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Carulli E, McGarvey M, Chabok M, Panoulas V, Rosser G, Akhtar M, Smith R, Chandra N, Al-Hussaini A, Kabir T, Barker L, Bruno F, Konstantinou K, de Silva R, Hill J, Xu Y, Lane R, Bucciarelli-Ducci C, Luescher T, Dalby M. Transcoronary cooling and dilution for cardioprotection during revascularisation for ST-segment elevation myocardial infarction: Design and rationale of the STEMI-Cool study. Am Heart J 2025; 282:40-50. [PMID: 39742936 DOI: 10.1016/j.ahj.2024.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/11/2024] [Accepted: 12/20/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND ST-segment elevation myocardial infarction (STEMI) is treated with immediate primary percutaneous coronary intervention (pPCI) to restore coronary blood flow in the acutely ischaemic territory, but is associated with reperfusion injury limiting the benefit of the therapy. No treatment has proven effective in reducing reperfusion injury. Transcoronary hypothermia has been tested in clinical studies and is well tolerated, but is generally established after crossing the occlusion with a guidewire therefore after initial reperfusion, which might have contributed to the neutral outcomes. Transcatheter strategies may also offer additional benefit through haemodilution and the resultant controlled reperfusion, but this has not been fully investigated for pPCI. DESIGN STEMI-Cool is a pragmatic, registry-based randomised clinical pilot trial to test the recruitment rate, feasibility, and safety of a simple transcoronary cooling and dilution protocol. Sixty STEMI patients undergoing pPCI will be randomised 1:1 to standard of care or continuous infusion of room temperature saline through the guiding catheter to achieve intracoronary temperature reductions of 6 to 8°C, commencing before crossing the coronary occlusion with a guidewire. Mechanistic outcome measures will include microvascular resistance, biomarkers of inflammation before infusion and at 24 hour, and magnetic resonance imaging of myocardial salvage and infarct size. CONCLUSIONS STEMI-Cool will investigate the recruitment rate, feasibility and safety of an innovative and simple cooling and diluting strategy for cardioprotection before and during reperfusion with pPCI, aiming to address limitations faced in other studies. Mechanistic outcome measures will allow insight into inflammatory, microvascular and structural changes induced by transcoronary cooling and dilution.
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Affiliation(s)
- Ermes Carulli
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK; Doctoral school in Translational Medicine, University of Milan, Milan, Italy.
| | - Michael McGarvey
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK; Department of Cardiovascular Medicine, King's College Hospital NHS Foundation Trust, London, UK
| | - Mohssen Chabok
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK
| | - Vasileios Panoulas
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK
| | - Gareth Rosser
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK
| | - Mohammed Akhtar
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK
| | - Robert Smith
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK
| | - Navin Chandra
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK
| | - Abtehale Al-Hussaini
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK
| | - Tito Kabir
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK
| | - Laura Barker
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK
| | - Francesco Bruno
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK
| | | | - Ranil de Silva
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK
| | - Jonathan Hill
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK
| | - Yun Xu
- Department of Chemical Engineering, Imperial College London, London, UK
| | - Rebecca Lane
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK
| | - Chiara Bucciarelli-Ducci
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK; School of Biomedical Engineering and Imaging Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Thomas Luescher
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK; Cardiovascular Academic Group, King's College London, London, UK
| | - Miles Dalby
- Department of cardiology, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, London, UK; Cardiovascular Academic Group, King's College London, London, UK
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Lee OH, Heo SJ, Kim MH, Park JW, Bae S, Kim M, Roh JW, Kim Y, Im E, Jung IH, Cho DK. Therapeutic hypothermia in patients with acute myocardial infarction complicated by out-of-hospital cardiac arrest. BMC Med 2025; 23:179. [PMID: 40140891 PMCID: PMC11948712 DOI: 10.1186/s12916-025-03997-0] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Accepted: 03/12/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND There is a lack of data regarding outcomes of therapeutic hypothermia in patients with acute myocardial infarction (AMI) complicated by out-of-hospital cardiac arrest (OHCA). This study aimed to evaluate the effect of therapeutic hypothermia on clinical outcomes in comatose patients after percutaneous coronary intervention (PCI) for AMI following OHCA. METHODS Using a prospective nationwide registry from 2016 to 2021, we selected 2925 patients with AMI who underwent emergency PCI among 182,508 OHCA cases. These patients were divided into groups receiving hypothermia treatment (n = 624) and those not receiving hypothermia treatment (n = 2301). The primary endpoint was in-hospital mortality, and secondary endpoints were mortality rate at 24 h and neurological outcomes at discharge. RESULTS The hypothermia group showed a significantly lower rate of in-hospital mortality than the non-hypothermia group (odds ratio [OR] 0.71; 95% confidence interval [CI], 0.59-0.85; P < 0.001). However, there was no significant difference in neurological outcomes at discharge between the two groups. Furthermore, quartile analysis of door-to-cooling (DtC) time, defined as the time from hospital arrival to initiation of hypothermia, demonstrated that a shorter DtC time was associated with a decreased risk of mortality and poor neurological outcomes (mortality: adjusted OR, 0.40; 95% CI, 0.30-0.54; P < 0.001; poor neurological outcome: adjusted OR, 0.59; 95% CI, 0.45-0.77; P < 0.001 for quartile 1 versus quartile 4). CONCLUSIONS Therapeutic hypothermia reduced the rate of in-hospital mortality in patients with AMI complicated by OHCA. Moreover, early initiation of hypothermia demonstrated a reduction in mortality and poor neurological outcomes. PRE-REGISTERED CLINICAL TRIAL NUMBER URL: http://clinicaltrials.gov . Unique identifier: NCT05724914. In this large, government-controlled, nationwide, prospective real-world registry with AMI and complicated by OHCA, we demonstrated therapeutic hypothermia reduced the rate of in-hospital mortality, but it did not improve neurological outcomes at discharge. Our findings also showed that early initiation of hypothermia was significantly associated with reduced in-hospital mortality and poor neurological outcomes. The findings of this study suggest that therapeutic hypothermia reduces in-hospital mortality in patients with AMI complicated by OHCA. Early application of hypothermia should be considered as a potential means of improving neurological outcomes in patients with AMI-OHCA undergoing emergency PCI.
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Affiliation(s)
- Oh-Hyun Lee
- Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine and Cardiovascular Center, Yongin Severance Hospital, Yongin, Republic of Korea
| | - Seok-Jae Heo
- Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Moon-Hyun Kim
- Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine and Cardiovascular Center, Yongin Severance Hospital, Yongin, Republic of Korea
| | - Je-Wook Park
- Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine and Cardiovascular Center, Yongin Severance Hospital, Yongin, Republic of Korea
| | - SungA Bae
- Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine and Cardiovascular Center, Yongin Severance Hospital, Yongin, Republic of Korea.
| | - Minkwan Kim
- Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine and Cardiovascular Center, Yongin Severance Hospital, Yongin, Republic of Korea
| | - Ji Woong Roh
- Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine and Cardiovascular Center, Yongin Severance Hospital, Yongin, Republic of Korea
| | - Yongcheol Kim
- Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine and Cardiovascular Center, Yongin Severance Hospital, Yongin, Republic of Korea.
| | - Eui Im
- Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine and Cardiovascular Center, Yongin Severance Hospital, Yongin, Republic of Korea
| | - In Hyun Jung
- Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine and Cardiovascular Center, Yongin Severance Hospital, Yongin, Republic of Korea
| | - Deok-Kyu Cho
- Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine and Cardiovascular Center, Yongin Severance Hospital, Yongin, Republic of Korea
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Alotaibi K, Arulkumaran N, Dyson A, Singer M. Therapeutic strategies to ameliorate mitochondrial oxidative stress in ischaemia-reperfusion injury: A narrative review. Clin Sci (Lond) 2025; 139:CS20242074. [PMID: 39899361 DOI: 10.1042/cs20242074] [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: 09/12/2024] [Revised: 12/26/2024] [Accepted: 01/08/2025] [Indexed: 02/04/2025]
Abstract
Mitochondrial reactive oxygen species (mROS) play a crucial physiological role in intracellular signalling. However, high levels of ROS can overwhelm antioxidant defences and lead to detrimental modifications in protein, lipid and DNA structure and function. Ischaemia-reperfusion injury is a multifaceted pathological state characterised by excessive production of mROS. There is a significant clinical need for therapies mitigating mitochondrial oxidative stress. To date, a variety of strategies have been investigated, ranging from enhancing antioxidant reserve capacity to metabolism reduction. While success has been achieved in non-clinical models, no intervention has yet successfully transitioned into routine clinical practice. In this article, we explore the different strategies investigated and discuss the possible reasons for the lack of translation.
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Affiliation(s)
- Khalid Alotaibi
- Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, U.K
- King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Nishkantha Arulkumaran
- Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, U.K
| | - Alex Dyson
- Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, U.K
- Centre for Pharmaceutical Medicine Research, Institute of Pharmaceutical Science, King's College London, London, U.K
| | - Mervyn Singer
- Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, U.K
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Laborante R, Paglianiti DA, Galli M, Patti G, D'Amario D. Impact of Mild Hypothermia As Adjunctive Therapy in Patients With ST-Elevation Myocardial Infarction: A Meta-Analysis and Trial Sequential Analysis of Randomized Controlled Trials. Catheter Cardiovasc Interv 2025; 105:543-556. [PMID: 39676437 PMCID: PMC11831718 DOI: 10.1002/ccd.31351] [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: 10/04/2024] [Revised: 11/24/2024] [Accepted: 12/01/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND The prevention of reperfusion injury remains an unmet need in ST-elevation myocardial infarction (STEMI) patients. Several randomized controlled trials (RCTs) evaluated mild hypothermia as adjunctive therapy during STEMI, with conflicting results. AIMS To summarize the evidence about the efficacy and safety of mild hypothermia in patients with STEMI, as well as its conclusiveness through a trial sequential analysis (TSA). METHODS PubMed and Scopus electronic databases were screened for eligible studies until August 12, 2024. Efficacy endpoints were all-cause death, infarct size (IS), left ventricular ejection fraction (LVEF), the occurrence of microvascular obstruction (MVO), thrombolysis in myocardial infarction (TIMI) flow grade 3, and the resolution of ST-segment elevation (i.e., > 50-70% from baseline) after the procedure. Safety endpoints included: the incidence of atrial fibrillation (AF), infections, any bleeding, major bleeding, acute and subacute stent thrombosis (STh), cardiogenic shock/pulmonary oedema, and ventricular fibrillation/tachycardia. "Door-to-balloon time" was indicated as the procedural endpoint. Two pre-specified subgroup analyses were planned according to the mean ischemic time and the site of hypothermia induction (intra-coronary vs. extra-coronary). A TSA was run to explore whether the effect estimate of each efficacy outcome could be influenced by further studies. RESULTS Ten RCTs were included. Hypothermia did not provide a benefit for any of the specified efficacy endpoints. Furthermore, it enhanced the risk of infection, the risk of STh in patients with a mean ischemic time of less than 4 h, and the risk of AF in patients undergoing extra-coronary hypothermia. Finally, it was also associated with an increased "door-to-balloon time", and a trend toward an increased risk of any bleeding. No significant difference was found for the other endpoints. TSA showed conclusive evidence of an absence of benefit of hypothermia on IS, MVO, LVEF, and TIMI three flow. CONCLUSIONS Mild hypothermia is not beneficial and causes relevant delays in clinical management of STEMI patients, raising safety issues mainly related to the occurrence of STh, AF, and infections.
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Affiliation(s)
- Renzo Laborante
- Department of Cardiovascular ScienceFondazione Policlinico Agostino Gemelli IRCCSRomeItaly
| | | | - Mattia Galli
- Department of Medical‐Surgical Sciences and BiotechnologiesSapienza University of RomeLatinaItaly
- Maria Cecilia HospitalGVM Care & ResearchCotignolaItaly
| | - Giuseppe Patti
- Department of Translational MedicineUniversity of Eastern PiedmontNovaraItaly
- Thoraco‐Cardio‐Vascular DepartmentAzienda Ospedaliero‐Universitaria Maggiore della CaritàNovaraItaly
| | - Domenico D'Amario
- Department of Translational MedicineUniversity of Eastern PiedmontNovaraItaly
- Thoraco‐Cardio‐Vascular DepartmentAzienda Ospedaliero‐Universitaria Maggiore della CaritàNovaraItaly
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Li Y, Chen Y, Yu P, Zhang D, Tang X, Zhu Z, Xiao F, Deng W, Liu Y, Tan Z, Zhang J, Yu S. Mild therapeutic hypothermic protection activates the PI3K/AKT signaling pathway to inhibit TRPM7 and suppress ferroptosis induced by myocardial ischemia‑reperfusion injury. Mol Med Rep 2024; 30:220. [PMID: 39364741 PMCID: PMC11462392 DOI: 10.3892/mmr.2024.13345] [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: 04/03/2024] [Accepted: 09/04/2024] [Indexed: 10/05/2024] Open
Abstract
The present study aimed to investigate the role of PI3K‑mediated ferroptosis signaling induced by mild therapeutic hypothermia (MTH), which was defined as a temperature of 34˚C, in protecting against myocardial ischemia-reperfusion (I/R) injury (MIRI). To meet this aim, H9C2 cells underwent hypoxia‑reperfusion (H/R) and/or MTH. The MTT assay was used to assess cell viability, cytotoxicity was measured using a lactate dehydrogenase cytotoxicity assay, and Annexin V‑FITC/PI flow cytometric analysis was used to analyze early and late cell apoptosis. In addition, 84 healthy adult male Sprague‑Dawley rats were randomly divided into seven groups (n=12), and underwent I/R and various treatments. Hemodynamics were monitored, and the levels of myocardial injury marker enzymes and oxidative stress markers in myocardial tissue were measured using ELISA. The expression levels of PI3K, AKT, transient receptor potential cation channel subfamily M member 7 (TRPM7), glutathione peroxidase 4 (GPX4) and acyl‑CoA synthetase long chain family member 4 (ACSL4) in animals and cells were measured using western blot analysis. These experiments revealed that MTH could effectively reduce myocardial infarct size, improve hemodynamic performance following MIRI and suppress myocardial apoptosis, thereby contributing to the recovery from H/R injury. Mechanistically, MTH was revealed to be able to activate the PI3K/AKT signaling pathway in cells, upregulating GPX4, and downregulating the expression levels of TRPM7 and ACSL4. Treatment with 2‑aminoethoxydiphenyl borate (an inhibitor of TRPM7) could further strengthen the myocardial protective effects of MTH, whereas treatment with erastin (promoter of ferroptosis) and wortmannin (inhibitor of PI3K) led to the effective elimination of the myocardial protective effects of MTH. Compared with in the I/R group, the PI3K/AKT activation level and the expression levels of GPX4 were both significantly increased, whereas the expression levels of TRPM7 and ACSL4 were significantly decreased in the I/R + MTH group. Taken together, the results of the present study indicated that MTH may activate the PI3K/AKT signaling pathway to inhibit TRPM7 and suppress ferroptosis induced by MIRI.
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Affiliation(s)
- Yaqi Li
- Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- Department of Anesthesiology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi 330006, P.R. China
| | - Yixuan Chen
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Peng Yu
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, P.R. China
| | - Deju Zhang
- Food and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Hong Kong, SAR, P.R. China
| | - Xiaoyi Tang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zicheng Zhu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Fan Xiao
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Wei Deng
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yang Liu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhaoying Tan
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jing Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Shuchun Yu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Tamis-Holland JE, Abbott JD, Al-Azizi K, Barman N, Bortnick AE, Cohen MG, Dehghani P, Henry TD, Latif F, Madjid M, Yong CM, Sandoval Y. SCAI Expert Consensus Statement on the Management of Patients With STEMI Referred for Primary PCI. JOURNAL OF THE SOCIETY FOR CARDIOVASCULAR ANGIOGRAPHY & INTERVENTIONS 2024; 3:102294. [PMID: 39649824 PMCID: PMC11624394 DOI: 10.1016/j.jscai.2024.102294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
ST-elevation myocardial infarction (STEMI) remains a leading cause of morbidity and mortality in the United States. Timely reperfusion with primary percutaneous coronary intervention is associated with improved outcomes. The Society for Cardiovascular Angiography & Interventions puts forth this expert consensus document regarding best practices for cardiac catheterization laboratory team readiness, arterial access with an algorithm to help determine proper arterial access in STEMI, and diagnostic angiography. This consensus statement highlights the strengths and limitations of various diagnostic and therapeutic interventions to access and treat a patient with STEMI in the catheterization laboratory, reviews different options to manage large thrombus burden during STEMI, and reviews the management of STEMI across the spectrum of various anatomical and clinical circumstances.
