions such as stroke and SCI which may be translated to DCM will be reviewed. CONCLUSIONS We conclude that locomotor training and arm/hand therapy may benefit PwCM. Further, we conclude that body weight support, robotic assistance, and virtual/augmented reality therapies may be beneficial therapeutic analogs to locomotor and hand therapies.
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Affiliation(s)
- Timothy F. Boerger
- Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, USA
| | | | - Julio C. Furlan
- KITE Research Institute, University Health Network, Toronto, ON, Canada
- Division of Physical Medicine and Rehabilitation, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Sukhvinder Kalsi-Ryan
- KITE Research Institute, University Health Network, Toronto, ON, Canada
- Division of Physical Medicine and Rehabilitation, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Armin Curt
- University Spine Center, Balgrist University Hospital, Zurich, Switzerland
| | - Brian K. Kwon
- Department of Orthopedics, Vancouver Spine Surgery Institute, The University of British Columbia, Vancouver, BC, Canada
| | - Shekar N. Kurpad
- Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Michael G. Fehlings
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
| | - James S. Harrop
- Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA, USA
| | - Bizhan Aarabi
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Vafa Rahimi-Movaghar
- Department of Neurosurgery, Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - James D. Guest
- Department of Neurosurgery and The Miami Project to Cure Paralysis, The Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Jefferson R. Wilson
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
| | | | | | - Paul A. Koljonen
- Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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24
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A TRICk to Improve the Effectiveness of RIC: Role of Limb Temperature in Enhancing the Effectiveness of Remote Ischemic Conditioning. BIOLOGY 2022; 11:biology11010146. [PMID: 35053144 PMCID: PMC8773203 DOI: 10.3390/biology11010146] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/09/2022] [Accepted: 01/14/2022] [Indexed: 12/31/2022]
Abstract
Simple Summary Remote ischemic conditioning is a simple cardioprotective practice consisting in brief intermittent ischemia applied to a limb. Remote ischemic conditioning has been repeatedly validated in animal models. However, translation from animal experiments to clinics for remote ischemic conditioning has been disappointing. We have demonstrated that keeping the animal’s limb warm while performing intermittent ischemia reduces infarct size more effectively than cold intermittent ischemia; thus, we propose that a more accurate temperature control of the limb undergoing remote ischemic conditioning can increase the efficacy of this cardioprotective maneuver. A simple thermal blanket around the ischemic limb while performing remote ischemic conditioning could be an easy approach to test in humans, as it is simple and safe. Abstract Background: Treatment of myocardial ischemia/reperfusion (IR) injury is still an unmet clinical need. A large variability of remote ischemic conditioning (RIC) protection has been reported; however, no studies have considered the temperature of the ischemic limb. We analyzed the effects of temperature on RIC protection. Methods: Left hind-limbs of anesthetized male mice were immersed in warm (40 °C, warm-RIC) or cold (20 °C, cold-RIC) water and subjected to a RIC protocol (4 × 5 min limb ischemia/reperfusion). In the control groups (warm-CTR or cold-CTR), the limbs underwent thermic conditions only. Isolated hearts underwent 30 min ischemia and 60 min reperfusion. A PI3K-inhibitor, LY294002 (5 µM), was infused in warm-RIC hearts before the IR protocol (warm-RIC LY). Infarct size was evaluated by nitro blue tetrazolium staining and expressed as the percent of risk area. Results: While cold-RIC did not reduce the infarct size compared to cold-CTR (51 ± 1.62% vs. 54 ± 1.07% of risk area, p = NS), warm-RIC (44 ± 1.13%) significantly reduced the infarct size with respect to either cold-RIC (p < 0.001) or warm-CTR (58 ± 1.41%, p < 0.0001). LY294002 infusion revealed the PI3K/Akt involvement in the warm-RIC protection. Infarct size reduction was abrogated by LY294002 pretreatment (warm-RIC: 44 ± 1.13% vs. warm-CTR 58 ± 1.41% p < 0.0001; vs. warm-RIC LY 54 ± 1.69% p = 0.0002). Conclusion: our study shows a remarkable difference between warm-RIC and cold-RIC in terms of infarct size reduction, supporting a pivotal role for limb temperature in RIC-induced cardioprotection.
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Lieder HR, Tüller P, Braczko F, Zandi A, Kamler M, Thielmann M, Heusch G, Kleinbongard P. Bioassays of Humoral Cardioprotective Factors Released by Remote Ischemic Conditioning in Patients Undergoing Coronary Artery Bypass Surgery. J Cardiovasc Pharmacol Ther 2022; 27:10742484221097273. [PMID: 35510644 DOI: 10.1177/10742484221097273] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Remote ischemic conditioning (RIC) induces the release of circulating cardioprotective factors and attenuates myocardial ischemia/reperfusion injury. Evidence for such humoral cardioprotective factor(s) is derived from transfer with plasma (derivatives) from one individual undergoing RIC to another individual's heart, even across species. With transfer into an isolated perfused heart, only a single plasma (derivative) sample can be studied with infarct size as endpoint, and therefore the comparison of samples before and after RIC or between RIC and placebo is hampered by the inter-individual variation of infarct sizes in isolated perfused hearts. We therefore developed a preparation of cardiomyocytes from a single mouse heart, where aliquots of the same heart can undergo hypoxia/reoxygenation (H/R) with exposure to buffer, RIC, or placebo samples without or with pharmacological blockade. To validate this approach, we used plasma dialysates taken before and after RIC from patients undergoing coronary bypass grafting who had experienced protection by RIC (troponin release ↓ by 28% vs placebo). The cardiomyocyte bioassay had little variation after H/R with buffer (mean ± standard deviation; 7% ± 2% viable cells) and demonstrated preserved viability after RIC (15% ± 5% vs 6% ± 3% before). For comparison, infarct size in isolated mouse hearts after global ischemia and reperfusion was 22% ± 14% of left ventricular mass after versus 42% ± 14% before RIC. Stattic, an inhibitor of signal transducer and activator of transcription (STAT)3 protein, abrogated protection in the cardiomyocytes. We have thus established a cardiomyocyte bioassay to analyze RIC's protection which minimizes inter-individual variation and the use of animals.
