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1
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Jung JW, Yoon CE, Kwon I, Lee KO, Kim J, Kim YD, Heo JH, Nam HS. Mild hypercapnia before reperfusion reduces ischemia-reperfusion injury in hyperacute ischemic stroke rat model. J Cereb Blood Flow Metab 2025; 45:664-676. [PMID: 39473379 PMCID: PMC11563516 DOI: 10.1177/0271678x241296367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 10/04/2024] [Accepted: 10/15/2024] [Indexed: 11/17/2024]
Abstract
Endovascular thrombectomy has a recanalization rate over 80%; however, approximately 50% of ischemic stroke patients still experience dependency or mortality. Recently, clinical trials demonstrated the benefits of administering neuroprotective agents prior to endovascular thrombectomy. Additionally, recent studies showed neuroprotective effects of mild hypercapnia in patients resuscitated after cardiac arrest. However, its efficacy in ischemic stroke remains unclear. We aimed to investigate whether carbon dioxide (CO2) per-conditioning has neuroprotective effects in rat models with middle cerebral artery occlusion (MCAO). Rat models received intermittent inhalation of mixed gas during the MCAO period. After surgery, behavioral assessments, infarct size measurement, immunohistochemistry, and western blot analysis were performed. We found CO2 per-conditioning reduced infarct size and neurological deficit. The number of 8-hydroxy-2-deoxyguanosine (8-OHdG) positive cells and matrix metalloproteinase 9 (MMP-9)/platelet derived growth factor receptor beta (PDGFRβ) double positive cells were significantly decreased after CO2 per-conditioning. The expressions of tight junction protein and pericytes survival were preserved. This study underscores mild hypercapnia before reperfusion not only reduces neurologic deficit and infarct size, but also maintains the integrity of the blood-brain barrier and neurovascular unit, alongside mitigating oxidative stress in hyperacute stroke rat models. Therapeutic mild hypercapnia before reperfusion is promising and requires further clinical application.
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Affiliation(s)
- Jae Wook Jung
- Department of Neurology, Yonsei University College of Medicine, Seoul, Korea
| | - Chung Eun Yoon
- Department of Neurology, Yonsei University College of Medicine, Seoul, Korea
| | - Il Kwon
- Integrative Research Center for Cerebrovascular and Cardiovascular Diseases, Yonsei University College of Medicine, Seoul, Korea
| | - Kee Ook Lee
- Department of Neurology, CHA Bundang Medical Center, School of Medicine CHA University, Seongnam, Korea
| | - Jinkwon Kim
- Department of Neurology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
| | - Young Dae Kim
- Department of Neurology, Yonsei University College of Medicine, Seoul, Korea
- Integrative Research Center for Cerebrovascular and Cardiovascular Diseases, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Hoe Heo
- Department of Neurology, Yonsei University College of Medicine, Seoul, Korea
- Integrative Research Center for Cerebrovascular and Cardiovascular Diseases, Yonsei University College of Medicine, Seoul, Korea
| | - Hyo Suk Nam
- Department of Neurology, Yonsei University College of Medicine, Seoul, Korea
- Integrative Research Center for Cerebrovascular and Cardiovascular Diseases, Yonsei University College of Medicine, Seoul, Korea
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2
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Deng H, Ding D, Ma Y, Zhang H, Wang N, Zhang C, Yang G. Nicotinamide Mononucleotide: Research Process in Cardiovascular Diseases. Int J Mol Sci 2024; 25:9526. [PMID: 39273473 PMCID: PMC11394709 DOI: 10.3390/ijms25179526] [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: 07/29/2024] [Revised: 08/21/2024] [Accepted: 08/29/2024] [Indexed: 09/15/2024] Open
Abstract
Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite that plays a crucial role in diverse biological processes, including energy metabolism, gene expression, DNA repair, and mitochondrial function. An aberrant NAD+ level mediates the development of cardiovascular dysfunction and diseases. Both in vivo and in vitro studies have demonstrated that nicotinamide mononucleotide (NMN), as a NAD+ precursor, alleviates the development of cardiovascular diseases such as heart failure, atherosclerosis, and myocardial ischemia/reperfusion injury. Importantly, NMN has suggested pharmacological activities mostly through its involvement in NAD+ biosynthesis. Several clinical studies have been conducted to investigate the efficacy and safety of NMN supplementation, indicating its potential role in cardiovascular protection without significant adverse effects. In this review, we systematically summarize the impact of NMN as a nutraceutical and potential therapeutic drug on cardiovascular diseases and emphasize the correlation between NMN supplementation and cardiovascular protection.