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Affiliation(s)
| | - J. Dawn Abbott
- Lifespan Cardiovascular Institute, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Karim Al-Azizi
- Baylor Scott & White The Heart Hospital – Plano, Plano, Texas
| | | | - Anna E. Bortnick
- Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York
| | | | - Payam Dehghani
- University of Saskatchewan College of Medicine, Regina, Saskatchewan, Canada
| | - Timothy D. Henry
- The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, Cincinnati, Ohio
| | - Faisal Latif
- SSM Health St. Anthony Hospital and University of Oklahoma, Oklahoma City, Oklahoma
| | - Mohammad Madjid
- David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Celina M. Yong
- Stanford University School of Medicine, Stanford, California
- Palo Alto Veterans Affairs Healthcare System, Palo Alto, California
| | - Yader Sandoval
- Minneapolis Heart Institute, Abbott Northwestern Hospital, and Center for Coronary Artery Disease, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota
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Pei Z, Qiu J, Zhao Y, Song S, Wang R, Luo W, Cai X, Liu B, Chen H, Yin J, Weng X, Wu Y, Li C, Shen L, Ge J. A novel intracoronary hypothermia device reduces myocardial reperfusion injury in pigs. Chin Med J (Engl) 2024; 137:2461-2472. [PMID: 38445387 PMCID: PMC11479452 DOI: 10.1097/cm9.0000000000003033] [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: 09/19/2023] [Indexed: 03/07/2024] Open
Abstract
BACKGROUND Hypothermia therapy has been suggested to attenuate myocardial necrosis; however, the clinical implementation as a valid therapeutic strategy has failed, and new approaches are needed to translate into clinical applications. This study aimed to assess the feasibility, safety, and efficacy of a novel selective intracoronary hypothermia (SICH) device in mitigating myocardial reperfusion injury. METHODS This study comprised two phases. The first phase of the SICH was performed in a normal porcine model for 30 minutes ( n = 5) to evaluate its feasibility. The second phase was conducted in a porcine myocardial infarction (MI) model of myocardial ischemia/reperfusion which was performed by balloon occlusion of the left anterior descending coronary artery for 60 minutes and maintained for 42 days. Pigs in the hypothermia group ( n = 8) received hypothermia intervention onset reperfusion for 30 minutes and controls ( n = 8) received no intervention. All animals were followed for 42 days. Cardiac magnetic resonance analysis (five and 42 days post-MI) and a series of biomarkers/histological studies were performed. RESULTS The average time to lower temperatures to a steady state was 4.8 ± 0.8 s. SICH had no impact on blood pressure or heart rate and was safely performed without complications by using a 3.9 F catheter. Interleukin-6 (IL-6), tumor necrosis factor-α, C-reactive protein (CRP), and brain natriuretic peptide (BNP) were lower at 60 min post perfusion in pigs that underwent SICH as compared with the control group. On day 5 post MI/R, edema, intramyocardial hemorrhage, and microvascular obstruction were reduced in the hypothermia group. On day 42 post MI/R, the infarct size, IL-6, CRP, BNP, and matrix metalloproteinase-9 were reduced, and the ejection fraction was improved in pigs that underwent SICH. CONCLUSIONS The SICH device safely and effectively reduced the infarct size and improved heart function in a pig model of MI/R. These beneficial effects indicate the clinical potential of SICH for treatment of myocardial reperfusion injury.
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Affiliation(s)
- Zhiqiang Pei
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
| | - Jin Qiu
- Department of Cardiology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi 030009, China
| | - Yongchao Zhao
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Shuai Song
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
- National Clinical Research for Interventional Medicine, Shanghai 200032, China
| | - Rui Wang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
- National Clinical Research for Interventional Medicine, Shanghai 200032, China
| | - Wei Luo
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
- National Clinical Research for Interventional Medicine, Shanghai 200032, China
| | - Xingxing Cai
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 201322, China
| | - Bin Liu
- Department of Cardiology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi 030009, China
| | - Han Chen
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
- National Clinical Research for Interventional Medicine, Shanghai 200032, China
| | - Jiasheng Yin
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
- National Clinical Research for Interventional Medicine, Shanghai 200032, China
| | - Xinyu Weng
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- National Clinical Research for Interventional Medicine, Shanghai 200032, China
| | - Yizhe Wu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- National Clinical Research for Interventional Medicine, Shanghai 200032, China
| | - Chenguang Li
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- National Clinical Research for Interventional Medicine, Shanghai 200032, China
| | - Li Shen
- National Clinical Research for Interventional Medicine, Shanghai 200032, China
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
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Pyrpyris N, Dimitriadis K, Iliakis P, Theofilis P, Beneki E, Terentes-Printzios D, Sakalidis A, Antonopoulos A, Aznaouridis K, Tsioufis K. Hypothermia for Cardioprotection in Acute Coronary Syndrome Patients: From Bench to Bedside. J Clin Med 2024; 13:5390. [PMID: 39336877 PMCID: PMC11432135 DOI: 10.3390/jcm13185390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 09/05/2024] [Accepted: 09/09/2024] [Indexed: 09/30/2024] Open
Abstract
Early revascularization for patients with acute myocardial infarction (AMI) is of outmost importance in limiting infarct size and associated complications, as well as for improving long-term survival and outcomes. However, reperfusion itself may further damage the myocardium and increase the infarct size, a condition commonly recognized as myocardial reperfusion injury. Several strategies have been developed for limiting the associated with reperfusion myocardial damage, including hypothermia. Hypothermia has been shown to limit the degree of infarct size increase, when started before reperfusion, in several animal models. Systemic hypothermia, however, failed to show any benefit, due to adverse events and potentially insufficient myocardial cooling. Recently, the novel technique of intracoronary selective hypothermia is being tested, with preclinical and clinical results being of particular interest. Therefore, in this review, we will describe the pathophysiology of myocardial reperfusion injury and the cardioprotective mechanics of hypothermia, report the animal and clinical evidence in both systemic and selective hypothermia and discuss the potential future directions and clinical perspectives in the context of cardioprotection for myocardial reperfusion injury.
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Affiliation(s)
| | - Kyriakos Dimitriadis
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, 115 27 Athens, Greece; (N.P.); (P.I.); (P.T.); (E.B.); (D.T.-P.); (A.S.); (A.A.); (K.A.); (K.T.)
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Mir A, Rahman MF, Ragab KM, Fathallah AH, Daloub S, Alwifati N, Hagrass AI, Nourelden AZ, Elsayed SM, Kamal I, Elhady MM, Khan R. Efficacy and Safety of Therapeutic Hypothermia as an Adjuvant Therapy for Percutaneous Coronary Intervention in Acute Myocardial Infarction: A Systematic Review and Meta-Analysis. Ther Hypothermia Temp Manag 2024; 14:152-171. [PMID: 37792341 DOI: 10.1089/ther.2023.0007] [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: 10/05/2023] Open
Abstract
The study aims to compare the use of hypothermia in patients with myocardial infarction (MI) undergoing percutaneous coronary intervention (PCI) with control. We systematically searched four electronic databases until March 2022. The inclusion criteria were any study design that compared hypothermia in patients with MI undergoing PCI with control. The risk of bias assessment of the included randomized controlled trials was conducted through Cochrane Tool, while the quality of the included cohort studies was assessed by the NIH tool. The meta-analysis was performed on RevMan. A total of 19 studies were entered. Regarding the mortality, there were nonsignificant differences between hypothermia and control (odds ratio [OR] = 1.06, 95% confidence interval [CI] 0.75 to 1.50, p = 0.73). There was also no significant difference between the control and hypothermia in recurrent MI (OR = 1.21, 95% CI 0.64 to 2.30, p = 0.56). On the other hand, the analysis showed a significant favor for hypothermia over the control infarct size (mean difference = -1.76, 95% CI -3.04 to -0.47, p = 0.007), but a significant favor for the control over hypothermia in the overall bleeding complications (OR = 1.88, 95% CI 1.11 to 3.18, p = 0.02). Compared with the control, hypothermia reduced the infarct size of the heart, but this finding was not consistent across studies. However, the control had lower rates of bleeding problems. The other outcomes, such as death and the incidence of recurrent MI, were similar between the two groups.
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Affiliation(s)
- Ali Mir
- Department of Internal Medicine, University at Buffalo, Buffalo, New York, USA
| | | | | | | | - Shaden Daloub
- Department of Internal Medicine, Marshall University Joan C. Edwards School of Medicine, Huntington, West Virginia, USA
| | - Nader Alwifati
- Department of Internal Medicine, Rochester General Hospital, Rochester, New York, USA
| | | | | | | | - Ibrahim Kamal
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | | | - Raheel Khan
- Department of Internal Medicine, University at Buffalo, Buffalo, New York, USA
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10
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Ma S, Song Y, Xu Y, Wang C, Yang Y, Zheng Y, Lu Q, Chen Q, Wu J, Wang B, Chen M. Mild Therapeutic Hypothermia Alleviated Myocardial Ischemia/Reperfusion Injury via Targeting SLC25A10 to Suppress Mitochondrial Apoptosis. J Cardiovasc Transl Res 2024; 17:946-958. [PMID: 38568407 PMCID: PMC11371862 DOI: 10.1007/s12265-024-10503-z] [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: 11/07/2023] [Accepted: 02/19/2024] [Indexed: 09/04/2024]
Abstract
Myocardial ischemia/reperfusion injury (MI/RI) is identified as a severe vascular emergency, and the treatment strategy of MI/RI still needs further improvement. The present study aimed to investigate the potential effects of mild therapeutic hypothermia (MTH) on MI/RI and underlying mechanisms. In ischemia/reperfusion (I/R) rats, MTH treatment significantly improved myocardial injury, attenuated myocardial infarction, and inhibited the mitochondrial apoptosis pathway. The results of proteomics identified SLC25A10 as the main target of MTH treatment. Consistently, SLC25A10 expressions in I/R rat myocardium and hypoxia and reoxygenation (H/R) cardiomyocytes were significantly suppressed, which was effectively reversed by MTH treatment. In H/R cardiomyocytes, MTH treatment significantly improved cell injury, mitochondrial dysfunction, and inhibited the mitochondrial apoptosis pathway, which were partially reversed by SLC25A10 deletion. These findings suggested that MTH treatment could protect against MI/RI by modulating SLC25A10 expression to suppress mitochondrial apoptosis pathway, providing new theoretical basis for clinical application of MTH treatment for MI/RI.
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MESH Headings
- Animals
- Myocardial Reperfusion Injury/prevention & control
- Myocardial Reperfusion Injury/metabolism
- Myocardial Reperfusion Injury/pathology
- Myocardial Reperfusion Injury/genetics
- Apoptosis
- Mitochondria, Heart/metabolism
- Mitochondria, Heart/pathology
- Mitochondria, Heart/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Myocytes, Cardiac/drug effects
- Male
- Disease Models, Animal
- Hypothermia, Induced
- Rats, Sprague-Dawley
- Signal Transduction
- Myocardial Infarction/metabolism
- Myocardial Infarction/pathology
- Myocardial Infarction/genetics
- Myocardial Infarction/therapy
- Cells, Cultured
- Apoptosis Regulatory Proteins/metabolism
- Apoptosis Regulatory Proteins/genetics
- Rats
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Affiliation(s)
- Senlin Ma
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Yun Song
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Yanxin Xu
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Chao Wang
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Yifan Yang
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Yanchao Zheng
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Qiuxin Lu
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Qingjiang Chen
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Jian Wu
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Bin Wang
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China.
| | - Mingquan Chen
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, 200040, China.
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11
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El Farissi M, Pijls NHJ, Good R, Engström T, Keeble TR, Beleslin B, De Bruyne B, Fröbert O, Erlinge D, Teeuwen K, Eerdekens R, Demandt JPA, Mangion K, Lonborg J, Setz-Pels W, Karamasis G, Wijnbergen I, Vlaar PJ, de Vos A, Brueren GR, Oldroyd K, Berry C, Tonino PAL, Van't Veer M, Otterspoor LC. A randomised trial of selective intracoronary hypothermia during primary PCI. EUROINTERVENTION 2024; 20:e740-e749. [PMID: 38887884 PMCID: PMC11165355 DOI: 10.4244/eij-d-23-01042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 04/04/2024] [Indexed: 06/20/2024]
Abstract
BACKGROUND While experimental data suggest that selective intracoronary hypothermia decreases infarct size, studies in patients with ST-elevation myocardial infarction (STEMI) are lacking. AIMS We investigated the efficacy of selective intracoronary hypothermia during primary percutaneous coronary intervention (PCI) to decrease infarct size in patients with STEMI. METHODS In this multicentre randomised controlled trial, 200 patients with large anterior wall STEMI were randomised 1:1 to selective intracoronary hypothermia during primary PCI or primary PCI alone. Using an over-the-wire balloon catheter for infusion of cold saline and a pressure-temperature wire to monitor the intracoronary temperature, the anterior myocardium distal to the occlusion was selectively cooled to 30-33°C for 7-10 minutes before reperfusion (occlusion phase), immediately followed by 10 minutes of cooling after reperfusion (reperfusion phase). The primary endpoint was infarct size as a percentage of left ventricular mass on cardiovascular magnetic resonance imaging after 3 months. RESULTS Selective intracoronary hypothermia was performed in 94/100 patients randomised to cooling. Distal coronary temperature decreased by 6°C within 43 seconds (interquartile range [IQR] 18-113). The median duration of the occlusion phase and reperfusion phase were 8.2 minutes (IQR 7.2-9.0) and 9.1 minutes (IQR 8.2-10.0), respectively. The infarct size at 3 months was 23.1±12.5% in the selective intracoronary hypothermia group and 21.6±12.2% in the primary PCI alone group (p=0.43). The left ventricular ejection fraction at 3 months in each group were 49.1±10.2% and 50.1±10.4%, respectively (p=0.53). CONCLUSIONS Selective intracoronary hypothermia during primary PCI in patients with anterior wall STEMI was feasible and safe but did not decrease infarct size compared with standard primary PCI. (ClinicalTrials.gov: NCT03447834).
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Affiliation(s)
- Mohamed El Farissi
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
| | - Nico H J Pijls
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
| | - Richard Good
- Department of Cardiology, Golden Jubilee National Hospital, Clydebank, United Kingdom
| | - Thomas Engström
- Department of Cardiology, Rigshospitalet, Copenhagen, Denmark
| | - Thomas R Keeble
- Department of Cardiology, Essex Cardiothoracic Centre, Basildon, United Kingdom
| | - Branko Beleslin
- Department of Cardiology, Clinical Center of Serbia, Belgrade, Serbia
| | | | - Ole Fröbert
- Örebro University, Faculty of Health, Department of Cardiology, Örebro, Sweden
| | - David Erlinge
- Department of Cardiology, Skåne University Hospital, Clinical Sciences, Lund University, Lund, Sweden
| | - Koen Teeuwen
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
| | - Rob Eerdekens
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
| | - Jesse P A Demandt
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
| | - Kenneth Mangion
- Department of Cardiology, Golden Jubilee National Hospital, Clydebank, United Kingdom
| | - Jakob Lonborg
- Department of Cardiology, Rigshospitalet, Copenhagen, Denmark
| | - Wikke Setz-Pels
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
| | - Grigoris Karamasis
- Department of Cardiology, Essex Cardiothoracic Centre, Basildon, United Kingdom
| | - Inge Wijnbergen
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
| | - Pieter Jan Vlaar
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
| | - Annemiek de Vos
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
| | - Guus R Brueren
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
| | - Keith Oldroyd
- Department of Cardiology, Golden Jubilee National Hospital, Clydebank, United Kingdom
| | - Colin Berry
- Department of Cardiology, Golden Jubilee National Hospital, Clydebank, United Kingdom
| | - Pim A L Tonino
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
| | - Marcel Van't Veer
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
| | - Luuk C Otterspoor
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
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12
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Gao Y, Li M, Jiang M, Zhang Y, Ji X. A narrative review of intravascular catheters in therapeutic hypothermia. Brain Circ 2024; 10:11-20. [PMID: 38655445 PMCID: PMC11034446 DOI: 10.4103/bc.bc_32_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 07/22/2023] [Accepted: 07/27/2023] [Indexed: 04/26/2024] Open
Abstract
Therapeutic hypothermia (TH) has been regarded as a promising neuroprotective method for acute ischemic stroke (AIS) for decades. During the development of TH, most researchers focused on improving hypothermic benefits by optimizing treatment processes and conditions. Intravenous thrombolysis and endovascular thrombectomy, for instance, have been introduced into AIS treatment. However, the lack of specialized intervention consumables, especially intervention catheter, led to inaccurate and uncontrolled hypothermic temperature, limited the efficacy of TH. In this review, intervention catheters as well as accessory equipment utilized in TH treatment has been summarized. Hopefully, this review may inspire the future development of TH specialized intervention catheter, enhance the outcome of TH, and neuroprotective efficacy in AIS.