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Affiliation(s)
- Helmut Raphael Lieder
- Institute for Pathophysiology, West German Heart and Vascular Center, 123109University of Essen Medical School, Essen, Germany
| | - Pia Tüller
- Institute for Pathophysiology, West German Heart and Vascular Center, 123109University of Essen Medical School, Essen, Germany
| | - Felix Braczko
- Institute for Pathophysiology, West German Heart and Vascular Center, 123109University of Essen Medical School, Essen, Germany
| | - Afsaneh Zandi
- Heart Center Essen-Huttrop, West German Heart and Vascular Center, 123109University of Essen Medical School, Essen, Germany
| | - Markus Kamler
- Heart Center Essen-Huttrop, West German Heart and Vascular Center, 123109University of Essen Medical School, Essen, Germany.,Department of Thoracic and Cardiovascular Surgery, West German Heart and Vascular Center, 123109University of Essen Medical School, Essen, Germany
| | - Matthias Thielmann
- Department of Thoracic and Cardiovascular Surgery, West German Heart and Vascular Center, 123109University of Essen Medical School, Essen, Germany
| | - Gerd Heusch
- Institute for Pathophysiology, West German Heart and Vascular Center, 123109University of Essen Medical School, Essen, Germany
| | - Petra Kleinbongard
- Institute for Pathophysiology, West German Heart and Vascular Center, 123109University of Essen Medical School, Essen, Germany
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HIF-1α mediates the protective effect of plasma extracellular particles induced by remote ischaemic preconditioning on oxidative stress injury in human umbilical vein endothelial cells. Exp Ther Med 2021; 23:48. [PMID: 34917179 PMCID: PMC8630441 DOI: 10.3892/etm.2021.10970] [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: 07/17/2020] [Accepted: 10/15/2021] [Indexed: 12/18/2022] Open
Abstract
Remote ischaemic preconditioning (RIPC) is considered to alleviate myocardial ischaemia/reperfusion (I/R) injury. The present study explored whether blood plasma particulate matter, which is termed extracellular particles (EPs), and is released from cells during RIPC, could reduce H2O2-induced damage in human umbilical vein endothelial cells (HUVECs). Firstly, EPs were derived from volunteers who did or did not undergo RIPC. To induce RIPC in volunteers, a blood pressure cuff was alternatively inflated for 5 min and deflated for the same duration for four successive cycles. HUVECs were assigned to two groups: i) Group 1 was preincubated for 24 h with EPs from volunteers after sham-RIPC, then treated with H2O2 (1 mM; 6 h) to mimic the in vivo conditions of I/R-induced oxidative stress; and ii) group 2 was preincubated for 24 h with EPs from volunteers after RIPC, then treated with H2O2. Subsequently, EPs were derived from rats received sham-RIPC or RIPC and/or cadmium (Cd) pre-treatment. To induce RIPC in rats, a remote hind limb preconditioning stimulus was delivered using a blood pressure cuff attached at the inguinal level of the rat. The blood pressure cuff was alternatively inflated for 5 min and deflated for the same time period for four successive cycles. HUVECs were assigned to six groups: i) Group 1 was untreated; ii) group 2 received only H2O2 treatment (1 mM; 6 h); iii) group 3 was preincubated for 24 h with EPs from rats exposed to sham-RIPC, then treated with H2O2; iv) group 4 was preincubated for 24 h with EPs from rats that received an intraperitoneal injection of 1 mg/kg Cd [a pharmacological inhibitor of hypoxia-inducible factor 1-α (HIF-1α) in vivo] 180 min before sham-RIPC, then treated with H2O2; v) group 5 was preincubated for 24 h with EPs from rats exposed to RIPC, then treated with H2O2; and vi) group 6 was preincubated for 24 h with EPs from rats that received an intraperitoneal injection of 1 mg/kg Cd 180 min before RIPC, then treated with H2O2. Cell viability and cytotoxicity were monitored using Cell Counting Kit-8 and lactate dehydrogenase assays. Cell apoptosis and necrosis were assessed via flow cytometry and western blot analysis. A notable increase in EP concentration in the plasma of volunteers after RIPC compared with that in the plasma of volunteers after sham-RIPC was observed. RIPC-associated EPs (RIPC-EPs) from volunteers could improve cell viability and reduce cytotoxicity, cell apoptosis and necrosis in HUVECs treated with H2O2in vitro. Furthermore, RIPC caused a significant increase in HIF-1α expression in the rat limb musculature. The apoptosis-reducing effect of RIPC-EPs was demonstrated to be counteracted by an intraperitoneal injection of Cd before RIPC in rats. A significant decrease in the EP levels precipitated from the plasma of rats that received Cd treatment before RIPC was observed compared with rats that did not receive Cd treatment. The present study suggested that HIF-1α mediated at least partly the protective effect of plasma RIPC-EPs on oxidative stress injury in HUVECs.
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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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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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Liu Z, Zhao Y, Lei M, Zhao G, Li D, Sun R, Liu X. Remote Ischemic Preconditioning to Prevent Acute Kidney Injury After Cardiac Surgery: A Meta-Analysis of Randomized Controlled Trials. Front Cardiovasc Med 2021; 8:601470. [PMID: 33816572 PMCID: PMC8012491 DOI: 10.3389/fcvm.2021.601470] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 02/15/2021] [Indexed: 11/18/2022] Open
Abstract
Objective: Randomized controlled trials (RCTs) evaluating the influence of remote ischemic preconditioning (RIPC) on acute kidney injury (AKI) after cardiac surgery showed inconsistent results. We performed a meta-analysis to evaluate the efficacy of RIPC on AKI after cardiac surgery. Methods: Relevant studies were obtained by search of PubMed, Embase, and Cochrane's Library databases. A random-effect model was used to pool the results. Meta-regression and subgroup analyses were used to determine the source of heterogeneity. Results: Twenty-two RCTs with 5,389 patients who received cardiac surgery −2,702 patients in the RIPC group and 2,687 patients in the control group—were included. Moderate heterogeneity was detected (p for Cochrane's Q test = 0.03, I2 = 40%). Pooled results showed that RIPC significantly reduced the incidence of AKI compared with control [odds ratio (OR): 0.76, 95% confidence intervals (CI): 0.61–0.94, p = 0.01]. Results limited to on-pump surgery (OR: 0.78, 95% CI: 0.64–0.95, p = 0.01) or studies with acute RIPC (OR: 0.78, 95% CI: 0.63–0.97, p = 0.03) showed consistent results. Meta-regression and subgroup analyses indicated that study characteristics, including study design, country, age, gender, diabetic status, surgery type, use of propofol or volatile anesthetics, cross-clamp time, RIPC protocol, definition of AKI, and sample size did not significantly affect the outcome of AKI. Results of stratified analysis showed that RIPC significantly reduced the risk of mild-to-moderate AKI that did not require renal replacement therapy (RRT, OR: 0.76, 95% CI: 0.60–0.96, p = 0.02) but did not significantly reduce the risk of severe AKI that required RRT in patients after cardiac surgery (OR: 0.73, 95% CI: 0.50–1.07, p = 0.11). Conclusions: Current evidence supports RIPC as an effective strategy to prevent AKI after cardiac surgery, which seems to be mainly driven by the reduced mild-to-moderate AKI events that did not require RRT. Efforts are needed to determine the influences of patient characteristics, procedure, perioperative drugs, and RIPC protocol on the outcome.
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Affiliation(s)
- Zigang Liu
- Department of Thoracic and Cardiovascular Surgery, Shenzhen Baoan Women's and Children's Hospital, Jinan University, Guangzhou, China
| | - Yongmei Zhao
- Department of Thoracic and Cardiovascular Surgery, Shenzhen Baoan Women's and Children's Hospital, Jinan University, Guangzhou, China
| | - Ming Lei
- Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Beijing, China
| | - Guancong Zhao
- Department of Thoracic and Cardiovascular Surgery, Shenzhen Baoan Women's and Children's Hospital, Jinan University, Guangzhou, China
| | - Dongcheng Li
- Department of Thoracic and Cardiovascular Surgery, Shenzhen Baoan Women's and Children's Hospital, Jinan University, Guangzhou, China
| | - Rong Sun
- Department of Thoracic and Cardiovascular Surgery, Shenzhen Baoan Women's and Children's Hospital, Jinan University, Guangzhou, China
| | - Xian Liu
- Department of Thoracic and Cardiovascular Surgery, Shenzhen Baoan Women's and Children's Hospital, Jinan University, Guangzhou, China
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Improving gait efficiency to increase movement and physical activity - The impact of abnormal gait patterns and strategies to correct. Prog Cardiovasc Dis 2020; 64:83-87. [PMID: 33359569 DOI: 10.1016/j.pcad.2020.12.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 12/20/2020] [Indexed: 01/12/2023]
Abstract
Increasing daily steps is important to maintain health and prevent both initial and subsequent cardiovascular (CV) disease (CVD) events. Even 5000 steps have been associated with reduced risk of CVD, however many adults and those with CVD walk fewer than 5000 daily steps. Reduced gait speed is a precursor to decreased physical engagement and is associated with biomarker changes linked to higher risk of CVD. Gait speed is decreased in those with CVD, which may be from changes in biomechanics including reduced step length and increased gait variability. Changes in gait and daily steps are often most discernable post-stroke, which may be from limitations of the CV system in meeting the metabolic demands of walking and the nervous system in exciting motoneuron pools to generate muscle force. This leads to gait asymmetries and decreased speed. Information regarding the effects of rehabilitation interventions (e.g., physical therapy) to increase physical activity (PA) in stroke survivors is limited. Current interventions include high intensity gait training and ischemic conditioning to improve walking speed and fatigability. Given the potential benefits of increased PA and daily steps following stroke, there is a need for more research investigating optimal dosage of daily steps and interventions to improve PA.