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Affiliation(s)
- Haoyuan Deng
- Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, Dalian 116044, China
| | - Ding Ding
- School of Public Health, Dalian Medical University, Dalian 116044, China
| | - Yu Ma
- Department of Health Toxicology, School of Public Health, Dalian Medical University, Dalian 116044, China
| | - Hao Zhang
- School of Public Health, Dalian Medical University, Dalian 116044, China
| | - Ningning Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, Dalian 116044, China
| | - Cong Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, Dalian 116044, China
| | - Guang Yang
- Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, Dalian 116044, China
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3
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Melberg MB, Flaa A, Andersen GØ, Sunde K, Bellomo R, Eastwood G, Olasveengen TM, Qvigstad E. Effects of mild hypercapnia on myocardial injury after out-of-hospital cardiac arrest. A sub-study of the TAME trial. Resuscitation 2024; 201:110295. [PMID: 38936652 DOI: 10.1016/j.resuscitation.2024.110295] [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: 05/06/2024] [Revised: 06/21/2024] [Accepted: 06/21/2024] [Indexed: 06/29/2024]
Abstract
PURPOSE Mild hypercapnia did not improve neurological outcomes for resuscitated out-of-hospital cardiac arrest (OHCA) patients in the Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest (TAME) trial. However, the effects of hypercapnic acidosis on myocardial injury in patients with cardiac arrest is unexplored. We investigated whether mild hypercapnia compared to normocapnia, following emergency coronary intervention, increased myocardial injury in comatose OHCA-patients with AMI. METHODS Single-centre, prospective, pre-planned sub-study of the TAME trial. Patients were randomised to targeted mild hypercapnia (PaCO2 = 6.7-7.3 kPa) or normocapnia (PaCO2 = 4.7-6.0 kPa) for 24 h. Myocardial injury was assessed with high-sensitive cardiac troponin T (hs-cTnT) measured at baseline, 24, 48 and 72 h. Haemodynamics were assessed with right heart catheterisation and blood-gas analyses every 4th hour for 48 h. RESULTS We included 125 OHCA-patients. 57 (46%) had an AMI, with 31 and 26 patients randomised to hypercapnia and normocapnia, respectively. Median peak hs-cTnT in AMI-patients was 58% lower in the hypercapnia-group: 2136 (IQR: 861-4462) versus 5165 ng/L (IQR: 2773-7519), p = 0.007. Lower average area under the hs-cTnT curve was observed in the hypercapnia-group: 2353 (95% CI 1388-3319) versus 4953 ng/L (95% CI 3566-6341), P-group = 0.002. Hypercapnia was associated with increased cardiac power output (CPO) and lower lactate levels in patients with AMI (P-group < 0.05). hs-cTnT, lactate and CPO were not significantly different between intervention groups in OHCA-patients without AMI (p > 0.05). CONCLUSIONS Mild hypercapnia was not associated with increased myocardial injury in resuscitated OHCA-patients. In AMI-patients, mild hypercapnia was associated with lower hs-cTnT and lactate, and improved cardiac performance. TRIAL REGISTRATION NUMBER NCT03114033.
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Affiliation(s)
- Mathias Baumann Melberg
- Department of Research and Development, Division of Emergencies and Critical Care, Department of Cardiology, Division of Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Norway.