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Affiliation(s)
- Yuan Gao
- School of Instrumentation and Optoelectronic Engineering, Beihang University, Beijing, China
- Research Institute for Frontier Science, Beihang University, Beijing, China
| | - Ming Li
- Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Miaowen Jiang
- School of Instrumentation and Optoelectronic Engineering, Beihang University, Beijing, China
- Research Institute for Frontier Science, Beihang University, Beijing, China
| | - Yang Zhang
- Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Xunming Ji
- School of Instrumentation and Optoelectronic Engineering, Beihang University, Beijing, China
- Research Institute for Frontier Science, Beihang University, Beijing, China
- Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
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13
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Heusch G, Andreadou I, Bell R, Bertero E, Botker HE, Davidson SM, Downey J, Eaton P, Ferdinandy P, Gersh BJ, Giacca M, Hausenloy DJ, Ibanez B, Krieg T, Maack C, Schulz R, Sellke F, Shah AM, Thiele H, Yellon DM, Di Lisa F. Health position paper and redox perspectives on reactive oxygen species as signals and targets of cardioprotection. Redox Biol 2023; 67:102894. [PMID: 37839355 PMCID: PMC10590874 DOI: 10.1016/j.redox.2023.102894] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/04/2023] [Accepted: 09/15/2023] [Indexed: 10/17/2023] Open
Abstract
The present review summarizes the beneficial and detrimental roles of reactive oxygen species in myocardial ischemia/reperfusion injury and cardioprotection. In the first part, the continued need for cardioprotection beyond that by rapid reperfusion of acute myocardial infarction is emphasized. Then, pathomechanisms of myocardial ischemia/reperfusion to the myocardium and the coronary circulation and the different modes of cell death in myocardial infarction are characterized. Different mechanical and pharmacological interventions to protect the ischemic/reperfused myocardium in elective percutaneous coronary interventions and coronary artery bypass grafting, in acute myocardial infarction and in cardiotoxicity from cancer therapy are detailed. The second part keeps the focus on ROS providing a comprehensive overview of molecular and cellular mechanisms involved in ischemia/reperfusion injury. Starting from mitochondria as the main sources and targets of ROS in ischemic/reperfused myocardium, a complex network of cellular and extracellular processes is discussed, including relationships with Ca2+ homeostasis, thiol group redox balance, hydrogen sulfide modulation, cross-talk with NAPDH oxidases, exosomes, cytokines and growth factors. While mechanistic insights are needed to improve our current therapeutic approaches, advancements in knowledge of ROS-mediated processes indicate that detrimental facets of oxidative stress are opposed by ROS requirement for physiological and protective reactions. This inevitable contrast is likely to underlie unsuccessful clinical trials and limits the development of novel cardioprotective interventions simply based upon ROS removal.
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Affiliation(s)
- Gerd Heusch
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany.
| | - Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Robert Bell
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Edoardo Bertero
- Chair of Cardiovascular Disease, Department of Internal Medicine and Specialties, University of Genova, Genova, Italy
| | - Hans-Erik Botker
- Department of Cardiology, Institute for Clinical Medicine, Aarhus University, Aarhus N, Denmark
| | - Sean M Davidson
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - James Downey
- Department of Physiology, University of South Alabama, Mobile, AL, USA
| | - Philip Eaton
- William Harvey Research Institute, Queen Mary University of London, Heart Centre, Charterhouse Square, London, United Kingdom
| | - Peter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; Pharmahungary Group, Szeged, Hungary
| | - Bernard J Gersh
- Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Mauro Giacca
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College, London, United Kingdom
| | - Derek J Hausenloy
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom; Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, National Heart Research Institute Singapore, National Heart Centre, Yong Loo Lin School of Medicine, National University Singapore, Singapore
| | - Borja Ibanez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), IIS-Fundación Jiménez Díaz University Hospital, and CIBERCV, Madrid, Spain
| | - Thomas Krieg
- Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Christoph Maack
- Department of Translational Research, Comprehensive Heart Failure Center, University Clinic Würzburg, Würzburg, Germany
| | - Rainer Schulz
- Institute for Physiology, Justus-Liebig -Universität, Giessen, Germany
| | - Frank Sellke
- Division of Cardiothoracic Surgery, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI, USA
| | - Ajay M Shah
- King's College London British Heart Foundation Centre of Excellence, London, United Kingdom
| | - Holger Thiele
- Heart Center Leipzig at University of Leipzig and Leipzig Heart Science, Leipzig, Germany
| | - Derek M Yellon
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Fabio Di Lisa
- Dipartimento di Scienze Biomediche, Università degli studi di Padova, Padova, Italy.
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14
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Berg J, Jablonowski R, Nordlund D, Ryd D, Heiberg E, Carlsson M, Arheden H. Mild hypothermia attenuates ischaemia/reperfusion injury: insights from serial non-invasive pressure-volume loops. Cardiovasc Res 2023; 119:2230-2243. [PMID: 36734080 PMCID: PMC10578916 DOI: 10.1093/cvr/cvad028] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 10/31/2022] [Accepted: 12/20/2022] [Indexed: 02/04/2023] Open
Abstract
AIMS Mild hypothermia, 32-35°C, reduces infarct size in experimental studies, potentially mediating reperfusion injuries, but human trials have been ambiguous. To elucidate the cardioprotective mechanisms of mild hypothermia, we analysed cardiac performance in a porcine model of ischaemia/reperfusion, with serial cardiovascular magnetic resonance (CMR) imaging throughout 1 week using non-invasive pressure-volume (PV) loops. METHODS AND RESULTS Normothermia and Hypothermia group sessions (n = 7 + 7 pigs, non-random allocation) were imaged with Cardiovascular magnetic resonance (CMR) at baseline and subjected to 40 min of normothermic ischaemia by catheter intervention. Thereafter, the Hypothermia group was rapidly cooled (mean 34.5°C) for 5 min before reperfusion. Additional CMR sessions at 2 h, 24 h, and 7 days acquired ventricular volumes and ischaemic injuries (unblinded analysis). Stroke volume (SV: -24%; P = 0.029; Friedmans test) and ejection fraction (EF: -20%; P = 0.068) were notably reduced at 24 h in the Normothermia group compared with baseline. In contrast, the decreases were ameliorated in the Hypothermia group (SV: -6%; P = 0.77; EF: -6%; P = 0.13). Mean arterial pressure remained stable in Normothermic animals (-3%, P = 0.77) but dropped 2 h post-reperfusion in hypothermic animals (-18%, P = 0.007). Both groups experienced a decrease and partial recovery pattern for PV loop-derived variables over 1 week, but the adverse effects tended to attenuate in the Hypothermia group. Infarct sizes were 10 ± 8% in Hypothermic and 15 ± 8% in Normothermic animals (P = 0.32). Analysis of covariance at 24 h indicated that hypothermia has cardioprotective properties incremental to reducing infarct size, such as higher external power (P = 0.061) and lower arterial elastance (P = 0.015). CONCLUSION Using non-invasive PV loops by CMR, we observed that mild hypothermia at reperfusion alleviates the heart's work after ischaemia/reperfusion injuries during the first week and preserves short-term cardiac performance. This hypothesis-generating study suggests hypothermia to have cardioprotective properties, incremental to reducing infarct size. The primary cardioprotective mechanism was likely an afterload reduction acutely unloading the left ventricle.
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Affiliation(s)
- Jonathan Berg
- Clinical Physiology, Department of Clinical Sciences LundFaculty of Medicine, Lund University, Box 117 221 00 Lund, Sweden
- Skåne University Hospital, Carl-Bertil Laurells gata 9, 214 28 Malmö, Sweden
- Syntach AB, Lund, Sweden
| | - Robert Jablonowski
- Skåne University Hospital, Carl-Bertil Laurells gata 9, 214 28 Malmö, Sweden
| | - David Nordlund
- Skåne University Hospital, Carl-Bertil Laurells gata 9, 214 28 Malmö, Sweden
| | - Daniel Ryd
- Skåne University Hospital, Carl-Bertil Laurells gata 9, 214 28 Malmö, Sweden
| | - Einar Heiberg
- Skåne University Hospital, Carl-Bertil Laurells gata 9, 214 28 Malmö, Sweden
| | - Marcus Carlsson
- Skåne University Hospital, Carl-Bertil Laurells gata 9, 214 28 Malmö, Sweden
| | - Håkan Arheden
- Skåne University Hospital, Carl-Bertil Laurells gata 9, 214 28 Malmö, Sweden
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15
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Hypothermia as an Adjunctive Therapy to Percutaneous Intervention in ST-Elevation Myocardial Infarction: A Systematic Review and Meta-Analysis of Randomized Control Trials. CARDIOVASCULAR REVASCULARIZATION MEDICINE 2023; 47:8-15. [PMID: 36115819 DOI: 10.1016/j.carrev.2022.09.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/07/2022] [Accepted: 09/08/2022] [Indexed: 02/06/2023]
Abstract
INTRODUCTION In the setting of acute ST-elevation myocardial infarction (STEMI), several randomized control trials (RCTs) suggested a potential benefit with the use of therapeutic hypothermia (TH). However, results from previous studies are contradictory. METHOD We performed a comprehensive literature search for studies that evaluated the efficacy and safety of adjunctive TH compared to the standard percutaneous coronary intervention (PCI) in awake patients with STEMI. The primary outcomes were the infarct size (IS) and microvascular obstruction (MVO) assessed by cardiac imaging at the end of follow-up. The secondary outcomes were major adverse cardiovascular events (MACE), procedure-related complications, and door-to-balloon time. Relative risk (RR) or the mean difference (MD) and corresponding 95 % confidence intervals (CIs) were calculated using the random-effects model. RESULTS A total of 10 RCTs, including 706 patients were included. As compared to standard PCI, TH was not associated with a statistically significant improvement in the IS (MD: -0.87 %, 95%CI: -2.97, 1.23; P = 0.42) or in the MVO (MD: 0.11 %, 95%CI: -0.06, 0.27; P = 0.21). MACE and its components were comparable between the two groups. However, the TH approach was associated with an increased risk of infection and prolonged door-to-balloon time. Furthermore, there was a trend in the TH group toward an increased incidence of stent thrombosis and paroxysmal atrial fibrillation. CONCLUSIONS According to our meta-analysis of published RCTs, TH is not beneficial in awake patients with STEMI and has a marginal safety profile with potential for care delays. Larger-scale RCTs are needed to further clarify our results.
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16
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Soldozy S, Dalzell C, Skaff A, Ali Y, Norat P, Yagmurlu K, Park MS, Kalani MYS. Reperfusion injury in acute ischemic stroke: Tackling the irony of revascularization. Clin Neurol Neurosurg 2023; 225:107574. [PMID: 36696846 DOI: 10.1016/j.clineuro.2022.107574] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 12/12/2022] [Accepted: 12/23/2022] [Indexed: 01/06/2023]
Abstract
Reperfusion injury is an unfortunate consequence of restoring blood flow to tissue after a period of ischemia. This phenomenon can occur in any organ, although it has been best studied in cardiac cells. Based on cardiovascular studies, neuroprotective strategies have been developed. The molecular biology of reperfusion injury remains to be fully elucidated involving several mechanisms, however these mechanisms all converge on a similar final common pathway: blood brain barrier disruption. This results in an inflammatory cascade that ultimately leads to a loss of cerebral autoregulation and clinical worsening. In this article, the authors present an overview of these mechanisms and the current strategies being employed to minimize injury after restoration of blood flow to compromised cerebral territories.
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Affiliation(s)
- Sauson Soldozy
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, VA, USA; Department of Neurosurgery, Westchester Medical Center, Valhalla, NY, USA
| | - Christina Dalzell
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, VA, USA
| | - Anthony Skaff
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, VA, USA
| | - Yusuf Ali
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, VA, USA
| | - Pedro Norat
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, VA, USA
| | - Kaan Yagmurlu
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, VA, USA
| | - Min S Park
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, VA, USA
| | - M Yashar S Kalani
- Department of Surgery, University of Oklahoma, and St. John's Neuroscience Institute, Tulsa, OK, USA.
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17
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Keller K, Sagoschen I, Schmitt VH, Münzel T, Gori T, Hobohm L. Hypothermia and its role in patients with ST-segment-elevation myocardial infarction and cardiac arrest. Front Cardiovasc Med 2022; 9:1051978. [PMID: 36523354 PMCID: PMC9745156 DOI: 10.3389/fcvm.2022.1051978] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 11/07/2022] [Indexed: 07/23/2024] Open
Abstract
Background Patients suffering cardiac arrest resulting from ST-segment-elevation myocardial infarction (STEMI) are at very high risk of death. In addition to reperfusion strategies, therapeutic hypothermia is recommended for cardiac arrest patients who remain unconscious after resuscitation. However, data analysis of the impact of therapeutic hypothermia on survival showed inconsistent results. We aimed to investigate the benefits of therapeutic hypothermia in STEMI patients after cardiopulmonary resuscitation (CPR). Methods Patients with STEMI who received CPR were identified after nationwide German inpatient data (2005-2019) were screened. These patients were stratified for therapeutic hypothermia. The impact of hypothermia on mortality and adverse in-hospital outcomes was analyzed. Results Overall, 133,070 inpatients with STEMI and CPR (53.3% aged ≥70 years; 34% females) were recorded in Germany between 2005 and 2019, of which 12.3% (16,386 patients) underwent therapeutic hypothermia. Females (23.8 vs. 35.4%, p < 0.001) and patients aged ≥70 years (34.9 vs. 55.9%, p < 0.001) were less frequently treated with therapeutic hypothermia. The in-hospital case fatality rate was lower for STEMI with CPR and subsequent therapeutic hypothermia than for treatment without therapeutic hypothermia (53.5 vs. 66.7%, p < 0.001). Therapeutic hypothermia was independently associated with a reduced in-hospital case fatality rate {OR 0.83 [95% confidence interval (CI) 0.80-0.86], p < 0.001}. In addition, therapeutic hypothermia was associated with an increased risk for stroke (OR 1.37 [95% CI 1.25-1.49], p < 0.001), pneumonia (OR 1.75 [95% CI 1.68-1.82], p < 0.001), and acute kidney injury (OR 2.21 [95% CI 2.07-2.35], p < 0.001). Conclusion Therapeutic hypothermia is associated with a survival benefit for STEMI patients after cardiac arrest.
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Affiliation(s)
- Karsten Keller
- Department of Cardiology, Cardiology I, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- Medical Clinic VII, Department of Sports Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Ingo Sagoschen
- Department of Cardiology, Cardiology I, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Volker H. Schmitt
- Department of Cardiology, Cardiology I, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine Main, Mainz, Germany
| | - Thomas Münzel
- Department of Cardiology, Cardiology I, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine Main, Mainz, Germany
| | - Tommaso Gori
- Department of Cardiology, Cardiology I, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine Main, Mainz, Germany
| | - Lukas Hobohm
- Department of Cardiology, Cardiology I, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
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18
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Larsen AI, Grejs AM, Vistisen ST, Strand K, Skadberg Ø, Jeppesen AN, Duez CHV, Kirkegaard H, Søreide E. Kinetics of 2 different high-sensitive troponins during targeted temperature management in out-of-hospital cardiac arrest patients with acute myocardial infarction: a post hoc sub-study of a randomised clinical trial. BMC Cardiovasc Disord 2022; 22:342. [PMID: 35907787 PMCID: PMC9339199 DOI: 10.1186/s12872-022-02778-4] [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: 02/07/2022] [Accepted: 07/13/2022] [Indexed: 11/15/2022] Open
Abstract
Introduction Short term hypothermia has been suggested to have cardio protective properties in acute myocardial infarction (AMI) by reducing infarct size as assessed by troponins. There are limited data on the kinetics of these biomarkers in comatose out-of-hospital cardiac arrest (OHCA) patients, with and without AMI, undergoing targeted temperature management (TTM) in the ICU.