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de Miranda DC, de Oliveira Faria G, Hermidorff MM, Dos Santos Silva FC, de Assis LVM, Isoldi MC. Pre- and Post-Conditioning of the Heart: An Overview of Cardioprotective Signaling Pathways. Curr Vasc Pharmacol 2020; 19:499-524. [PMID: 33222675 DOI: 10.2174/1570161119666201120160619] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 11/02/2020] [Accepted: 11/02/2020] [Indexed: 11/22/2022]
Abstract
Since the discovery of ischemic pre- and post-conditioning, more than 30 years ago, the knowledge about the mechanisms and signaling pathways involved in these processes has significantly increased. In clinical practice, on the other hand, such advancement has yet to be seen. This article provides an overview of ischemic pre-, post-, remote, and pharmacological conditioning related to the heart. In addition, we reviewed the cardioprotective signaling pathways and therapeutic agents involved in the above-mentioned processes, aiming to provide a comprehensive evaluation of the advancements in the field. The advancements made over the last decades cannot be ignored and with the exponential growth in techniques and applications. The future of pre- and post-conditioning is promising.
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Affiliation(s)
- Denise Coutinho de Miranda
- Laboratory of Cell Signaling, Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Gabriela de Oliveira Faria
- Laboratory of Cell Signaling, Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Milla Marques Hermidorff
- Laboratory of Cell Signaling, Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Fernanda Cacilda Dos Santos Silva
- Laboratory of Cardiovascular Physiology, Department of Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Leonardo Vinícius Monteiro de Assis
- Laboratory of Comparative Physiology of Pigmentation, Department of Physiology, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Mauro César Isoldi
- Laboratory of Cell Signaling, Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
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Sogorski A, Spindler S, Wallner C, Dadras M, Wagner JM, Behr B, Lehnhardt M, Kolbenschlag J. Optimizing remote ischemic conditioning (RIC) of cutaneous microcirculation in humans: Number of cycles and duration of acute effects. J Plast Reconstr Aesthet Surg 2020; 74:819-827. [PMID: 33172821 DOI: 10.1016/j.bjps.2020.10.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 08/12/2020] [Accepted: 10/11/2020] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Non-invasive Remote Ischemic Conditioning (RIC) offers an approach to reduce tissue damage in various organs/tissues. Besides attenuation of Ischemia-Reperfusion injury (I/R), beneficial effects on cutaneous microcirculation of free microsurgical flaps have been reported. Given the recency of this technique, there are considerable gaps in the current understanding of its mechanism of action. As a result, clinical transfer of RIC is prolongated in several fields. We aimed to optimize the RIC protocol by examination of different RIC-cycle numbers and its effect on changes of cutaneous microcirculation and duration. METHODS 80 subjects were divided into groups (1, 3, 5, 7 RIC cycles). RIC was applied via an inflatable tourniquet. Cutaneous microcirculation was continuously assessed at the contralateral anterior lateral thigh utilizing a ©O2C-device continuously. RESULTS RIC caused significant and sustained changes in microcirculation. Four hours after completion of RIC, a maximum increase of +80.8% (CI 1.395-2.221) in blood flow and +23.5% (CI 1.098-1.372) in tissue oxygen saturation was measured (three-cycle group). A higher number of applied cycles was accompanied with significant higher mean pain. CONCLUSION Acute improvement of cutaneous microcirculation due to RIC lasted for at least 4 h after completion of the RIC-protocol. Dose-dependent effects of RIC are likely. With regard to the increase in pain, we recommend a RIC protocol of 3 cycles for future clinical application.
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Affiliation(s)
- A Sogorski
- Department of Plastic Surgery and Hand Surgery, Burn Center, BG University Hospital Bergmannsheil Bochum, Ruhr-University Bochum, Buerkle-de-la-Camp-Platz 1, 44789 Bochum, Germany.
| | - S Spindler
- Department of Plastic Surgery and Hand Surgery, Burn Center, BG University Hospital Bergmannsheil Bochum, Ruhr-University Bochum, Buerkle-de-la-Camp-Platz 1, 44789 Bochum, Germany
| | - C Wallner
- Department of Plastic Surgery and Hand Surgery, Burn Center, BG University Hospital Bergmannsheil Bochum, Ruhr-University Bochum, Buerkle-de-la-Camp-Platz 1, 44789 Bochum, Germany
| | - M Dadras
- Department of Plastic Surgery and Hand Surgery, Burn Center, BG University Hospital Bergmannsheil Bochum, Ruhr-University Bochum, Buerkle-de-la-Camp-Platz 1, 44789 Bochum, Germany
| | - J M Wagner
- Department of Plastic Surgery and Hand Surgery, Burn Center, BG University Hospital Bergmannsheil Bochum, Ruhr-University Bochum, Buerkle-de-la-Camp-Platz 1, 44789 Bochum, Germany
| | - B Behr
- Department of Plastic Surgery and Hand Surgery, Burn Center, BG University Hospital Bergmannsheil Bochum, Ruhr-University Bochum, Buerkle-de-la-Camp-Platz 1, 44789 Bochum, Germany
| | - M Lehnhardt
- Department of Plastic Surgery and Hand Surgery, Burn Center, BG University Hospital Bergmannsheil Bochum, Ruhr-University Bochum, Buerkle-de-la-Camp-Platz 1, 44789 Bochum, Germany
| | - J Kolbenschlag
- Department of Hand, Plastic and Reconstructive Surgery, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, Schnarrenbergstraße 95, 72076 Tuebingen, Germany
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Ganesh A, Barber P, Black SE, Corbett D, Field TS, Frayne R, Hachinski V, Ismail Z, Mai LM, McCreary CR, Sahlas D, Sharma M, Swartz RH, Smith EE. Trial of remote ischaemic preconditioning in vascular cognitive impairment (TRIC-VCI): protocol. BMJ Open 2020; 10:e040466. [PMID: 33055122 PMCID: PMC7559076 DOI: 10.1136/bmjopen-2020-040466] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
INTRODUCTION Cerebral small vessel disease (cSVD) accounts for 20%-25% of strokes and is the most common cause of vascular cognitive impairment (VCI). In an animal VCI model, inducing brief periods of limb ischaemia-reperfusion reduces subsequent ischaemic brain injury with remote and local protective effects, with hindlimb remote ischaemic conditioning (RIC) improving cerebral blood flow, decreasing white-matter injury and improving cognition. Small human trials suggest RIC is safe and may prevent recurrent strokes. It remains unclear what doses of chronic daily RIC are tolerable and safe, whether effects persist after treatment cessation, and what parameters are optimal for treatment response. METHODS AND ANALYSIS This prospective, open-label, randomised controlled trial (RCT) with blinded end point assessment and run-in period, will recruit 24 participants, randomised to one of two RIC intensity groups: one arm treated once daily or one arm twice daily for 30 consecutive days. RIC will consistent of 4 cycles of blood pressure cuff inflation to 200 mm Hg for 5 min followed by 5 min deflation (total 35 min). Selection criteria include: age 60-85 years, evidence of cSVD on brain CT/MRI, Montreal Cognitive Assessment (MoCA) score 13-24 and preserved basic activities of living. Outcomes will be assessed at 30 days and 90 days (60 days after ceasing treatment). The primary outcome is adherence (completing ≥80% of sessions). Secondary safety/tolerability outcomes include the per cent of sessions completed and pain/discomfort scores from patient diaries. Efficacy outcomes include changes in cerebral blood flow (per arterial spin-label MRI), white-matter hyperintensity volume, diffusion tensor imaging, MoCA and Trail-Making tests. ETHICS AND DISSEMINATION Research Ethics Board approval has been obtained. The results will provide information on feasibility, dose, adherence, tolerability and outcome measures that will help design a phase IIb RCT of RIC, with the potential to prevent VCI. Results will be disseminated through peer-reviewed publications, organisations and meetings. TRIAL REGISTRATION NUMBER NCT04109963.