| | - Arnljot Flaa
- Department of Research and Development, Division of Emergencies and Critical Care, Department of Cardiology, Division of Medicine, Oslo University Hospital, Oslo, Norway
| | - Geir Øystein Andersen
- Department of Research and Development, Division of Emergencies and Critical Care, Department of Cardiology, Division of Medicine, Oslo University Hospital, Oslo, Norway
| | - Kjetil Sunde
- Department of Anaesthesiology and Intensive Care, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway and Institute of Clinical Medicine, University of Oslo, Norway
| | - Rinaldo Bellomo
- Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia; Australian and New Zealand Intensive Care Research Centre, Monash University, Victoria, Melbourne, Australia; Department of Critical Care, Melbourne University, Melbourne, Australia; Department of Intensive Care, Royal Melbourne Hospital, Melbourne, Australia
| | - Glenn Eastwood
- Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia; Australian and New Zealand Intensive Care Research Centre, Monash University, Victoria, Melbourne, Australia
| | - Theresa Mariero Olasveengen
- Department of Anaesthesiology and Intensive Care, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway and Institute of Clinical Medicine, University of Oslo, Norway
| | - Eirik Qvigstad
- Department of Research and Development, Division of Emergencies and Critical Care, Department of Cardiology, Division of Medicine, Oslo University Hospital, Oslo, Norway
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4
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Chiari P, Fellahi JL. Myocardial protection in cardiac surgery: a comprehensive review of current therapies and future cardioprotective strategies. Front Med (Lausanne) 2024; 11:1424188. [PMID: 38962735 PMCID: PMC11220133 DOI: 10.3389/fmed.2024.1424188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 05/23/2024] [Indexed: 07/05/2024] Open
Abstract
Cardiac surgery with cardiopulmonary bypass results in global myocardial ischemia-reperfusion injury, leading to significant postoperative morbidity and mortality. Although cardioplegia is the cornerstone of intraoperative cardioprotection, a number of additional strategies have been identified. The concept of preconditioning and postconditioning, despite its limited direct clinical application, provided an essential contribution to the understanding of myocardial injury and organ protection. Therefore, physicians can use different tools to limit perioperative myocardial injury. These include the choice of anesthetic agents, remote ischemic preconditioning, tight glycemic control, optimization of respiratory parameters during the aortic unclamping phase to limit reperfusion injury, appropriate choice of monitoring to optimize hemodynamic parameters and limit perioperative use of catecholamines, and early reintroduction of cardioprotective agents in the postoperative period. Appropriate management before, during, and after cardiopulmonary bypass will help to decrease myocardial damage. This review aimed to highlight the current advancements in cardioprotection and their potential applications during cardiac surgery.
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Affiliation(s)
- Pascal Chiari
- Service d’Anesthésie Réanimation, Hôpital Universitaire Louis Pradel, Hospices Civils de Lyon, Lyon, France
- Laboratoire CarMeN, Inserm UMR 1060, Université Claude Bernard Lyon 1, Lyon, France
| | - Jean-Luc Fellahi
- Service d’Anesthésie Réanimation, Hôpital Universitaire Louis Pradel, Hospices Civils de Lyon, Lyon, France
- Laboratoire CarMeN, Inserm UMR 1060, Université Claude Bernard Lyon 1, Lyon, France
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5
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Takeuchi T, Kitani Y, Minoshima A, Ota H, Nakagawa N, Sumitomo K, Ishii Y, Hasebe N. Potential Effects of Ischemic Postconditioning and Changes in Heat Shock Protein 72 in Patients with Acute Myocardial Infarction without Prodromal Angina. Int Heart J 2024; 65:395-403. [PMID: 38749746 DOI: 10.1536/ihj.23-651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
The effectiveness of ischemic postconditioning (iPoC) in patients with ST-elevation myocardial infarction (STEMI) without ischemic preconditioning has not been determined. Therefore, we investigated the impact of iPoC and its potential mechanism related to heat shock protein 72 (HSP72) induction on myocardial salvage in patients with STEMI without prodromal angina (PA).We retrospectively analyzed data from 102 patients with STEMI with successful reperfusion among 323 consecutive patients with acute coronary syndrome. Among these, 55 patients with iPoC (iPoC (+) ) underwent 4 cycles of 60-second inflation and 30-second deflation of the angioplasty balloon. Both the iPoC (+) and iPoC (-) groups were divided into 2 further subgroups: patients with PA (PA (+) ) and those without (PA (-) ). We analyzed HSP72 levels in neutrophils, which were measured until 48 hours after reperfusion. I-123 β-methyl-p-iodophenyl-pentadecanoic acid (BMIPP) scintigraphy was performed within a week of reperfusion therapy. In 64% of patients, thallium-201 (TL) scintigraphy was performed 6-8 months after STEMI onset.Using BMIPP and TL, in the PA (-) subgroups, the iPoC (+) group had a significantly greater myocardial salvage ratio than the iPoC (-) group. iPoC was identified as an independent predictor of the myocardial salvage ratio. The HSP72 increase ratio was significantly elevated in the iPoC (+) PA (-) group. Importantly, the myocardial salvage effect in patients without PA was significantly correlated with the HSP72 increase ratio, which was greater in patients with iPoC.These results suggest the potential impact of iPoC via HSP72 induction on myocardial salvage; however, the effects may be limited to patients with STEMI without PA.