Purpose The aim of this post hoc analyses was to evaluate and compare the kinetics of two high-sensitivity cardiac troponins in OHCA survivors, with and without acute myocardial infarction (AMI), during TTM of different durations [24 h (standard) vs. 48 h (prolonged)]. Methods In a sub-cohort (n = 114) of the international, multicentre, randomized controlled study “TTH48” we measured high-sensitive troponin T (hs-cTnT), high-sensitive troponin I (hs-cTnI) and CK-MB at the following time points: Arrival, 24 h, 48 h and 72 h from reaching the target temperature range of 33 ± 1 °C. All patients diagnosed with an AMI at the immediate coronary angiogram (CAG)—18 in the 24-h group and 25 in the 48-h group—underwent PCI with stent implantation. There were no stent thromboses.
Results Both the hs-cTnT and hs-cTnI changes over time were highly influenced by the cause of OHCA (AMI vs. non-AMI). In contrast to non-AMI patients, both troponins remained elevated at 72 h in AMI patients. There was no difference between the two time-differentiated TTM groups in the kinetics for the two troponins.
Conclusion In comatose OHCA survivors with an aetiology of AMI levels of both hs-cTnI and hs-cTnT remained elevated for 72 h, which is in contrast to the well-described kinetic profile of troponins in normotherm AMI patients. There was no difference in kinetic profile between the two high sensitive assays. Different duration of TTM did not influence the kinetics of the troponins. Trial registration: Clinicaltrials.gov Identifier: NCT01689077, 20/09/2012.
Supplementary Information The online version contains supplementary material available at 10.1186/s12872-022-02778-4.
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Affiliation(s)
- Alf Inge Larsen
- Department of Cardiology, Stavanger University Hospital, Stavanger, Norway. .,Department of Clinical Sciences, University of Bergen, Bergen, Norway.
| | - Anders Morten Grejs
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.,Department of Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Simon Tilma Vistisen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.,Department of Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Kristian Strand
- Department of Intensive Care, Stavanger University Hospital, Stavanger, Norway
| | - Øyvind Skadberg
- Laboratory of Clinical Biochemistry, Stavanger University Hospital, Stavanger, Norway
| | - Anni Nørgaard Jeppesen
- Division for Heart- Lung- and Vascular Surgery, Anaesthesiology section, Aarhus University Hospital, Aarhus, Denmark
| | - Christophe H V Duez
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.,Research Centre for Emergency Medicine, Emergency Department, Aarhus University Hospital, Aarhus, Denmark
| | - Hans Kirkegaard
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.,Research Centre for Emergency Medicine, Emergency Department, Aarhus University Hospital, Aarhus, Denmark
| | - Eldar Søreide
- Department of Clinical Sciences, University of Bergen, Bergen, Norway.,Critical Care and Anaesthesiology Research Group, Stavanger University Hospital, Stavanger, Norway
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19
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Jung KT, Bapat A, Kim YK, Hucker WJ, Lee K. Therapeutic hypothermia for acute myocardial infarction: a narrative review of evidence from animal and clinical studies. Korean J Anesthesiol 2022; 75:216-230. [PMID: 35350095 PMCID: PMC9171548 DOI: 10.4097/kja.22156] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 03/27/2022] [Accepted: 03/29/2022] [Indexed: 11/21/2022] Open
Abstract
Myocardial infarction (MI) is the leading cause of death from coronary heart disease and requires immediate reperfusion therapy with thrombolysis, primary percutaneous coronary intervention, or coronary artery bypass grafting. However, myocardial reperfusion therapy is often accompanied by cardiac ischemia/reperfusion (I/R) injury, which leads to myocardial injury with detrimental consequences. The causes of I/R injury are unclear, but are multifactorial, including free radicals, reactive oxygen species, calcium overload, mitochondria dysfunction, inflammation, and neutrophil-mediated vascular injury. Mild hypothermia has been introduced as one of the potential inhibitors of myocardial I/R injury. Although animal studies have demonstrated that mild hypothermia significantly reduces or delays I/R myocardium damage, human trials have not shown clinical benefits in acute MI (AMI). In addition, the practice of hypothermia treatment is increasing in various fields such as surgical anesthesia and intensive care units. Adequate sedation for anesthetic procedures and protection from body shivering has become essential during therapeutic hypothermia. Therefore, anesthesiologists should be aware of the effects of therapeutic hypothermia on the metabolism of anesthetic drugs. In this paper, we review the existing data on the use of therapeutic hypothermia for AMI in animal models and human clinical trials to better understand the discrepancy between perceived benefits in preclinical animal models and the absence thereof in clinical trials thus far.
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Affiliation(s)
- Ki Tae Jung
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Department of Anesthesiology and Pain Medicine, College of Medicine and Medical School, Chosun University, Gwangju, Korea
| | - Aneesh Bapat
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA
| | - Young-Kug Kim
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - William J. Hucker
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA
| | - Kichang Lee
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA
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20
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Li F, Gao J, Kohls W, Geng X, Ding Y. Perspectives on benefit of early and prereperfusion hypothermia by pharmacological approach in stroke. Brain Circ 2022; 8:69-75. [PMID: 35909706 PMCID: PMC9336590 DOI: 10.4103/bc.bc_27_22] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/01/2022] [Accepted: 06/01/2022] [Indexed: 11/18/2022] Open
Abstract
Stroke kills or disables approximately 15 million people worldwide each year. It is the leading cause of brain injury, resulting in persistent neurological deficits and profound physical handicaps. In spite of over 100 clinical trials, stroke treatment modalities are limited in applicability and efficacy, and therefore, identification of new therapeutic modalities is required to combat this growing problem. Poststroke oxidative damage and lactic acidosis are widely-recognized forms of brain ischemia/reperfusion injury. However, treatments directed at these injury mechanisms have not been effective. In this review, we offer a novel approach combining these well-established damage mechanisms with new insights into brain glucose handling. Specifically, emerging evidence of brain gluconeogenesis provides a missing link for understanding oxidative injury and lactate toxicity after ischemia. Therefore, dysfunctional gluconeogenesis may substantially contribute to oxidative and lactate damage. We further review that hypothermia initiated early in ischemia and before reperfusion may ameliorate gluconeogenic dysfunction and subsequently provide an important mechanism of hypothermic protection. We will focus on the efficacy of pharmacologically assisted hypothermia and suggest a combination that minimizes side effects. Together, this study will advance our knowledge of basic mechanisms of ischemic damage and apply this knowledge to develop new therapeutic strategies that are desperately needed in the clinical treatment of stroke.
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Affiliation(s)
- Fengwu Li
- Department of Neurology, Luhe Hospital, Capital Medical University, Beijing, China
| | - Jie Gao
- Department of Neurology, Luhe Hospital, Capital Medical University, Beijing, China
| | - Wesley Kohls
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - Xiaokun Geng
- Department of Neurology, Luhe Hospital, Capital Medical University, Beijing, China.,Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA.,Department of Neurology, China-America Institute of Neuroscience, Luhe Hospital, Capital Medical University, Beijing, China
| | - Yuchuan Ding
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA
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21
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Li N, Chau CYC, Liu J, Yao M, Kiang KMY, Zhu Z, Zhang P, Cheng H, Leung GKK. Postcooling But Not Precooling Benefits Motor Recovery by Suppressing Cell Death After Surgical Spinal Cord Injury in Rats. World Neurosurg 2022; 159:e356-e364. [PMID: 34942389 DOI: 10.1016/j.wneu.2021.12.049] [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: 09/21/2021] [Revised: 12/13/2021] [Accepted: 12/14/2021] [Indexed: 11/20/2022]
Abstract
BACKGROUND Surgical spinal cord injury (SSCI) is often inevitable in patients with intramedullary lesions. Although regional hypothermia (RH) has been demonstrated neuroprotective, the value of priming RH in SSCI has never been studied. Herein, the authors investigated the impact of pre- and post-RH on neurologic recovery in a clinically relevant model. METHODS An SSCI model was established at T10. RH was conducted by focal 4oC saline perfusion; room temperature (RT) saline was used as controls. Animals were randomized into 6 groups: SHAM-RT/RH, Pre-RT/RH, and Post-RT/RH. Motor and sensory functions were evaluated using the Basso, Beattie, and Bresnahan rating scale and Plantar test 2 weeks after surgery. TUNEL assay and Fluoro-Jade C staining were conducted to examine the cell death, and the alterations of apoptotic markers including total and cleaved casepase 3, Bcl-2, and Bax, as well as the pyroptotic proteins including NLRP3, ASC, and caspase 1, were determined. RESULTS RH perfusion successfully created an intramedullary hypothermia approximately at 24oC, while RT controls remained above 30oC. Animals receiving postinjury RH had the least cell death and the best motor performance, while pre-RH showed the most dead cells and worst hind limb movements. Immunoblotting depicted that post-RH suppressed both apoptotic and pyroptotic death as the cleaved/total caspase 3, Bcl-2/Bax ratio, and NLRP3/ASC/caspase 1 signaling were inhibited. Priming cooling, on the contrary, elevated pyroptosis and did not affect apoptosis significantly. CONCLUSIONS Priming RH before surgical incision could not be supported as it caused excessive cell death. In contrast, instant introduction of RH is beneficial in rescuing neurologic function.
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Affiliation(s)
- Ning Li
- Department of Neurosurgery, Zhongda Hospital, Southeast University, Nanjing, China; Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Charlene Y C Chau
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Jiaxin Liu
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Min Yao
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China
| | - Karrie M Y Kiang
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Zhiyuan Zhu
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Pingde Zhang
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Huilin Cheng
- Department of Neurosurgery, Zhongda Hospital, Southeast University, Nanjing, China
| | - Gilberto K K Leung
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR.
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22
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El Farissi M, Mast TP, van de Kar MRD, Dillen DMM, Demandt JPA, Vervaat FE, Eerdekens R, Dello SAG, Keulards DC, Zelis JM, van ‘t Veer M, Zimmermann FM, Pijls NHJ, Otterspoor LC. Hypothermia for Cardioprotection in Patients with St-Elevation Myocardial Infarction: Do Not Give It the Cold Shoulder Yet! J Clin Med 2022; 11:1082. [PMID: 35207350 PMCID: PMC8878494 DOI: 10.3390/jcm11041082] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/11/2022] [Accepted: 02/15/2022] [Indexed: 12/10/2022] Open
Abstract
The timely revascularization of an occluded coronary artery is the cornerstone of treatment in patients with ST-elevation myocardial infarction (STEMI). As essential as this treatment is, it can also cause additional damage to cardiomyocytes that were still viable before reperfusion, increasing infarct size. This has been termed "myocardial reperfusion injury". To date, there is still no effective treatment for myocardial reperfusion injury in patients with STEMI. While numerous attempts have been made to overcome this hurdle with various experimental therapies, the common denominator of these therapies is that, although they often work in the preclinical setting, they fail to demonstrate the same results in human trials. Hypothermia is an example of such a therapy. Although promising results were derived from experimental studies, multiple randomized controlled trials failed to do the same. This review includes a discussion of hypothermia as a potential treatment for myocardial reperfusion injury, including lessons learned from previous (negative) trials, advanced techniques and materials in current hypothermic treatment, and the possible future of hypothermia for cardioprotection in patients with STEMI.
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Affiliation(s)
- Mohamed El Farissi
- Department of Cardiology, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands; (T.P.M.); (M.R.D.v.d.K.); (D.M.M.D.); (J.P.A.D.); (F.E.V.); (R.E.); (S.A.G.D.); (D.C.K.); (J.M.Z.); (M.v.‘t.V.); (F.M.Z.); (N.H.J.P.); (L.C.O.)
| | - Thomas P. Mast
- Department of Cardiology, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands; (T.P.M.); (M.R.D.v.d.K.); (D.M.M.D.); (J.P.A.D.); (F.E.V.); (R.E.); (S.A.G.D.); (D.C.K.); (J.M.Z.); (M.v.‘t.V.); (F.M.Z.); (N.H.J.P.); (L.C.O.)
| | - Mileen R. D. van de Kar
- Department of Cardiology, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands; (T.P.M.); (M.R.D.v.d.K.); (D.M.M.D.); (J.P.A.D.); (F.E.V.); (R.E.); (S.A.G.D.); (D.C.K.); (J.M.Z.); (M.v.‘t.V.); (F.M.Z.); (N.H.J.P.); (L.C.O.)
| | - Daimy M. M. Dillen
- Department of Cardiology, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands; (T.P.M.); (M.R.D.v.d.K.); (D.M.M.D.); (J.P.A.D.); (F.E.V.); (R.E.); (S.A.G.D.); (D.C.K.); (J.M.Z.); (M.v.‘t.V.); (F.M.Z.); (N.H.J.P.); (L.C.O.)
| | - Jesse P. A. Demandt
- Department of Cardiology, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands; (T.P.M.); (M.R.D.v.d.K.); (D.M.M.D.); (J.P.A.D.); (F.E.V.); (R.E.); (S.A.G.D.); (D.C.K.); (J.M.Z.); (M.v.‘t.V.); (F.M.Z.); (N.H.J.P.); (L.C.O.)
| | - Fabienne E. Vervaat
- Department of Cardiology, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands; (T.P.M.); (M.R.D.v.d.K.); (D.M.M.D.); (J.P.A.D.); (F.E.V.); (R.E.); (S.A.G.D.); (D.C.K.); (J.M.Z.); (M.v.‘t.V.); (F.M.Z.); (N.H.J.P.); (L.C.O.)
| | - Rob Eerdekens
- Department of Cardiology, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands; (T.P.M.); (M.R.D.v.d.K.); (D.M.M.D.); (J.P.A.D.); (F.E.V.); (R.E.); (S.A.G.D.); (D.C.K.); (J.M.Z.); (M.v.‘t.V.); (F.M.Z.); (N.H.J.P.); (L.C.O.)
| | - Simon A. G. Dello
- Department of Cardiology, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands; (T.P.M.); (M.R.D.v.d.K.); (D.M.M.D.); (J.P.A.D.); (F.E.V.); (R.E.); (S.A.G.D.); (D.C.K.); (J.M.Z.); (M.v.‘t.V.); (F.M.Z.); (N.H.J.P.); (L.C.O.)
| | - Danielle C. Keulards
- Department of Cardiology, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands; (T.P.M.); (M.R.D.v.d.K.); (D.M.M.D.); (J.P.A.D.); (F.E.V.); (R.E.); (S.A.G.D.); (D.C.K.); (J.M.Z.); (M.v.‘t.V.); (F.M.Z.); (N.H.J.P.); (L.C.O.)
| | - Jo M. Zelis
- Department of Cardiology, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands; (T.P.M.); (M.R.D.v.d.K.); (D.M.M.D.); (J.P.A.D.); (F.E.V.); (R.E.); (S.A.G.D.); (D.C.K.); (J.M.Z.); (M.v.‘t.V.); (F.M.Z.); (N.H.J.P.); (L.C.O.)
| | - Marcel van ‘t Veer
- Department of Cardiology, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands; (T.P.M.); (M.R.D.v.d.K.); (D.M.M.D.); (J.P.A.D.); (F.E.V.); (R.E.); (S.A.G.D.); (D.C.K.); (J.M.Z.); (M.v.‘t.V.); (F.M.Z.); (N.H.J.P.); (L.C.O.)
- Department of Biomedical Engineering, Eindhoven University of Technology, 5612 AZ Eindhoven, The Netherlands
| | - Frederik M. Zimmermann
- Department of Cardiology, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands; (T.P.M.); (M.R.D.v.d.K.); (D.M.M.D.); (J.P.A.D.); (F.E.V.); (R.E.); (S.A.G.D.); (D.C.K.); (J.M.Z.); (M.v.‘t.V.); (F.M.Z.); (N.H.J.P.); (L.C.O.)
| | - Nico H. J. Pijls
- Department of Cardiology, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands; (T.P.M.); (M.R.D.v.d.K.); (D.M.M.D.); (J.P.A.D.); (F.E.V.); (R.E.); (S.A.G.D.); (D.C.K.); (J.M.Z.); (M.v.‘t.V.); (F.M.Z.); (N.H.J.P.); (L.C.O.)
- Department of Biomedical Engineering, Eindhoven University of Technology, 5612 AZ Eindhoven, The Netherlands
| | - Luuk C. Otterspoor
- Department of Cardiology, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands; (T.P.M.); (M.R.D.v.d.K.); (D.M.M.D.); (J.P.A.D.); (F.E.V.); (R.E.); (S.A.G.D.); (D.C.K.); (J.M.Z.); (M.v.‘t.V.); (F.M.Z.); (N.H.J.P.); (L.C.O.)