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Affiliation(s)
- Aravind Ganesh
- Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
| | - Philip Barber
- Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
| | - Sandra E Black
- Department of Medicine (Neurology), Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Dale Corbett
- Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Thalia S Field
- Department of Medicine (Neurology), University of British Columbia, Vancouver, British Columbia, Canada
| | - Richard Frayne
- Seaman Family MR Centre, University of Calgary, Calgary, Alberta, Canada
- Department of Radiology and Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
| | - Vladimir Hachinski
- Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada
| | - Zahinoor Ismail
- Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
| | - Lauren M Mai
- Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada
| | - Cheryl R McCreary
- Department of Clinical Neurosciences and Radiology, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada
| | - Demetrios Sahlas
- Department of Medicine (Neurology), McMaster University Population Health Research Institute, Hamilton, Ontario, Canada
| | - Mukul Sharma
- Department of Medicine (Neurology), McMaster University Population Health Research Institute, Hamilton, Ontario, Canada
| | - Richard H Swartz
- Department of Medicine (Neurology), Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Eric E Smith
- Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
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Raval RN, Small O, Magsino K, Chakravarthy V, Austin B, Applegate R, Dorotta I. Remote Ischemic Pre-conditioning in Subarachnoid Hemorrhage: A Prospective Pilot Trial. Neurocrit Care 2020; 34:968-973. [PMID: 33051793 DOI: 10.1007/s12028-020-01122-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 09/21/2020] [Indexed: 01/08/2023]
Abstract
BACKGROUND Cerebral injury from aneurysmal subarachnoid hemorrhage (aSAH) is twofold. The initial hemorrhage causes much of the injury; secondary injury can occur from delayed cerebral ischemia (DCI). Remote ischemic preconditioning (RIPC) is a mechanism of organ protection in response to transient ischemia within a distant organ. This pilot trial sought to apply RIPC in patients with aSAH to evaluate its effect on secondary cerebral injury and resultant outcomes. METHODS Patients were randomized to the high-pressure occlusion group (HPO) or the low-pressure occlusion group (LPO). Lower extremity RIPC treatment was initiated within 72 h of symptom onset and every other day for 14 days or until Intensive Care Unit (ICU) discharge. In HPO, each treatment consisted of 4 five-minute cycles of manual blood pressure cuff inflation with loss of distal pulses. LPO received cuff inflation with lower pressures while preserving distal pulses. Retrospectively matched controls were also analyzed. Efficacy of treatment was measured by total days spent in vasospasm out of study enrollment days, hospital and ICU length of stay (LOS), cerebral infarction, one and six month modified Rankin score, and mortality. RESULTS The final analysis included 33 patients with 11 in each group. Patient demographics, aneurysm location, admission airway status, Glasgow Coma Scale (GCS), modified Rankin score, Hunt and Hess score, modified Fisher Score and aneurysm management were not significantly different between groups. Hospital and ICU LOS was shorter in LPO compared to the control (p = 0·0468 and p = 0·0409, respectively). Total vasospasm days/study enrollment days, cerebral infarction, one and six month modified Rankin score, and mortality were not significantly different between the groups. CONCLUSIONS This pilot trial did demonstrate feasibility and safety. The shortened LOS in the LPO may implicate a protective role of RIPC and warrants future study.
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Affiliation(s)
- Ronak N Raval
- Department of Anesthesiology and Critical Care Center, Loma Linda University Medical Center, 11234 Anderson Street, Loma Linda, CA, 92354, USA. .,Department of Surgery, VA Loma Linda Healthcare System, Loma Linda, USA.
| | - Oliver Small
- Department of Anesthesiology, Swedish Medical Center, Seattle, USA
| | - Kristel Magsino
- Department of Anesthesiology and Critical Care Center, Loma Linda University Medical Center, 11234 Anderson Street, Loma Linda, CA, 92354, USA
| | - Vikram Chakravarthy
- Department of Neurosurgery, Cleveland Clinic of Case Western Reserve School of Medicine, Cleveland, USA
| | - Briahnna Austin
- Department of Anesthesiology and Critical Care Center, Loma Linda University Medical Center, 11234 Anderson Street, Loma Linda, CA, 92354, USA
| | - Richard Applegate
- Department of Anesthesiology, Davis Medical Center, University of California, Sacramento, USA
| | - Ihab Dorotta
- Department of Anesthesiology and Critical Care Center, Loma Linda University Medical Center, 11234 Anderson Street, Loma Linda, CA, 92354, USA
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Gardner RN, Sabino-Carvalho JL, Kim J, Vianna LC, Lang JA. Two weeks of remote ischaemic preconditioning alters sympathovagal balance in healthy humans. Exp Physiol 2020; 105:1500-1506. [PMID: 32691505 DOI: 10.1113/ep088789] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 07/17/2020] [Indexed: 12/16/2022]
Abstract
NEW FINDINGS What is the central question of this study? Delayed cardiovascular responses occur following a single bout of remote ischaemic preconditioning (RIPC). Is heart rate variability (HRV), a surrogate marker of cardiac vagal control, able to detect a delayed effect after a single bout of RIPC? Do repeated bouts of RIPC further alter HRV? What is the main finding and its importance? Indices of HRV indicated a shift in sympathovagal balance toward greater parasympathetic activity following 2 weeks of RIPC but not after a single bout of RIPC. Thus, repeated bouts of RIPC were necessary to elicit changes in autonomic function. ABSTRACT Remote ischaemic preconditioning (RIPC), induced by brief periods of ischaemia followed by reperfusion, protects against ischaemia-reperfusion injury and improves microvascular function. However, the effect of RIPC on autonomic function remains unclear. We hypothesized that RIPC, administered as a single bout or repeated over a 2-week period, will increase markers of cardiac vagal control measured by heart rate variability (HRV). Thirty-two young adults performed a single bout (n = 13), repeated bouts (n = 11), or served as a time control (n = 8). RIPC sessions consisted of four repetitions of 5 min unilateral brachial artery occlusion interspersed by 5 min of reperfusion. For the single bout protocol, resting lead II electrocardiogram (ECG) was collected before and 24, 48, 72 and 168 h post-RIPC. The repeated bout protocol consisted of three 4-day periods of RIPC training, each interspersed by a 1-day break. Similar to time controls, ECG was collected before and 24 h after the last RIPC bout. HRV was analysed by power spectral density and symbolic dynamics using 350-beat ECG segments. After a single bout of RIPC, no changes in HRV were observed at any time point (P > 0.05). After 2 weeks of repeated RIPC, the percentage of zero-variation fragments (baseline = 13.1 ± 1.9%, post-RIPC = 6.9 ± 1.5%, P < 0.05) and the LF/HF ratio decreased (baseline = 1.1 ± 0.2, post-RIPC = 0.7 ± 0.1, P < 0.01), whereas the percentage of two-variation fragments increased (baseline = 42.9 ± 3.6%, post-RIPC = 52.5 ± 3.0%, P < 0.01). These data indicate that repeated RIPC is necessary to elicit changes in sympathovagal balance, specifically resulting in increased vagal and decreased sympathetic activity.