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Affiliation(s)
- Toshiharu Takeuchi
- Division of Cardiology, Department of Internal Medicine, Asahikawa Medical University
| | - Yuya Kitani
- Division of Cardiology, Department of Internal Medicine, Asahikawa Medical University
| | - Akiho Minoshima
- Division of Cardiology, Department of Internal Medicine, Asahikawa Medical University
| | - Hisanobu Ota
- Division of Cardiology, Department of Internal Medicine, Asahikawa Medical University
| | - Naoki Nakagawa
- Division of Cardiology, Department of Internal Medicine, Asahikawa Medical University
| | - Kazuhiro Sumitomo
- Department of Community Medicine, Tohoku Medical and Pharmaceutical University Wakabayashi Hospital
| | - Yoshinao Ishii
- Division of Cardiology, Department of Internal Medicine, Asahikawa City Hospital
| | - Naoyuki Hasebe
- Division of Cardiology, Department of Internal Medicine, Asahikawa Medical University
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6
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Cohen MV, Downey JM. Initial Despair and Current Hope of Identifying a Clinically Useful Treatment of Myocardial Reperfusion Injury: Insights Derived from Studies of Platelet P2Y 12 Antagonists and Interference with Inflammation and NLRP3 Assembly. Int J Mol Sci 2024; 25:5477. [PMID: 38791515 PMCID: PMC11122283 DOI: 10.3390/ijms25105477] [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: 03/28/2024] [Accepted: 05/11/2024] [Indexed: 05/26/2024] Open
Abstract
Myocardial necrosis following the successful reperfusion of a coronary artery occluded by thrombus in a patient presenting with ST-elevation myocardial infarction (STEMI) continues to be a serious problem, despite the multiple attempts to attenuate the necrosis with agents that have shown promise in pre-clinical investigations. Possible reasons include confounding clinical risk factors, the delayed application of protective agents, poorly designed pre-clinical investigations, the possible effects of routinely administered agents that might unknowingly already have protected the myocardium or that might have blocked protection, and the biological differences of the myocardium in humans and experimental animals. A better understanding of the pathobiology of myocardial infarction is needed to stem this reperfusion injury. P2Y12 receptor antagonists minimize platelet aggregation and are currently part of the standard treatment to prevent thrombus formation and propagation in STEMI protocols. Serendipitously, these P2Y12 antagonists also dramatically attenuate reperfusion injury in experimental animals and are presumed to provide a similar protection in STEMI patients. However, additional protective agents are needed to further diminish reperfusion injury. It is possible to achieve additive protection if the added intervention protects by a mechanism different from that of P2Y12 antagonists. Inflammation is now recognized to be a critical factor in the complex intracellular response to ischemia and reperfusion that leads to tissue necrosis. Interference with cardiomyocyte inflammasome assembly and activation has shown great promise in attenuating reperfusion injury in pre-clinical animal models. And the blockade of the executioner protease caspase-1, indeed, supplements the protection already seen after the administration of P2Y12 antagonists. Importantly, protective interventions must be applied in the first minutes of reperfusion, if protection is to be achieved. The promise of such a combination of protective strategies provides hope that the successful attenuation of reperfusion injury is attainable.
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Affiliation(s)
- Michael V. Cohen
- The Departments of Physiology and Cell Biology, Frederick P. Whiddon College of Medicine, Mobile, AL 36688, USA;
- The Departments of Medicine, Frederick P. Whiddon College of Medicine, Mobile, AL 36688, USA
| | - James M. Downey
- The Departments of Physiology and Cell Biology, Frederick P. Whiddon College of Medicine, Mobile, AL 36688, USA;
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7
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Jiahao M, Fan Z, Junsheng M. Influence of acidic metabolic environment on differentiation of stem cell-derived cardiomyocytes. Front Cardiovasc Med 2024; 11:1288710. [PMID: 38572303 PMCID: PMC10987843 DOI: 10.3389/fcvm.2024.1288710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 02/28/2024] [Indexed: 04/05/2024] Open
Abstract
Stem cell-based myocardial regeneration is a frontier topic in the treatment of myocardial infarction. Manipulating the metabolic microenvironment of stem cells can influence their differentiation into cardiomyocytes, which have promising clinical applications. pH is an important indicator of the metabolic environment during cardiomyocyte development. And lactate, as one of the main acidic metabolites, is a major regulator of the acidic metabolic environment during early cardiomyocyte development. Here, we summarize the progress of research into the influence of pH value and lactate on cardiomyocyte survival and differentiation, as well as related mechanisms.