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23
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Nishi M, Ogata T, Kobayakawa K, Kobayakawa R, Matsuo T, Cannistraci CV, Tomita S, Taminishi S, Suga T, Kitani T, Higuchi Y, Sakamoto A, Tsuji Y, Soga T, Matoba S. Energy-sparing by 2-methyl-2-thiazoline protects heart from ischaemia/reperfusion injury. ESC Heart Fail 2021; 9:428-441. [PMID: 34854235 PMCID: PMC8787978 DOI: 10.1002/ehf2.13732] [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: 07/10/2021] [Revised: 10/13/2021] [Accepted: 11/11/2021] [Indexed: 11/06/2022] Open
Abstract
AIMS Cardiac ischaemia/reperfusion (I/R) injury remains a critical issue in the therapeutic management of ischaemic heart failure. Although mild hypothermia has a protective effect on cardiac I/R injury, more rapid and safe methods that can obtain similar results to hypothermia therapy are required. 2-Methyl-2-thiazoline (2MT), an innate fear inducer, causes mild hypothermia resulting in resistance to critical hypoxia in cutaneous or cerebral I/R injury. The aim of this study is to demonstrate the protective effect of systemically administered 2MT on cardiac I/R injury and to elucidate the mechanism underlying this effect. METHODS AND RESULTS A single subcutaneous injection of 2MT (50 mg/kg) was given prior to reperfusion of the I/R injured 10 week-old male mouse heart and its efficacy was evaluated 24 h after the ligation of the left anterior descending coronary artery. 2MT preserved left ventricular systolic function following I/R injury (ejection fraction, %: control 37.9 ± 6.7, 2MT 54.1 ± 6.4, P < 0.01). 2MT also decreased infarct size (infarct size/ischaemic area at risk, %: control 48.3 ± 12.1, 2MT 25.6 ± 4.2, P < 0.05) and serum cardiac troponin levels (ng/mL: control 8.9 ± 1.1, 2MT 1.9 ± 0.1, P < 0.01) after I/R. Moreover, 2MT reduced the oxidative stress-exposed area within the heart (%: control 25.3 ± 4.7, 2MT 10.8 ± 1.4, P < 0.01). These results were supported by microarray analysis of the mouse hearts. 2MT induced a transient, mild decrease in core body temperature (°C: -2.4 ± 1.4), which gradually recovered over several hours. Metabolome analysis of the mouse hearts suggested that 2MT minimized energy metabolism towards suppressing oxidative stress. Furthermore, 18F-fluorodeoxyglucose-positron emission tomography/computed tomography imaging revealed that 2MT reduced the activity of brown adipose tissue (standardized uptake value: control 24.3 ± 6.4, 2MT 18.4 ± 5.8, P < 0.05). 2MT also inhibited mitochondrial respiration and glycolysis in rat cardiomyoblasts. CONCLUSIONS We identified the cardioprotective effect of systemically administered 2MT on cardiac I/R injury by sparing energy metabolism with reversible hypothermia. Our results highlight the potential of drug-induced hypothermia therapy as an adjunct to coronary intervention in severe ischaemic heart disease.
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Affiliation(s)
- Masahiro Nishi
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.,Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Takehiro Ogata
- Department of Pathology and Cell Regulation, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Ko Kobayakawa
- Functional Neuroscience Lab, Kansai Medical University, Hirakata, Japan
| | - Reiko Kobayakawa
- Functional Neuroscience Lab, Kansai Medical University, Hirakata, Japan
| | - Tomohiko Matsuo
- Functional Neuroscience Lab, Kansai Medical University, Hirakata, Japan
| | - Carlo Vittorio Cannistraci
- Center for Complex Network Intelligence (CCNI), Tsinghua Laboratory of Brain and Intelligence (THBI), Department of Computer Science, Department of Biomedical Engineering, Tsinghua University, China.,Center for Systems Biology Dresden (CSBD), Dresden, Germany
| | - Shinya Tomita
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shunta Taminishi
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takaomi Suga
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tomoya Kitani
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yusuke Higuchi
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Akira Sakamoto
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yumika Tsuji
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan
| | - Satoaki Matoba
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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24
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Watson N, Karamasis G, Stathogiannis K, Potter M, Damian M, Cook C, Pottinger R, Clesham G, Gamma R, Aggarwal R, Sayer J, Robinson N, Jagathesan R, Kabir A, Tang K, Kelly P, Maccaroni M, Kadayam R, Nalgirkar R, Namjoshi G, Urovi S, Pai A, Waghmare K, Caruso V, Polderman K, Noc M, Davies JR, Keeble TR. Feasibility of early waking cardiac arrest patients whilst receiving therapeutic hypothermia: The therapeutic hypothermia and early waking (THAW) trial. Resuscitation 2021; 171:114-120. [PMID: 34848275 DOI: 10.1016/j.resuscitation.2021.11.031] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 11/22/2021] [Accepted: 11/22/2021] [Indexed: 11/29/2022]
Abstract
AIM To determine the safety and feasibility of an early (12 h) waking and extubation protocol for out-of-hospital cardiac arrest (OHCA) patients receiving targeted temperature management (TTM). METHODS This was a single-centre, prospective, non-randomised, observational, safety and feasibility pilot study which included successfully resuscitated OHCA patients, of presumed cardiac cause. Inclusion criteria were: OHCA patients aged over 18 years with a return of spontaneous circulation, who were going to receive TTM33 (TTM at 33 °C for 24 h and prevention of hyperthermia for 72 h) as part of their post cardiac arrest care. Clinical stability was measured against physiological and neurological parameters as well as clinical assessment. RESULTS 50 consecutive patients were included (median age 65.5 years, 82% male) in the study. Four (8%) patients died within the first twelve hours and were excluded from the final cohort (n = 46). Twenty-three patients (46%) were considered clinically stable and suitable for early waking based on the intention to treat analysis; 12 patients were extubated early based on a variety of clinical factors (21.4 ± 8.6 h) whilst continuing to receive TTM33 with a mean core temperature of 34.2 °C when extubated. Of these, five patients were discharged from the intensive care unit (ICU) <48 h after admission with a mean ICU length of stay 1.8 ± 0.4 days. Twenty-eight patients (56%) were discharged from the ICU with a modified Rankin Score of 0-2. The overall intra-hospital mortality was 50% (n = 25). CONCLUSIONS It is safe and feasible to wake selected comatose OHCA patients at 12 h, allowing for earlier positive neuro-prognostication and reduced ICU stay.
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Affiliation(s)
- Noel Watson
- Essex Cardiothoracic Centre, Basildon, Essex, UK
| | - Grigoris Karamasis
- Essex Cardiothoracic Centre, Basildon, Essex, UK; MTRC, Anglia Ruskin School of Medicine, Chelmsford, Essex, UK
| | | | - Matt Potter
- Essex Cardiothoracic Centre, Basildon, Essex, UK
| | - Max Damian
- Essex Cardiothoracic Centre, Basildon, Essex, UK
| | - Christopher Cook
- Essex Cardiothoracic Centre, Basildon, Essex, UK; MTRC, Anglia Ruskin School of Medicine, Chelmsford, Essex, UK
| | | | - Gerald Clesham
- Essex Cardiothoracic Centre, Basildon, Essex, UK; MTRC, Anglia Ruskin School of Medicine, Chelmsford, Essex, UK
| | - Reto Gamma
- Essex Cardiothoracic Centre, Basildon, Essex, UK
| | | | - Jeremy Sayer
- Essex Cardiothoracic Centre, Basildon, Essex, UK
| | | | | | | | - Kare Tang
- Essex Cardiothoracic Centre, Basildon, Essex, UK
| | - Paul Kelly
- Essex Cardiothoracic Centre, Basildon, Essex, UK
| | | | | | | | | | - Sali Urovi
- Essex Cardiothoracic Centre, Basildon, Essex, UK
| | - Anirudda Pai
- Essex Cardiothoracic Centre, Basildon, Essex, UK
| | | | | | - Kees Polderman
- United Memorial Medical Center, Houston, TX, United States
| | - Marko Noc
- University Medical Centre, Ljubljana, Slovenia
| | - John R Davies
- Essex Cardiothoracic Centre, Basildon, Essex, UK; MTRC, Anglia Ruskin School of Medicine, Chelmsford, Essex, UK
| | - Thomas R Keeble
- Essex Cardiothoracic Centre, Basildon, Essex, UK; MTRC, Anglia Ruskin School of Medicine, Chelmsford, Essex, UK.
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25
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Short-duration hypothermia completed prior to reperfusion prevents intracranial pressure elevation following ischaemic stroke in rats. Sci Rep 2021; 11:22354. [PMID: 34785754 PMCID: PMC8595681 DOI: 10.1038/s41598-021-01838-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 11/01/2021] [Indexed: 11/08/2022] Open
Abstract
Reperfusion therapies re-establish blood flow after arterial occlusion and improve outcome for ischaemic stroke patients. Intracranial pressure (ICP) elevation occurs 18-24 h after experimental stroke. This elevation is prevented by short-duration hypothermia spanning the time of reperfusion. We aimed to determine whether hypothermia-rewarming completed prior to reperfusion, also prevents ICP elevation 24 h post-stroke. Transient middle cerebral artery occlusion was performed on male outbred Wistar rats. Sixty-minute hypothermia to 33 °C, followed by rewarming was induced prior to reperfusion in one group, and after reperfusion in another group. Normothermia controls received identical anaesthesia protocols. ΔICP from pre-stroke to 24 h post-stroke was measured, and infarct volumes were calculated. Rewarming pre-reperfusion prevented ICP elevation (ΔICP = 0.3 ± 3.9 mmHg vs. normothermia ΔICP = 5.2 ± 2.1 mmHg, p = 0.02) and reduced infarct volume (pre-reperfusion = 78.6 ± 23.7 mm3 vs. normothermia = 125.1 ± 44.3 mm3, p = 0.04) 24 h post-stroke. There were no significant differences in ΔICP or infarct volumes between hypothermia groups rewarmed pre- or post-reperfusion. Hypothermia during reperfusion is not necessary for prevention of ICP rise or infarct volume reduction. Short-duration hypothermia may be an applicable early treatment strategy for stroke patients prior to- during-, and after reperfusion therapy.
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26
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Noc M, Fister M, Mikuz U. Searching for a New Cooling Method to Reduce Infarct Size Beyond Primary PCI. JACC Cardiovasc Interv 2021; 14:2056-2058. [PMID: 34454853 DOI: 10.1016/j.jcin.2021.06.037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 06/29/2021] [Indexed: 11/26/2022]
Affiliation(s)
- Marko Noc
- Center for Intensive Internal Medicine, University Medical Center, Ljubljana, Slovenia.
| | - Misa Fister
- Center for Intensive Internal Medicine, University Medical Center, Ljubljana, Slovenia
| | - Ursa Mikuz
- Center for Intensive Internal Medicine, University Medical Center, Ljubljana, Slovenia
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27
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Topical Neck Cooling Prolongs Survival of Rats with Intra-Abdominal Feculent Sepsis by Activation of the Vagus Nerve. Int J Mol Sci 2021; 22:ijms22189828. [PMID: 34575994 PMCID: PMC8465551 DOI: 10.3390/ijms22189828] [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: 08/23/2021] [Revised: 09/05/2021] [Accepted: 09/07/2021] [Indexed: 11/18/2022] Open
Abstract
Global hypothermia prolongs survival in rats with intraabdominal feculent sepsis by inhibiting inflammatory responses. We hypothesized that topical neck cooling (TNC) has similar benefits. Septic shock was induced by cecal ligation and incision (CLI) in Sprague Dawley rats. Rats were randomized to sham laparotomy, control with CLI, CLI with TNC, or vagotomy at the gastroesophageal junction before CLI and TNC. Two more groups underwent peritoneal washout with and without TNC two hours after CLI. TNC significantly lowered neck skin temperature (16.7 ± 1.4 vs. 30.5 ± 0.6 °C, p < 0.05) while maintaining core body normothermia. TNC rats recovered from anesthesia 70 min earlier than the control (p < 0.05). Three hours following CLI, the control and vagotomy with TNC groups had significantly more splenic contraction, fewer circulating leukocytes and higher plasma IL-1β, IL-10 and TNF-α levels than TNC rats (p < 0.05). TNC prolonged survival duration after CLI by a median of four hours vs. control (p < 0.05), but no benefit was seen if vagotomy preceded TNC. Peritoneal washout alone increased survival by 3 h (9.2 (7.8–10.5) h). Survival duration increased dramatically with TNC preceding washout, to a 56% survival rate (>10 days). TNC significantly prolonged the survival of rats with severe intraabdominal sepsis by inhibiting systemic proinflammatory responses by activating vagal anti-inflammatory pathways.
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28
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Dallan LAP, Giannetti NS, Rochitte CE, Polastri TF, San Martin CYB, Hajjar LA, Lima FG, Nicolau JC, Oliveira MTD, Dae M, Ribeiro da Silva EE, Kalil Filho R, Lemos Neto PA, Timerman S. Cooling as an Adjunctive Therapy to Percutaneous Intervention in Acute Myocardial Infarction: COOL-MI InCor Trial. Ther Hypothermia Temp Manag 2021; 11:135-144. [DOI: 10.1089/ther.2020.0018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Luis Augusto Palma Dallan
- Department of Cardiology, InCor, Heart Institute, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil
| | - Natali Schiavo Giannetti
- Department of Cardiology, InCor, Heart Institute, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil
| | - Carlos Eduardo Rochitte
- Department of Cardiology, InCor, Heart Institute, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil
| | - Thatiane Facholi Polastri
- Department of Cardiology, InCor, Heart Institute, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil
| | | | - Ludhmila Abrahao Hajjar
- Department of Cardiology, InCor, Heart Institute, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil
| | - Felipe Gallego Lima
- Department of Cardiology, InCor, Heart Institute, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil
| | - Jose Carlos Nicolau
- Department of Cardiology, InCor, Heart Institute, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil
| | - Mucio Tavares de Oliveira
- Department of Cardiology, InCor, Heart Institute, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil
| | - Michael Dae
- Department of Radiology, UCSF, University of California, San Francisco, California, USA
| | | | - Roberto Kalil Filho
- Department of Cardiology, InCor, Heart Institute, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil
| | - Pedro Alves Lemos Neto
- Department of Cardiology, InCor, Heart Institute, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil
| | - Sergio Timerman
- Department of Cardiology, InCor, Heart Institute, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil
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29
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Noc M, Laanmets P, Neskovic A, Petrović M, Stanetic B, Aradi D, Kiss R, Ungi I, Merkely B, Hudec M, Blasko P, Horvath I, Davies J, Vukcevic V, Holzer M, Metzler B, Witkowski AR, Erglis A, Fister M, Nagy G, Bulum J, Édes I, Peruga J, Średniawa B, Erlinge D, Keeble TR. A multicentre, prospective, randomised controlled trial to assess the safety and effectiveness of cooling as an adjunctive therapy to percutaneous intervention in patients with acute myocardial infarction: the COOL AMI EU Pivotal Trial. EUROINTERVENTION 2021; 17:466-473. [PMID: 34031023 PMCID: PMC9725068 DOI: 10.4244/eij-d-21-00348] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND Despite primary PCI (PPCI), ST-elevation myocardial infarction (STEMI) can still result in large infarct size (IS). New technology with rapid intravascular cooling showed positive signals for reduction in IS in anterior STEMI. AIMS We investigated the effectiveness and safety of rapid systemic intravascular hypothermia as an adjunct to PPCI in conscious patients, with anterior STEMI, without cardiac arrest. METHODS Hypothermia was induced using the ZOLL® Proteus™ intravascular cooling system. After randomisation of 111 patients, 58 to hypothermia and 53 to control groups, the study was prematurely discontinued by the sponsor due to inconsistent patient logistics between the groups resulting in significantly longer total ischaemic delay in the hypothermia group (232 vs 188 minutes; p<0.001). RESULTS There were no differences in angiographic features and PPCI result between the groups. Intravascular temperature at wire crossing was 33.3+0.9°C. Infarct size/left ventricular (IS/LV) mass by cardiac magnetic resonance (CMR) at day 4-6 was 21.3% in the hypothermia group and 20.0% in the control group (p=0.540). Major adverse cardiac events at 30 days increased non-significantly in the hypothermia group (8.6% vs 1.9%; p=0.117) while cardiogenic shock (10.3% vs 0%; p=0.028) and paroxysmal atrial fibrillation (43.1% vs 3.8%; p<0.001) were significantly more frequent in the hypothermia group. CONCLUSIONS The ZOLL Proteus intravascular cooling system reduced temperature to 33.3°C before PPCI in patients with anterior STEMI. Due to inconsistent patient logistics between the groups, this hypothermia protocol resulted in a longer ischaemic delay, did not reduce IS/LV mass and was associated with increased adverse events.