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Affiliation(s)
| | - Jeann L Sabino-Carvalho
- Department of Kinesiology, Iowa State University, Ames, IA, USA.,Faculty of Physical Education, University of Brasília, Distrito Federal, Brazil
| | - Jahyun Kim
- Department of Kinesiology, Iowa State University, Ames, IA, USA
| | - Lauro C Vianna
- Faculty of Physical Education, University of Brasília, Distrito Federal, Brazil
| | - James A Lang
- Department of Kinesiology, Iowa State University, Ames, IA, USA
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Changes in Circulating Extracellular Vesicles in Patients with ST-Elevation Myocardial Infarction and Potential Effects of Remote Ischemic Conditioning-A Randomized Controlled Trial. Biomedicines 2020; 8:biomedicines8070218. [PMID: 32708657 PMCID: PMC7400268 DOI: 10.3390/biomedicines8070218] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 07/06/2020] [Accepted: 07/13/2020] [Indexed: 12/16/2022] Open
Abstract
(1) Background: Extracellular vesicles (EVs) have been recognized as a cellular communication tool with cardioprotective properties; however, it is unknown whether cardioprotection by remote ischemic conditioning (RIC) involves EVs. (2) Methods: We randomized patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) to additionally receive a protocol of RIC or a sham-intervention. Blood was taken before and immediately, 24 h, four days and one month after PCI. Additionally, we investigated EVs from healthy volunteers undergoing RIC. EVs were characterized by a high-sensitive flow cytometer (Beckman Coulter Cytoflex S, Krefeld, Germany). (3) Results: We analyzed 32 patients (16 RIC, 16 control) and five healthy volunteers. We investigated platelet-, endothelial-, leukocyte-, monocyte- and granulocyte-derived EVs and their pro-thrombotic sub-populations expressing superficial phosphatidylserine (PS+). We did not observe a significant effect of RIC on the numbers of circulating EVs, although granulocyte-derived EVs were significantly higher in the RIC group. In line, RIC had not impact on EVs in healthy volunteers. Additionally, we observed changes of PS+/PEV, EEVs and PS+/CD15+ EVs irrespective of RIC with time following STEMI. 4) Conclusion: We provide further insights into the course of different circulating EVs during the acute and sub-acute phases of STEMI. With respect to the investigated EV populations, RIC seems to have no effect, with only minor differences found for granulocyte EVs.
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Sawashita Y, Hirata N, Yoshikawa Y, Terada H, Tokinaga Y, Yamakage M. Remote ischemic preconditioning reduces myocardial ischemia-reperfusion injury through unacylated ghrelin-induced activation of the JAK/STAT pathway. Basic Res Cardiol 2020; 115:50. [PMID: 32607622 DOI: 10.1007/s00395-020-0809-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 06/24/2020] [Indexed: 01/06/2023]
Abstract
Remote ischemic preconditioning (RIPC) offers cardioprotection against myocardial ischemia-reperfusion injury. The humoral factors involved in RIPC that are released from parasympathetically innervated organs have not been identified. Previous studies showed that ghrelin, a hormone released from the stomach, is associated with cardioprotection. However, it is unknown whether or not ghrelin is involved in the mechanism of RIPC. This study aimed to determine whether ghrelin serves as one of the humoral factors in RIPC. RIPC group rats were subjected to three cycles of ischemia and reperfusion for 5 min in two limbs before left anterior descending (LAD) coronary artery ligation. Unacylated ghrelin (UAG) group rats were given 0.5 mcg/kg UAG intravenously 30 min before LAD ligation. Plasma levels of UAG in all groups were measured before and after RIPC procedures and UAG administration. Additionally, JAK2/STAT3 pathway inhibitor (AG490) was injected in RIPC and UAG groups to investigate abolishment of the cardioprotection of RIPC and UAG. Plasma levels of UAG, infarct size and phosphorylation of STAT3 were compared in all groups. Infarct size was significantly reduced in RIPC and UAG groups, compared to the other groups. Plasma levels of UAG in RIPC and UAG groups were significantly increased after RIPC and UAG administration, respectively. The cardioprotective effects of RIPC and UAG were accompanied by an increase in phosphorylation of STAT3 and abolished by AG490. This study indicated that RIPC reduces myocardial ischemia and reperfusion injury through UAG-induced activation of JAK/STAT pathway. UAG may be one of the humoral factors involved in the cardioprotective effects of RIPC.
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Affiliation(s)
- Yasuaki Sawashita
- Department of Anesthesiology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
| | - Naoyuki Hirata
- Department of Anesthesiology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Yusuke Yoshikawa
- Department of Anesthesiology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Hirofumi Terada
- Department of Anesthesiology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Yasuyuki Tokinaga
- Department of Anesthesiology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Michiaki Yamakage
- Department of Anesthesiology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
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Pearce L, Davidson SM, Yellon DM. The cytokine storm of COVID-19: a spotlight on prevention and protection. Expert Opin Ther Targets 2020; 24:723-730. [PMID: 32594778 DOI: 10.1080/14728222.2020.1783243] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION The cytokine release syndrome (CRS) of COVID-19 is associated with the development of critical illness requiring multi-organ support. Further research is required to halt progression of multi-organ injury induced by hyper-inflammation. AREAS COVERED PubMed/MEDLINETM databases were accessed between May 9th-June 9th, 2020, to review the latest perspectives on the treatment and pathogenesis of CRS. EXPERT OPINION Over-activity of chemotaxis triggers a macrophage activation syndrome (MAS) resulting in the release of pro-inflammatory cytokines. IL-6 and TNF- α are at the forefront of hyper-inflammation. The inflammatory cascade induces endothelial activation and capillary leak, leading to circulatory collapse and shock. As endothelial dysfunction persists, there is activation of the clotting cascade and microvascular obstruction. Continued endothelial activation results in multi-organ failure, regardless of pulmonary tissue damage. We propose that targeting the endothelium may interrupt this cycle. Immuno-modulating therapies have been suggested, however, further data is necessary to confirm that they do not jeopardize adaptive immunity. Inhibition of IL-6 and the Janus Kinase, signal transducer and activator of transcription proteins pathway (JAK/STAT), are favorable targets. Remote ischemic conditioning (RIC) reduces the inflammation of sepsis in animal models and should be considered as a low risk intervention, in combination with cardiovascular protection.
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Affiliation(s)
- Lucie Pearce
- The Hatter Cardiovascular Institute, University College London , London, UK
| | - Sean M Davidson
- The Hatter Cardiovascular Institute, University College London , London, UK
| | - Derek M Yellon
- The Hatter Cardiovascular Institute, University College London , London, UK
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Hausenloy DJ, Bøtker HE, Ferdinandy P, Heusch G, Ng GA, Redington A, Garcia-Dorado D. Cardiac innervation in acute myocardial ischaemia/reperfusion injury and cardioprotection. Cardiovasc Res 2020; 115:1167-1177. [PMID: 30796814 DOI: 10.1093/cvr/cvz053] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 12/21/2018] [Accepted: 02/21/2019] [Indexed: 12/13/2022] Open
Abstract
Acute myocardial infarction (AMI) and the heart failure (HF) that often complicates this condition, are among the leading causes of death and disability worldwide. To reduce myocardial infarct (MI) size and prevent heart failure, novel therapies are required to protect the heart against the detrimental effects of acute ischaemia/reperfusion injury (IRI). In this regard, targeting cardiac innervation may provide a novel therapeutic strategy for cardioprotection. A number of cardiac neural pathways mediate the beneficial effects of cardioprotective strategies such as ischaemic preconditioning and remote ischaemic conditioning, and nerve stimulation may therefore provide a novel therapeutic strategy for cardioprotection. In this article, we provide an overview of cardiac innervation and its impact on acute myocardial IRI, the role of extrinsic and intrinsic cardiac neural pathways in cardioprotection, and highlight peripheral and central nerve stimulation as a cardioprotective strategy with therapeutic potential for reducing MI size and preventing HF following AMI. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.