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Affiliation(s)
- Marko Noc
- Center for Intensive Internal Medicine, University Medical Center, Zaloska 7, 1000 Ljubljana, Slovenia
| | - Peep Laanmets
- North-Estonia Medical Centre Foundation, Tallinn, Estonia
| | - Aleksandar Neskovic
- Clinical Hospital Center Zemun, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Milovan Petrović
- Institute of Cardiovascular Diseases of Vojvodina, Sremska Kamenica, Faculty of Medicine, Novi Sad, Serbia
| | - Bojan Stanetic
- University Clinical Center of the Republic of Srpska, Medical Faculty of University of Banja Luka, Banja Luka, Bosnia
| | | | | | - Imre Ungi
- University of Szeged, Szeged, Hungary
| | - Béla Merkely
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Martin Hudec
- Stredoslovenski Ustav Srdcovych a Cievnych Chorob, Banska Bystrica, Slovakia
| | | | - Ivan Horvath
- Department of Cardiology, Health Faculty of Medicine, University of Pecs, Hungary
| | - John Davies
- Essex Cardiothoracic Centre, Basildon and Thurrock University Hospital NHS Foundation Trust, Basildon, UK
| | | | - Michael Holzer
- Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria
| | - Bernhard Metzler
- University Hospital of Internal Medicine lll/Cardiology and Angiology, Medical University Innsbruck, Innsbruck, Austria
| | | | - Andrejs Erglis
- Pauls Stradiņš Clinical University Hospital, University of Latvia, Riga, Latvia
| | - Misa Fister
- University Medical Centre Ljubljana, Slovenia
| | - Gergely Nagy
- Borsod-Abauj-Zemplen County Central Hospital and University Teaching Hospital, 1st Department of Internal Medicine and Cardiology, Miskolc, Miskolc, Hungary
| | - Josko Bulum
- University Hospital Center Zagreb, Zagreb, Croatia
| | - István Édes
- Department of Cardiology, Faculty of Medicine, Medical and Health Science Center, University of Debrecen, Debrbrecen, Hungary
| | - Jan Peruga
- Medical University in Łódź, Bieganski Hospital, Łódź, Poland
| | - Beata Średniawa
- Silesian Center for Heart Diseases, Department of Cardiology, Medical University of Silesia, DMS in Zabrze, Zabrze, Poland
| | - David Erlinge
- Department of Cardiology, Lund University, Clinical Sciences, Skane University Hospital, Lund, Sweden
| | - Thomas R. Keeble
- Essex Cardiothoracic Centre, Basildon and Thurrock University Hospital NHS Foundation Trust, Basildon, UK,Anglia Ruskin School of Medicine, Chelmsford, Essex, UK
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30
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Vidal-Calés P, Cepas-Guillén PL, Brugaletta S, Sabaté M. New Interventional Therapies beyond Stenting to Treat ST-Segment Elevation Acute Myocardial Infarction. J Cardiovasc Dev Dis 2021; 8:jcdd8090100. [PMID: 34564118 PMCID: PMC8469769 DOI: 10.3390/jcdd8090100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/17/2021] [Accepted: 08/20/2021] [Indexed: 11/29/2022] Open
Abstract
Myocardial infarction remains the principal cause of death in Europe. In patients with ST-segment-elevation myocardial infarction (STEMI), a promptly revascularization with primary percutaneous intervention (PCI) has transformed prognosis in the last decades. However, despite increasing successful PCI procedures, mortality has remained unchanged in recent years. Also, due to an unsatisfactory reperfusion, some patients have significant myocardial damage and suffer left ventricular adverse remodeling with reduced function—all that resulting in the onset of heart failure with all its inherent clinical and socioeconomic burden. As a consequence of longer ischemic times, distal thrombotic embolization, ischemia-reperfusion injury and microvascular dysfunction, the resultant myocardial infarct size is the major prognostic determinant in STEMI patients. The improved understanding of all the pathophysiology underlying these events has derived to the development of several novel therapies aiming to reduce infarct size and to improve clinical outcomes in these patients. In this article, based on the mechanisms involved in myocardial infarction prognosis, we review the new interventional strategies beyond stenting that may solve the suboptimal results that STEMI patients still experience.
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Affiliation(s)
- Pablo Vidal-Calés
- Institut Clínic Cardiovascular, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain; (P.V.-C.); (P.L.C.-G.); (S.B.)
| | - Pedro L. Cepas-Guillén
- Institut Clínic Cardiovascular, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain; (P.V.-C.); (P.L.C.-G.); (S.B.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Salvatore Brugaletta
- Institut Clínic Cardiovascular, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain; (P.V.-C.); (P.L.C.-G.); (S.B.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Manel Sabaté
- Institut Clínic Cardiovascular, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain; (P.V.-C.); (P.L.C.-G.); (S.B.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red. Enfermedades Cardiovasculares (CIBERCV) CB16/11/00411, 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-932-275-519
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31
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El Farissi M, Keulards DCJ, Zelis JM, van 't Veer M, Zimmermann FM, Pijls NHJ, Otterspoor LC. Hypothermia for Reduction of Myocardial Reperfusion Injury in Acute Myocardial Infarction: Closing the Translational Gap. Circ Cardiovasc Interv 2021; 14:e010326. [PMID: 34266310 DOI: 10.1161/circinterventions.120.010326] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Myocardial reperfusion injury-triggered by an inevitable inflammatory response after reperfusion-may undo a considerable part of the myocardial salvage achieved through timely percutaneous coronary intervention in patients with acute myocardial infarction. Because infarct size is strongly correlated to mortality and risk of heart failure, the importance of endeavors for cardioprotective therapies to attenuate myocardial reperfusion injury and decrease infarct size remains undisputed. Myocardial reperfusion injury is the result of several complex nonlinear phenomena, and for a therapy to be effective, it should act on multiple targets involved in this injury. In this regard, hypothermia remains a promising treatment despite a number of negative randomized controlled trials in humans with acute myocardial infarction so far. To turn the tide for hypothermia in patients with acute myocardial infarction, sophisticated solutions for important limitations of systemic hypothermia should continue to be developed. In this review, we provide a comprehensive overview of the pathophysiology and clinical expression of myocardial reperfusion injury and discuss the current status and possible future of hypothermia for cardioprotection in patients with acute myocardial infarction.
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Affiliation(s)
- Mohamed El Farissi
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
| | | | - Jo M Zelis
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
| | - Marcel van 't Veer
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
| | | | - Nico H J Pijls
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
| | - Luuk C Otterspoor
- Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
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32
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Scherz T, Hofbauer TM, Ondracek AS, Simon D, Sterz F, Testori C, Lang IM, Mangold A. Mild Therapeutic Hypothermia Alters Hemostasis in ST Elevation Myocardial Infarction Patients. Front Cardiovasc Med 2021; 8:707367. [PMID: 34295929 PMCID: PMC8290912 DOI: 10.3389/fcvm.2021.707367] [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: 05/09/2021] [Accepted: 06/15/2021] [Indexed: 11/13/2022] Open
Abstract
Background and Rationale: Mild therapeutic hypothermia (MTH) is a concept to reduce infarct size and improve outcome after ST-segment elevation myocardial infarction (STEMI). In the STATIM trial, we investigated MTH as an additional therapy for STEMI patients. In the intention-to-treat set, 101 patients were included. No difference in primary and secondary endpoints measured by cardiac magnetic resonance imaging was found. Platelet activation and plasmatic coagulation are key in the pathophysiology of STEMI. In the present study, we investigated the effect of MTH on primary and secondary hemostasis in STEMI patients. Methods and Results: Platelet function and morphology were assessed by routine blood count, aggregometry testing, and flow cytometry. Soluble platelet markers were determined by enzyme-linked immunosorbent assay (ELISA) testing. Plasmatic coagulation was measured throughout the study. Platelet count remained unchanged, irrespective of treatment, whereas platelet size decreased in both patient groups. Platelet aggregometry indicated increased platelet reactivity in the MTH group. Furthermore, higher adenosine diphosphate (ADP) plasma levels were found in MTH patients. Expression of glycoprotein IIb/IIIa was increased on platelets of STEMI patients treated with MTH. Lower patient temperatures correlated with longer clotting times and resulted in reduced pH. Lower pH values were positively correlated with longer clotting times. Conclusion: Present data indicate longer clotting times and higher platelet reactivity in STEMI patients treated with MTH. These changes did not correspond to clinical bleeding events or larger infarct size.
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Affiliation(s)
- Thomas Scherz
- Division of Cardiology, Department of Internal Medicine II, Vienna General Hospital, Medical University of Vienna, Vienna, Austria.,Department of Dermatology, Landesklinikum Wiener Neustadt, Wiener Neustadt, Austria
| | - Thomas M Hofbauer
- Division of Cardiology, Department of Internal Medicine II, Vienna General Hospital, Medical University of Vienna, Vienna, Austria
| | - Anna S Ondracek
- Division of Cardiology, Department of Internal Medicine II, Vienna General Hospital, Medical University of Vienna, Vienna, Austria
| | - Daniel Simon
- Division of Cardiology, Department of Internal Medicine II, Vienna General Hospital, Medical University of Vienna, Vienna, Austria.,Department of Internal Medicine I, Cardiology, Klinikum Bamberg, Bamberg, Germany
| | - Fritz Sterz
- Department of Emergency Medicine, Vienna General Hospital, Medical University of Vienna, Vienna, Austria
| | - Christoph Testori
- Department of Emergency Medicine, Vienna General Hospital, Medical University of Vienna, Vienna, Austria.,Department of Internal Medicine, Cardiology and Nephrology, Landesklinikum Wiener Neustadt, Wiener Neustadt, Austria
| | - Irene M Lang
- Division of Cardiology, Department of Internal Medicine II, Vienna General Hospital, Medical University of Vienna, Vienna, Austria
| | - Andreas Mangold
- Division of Cardiology, Department of Internal Medicine II, Vienna General Hospital, Medical University of Vienna, Vienna, Austria
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33
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van Wincoop M, de Bijl-Marcus K, Lilien M, van den Hoogen A, Groenendaal F. Effect of therapeutic hypothermia on renal and myocardial function in asphyxiated (near) term neonates: A systematic review and meta-analysis. PLoS One 2021; 16:e0247403. [PMID: 33630895 PMCID: PMC7906340 DOI: 10.1371/journal.pone.0247403] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 02/08/2021] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Therapeutic hypothermia (TH) is a well-established neuroprotective therapy applied in (near) term asphyxiated infants. However, little is known regarding the effects of TH on renal and/or myocardial function. OBJECTIVES To describe the short- and long-term effects of TH on renal and myocardial function in asphyxiated (near) term neonates. METHODS An electronic search strategy incorporating MeSH terms and keywords was performed in October 2019 and updated in June 2020 using PubMed and Cochrane databases. Inclusion criteria consisted of a RCT or observational cohort design, intervention with TH in a setting of perinatal asphyxia and available long-term results on renal and myocardial function. We performed a meta-analysis and heterogeneity and sensitivity analyses using a random effects model. Subgroup analysis was performed on the method of cooling. RESULTS Of the 107 studies identified on renal function, 9 were included. None of the studies investigated the effects of TH on long-term renal function after perinatal asphyxia. The nine included studies described the effect of TH on the incidence of acute kidney injury (AKI) after perinatal asphyxia. Meta-analysis showed a significant difference between the incidence of AKI in neonates treated with TH compared to the control group (RR = 0.81; 95% CI 0.67-0.98; p = 0.03). No studies were found investigating the long-term effects of TH on myocardial function after neonatal asphyxia. Possible short-term beneficial effects were presented in 4 out of 5 identified studies, as observed by significant reductions in cardiac biomarkers and less findings of myocardial dysfunction on ECG and cardiac ultrasound. CONCLUSIONS TH in asphyxiated neonates reduces the incidence of AKI, an important risk factor for chronic kidney damage, and thus is potentially renoprotective. No studies were found on the long-term effects of TH on myocardial function. Short-term outcome studies suggest a cardioprotective effect.
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Affiliation(s)
- Maureen van Wincoop
- Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Karen de Bijl-Marcus
- Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Marc Lilien
- Department of Pediatric Nephrology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Agnes van den Hoogen
- Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Floris Groenendaal
- Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht and Utrecht University, Utrecht, The Netherlands
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Yamada KP, Kariya T, Aikawa T, Ishikawa K. Effects of Therapeutic Hypothermia on Normal and Ischemic Heart. Front Cardiovasc Med 2021; 8:642843. [PMID: 33659283 PMCID: PMC7919696 DOI: 10.3389/fcvm.2021.642843] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 01/21/2021] [Indexed: 12/24/2022] Open
Abstract
Therapeutic hypothermia has been used for treating brain injury after out-of-hospital cardiac arrest. Its potential benefit on minimizing myocardial ischemic injury has been explored, but clinical evidence has yet to confirm positive results in preclinical studies. Importantly, therapeutic hypothermia for myocardial infarction is unique in that it can be initiated prior to reperfusion, in contrast to its application for brain injury in resuscitated cardiac arrest patients. Recent advance in cooling technology allows more rapid cooling of the heart than ever and new clinical trials are designed to examine the efficacy of rapid therapeutic hypothermia for myocardial infarction. In this review, we summarize current knowledge regarding the effect of hypothermia on normal and ischemic hearts and discuss issues to be solved in order to realize its clinical application for treating acute myocardial infarction.
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Affiliation(s)
- Kelly P Yamada
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Taro Kariya
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Tadao Aikawa
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Kiyotake Ishikawa
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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Han Y, Geng XK, Lee H, Li F, Ding Y. Neuroprotective Effects of Early Hypothermia Induced by Phenothiazines and DHC in Ischemic Stroke. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:1207092. [PMID: 33531913 PMCID: PMC7834782 DOI: 10.1155/2021/1207092] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 12/11/2020] [Accepted: 12/31/2020] [Indexed: 12/27/2022]
Abstract
METHODS Adult male Sprague Dawley rats were studied in 4 groups: (1) sham; (2) stroke; (3) stroke treated with pharmacological hypothermia before reperfusion (interischemia hypothermia); and (4) stroke treated with pharmacological hypothermia after reperfusion is initiated (inter-reperfusion hypothermia). The combination of chlorpromazine and promethazine with dihydrocapsaicin (DHC) was used to induce hypothermia. To compare the neuroprotective effects of drug-induced hypothermia between the interischemia and inter-reperfusion groups, brain damage was evaluated using infarct volume and neurological deficits at 24 h reperfusion. In addition, mRNA expressions of NADPH oxidase (NOX) subunits (gp91phox, p67phox, p47phox, and p22phox) and glucose transporter subtypes (GLUT1 and GLUT3) were determined by real-time PCR at 6 and 24 h reperfusion. ROS production was measured by flow cytometry assay at the same time points. RESULTS In both hypothermia groups, the cerebral infarct volumes and neurological deficits were reduced in the ischemic rats. At 6 and 24 h reperfusion, ROS production and the expressions of NOX subunits and glucose transporter subtypes were also significantly reduced in both hypothermia groups as compared to the ischemic group. While there were no statistically significant differences between the two hypothermia groups at 6 h reperfusion, brain damage was significantly further decreased by interischemia hypothermia at 24 h. CONCLUSION Both interischemia and inter-reperfusion pharmacological hypothermia treatments play a role in neuroprotection after stroke. Interischemia hypothermia treatment may be better able to induce stronger neuroprotection after ischemic stroke. This study provides a new avenue and reference for stronger neuroprotective hypothermia before vascular recanalization in stroke patients.