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Affiliation(s)
- Derek J Hausenloy
- Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore.,National Heart Research Institute Singapore, National Heart Centre, Singapore.,Yong Loo Lin School of Medicine, National University Singapore, Singapore.,The Hatter Cardiovascular Institute, University College London, London, UK.,The National Institute of Health Research University College London Hospitals Biomedical Research Centre, Research & Development, London, UK.,Tecnologico de Monterrey, Centro de Biotecnologia-FEMSA, Nuevo Leon, Mexico
| | - Hans Erik Bøtker
- Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark
| | - Peter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,Pharmahungary Group, Szeged, Hungary
| | - Gerd Heusch
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany
| | - G André Ng
- Department of Cardiovascular Sciences, University of Leicester, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, UK
| | - Andrew Redington
- Cincinnati Children's Hospital Medical Center, Heart Institute, Cincinnati, OH, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - David Garcia-Dorado
- Department of Cardiology, Vascular Biology and Metabolism Area, Vall d'Hebron University Hospital and Research Institute (VHIR), Universitat Autónoma de Barcelona, Spain.,Instituto CIBER de Enfermedades Cardiovasculares (CIBERCV): Instituto de Salud Carlos III, Madrid, Spain
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Wang T, Xu Y, Wang N, Qi M, Cheng W, Qu X. Effect of Remote Ischemic Conditioning in Patients With Takotsubo Syndrome After Acute Stroke: Study Protocol for a Randomized Controlled Trial. Front Neurol 2020; 11:286. [PMID: 32425872 PMCID: PMC7212382 DOI: 10.3389/fneur.2020.00286] [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: 12/10/2019] [Accepted: 03/26/2020] [Indexed: 11/13/2022] Open
Abstract
Introduction: Takotsubo syndrome (TTS) is an acute heart failure syndrome which is preceded by a variety of emotional or physical triggers, with central nervous system conditions being an important trigger. Remote ischemic conditioning (RIC) is a promising interventional treatment based on the probability that both TTS and acute coronary syndrome may respond similarly to interventions. The heart protection effect of RIC has been repeatedly confirmed in animal models and observational clinical trials; however, it has never been studied in patients with TTS after acute stroke in randomized clinical trials with a higher level of evidence. The present study will be a proof-of-concept study to determine whether RIC can reduce cardiac injury and eventually improve the heart function and clinical outcomes of TTS patients after acute stroke. Methods and Analysis: A single-center, outcome-assessor-blinded, randomized controlled trial (RCT) will be conducted to evaluate the effect of RIC in TTS patients after acute stroke. Major eligibility criteria include TTS patients diagnosed with acute stroke, which can be confirmed on computed tomography or magnetic resonance imaging; patients aged 18-75 years; patients admitted to a hospital within 48 h after the onset of acute stroke; and patients diagnosed with Takotsubo cardiomyopathy with an InterTAK diagnostic score ≥50. A total of 60 eligible patients will be randomly allocated into either the RIC or the control group. The primary endpoint is a composite of death from any cause and major adverse cardiac and cerebrovascular events during the in-hospital period and at the 1- and 6-month follow-up. Ethics and dissemination: This study has been approved by the Medical Ethics Committee of Xuanwu Hospital, Capital Medical University ([2017] 072). The study findings will be presented at international conferences and published in a peer-reviewed journal. Trial registration: This study has been prospectively registered in the Chinese Clinical Trial Registry on September 10, 2018 (ChiCTR1800018290).
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Affiliation(s)
- Tao Wang
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yueqiao Xu
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Ning Wang
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Meng Qi
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Weitao Cheng
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Xin Qu
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
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Effect of Repeated Remote Ischemic Preconditioning on Peripheral Arterial Disease in Patients Suffering from Intermittent Claudication. Cardiovasc Ther 2020; 2019:9592378. [PMID: 31897086 PMCID: PMC6925938 DOI: 10.1155/2019/9592378] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 09/04/2019] [Accepted: 09/24/2019] [Indexed: 12/15/2022] Open
Abstract
Background/Objective Intermittent claudication (IC) is the symptom of peripheral artery disease (PAD) and causes functional disability. Remote ischemic preconditioning (RIPC), is a phenomenon in which a short period of sub-critical ischemia, protects tissues against ischemia/reperfusion/injury. We considered to test the hypothesis that RIPC in PAD patients suffering from IC would increase muscle resistance to ischemia and thus improve walking-capacity. Materials/Methods A total of 63 patients with proven-IC underwent two treadmill tests (graded treadmill protocol) with a 28-day interval in between. Patients were consecutively assigned for the non/RIPC-group and RIPC-group procedure one by one. Patients received 5-cycles of alternating 5-minute inflation and 5-minute deflation of blood-pressure cuffs on nondominant upper-limb every day for four weeks. Initial claudication distance (ICD), total walking distance (TWD) and time to relief of claudication (TRC) were recorded during procedure. Results Patients receiving-RIPC exhibited a marked increase in ICD and TWD between basal and last tests: 209.1 ± 15.4 m vs. 226 ± 15.0 m and 368.8 ± 21.0 m vs. 394 ± 19.9 m, respectively (p < 0.001). In addition, patients receiving-RIPC represented a significant decrease in TRC between basal and last tests: 7.8 ± 1.3 min vs. 6.4 ± 1.1 min, respectively (p < 0.001). Patients not receiving-RIPC did not exhibit improvement in ICD, TWD, and TRC between basal and last tests: 205.2 ± 12.1 min vs. 207.4 ± 9.9 min, 366.5 ± 24.2 min vs. 369.4 ± 23.2 min and 7.9 ± 1.4 min vs. 7.7 ± 1.3 min, respectively (p > 0.05). Conclusion A significant increase in ICD and TWD were observed in last/treadmill test in RIPC-group. In addition, a significant decrease in TRC was observed in last/treadmill test in RIPC-group. In non/RIPC-group, no improvement was observed in ICD, TWD and TRC.
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Cardioprotection by Humoral Factors Released After Remote Ischemic Preconditioning Depends on Anesthetic Regimen. Crit Care Med 2020; 47:e250-e255. [PMID: 30608281 DOI: 10.1097/ccm.0000000000003629] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Remote ischemic preconditioning (RIPC) is a practicable and noninvasive method to protect the heart against ischemia reperfusion injury. Unfortunately results from clinical studies are not convincing. Propofol is suggested to be an inhibiting factor of cardioprotection by RIPC, but the underlying mechanism is still unknown. We investigated whether after RIPC the release of humoral factors and/or the direct cardioprotective effect at the myocardium is inhibited by propofol. DESIGN Randomized, prospective, blinded laboratory investigation. SETTING Experimental laboratory. PATIENTS/SUBJECTS Male Wistar rats. INTERVENTIONS Repetitive hind limb ischemia in rats-blood plasma transfers to isolated rat heart. MEASUREMENTS AND MAIN RESULTS In male Wistar rats (six groups, each n = 6/group), RIPC was induced by four cycles of 5 minutes bilateral hind limb ischemia alternately with 5 minutes of reperfusion. Blood samples were taken with (RIPC) and without RIPC (Con). Rats received continuous anesthesia with pentobarbital (Pento, 40 mg/kg body weight/hr) or propofol (Prop, 12 mg/kg body weight/hr), respectively. Cardioprotective properties of the blood plasma was investigated in the rat heart in vitro (six groups, each n = 6/group) perfused with Krebs-Henseleit buffer alone or with propofol (10 µM). Plasma was administered over 10 minutes before myocardial ischemia. All hearts underwent 33 minutes of global ischemia followed by 1 hour of reperfusion. At the end of the experiments, infarct size was determined by triphenyl-tetrazolium-chloride staining. RIPC plasma from pentobarbital anesthetized rats (Pento-RIPC) reduced infarct size from 64% (62-71%) (Pento-Con) to 34% (30-39%) (p < 0.0001). Infarct size with control plasma from propofol anesthetized rats was 59% (58-64%) (Prop-Con). RIPC plasma could not induce cardioprotection (Prop-RIPC: 63% [56-70%] ns vs Prop-Con). In contrast, RIPC plasma from pentobarbital anesthetized rats induced a significant infarct size reduction under propofol perfusion (Pento-RIPC: 34% [30-42%] vs Pento-Con: 54% [53-63%]; p < 0.0001). CONCLUSIONS Loss of cardioprotection by RIPC during propofol anesthesia depends on inhibition of release of humoral factors.