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Affiliation(s)
- Yun Han
- Luhe Institute of Neuroscience, Capital Medical University, Beijing, China
- Department of Neurology, Luhe Clinical Institute, Capital Medical University, Beijing, China
| | - Xiao-kun Geng
- Luhe Institute of Neuroscience, Capital Medical University, Beijing, China
- Department of Neurology, Luhe Clinical Institute, Capital Medical University, Beijing, China
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Hangil Lee
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Fengwu Li
- Luhe Institute of Neuroscience, Capital Medical University, Beijing, China
| | - Yuchuan Ding
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan, USA
- Department of Research & Development Center, John D. Dingell VA Medical Center, Detroit, Michigan, USA
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Cardioprotective effect of combination therapy by mild hypothermia and local or remote ischemic preconditioning in isolated rat hearts. Sci Rep 2021; 11:265. [PMID: 33431942 PMCID: PMC7801421 DOI: 10.1038/s41598-020-79449-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 11/30/2020] [Indexed: 01/14/2023] Open
Abstract
A multitargeted strategy to treat the consequences of ischemia and reperfusion (IR) injury in acute myocardial infarction may add cardioprotection beyond reperfusion therapy alone. We investigated the cardioprotective effect of mild hypothermia combined with local ischemic preconditioning (IPC) or remote ischemic conditioning (RIC) on IR injury in isolated rat hearts. Moreover, we aimed to define the optimum timing of initiating hypothermia and evaluate underlying cardioprotective mechanisms. Compared to infarct size in normothermic controls (56 ± 4%), mild hypothermia during the entire or final 20 min of the ischemic period reduced infarct size (34 ± 2%, p < 0.01; 35 ± 5%, p < 0.01, respectively), while no reduction was seen when hypothermia was initiated at reperfusion (51 ± 4%, p = 0.90). In all groups with effect of mild hypothermia, IPC further reduced infarct size. In contrast, we found no additive effect on infarct size between hypothermic controls (20 ± 3%) and the combination of mild hypothermia and RIC (33 ± 4%, p = 0.09). Differences in temporal lactate dehydrogenase release patterns suggested an anti-ischemic effect by mild hypothermia, while IPC and RIC preferentially targeted reperfusion injury. In conclusion, additive underlying mechanisms seem to provide an additive effect of mild hypothermia and IPC, whereas the more clinically applicable RIC does not add cardioprotection beyond mild hypothermia.
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Chen J, Bian X, Li Y, Xiao X, Yin Y, Du X, Wang C, Li L, Bai Y, Liu X. Moderate hypothermia induces protection against hypoxia/reoxygenation injury by enhancing SUMOylation in cardiomyocytes. Mol Med Rep 2020; 22:2617-2626. [PMID: 32945433 PMCID: PMC7453665 DOI: 10.3892/mmr.2020.11374] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 03/04/2020] [Indexed: 02/05/2023] Open
Abstract
Moderate hypothermia plays a major role in myocardial cell death as a result of hypoxia/reoxygenation (H/R) injury. However, few studies have investigated the molecular mechanisms of hypothermic cardioprotection. Several responses to stress and other cell functions are regulated by post‑translational protein modifications controlled by small ubiquitin‑like modifier (SUMO). Previous studies have established that high SUMOylation of proteins potentiates the ability of cells to withstand hypoxic‑ischemic stress. The level to which moderate hypothermia affects SUMOylation is not fully understood, as the functions of SUMOylation in the heart have not been studied in depth. The aim of the present study was to investigate the effect of moderate hypothermia (33˚C) on the protective functions of SUMOylation on myocardial cells. HL‑1 and H9c2 cells were treated with the hypoxia‑mimetic chemical CoCl2 and complete medium to simulate H/R injury. Hypothermia intervention was then administered. A Cell Counting kit‑8 assay was used to analyze cell viability. Mitochondrial membrane potential and the generation of reactive oxygen species (ROS) were used as functional indexes of mitochondria dysfunction. Bcl‑2 and caspase‑3 expression levels were analyzed by western blotting. The present results suggested that moderate hypothermia significantly increased SUMO1 and Bcl‑2 expression levels, as well as the mitochondrial membrane potential, but significantly decreased the expression levels of caspase‑3 and mitochondrial ROS. Thus, moderate hypothermia may enhance SUMOylation and attenuate myocardial H/R injury. Moreover, a combination of SUMOylation and moderate hypothermia may be a potential cardiovascular intervention.
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Affiliation(s)
- Jinsheng Chen
- North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
- Department of Anesthesiology, Tangshan Maternity and Child Health Care Hospital, Tangshan, Hebei 063000, P.R. China
| | - Xiyun Bian
- Central Laboratory, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China
| | - Yanxia Li
- Central Laboratory, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China
| | - Xiaolin Xiao
- Central Laboratory, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China
| | - Yanying Yin
- Department of Neurology, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China
| | - Xinping Du
- Department of Cardiology, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China
| | - Cuancuan Wang
- Department of Cardiology, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China
| | - Lili Li
- Department of Bone and Soft Tissue Tumors, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
| | - Yaowu Bai
- North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
- Department of Anesthesiology, Tangshan Maternity and Child Health Care Hospital, Tangshan, Hebei 063000, P.R. China
| | - Xiaozhi Liu
- Central Laboratory, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China
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Kendziora B, Stier H, Schlattmann P, Dewey M. MRI for measuring therapy efficiency after revascularisation in ST-segment elevation myocardial infarction: a systematic review and meta-regression analysis. BMJ Open 2020; 10:e034359. [PMID: 32988935 PMCID: PMC7523216 DOI: 10.1136/bmjopen-2019-034359] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
OBJECTIVE To summarise existing data on the relation between the time from symptom onset until revascularisation (time to reperfusion) and the myocardial salvage index (MSI) calculated as proportion of non-necrotic myocardium inside oedematous myocardium on T2-weighted and T1-weighted late gadolinium enhancement MRI after ST-segment elevation myocardial infarction (STEMI). METHODS Studies including patients with revascularised STEMI and stating both the time to reperfusion and the MSI measured by T2-weighted and T1-weighted late gadolinium enhancement MRI were searched in MEDLINE, EMBASE and ISI Web of Science until 16 May 2020. A mixed effects model was used to evaluate the relation between the time to reperfusion and the MSI. The gender distribution and mean age in included patient groups, the timing of MRI, used MRI sequences and image interpretation methodology were included in the mixed effects model to explore between-study heterogeneity. RESULTS We included 38 studies with 5106 patients. The pooled MSI was 42.6% (95% CI: 38.1 to 47.1). The pooled time to reperfusion was 3.8 hours (95% CI: 3.5 to 4.0). Every hour of delay in reperfusion was associated with an absolute decrease of 13.1% (95% CI: 11.5 to 14.6; p<0.001) in the MSI. Between-study heterogeneity was considerable (σ2=167.8). Differences in the gender distribution, timing of MRI and image interpretation among studies explained 45.2% of the between-study heterogeneity. CONCLUSIONS The MSI on T2-weighted and T1-weighted late gadolinium enhancement MRI correlates inversely with the time to reperfusion, which indicates that cardioprotection achieved by minimising the time to reperfusion leads to a higher MSI. The analysis revealed considerable heterogeneity between studies. The heterogeneity could partly be explained by differences in the gender distribution, timing and interpretation of MRI suggesting that the MRI-assessed MSI is not only influenced by cardioprotective therapy but also by patient characteristics and MRI parameters.
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Affiliation(s)
- Benjamin Kendziora
- Institute of Radiology, Charité - Universitätsmedizin Berlin, Humboldt-Universität and Freie Universität, Berlin, Germany
| | - Heli Stier
- Institute of Radiology, Charité - Universitätsmedizin Berlin, Humboldt-Universität and Freie Universität, Berlin, Germany
| | - Peter Schlattmann
- Institute of Medical Statistics, Computer Sciences and Documentation, Universitätsklinikum Jena, Friedrich-Schiller-Universität, Jena, Germany
| | - Marc Dewey
- Institute of Radiology, Charité - Universitätsmedizin Berlin, Humboldt-Universität and Freie Universität, Berlin, Germany
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Tehrani BN, Basir MB, Kapur NK. Acute myocardial infarction and cardiogenic shock: Should we unload the ventricle before percutaneous coronary intervention? Prog Cardiovasc Dis 2020; 63:607-622. [PMID: 32920027 DOI: 10.1016/j.pcad.2020.09.001] [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: 09/03/2020] [Accepted: 09/03/2020] [Indexed: 12/22/2022]
Abstract
Despite early reperfusion and coordinated systems of care, cardiogenic shock (CS) remains the number one cause of morbidity and in-hospital mortality following acute myocardial infarction (AMI). CS is a complex clinical syndrome that begins with hemodynamic instability and can progress to multi-organ failure and profound hemo-metabolic compromise. To improve outcomes, a clear understanding of the treatment objectives in CS and developing time-sensitive management strategies aimed at stabilizing hemodynamics and restoring myocardial perfusion are critical. Left ventricular (LV) load has been identified as an independent predictor of heart failure and mortality following AMI. Decades of preclinical and clinical research have identified several effective LV unloading strategies. Recent initiatives from single and multi-center registries and more recently the Door to Unload (DTU)-STEMI pilot study have provided valuable insight to developing a standardized treatment approach to AMI, based on early invasive hemodynamics and tailored circulatory support to unload the LV. To follow is a review of the pathophysiology and prevalence of shock, limitations of current therapies, and the pre-clinical and translational basis for incorporating LV unloading into contemporary AMI and shock care.
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Affiliation(s)
- Behnam N Tehrani
- Inova Heart and Vascular Institute, Falls Church, VA, United States of America
| | - Mir B Basir
- Henry Ford Medical Center, Detroit, MI, United States of America
| | - Navin K Kapur
- The CardioVascular Center, Tufts Medical Center, Boston, MA, United States of America.
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Bashtawi Y, Almuwaqqat Z. Therapeutic Hypothermia in STEMI. CARDIOVASCULAR REVASCULARIZATION MEDICINE 2020; 29:77-84. [PMID: 32807668 DOI: 10.1016/j.carrev.2020.08.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 07/16/2020] [Accepted: 08/04/2020] [Indexed: 11/26/2022]
Abstract
In this review article we tried to find an answer to the question, should local coronary hypothermia be a part of the early reperfusion strategy in patients with STEMI to prevent reperfusion injury, no-reflow phenomenon, and to reduce the infarct size and mortality. Hypothermia can save cardiomyocytes if achieved in a timely fashion before reperfusion. Intracoronary hypothermia can be adjunct to PCI by lessening ischemia/reperfusion injury on cardiomyocytes and reduction in infarct size. Reperfusion induced Calcium overload, generation of ROS and subsequent activation of Mitochondrial permeability transition pore (MPT) are major contributors to reperfusion injury. Hypothermia reduces calcium loading of the cell and maintains cellular energy and tissue level glucose which can scavenger ROS. Hypothermia reduces MPT activation and thus reduces infarct size. Systemic cooling trials failed to reduce infarct size, perhaps because the target temperature was not reached fast enough, and it was associated with systemic side effects. The need for rapid induction of hypothermia to <35 °C with the ethical concern of delaying reperfusion while cooling the patient and the inconsistency of endovascular cooling results lead to a belief that endovascular cooling may exceed the acceptable level of invasiveness in the context of other novels cardioprotective, regenerative and reperfusion therapies. Clinical trials showed the safety and feasibility of novel intracoronary hypothermia with rapid induction and maintenance of hypothermia using routine PCI equipment ahead of reperfusion. Two phases of cooling were applied without significant delay in the door to balloon time. Cooling of the coronary artery leads to cooling of its dependant myocardium without affecting adjacent myocardium. Heat transfer occurred by heat conduction during the occlusion phase and heat convention during the reperfusion phase. Fine-tuning of saline temperature and infusion rate helped to improve the protocol. The best duration of hypothermia before and after reperfusion is not known and needs further investigation. A balance between the undoubted cardioprotective effects of hypothermia with iatrogenic prolongation of ischemia time needs to be established. A reduction in infarct size was observed but needs to be validated with large randomized trials. Furthermore, it might be possible to augment the cardioprotective effects of intracoronary hypothermia by combination with other cardioprotective approaches such as antioxidant drugs and afterload reducing agents.
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Affiliation(s)
- Yazan Bashtawi
- Department of Medicine, King Hussein Cancer Center, Amman, Jordan.
| | - Zakaria Almuwaqqat
- Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, United States of America
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Lee H, Ding Y. Temporal limits of therapeutic hypothermia onset in clinical trials for acute ischemic stroke: How early is early enough? Brain Circ 2020; 6:139-144. [PMID: 33210036 PMCID: PMC7646398 DOI: 10.4103/bc.bc_31_20] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 08/06/2020] [Accepted: 08/24/2020] [Indexed: 01/22/2023] Open
Abstract
Stroke is one of the leading causes of mortality and morbidity worldwide, and yet, current treatment is limited to thrombolysis through either t-PA or mechanical thrombectomy. While therapeutic hypothermia has been adopted in clinical contexts such as neuroprotection after cardiac resuscitation and neonatal hypoxic-ischemic encephalitis, it is yet to be used in the context of ischemic stroke. The lack of ameliorative effect in ischemic stroke patients may be tied to the delayed cooling induction onset. In the trials where the cooling was initiated with significant delay (mostly systemic cooling methods), minimal benefit was observed; on the other hand, when cooling was initiated very early (mostly selective cooling methods), there was significant efficacy. Another timing factor that may play a role in amelioration may be the onset of cooling relative to thrombolysis therapy. Current understanding of the pathophysiology of acute ischemic injury and ischemia-reperfusion injury suggests that hypothermia before thrombolysis may be the most beneficial compared to cooling initiation during or after reperfusion. As many of the systemic cooling methods tend to require longer induction periods and extensive, separate procedures from thrombolysis therapy, they are generally delayed to hours after recanalization. On the other hand, selective cooling was generally performed simultaneously to thrombolysis therapy. As we conduct and design therapeutic hypothermia trials for stroke patients, the key to their efficacy may lie in quick and early cooling induction, both respective to the symptom onset and thrombolysis therapy.
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Affiliation(s)
- Hangil Lee
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Yuchuan Ding
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan, USA
- Department of Research and Development Center, John D. Dingell VA Medical Center, Detroit, Michigan, USA
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Li J, Sun D, Li Y. Novel Findings and Therapeutic Targets on Cardioprotection of Ischemia/ Reperfusion Injury in STEMI. Curr Pharm Des 2020; 25:3726-3739. [PMID: 31692431 DOI: 10.2174/1381612825666191105103417] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 10/30/2019] [Indexed: 12/19/2022]
Abstract
Acute ST-segment elevation myocardial infarction (STEMI) remains a leading cause of morbidity and mortality around the world. A large number of STEMI patients after the infarction gradually develop heart failure due to the infarcted myocardium. Timely reperfusion is essential to salvage ischemic myocardium from the infarction, but the restoration of coronary blood flow in the infarct-related artery itself induces myocardial injury and cardiomyocyte death, known as ischemia/reperfusion injury (IRI). The factors contributing to IRI in STEMI are complex, and microvascular obstruction, inflammation, release of reactive oxygen species, myocardial stunning, and activation of myocardial cell death are involved. Therefore, additional cardioprotection is required to prevent the heart from IRI. Although many mechanical conditioning procedures and pharmacological agents have been identified as effective cardioprotective approaches in animal studies, their translation into the clinical practice has been relatively disappointing due to a variety of reasons. With new emerging data on cardioprotection in STEMI over the past few years, it is mandatory to reevaluate the effectiveness of "old" cardioprotective interventions and highlight the novel therapeutic targets and new treatment strategies of cardioprotection.
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Affiliation(s)
- Jianqiang Li
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China
| | - Danghui Sun
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China
| | - Yue Li
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China
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Kuroda Y, Kawakita K. Targeted temperature management for postcardiac arrest syndrome. JOURNAL OF NEUROCRITICAL CARE 2020. [DOI: 10.18700/jnc.200001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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Alushi B, Ndrepepa G, Lauten A, Lahmann AL, Bongiovanni D, Kufner S, Xhepa E, Laugwitz KL, Joner M, Landmesser U, Thiele H, Kastrati A, Cassese S. Hypothermia in patients with acute myocardial infarction: a meta-analysis of randomized trials. Clin Res Cardiol 2020; 110:84-92. [PMID: 32303830 DOI: 10.1007/s00392-020-01652-7] [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: 01/07/2020] [Accepted: 04/14/2020] [Indexed: 10/24/2022]
Abstract
BACKGROUND In patients with acute myocardial infarction (MI) receiving percutaneous coronary intervention (PCI), the role of systemic therapeutic hypothermia remains controversial. We sought to investigate the role of systemic therapeutic hypothermia versus standard of care in patients with acute MI treated with PCI. METHODS This is a study-level meta-analysis of randomized trials. The primary outcome was all-cause death. The main secondary outcome was infarct size. Other secondary outcomes were recurrent MI, ischemia-driven target vessel revascularization (TVR), major adverse cardiovascular events, and bleeding. RESULTS A total of 1012 patients with acute MI receiving a PCI in nine trials (503 randomly assigned to hypothermia and 509 to control) were available for the quantitative synthesis. The weighted median follow-up was 30 days. As compared to controls, patients assigned to hypothermia had similar risk of all-cause death (risk ratio, [95% confidence intervals], 1.25 [0.80; 1.95], p = 0.32), with a trend toward higher risk of ischemia-driven TVR (3.55 [0.80; 15.87], p = 0.09) mostly due to acute or subacute stent thrombosis. Although in the overall cohort, infarct size was comparable between groups (standardized mean difference [95% Confidence intervals], 0.06 [- 0.92; 1.04], p = 0.92), patients effectively achieving the protocol-defined target temperature in the hypothermia group had smaller infarct size as compared to controls (p for interaction = 0.016). Treatment strategies did not differ with respect to the other outcomes. CONCLUSIONS As compared to standard of care, systemic therapeutic hypothermia in acute MI patients treated with PCI provided similar mortality with a signal toward more frequent repeat revascularization. Among patients assigned to hypothermia, those effectively achieving the protocol-defined target temperature displayed smaller infarct size. TRIAL REGISTRATION PROSPERO, CRD42019138754.
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Affiliation(s)
- Brunilda Alushi
- Department of Cardiology, University Heart Center Berlin and Charité University Medicine Berlin, Berlin, Germany
| | - Gjin Ndrepepa
- Deutsches Herzzentrum München, Technische Universität München, Lazarettstrasse, 36, Munich, Germany
| | - Alexander Lauten
- Department of Cardiology, University Heart Center Berlin and Charité University Medicine Berlin, Berlin, Germany.,German Centre for Cardiovascular Research (DZHK), Berlin, Germany
| | - Anna Lena Lahmann
- Deutsches Herzzentrum München, Technische Universität München, Lazarettstrasse, 36, Munich, Germany
| | - Dario Bongiovanni
- 1. Medizinische Klinik, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany
| | - Sebastian Kufner
- Deutsches Herzzentrum München, Technische Universität München, Lazarettstrasse, 36, Munich, Germany
| | - Erion Xhepa
- Deutsches Herzzentrum München, Technische Universität München, Lazarettstrasse, 36, Munich, Germany
| | - Karl-Ludwig Laugwitz
- 1. Medizinische Klinik, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany.,German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Michael Joner
- Deutsches Herzzentrum München, Technische Universität München, Lazarettstrasse, 36, Munich, Germany.,German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Ulf Landmesser
- Department of Cardiology, University Heart Center Berlin and Charité University Medicine Berlin, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany.,German Centre for Cardiovascular Research (DZHK), Berlin, Germany
| | - Holger Thiele
- Department of Internal Medicine and Cardiology, Heart Centre Leipzig At University of Leipzig, Leipzig, Germany
| | - Adnan Kastrati
- Deutsches Herzzentrum München, Technische Universität München, Lazarettstrasse, 36, Munich, Germany.,German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Salvatore Cassese
- Deutsches Herzzentrum München, Technische Universität München, Lazarettstrasse, 36, Munich, Germany.
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Shanmugasundaram M, Truong HT, Harhash A, Ho D, Tran A, Smith N, Ciurlino B, Noc M, Hsu P, Kern KB. Extending Time to Reperfusion with Mild Therapeutic Hypothermia: A New Paradigm for Providing Primary Percutaneous Coronary Intervention to Remote ST Segment Elevation Myocardial Infarction Patients. Ther Hypothermia Temp Manag 2020; 11:45-52. [PMID: 32155385 DOI: 10.1089/ther.2019.0039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
Abstract
Primary percutaneous coronary intervention (PPCI) is the preferred treatment for acute ST segment elevation myocardial infarction (STEMI). The goal is reperfusion within 90 minutes of first medical contact (FMC) or 120 minutes if transfer is needed. Otherwise, fibrinolytic therapy is recommended. Mild therapeutic hypothermia (MTH) (≤35°C) before coronary reperfusion decreases myocardial infarct size. If applied before reperfusion, hypothermia could potentially lengthen the FMC-reperfusion time without increasing infarct size. Thirty-six swine had their mid left anterior descending coronary artery acutely occluded. All animals had an initial 30 minutes of occlusion to simulate typical delay before seeking medical attention. Eighteen animals were studied under normothermic conditions with reperfusion after an additional 40 minutes (the porcine equivalent of a 120-minute clinical FMC to reperfusion time) and 18 were treated with hypothermia but not reperfused until another 80 minutes (clinical equivalent of 240 minutes). Primary outcome was myocardial infarct size (infarct/area at risk [AAR]) at 24 hours. The two groups differed in systemic temperature at the time of reperfusion (39.1°C ± 1.0°C vs. 35.5°C ± 0.7°C; p < 0.0001). Myocardial infarct size was not significantly different despite the longer time to reperfusion in those treated with hypothermia (60.6% ± 12% of the AAR [normothermic] vs. 65.8% ± 11.8% of the AAR [hypothermic]; p = 0.39). Rapid induction of MTH during an anterior STEMI made it possible to extend the FMC to reperfusion time by the equivalent of an extra two clinical hours (120-240 minutes) without increasing the myocardial infarct size. This strategy could allow more STEMI patients to receive PPCI rather than the less effective intravenous fibrinolysis.
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Affiliation(s)
| | - Huu Tam Truong
- Department of Cardiology, Loma Linda University, Loma Linda, California, USA
| | - Ahmed Harhash
- Department of Cardiology, Sarver Heart Center, University of Arizona, Tucson, Arizona, USA
| | - David Ho
- Department of Cardiology, Sarver Heart Center, University of Arizona, Tucson, Arizona, USA
| | - Arielle Tran
- Department of Cardiology, Sarver Heart Center, University of Arizona, Tucson, Arizona, USA
| | - Nicole Smith
- Department of Cardiology, Sarver Heart Center, University of Arizona, Tucson, Arizona, USA
| | - Brian Ciurlino
- Department of Cardiology, Sarver Heart Center, University of Arizona, Tucson, Arizona, USA
| | - Marko Noc
- Department of Cardiology, University Medical Center, Ljubljana, Slovenia
| | - Paul Hsu
- Department of Biostatistics and Epidemiology, University of Arizona, Tucson, Arizona, USA
| | - Karl B Kern
- Department of Cardiology, Sarver Heart Center, University of Arizona, Tucson, Arizona, USA
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Mokhtari A, Akbarzadeh M, Sparv D, Bhiladvala P, Arheden H, Erlinge D, Khoshnood A. Oxygen therapy in patients with ST elevation myocardial infarction based on the culprit vessel: results from the randomized controlled SOCCER trial. BMC Emerg Med 2020; 20:12. [PMID: 32070283 PMCID: PMC7027294 DOI: 10.1186/s12873-020-00309-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 02/10/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Oxygen (O2) treatment has been a cornerstone in the treatment of patients with myocardial infarction. Recent studies, however, state that supplemental O2 therapy may have no effect or harmful effects in these patients. The aim of this study was thus to evaluate the effect of O2 therapy in patients with ST Elevation Myocardial Infarction (STEMI) based on the culprit vessel; Left Anterior Descending Artery (LAD) or Non-LAD. METHODS This was a two-center, investigator-initiated, single-blind, parallel-group, randomized controlled trial at the Skåne university hospital, Sweden. A simple computer-generated randomization was used. Patients were either randomized to standard care with O2 therapy (10 l/min) or air until the end of the primary percutaneous coronary intervention. The patients underwent a Cardiac Magnetic Resonance Imaging (CMRI) days 2-6. The main outcome measures were Myocardium at Risk (MaR), Infarct Size (IS) and Myocardial Salvage Index (MSI) as measured by CMRI, and median high-sensitive troponin T (hs-cTnT). RESULTS A total of 229 patients were assessed for eligibility, and 160 of them were randomized to the oxygen or air arm. Because of primarily technical problems with the CMRI, 95 patients were included in the final analyses; 46 in the oxygen arm and 49 in the air arm. There were no significant differences between patients with LAD and Non-LAD as culprit vessel with regard to their allocation (oxygen or air) with regards to MSI, MaR, IS and hs-cTnT. CONCLUSION The results indicate that the location of the culprit vessel has probably no effect on the role of supplemental oxygen therapy in STEMI patients. TRIAL REGISTRATION Swedish Medical Products Agency (EudraCT No. 2011-001452-11) and ClinicalTrials.gov Identifier (NCT01423929).
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Affiliation(s)
- Arash Mokhtari
- Department of Clinical Sciences Lund, Cardiology, Lund University, Skåne University Hospital, Lund, Sweden
| | - Mahin Akbarzadeh
- Department of Clinical Sciences Lund, Emergency and Internal Medicine, Lund University, Skåne University Hospital, Akutmottagningen, EA10, SUS Lund, 221 85, Lund, Sweden
| | - David Sparv
- Department of Clinical Sciences Lund, Cardiology, Lund University, Skåne University Hospital, Lund, Sweden
| | | | - Håkan Arheden
- Department of Clinical Sciences Lund, Clinical Physiology, Lund University, Skåne University Hospital, Lund, Sweden
| | - David Erlinge
- Department of Clinical Sciences Lund, Cardiology, Lund University, Skåne University Hospital, Lund, Sweden
| | - Ardavan Khoshnood
- Department of Clinical Sciences Lund, Emergency and Internal Medicine, Lund University, Skåne University Hospital, Akutmottagningen, EA10, SUS Lund, 221 85, Lund, Sweden.
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47
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Barzyc A, Łysik W, Słyk J, Kuszewski M, Zarębiński M, Wojciechowska M, Cudnoch-Jędrzejewska A. Reperfusion injury as a target for diminishing infarct size. Med Hypotheses 2020; 137:109558. [PMID: 31958650 DOI: 10.1016/j.mehy.2020.109558] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 12/15/2019] [Accepted: 01/07/2020] [Indexed: 12/30/2022]
Abstract
Therapies for preventing reperfusion injury (RI) have been widely studied. However, the attempts to transfer cardioprotective therapies for reducing RI from experiments into clinical practice have been so far unsuccessful. Pathophysiological mechanisms of RI are complicated and compose of many pathways e.g. hypercontracture-mediated sarcolemma rupture, mitochondrial permeability transition pore persistent opening, reactive oxygen species formation, inflammation and no-reflow phenomenon. Based on research, it cannot be determined which mechanism dominates, probably they cooperate with a domination of one or another in different clinical circumstances. Our hypothesis is, that only intervention that at the same time interferes with different (all?) pathways of RI may turn out to be effective in decreasing the final area of infarction.
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Affiliation(s)
- A Barzyc
- Department of Experimental and Clinical Physiology, Laboratory of Center for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - W Łysik
- Department of Experimental and Clinical Physiology, Laboratory of Center for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - J Słyk
- Department of Experimental and Clinical Physiology, Laboratory of Center for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - M Kuszewski
- Department of Experimental and Clinical Physiology, Laboratory of Center for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - M Zarębiński
- Independent Public Specialist Western Hospital John Paul II in Grodzisk Mazowiecki, Poland
| | - M Wojciechowska
- Department of Experimental and Clinical Physiology, Laboratory of Center for Preclinical Research, Medical University of Warsaw, Warsaw, Poland; Independent Public Specialist Western Hospital John Paul II in Grodzisk Mazowiecki, Poland.
| | - A Cudnoch-Jędrzejewska
- Department of Experimental and Clinical Physiology, Laboratory of Center for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
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48
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Drabek T, Kochanek PM. Is there a role for therapeutic hypothermia in critical care? EVIDENCE-BASED PRACTICE OF CRITICAL CARE 2020:179-185.e1. [DOI: 10.1016/b978-0-323-64068-8.00035-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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The Impact of Emergency Interventions and Patient Characteristics on the Risk of Heart Failure in Patients with Nontraumatic OHCA. Emerg Med Int 2019; 2019:6218389. [PMID: 31934452 PMCID: PMC6942846 DOI: 10.1155/2019/6218389] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 11/08/2019] [Accepted: 11/18/2019] [Indexed: 12/20/2022] Open
Abstract
Background Since out-of-hospital cardiac arrest- (OHCA-) related dysfunction (ischemic/reperfusion injury and inflammatory response) might result in long-term impairment, we suspect that new-onset heart failure might be common in long-term survivors. However, these relationships had not been well addressed, and we aimed to analyze the impact of emergency interventions and patient characteristics on the risk of new-onset heart failure in patients with nontraumatic OHCA. Methods The Taiwanese government healthcare database contains data for 49,101 nontraumatic OHCA adult patients from 2011-2012, which were analyzed in this study. Nontraumatic OHCA patients who survived to the intensive care unit (ICU) were included as the study group (n = 7,321). Matched patients (n = 21,963) were recruited as a comparison group. Patients with any history of heart failure or cardiac arrest were not included in either group. All patients were followed-up for 6 months for the identification of new-onset heart failure. Adjustments were made for demographics, age, emergency interventions, and comorbidities as potential risk factors. Results In all, 3.84% (n = 281) of OHCA patients suffered new-onset heart failure, while only 1.24% (n = 272) of matched patients in the comparison group suffered new-onset heart failure. Strong risk factors for heart failure were age (60-75 years, HR: 11.4; 95% CI: 9-14.4), medical history (myocardial infarction, HR: 2.47; 95% CI: 2.05-2.98 and cardiomyopathy, HR: 2.94; 95% CI: 1.45-5.94), and comorbidities during hospitalization (ischemic heart disease, HR: 4.5; 95% CI: 3.46-5.86). Only extracorporeal membrane oxygenation (ECMO) decreased the risk of heart failure. Most (53.6%) heart failure events occurred within 60 days after OHCA. Conclusion An age from 61 to 75 years, a history of myocardial infarction or cardiomyopathy, and ischemic heart disease or infection as comorbidities occurring during hospitalization were strong risk factors for new-onset heart failure in OHCA patients. However, ECMO could decrease this risk. More importantly, most heart failure events occurred within 60 days after OHCA.
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50
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Rios-Navarro C, Marcos-Garces V, Bayes-Genis A, Husser O, Nuñez J, Bodi V. Microvascular Obstruction in ST-Segment Elevation Myocardial Infarction: Looking Back to Move Forward. Focus on CMR. J Clin Med 2019; 8:E1805. [PMID: 31661823 PMCID: PMC6912395 DOI: 10.3390/jcm8111805] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 10/22/2019] [Accepted: 10/25/2019] [Indexed: 12/14/2022] Open
Abstract
After a myocardial infarction (MI), despite the resolution of the coronary occlusion, the deterioration of myocardial perfusion persists in a considerable number of patients. This phenomenon is known as microvascular obstruction (MVO). Initially, the focus was placed on re-establishing blood flow in the epicardial artery. Then, the observation that MVO has profound negative structural and prognostic repercussions revived interest in microcirculation. In the near future, the availability of co-adjuvant therapies (beyond timely coronary reperfusion) aimed at preventing, minimizing, and repairing MVOs and finding convincing answers to questions regarding what, when, how, and where to administer these therapies will be of utmost importance. The objective of this work is to review the state-of-the-art concepts on pathophysiology, diagnostic methods, and structural and clinical implications of MVOs in patients with ST-segment elevation MIs. Based on this knowledge we discuss previously-tested and future opportunities for the prevention and repair of MVO.
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Affiliation(s)
| | | | - Antoni Bayes-Genis
- Centro de Investigación Biomédica en Red-Cardiovascular (CIBER-CV), 28029 Madrid, Spain.
- Cardiology Department and Heart Failure Unit, Hospital Universitari Germans Trias i Pujol (Badalona) and Department of Medicine Universitat Autonoma de Barcelona, 08916 Barcelona, Spain.
| | - Oliver Husser
- Department of Cardiology, St-Johannes Hospital, 44137 Dortmund, Germany.
| | - Julio Nuñez
- Institute of Health Research INCLIVA, 46010 Valencia, Spain.
- Cardiology Department, Hospital Clínico Universitario, 46010 Valencia, Spain.
- Centro de Investigación Biomédica en Red-Cardiovascular (CIBER-CV), 28029 Madrid, Spain.
- Department of Medicine, Universidad de Valencia, 46010 Valencia, Spain.
| | - Vicente Bodi
- Institute of Health Research INCLIVA, 46010 Valencia, Spain.
- Cardiology Department, Hospital Clínico Universitario, 46010 Valencia, Spain.
- Centro de Investigación Biomédica en Red-Cardiovascular (CIBER-CV), 28029 Madrid, Spain.
- Department of Medicine, Universidad de Valencia, 46010 Valencia, Spain.
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