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Yellon DM, Walker JM, Arjun S. Preventing the Cancer Patient of Today From Becoming the Heart Failure Patient of Tomorrow. JACC CardioOncol 2019; 1:235-237. [PMID: 34396186 PMCID: PMC8352327 DOI: 10.1016/j.jaccao.2019.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Affiliation(s)
- Derek M. Yellon
- Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - John Malcolm Walker
- Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Sapna Arjun
- Hatter Cardiovascular Institute, University College London, London, United Kingdom
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Khaliulin I, Fleishman AN, Shumeiko NI, Korablina T, Petrovskiy SA, Ascione R, Suleiman MS. Neuro-autonomic changes induced by remote ischemic preconditioning (RIPC) in healthy young adults: Implications for stress. Neurobiol Stress 2019; 11:100189. [PMID: 31388518 PMCID: PMC6675953 DOI: 10.1016/j.ynstr.2019.100189] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 06/22/2019] [Accepted: 06/24/2019] [Indexed: 01/12/2023] Open
Abstract
The mechanisms underlying the protective effects of remote ischemic preconditioning (RIPC) are not presently clear. Recent studies in experimental models suggest the involvement of the autonomic nervous system (ANS) in cardioprotection. The aim of this study was to investigate the changes in ANS in healthy young volunteers divided into RIPC (n = 22) or SHAM (n = 18) groups. RIPC was induced by 1 cycle of 4 min inflation/5 min deflation followed by 2 cycles of 5 min inflation/5 min deflation of a cuff placed on the upper left limb. The study included analysis of heart rate (HR), blood pressure (BP), heart rate variability (HRV), measurements of microcirculation and porphyrin fluorescence in the limb before and after the RIPC. RIPC caused reactive hyperemia in the limb and reduced blood porphyrin level. A mental load (serial sevens test) and mild motor stress (hyperventilation) were performed on all subjects before and after RIPC or corresponding rest in the SHAM group. Reduction of HR occurred during the experiments in both RIPC and SHAM groups reflecting RIPC-independent adaptation of the subjects to the experimental procedure. However, in contrast to the SHAM group, RIPC altered several of the spectral indices of HRV during the serial sevens test and hyperventilation. This was expressed predominantly as an increase in power of the very low-frequency band of the spectrum, increased values of detrended fluctuation analysis and weakening of correlation between the HRV parameters and HR. In conclusion, RIPC induces changes in the activity of ANS that are linked to stress resistance.
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Key Words
- ANS, autonomic nervous system
- Autonomic nervous system
- BP, blood pressure
- DBP, diastolic blood pressure
- DFA, detrended fluctuation analysis
- HF, high frequency
- HR, heart rate
- HRV, heart rate variability
- Heart rhythm variability
- LF, low frequency
- RIPC, remote ischaemic preconditioning
- Remote ischemic preconditioning
- SBP, systolic blood pressure
- VLF, very low frequency
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Affiliation(s)
- Igor Khaliulin
- Bristol Medical School, University of Bristol, Level 7, Bristol Royal Infirmary, Upper Maudlin Street, Bristol, BS2 8HW, UK
| | - Arnold N. Fleishman
- Research Institute for Complex Problems of Hygiene and Occupational Diseases, 23 Ulitsa Kutuzova, Novokuznetsk, Kemerovo Oblast, 654041, Russia
| | - Nadezhda I. Shumeiko
- Research Institute for Complex Problems of Hygiene and Occupational Diseases, 23 Ulitsa Kutuzova, Novokuznetsk, Kemerovo Oblast, 654041, Russia
| | - TatyanaV. Korablina
- Information Technology Department, Siberian State Industrial University, Ulitsa Kirova, 42, Novokuznetsk, Kemerovo Oblast, 654007, Russia
| | - Stanislav A. Petrovskiy
- Research Institute for Complex Problems of Hygiene and Occupational Diseases, 23 Ulitsa Kutuzova, Novokuznetsk, Kemerovo Oblast, 654041, Russia
| | - Raimondo Ascione
- Bristol Medical School, University of Bristol, Level 7, Bristol Royal Infirmary, Upper Maudlin Street, Bristol, BS2 8HW, UK
| | - M.-Saadeh Suleiman
- Bristol Medical School, University of Bristol, Level 7, Bristol Royal Infirmary, Upper Maudlin Street, Bristol, BS2 8HW, UK
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Lieder HR, Skyschally A, Heusch G, Kleinbongard P. Plasma from remotely conditioned pigs reduces infarct size when given before or after ischemia to isolated perfused rat hearts. Pflugers Arch 2019; 471:1371-1379. [PMID: 31631252 DOI: 10.1007/s00424-019-02314-y] [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: 06/18/2019] [Revised: 08/28/2019] [Accepted: 09/26/2019] [Indexed: 12/16/2022]
Abstract
Short cycles of ischemia/reperfusion in a tissue/organ remote from the heart reduce myocardial ischemia/reperfusion injury. Such remote ischemic conditioning (RIC) can be induced before (pre-), during (per-), or after (post-) the onset of myocardial ischemia. RIC's protection can be transferred with plasma between different individuals, even across species. Infusion of plasma from pigs with remote ischemic per-conditioning(RPERC) reduces infarct size in isolated perfused rat hearts when given before and after the index ischemia. We here determined whether or not infusion of pig plasma is equally protective when given exclusively before or after the index ischemia in isolated perfused rat hearts. Blood was sampled at 10 min reperfusion from Göttingen mini-pigs with 60/180 min coronary occlusion/reperfusion without (placebo, n = 8) or with RPERC (4 × 5 min/5 min hindlimb ischemia/reperfusion, n = 7) starting at 20 min coronary occlusion. Plasma was separated, diluted (1:6), and infused into isolated perfused rat hearts before (plasmabefore) or after (plasmaafter) 30/120 min global zero-flow ischemia/reperfusion. Infarct size (IS) was demarcated and calculated as percent of ventricular mass (means ± standard deviations). The activation of cardioprotective intracellular signaling cascades was analyzed by Western blot. RPERC-plasma reduced IS (placebo-plasmabefore 36 ± 5% and placebo-plasmaafter 36 ± 7% versus RPERC-plasmabefore 19 ± 3% and RPERC-plasmaafter 21 ± 4%; P < 0.001 versus placebo-plasma) and increased the phosphorylation of signal transducer and activator of transcription 3, no matter whether plasma was given before ischemia or during reperfusion. Obviously, the protection, which the released factors exert, is operative during reperfusion. However, pre-ischemic exposure to such cardioprotective factors is remembered throughout ischemia.
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Affiliation(s)
- Helmut Raphael Lieder
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Hufelandstr. 55, 45122, Essen, Germany
| | - Andreas Skyschally
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Hufelandstr. 55, 45122, Essen, Germany
| | - Gerd Heusch
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Hufelandstr. 55, 45122, Essen, Germany
| | - Petra Kleinbongard
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Hufelandstr. 55, 45122, Essen, Germany.
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Cho YJ, Kim WH. Perioperative Cardioprotection by Remote Ischemic Conditioning. Int J Mol Sci 2019; 20:ijms20194839. [PMID: 31569468 PMCID: PMC6801656 DOI: 10.3390/ijms20194839] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 09/11/2019] [Accepted: 09/27/2019] [Indexed: 12/24/2022] Open
Abstract
Remote ischemic conditioning has been investigated for cardioprotection to attenuate myocardial ischemia/reperfusion injury. In this review, we provide a comprehensive overview of the current knowledge of the signal transduction pathways of remote ischemic conditioning according to three stages: Remote stimulus from source organ; protective signal transfer through neuronal and humoral factors; and target organ response, including myocardial response and coronary vascular response. The neuronal and humoral factors interact on three levels, including stimulus, systemic, and target levels. Subsequently, we reviewed the clinical studies evaluating the cardioprotective effect of remote ischemic conditioning. While clinical studies of percutaneous coronary intervention showed relatively consistent protective effects, the majority of multicenter studies of cardiac surgery reported neutral results although there have been several promising initial trials. Failure to translate the protective effects of remote ischemic conditioning into cardiac surgery may be due to the multifactorial etiology of myocardial injury, potential confounding factors of patient age, comorbidities including diabetes, concomitant medications, and the coadministered cardioprotective general anesthetic agents. Given the complexity of signal transfer pathways and confounding factors, further studies should evaluate the multitarget strategies with optimal measures of composite outcomes.
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Affiliation(s)
- Youn Joung Cho
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Korea.
| | - Won Ho Kim
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Korea.
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Lieder HR, Kleinbongard P, Skyschally A, Hagelschuer H, Chilian WM, Heusch G. Vago-Splenic Axis in Signal Transduction of Remote Ischemic Preconditioning in Pigs and Rats. Circ Res 2019; 123:1152-1163. [PMID: 30359199 DOI: 10.1161/circresaha.118.313859] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
RATIONALE The signal transduction of remote ischemic conditioning is still largely unknown. OBJECTIVE Characterization of neurohumoral signal transfer and vago-splenic axis in remote ischemic preconditioning (RIPC). METHODS AND RESULTS Anesthetized pigs were subjected to 60 minutes of coronary occlusion and 180 minutes of reperfusion (placebo+ischemia/reperfusion [PLA+I/R]). RIPC was induced by 4×5/5 minutes of hindlimb I/R 90 minutes before coronary occlusion (RIPC+I/R). Arterial blood samples were taken after placebo or RIPC before I/R. In subgroups of pigs, bilateral cervical vagotomy, splenectomy, or splenic denervation were performed before PLA+I/R or RIPC+I/R, respectively. In pigs with RIPC+I/R, infarct size (percentage of area at risk) was less than in those with PLA+I/R (23±12% versus 45±8%); splenectomy or splenic denervation abrogated (splenectomy+RIPC+I/R: 38±15%; splenic denervation+RIPC+I/R: 43±5%), and vagotomy attenuated (vagotomy+RIPC+I/R: 36±11%) RIPC protection. RIPC increased phosphorylation of STAT3 (signal transducer and activator of transcription 3) in left ventricular biopsies taken at early reperfusion. Splenectomy or splenic denervation, but not vagotomy, abolished this increased phosphorylation. In rats with vagotomy, splenectomy, or splenic denervation, RIPC (3×5/5 minutes of hindlimb occlusion/reperfusion) or placebo was performed, respectively. Hearts were isolated, saline perfused, and subjected to 30/120-minute global I/R. With RIPC, infarct size (percentage of ventricular mass) was less (20±7%) than with placebo (37±6%), and vagotomy, splenectomy, or splenic denervation abrogated RIPC protection (38±12%, 36±9%, and 36±7%), respectively. Rat spleens were isolated, saline perfused, and splenic effluate (SEff) was sampled after infusion with carbachol (SEffcarbachol) or saline (SEffsaline). Pig plasma or SEff was infused into isolated perfused rat hearts subjected to global I/R. Infarct size was less with infusion of RIPC+I/Rplasma+ (24±6%) than with PLA+I/Rplasma (40±8%), vagotomy+PLA+I/Rplasma (39±11%), splenectomy+PLA+I/Rplasma (35±8%), vagotomy+RIPC+I/Rplasma (40±9%), splenectomy+RIPC+I/Rplasma (33±9%), or splenic denervation+RIPC+I/Rplasma (39±8%), respectively. With infusion of SEffcarbachol, infarct size was less than with infusion of SEffsaline (24 [19-27]% versus 35 [32-38]%). CONCLUSIONS Activation of a vago-splenic axis is causally involved in RIPC cardioprotection.
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Affiliation(s)
- Helmut Raphael Lieder
- From the Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Germany (H.R.L., P.K., A.S., H.H., G.H.)
| | - Petra Kleinbongard
- From the Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Germany (H.R.L., P.K., A.S., H.H., G.H.)
| | - Andreas Skyschally
- From the Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Germany (H.R.L., P.K., A.S., H.H., G.H.)
| | - Helene Hagelschuer
- From the Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Germany (H.R.L., P.K., A.S., H.H., G.H.)
| | | | - Gerd Heusch
- From the Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Germany (H.R.L., P.K., A.S., H.H., G.H.)
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Cho YJ, Lee HC, Choi EK, Park S, Yu JH, Nam K, Kim TK, Jeon Y. Effects of ischaemic conditioning on tissue oxygen saturation and heart rate variability: an observational study. J Int Med Res 2019; 47:3025-3039. [PMID: 31154876 PMCID: PMC6683943 DOI: 10.1177/0300060519851656] [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: 11/22/2022] Open
Abstract
Objective Ischaemic conditioning (IC) has organ-protective effects, but its clinical results have been inconsistent. Tissue oxygen saturation (StO2) and heart rate variability (HRV) reflect peripheral microcirculation and autonomic nervous system activity, but their changes during IC have not been well documented. We assessed StO2 and HRV during IC in patients undergoing cardiac surgery and healthy volunteers. Methods Ten patients undergoing cardiac surgery and 10 healthy male volunteers underwent remote IC (four 5-minute cycles of ischaemia/reperfusion) applied to the upper arm. Changes in StO2 at the thenar eminence and HRV according to the R-R intervals were recorded during IC. Results The lowest StO2 during ischaemia significantly decreased in patients and significantly increased in volunteers. Among the HRV parameters, the low-frequency domain, which corresponds to sympathetic activity, significantly increased after IC in volunteers but not in patients. Other variables were similar between the groups. Conclusions These results suggest that the minimum tissue oxygen content is depleted during ischaemia in patients and preserved in healthy volunteers. Sympathetic nervous activity seems to increase after IC in healthy volunteers but remains unaffected in patients. Thus, IC may act differently between patients undergoing cardiac surgery and healthy subjects.
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Affiliation(s)
- Youn Joung Cho
- 1 Department of Anaesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyung-Chul Lee
- 1 Department of Anaesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Eue-Keun Choi
- 2 Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seoyeong Park
- 1 Department of Anaesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Je Hyuk Yu
- 1 Department of Anaesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Karam Nam
- 1 Department of Anaesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Tae Kyong Kim
- 3 Department of Anaesthesiology and Pain Medicine, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea
| | - Yunseok Jeon
- 1 Department of Anaesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
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Benstoem C, Goetzenich A, Stoppe C. The role of propofol for remote ischaemic preconditioning in the setting of cardiac surgery - a Cochrane systematic review. Br J Anaesth 2019; 119:1234-1235. [PMID: 29156026 DOI: 10.1093/bja/aex357] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Heusch G. Vagal Cardioprotection in Reperfused Acute Myocardial Infarction. JACC Cardiovasc Interv 2019; 10:1521-1522. [PMID: 28797428 DOI: 10.1016/j.jcin.2017.05.063] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 05/09/2017] [Indexed: 10/19/2022]
Affiliation(s)
- Gerd Heusch
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany.
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