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Affiliation(s)
- Mao Jiahao
- Department of Cardiac Surgery, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Zhou Fan
- Department of Ultrasound, The Third Medical Center of PLA General Hospital, Beijing, China
| | - Mu Junsheng
- Department of Cardiac Surgery, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
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8
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Baglini E, Poggetti V, Cavallini C, Petroni D, Forini F, Nicolini G, Barresi E, Salerno S, Costa B, Iozzo P, Neglia D, Menichetti L, Taliani S, Da Settimo F. Targeting the Translocator Protein (18 kDa) in Cardiac Diseases: State of the Art and Future Opportunities. J Med Chem 2024; 67:17-37. [PMID: 38113353 PMCID: PMC10911791 DOI: 10.1021/acs.jmedchem.3c01716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 11/16/2023] [Accepted: 11/24/2023] [Indexed: 12/21/2023]
Abstract
Mitochondria dysfunctions are typical hallmarks of cardiac disorders (CDs). The multiple tasks of this energy-producing organelle are well documented, but its pathophysiologic involvement in several manifestations of heart diseases, such as altered electromechanical coupling, excitability, and arrhythmias, is still under investigation. The human 18 kDa translocator protein (TSPO) is a protein located on the outer mitochondrial membrane whose expression is altered in different pathological conditions, including CDs, making it an attractive therapeutic and diagnostic target. Currently, only a few TSPO ligands are employed in CDs and cardiac imaging. In this Perspective, we report an overview of the emerging role of TSPO at the heart level, focusing on the recent literature concerning the development of TSPO ligands used for fighting and imaging heart-related disease conditions. Accordingly, targeting TSPO might represent a successful strategy to achieve novel therapeutic and diagnostic strategies to unravel the fundamental mechanisms and to provide solutions to still unanswered questions in CDs.
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Affiliation(s)
- Emma Baglini
- Institute
of Clinical Physiology, National Research Council of Italy, CNR Research Area, Via G. Moruzzi 1, Pisa 56124, Italy
| | - Valeria Poggetti
- Department
of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy
| | - Chiara Cavallini
- Institute
of Clinical Physiology, National Research Council of Italy, CNR Research Area, Via G. Moruzzi 1, Pisa 56124, Italy
| | - Debora Petroni
- Institute
of Clinical Physiology, National Research Council of Italy, CNR Research Area, Via G. Moruzzi 1, Pisa 56124, Italy
| | - Francesca Forini
- Institute
of Clinical Physiology, National Research Council of Italy, CNR Research Area, Via G. Moruzzi 1, Pisa 56124, Italy
| | - Giuseppina Nicolini
- Institute
of Clinical Physiology, National Research Council of Italy, CNR Research Area, Via G. Moruzzi 1, Pisa 56124, Italy
| | - Elisabetta Barresi
- Department
of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy
| | - Silvia Salerno
- Department
of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy
| | - Barbara Costa
- Department
of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy
| | - Patricia Iozzo
- Institute
of Clinical Physiology, National Research Council of Italy, CNR Research Area, Via G. Moruzzi 1, Pisa 56124, Italy
| | - Danilo Neglia
- Fondazione
CNR/Regione Toscana Gabriele Monasterio, Cardiovascular and Imaging
Departments, CNR Research Area, Via G. Moruzzi 1, Pisa 56124, Italy
| | - Luca Menichetti
- Institute
of Clinical Physiology, National Research Council of Italy, CNR Research Area, Via G. Moruzzi 1, Pisa 56124, Italy
| | - Sabrina Taliani
- Department
of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy
| | - Federico Da Settimo
- Department
of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy
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9
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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: 46] [Impact Index Per Article: 23.0] [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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10
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Zhao K, Chen X, Bian Y, Zhou Z, Wei X, Zhang J. Broadening horizons: The role of ferroptosis in myocardial ischemia-reperfusion injury. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:2269-2286. [PMID: 37119287 DOI: 10.1007/s00210-023-02506-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 04/19/2023] [Indexed: 05/01/2023]
Abstract
Ferroptosis is a novel type of regulated cell death (RCD) discovered in recent years, where abnormal intracellular iron accumulation leads to the onset of lipid peroxidation, which further leads to the disruption of intracellular redox homeostasis and triggers cell death. Iron accumulation with lipid peroxidation is considered a hallmark of ferroptosis that distinguishes it from other RCDs. Myocardial ischemia-reperfusion injury (MIRI) is a process of increased myocardial cell injury that occurs during coronary reperfusion after myocardial ischemia and is associated with high post-infarction mortality. Multiple experiments have shown that ferroptosis plays an important role in MIRI pathophysiology. This review systematically summarized the latest research progress on the mechanisms of ferroptosis. Then we report the possible link between the occurrence of MIRI and ferroptosis in cardiomyocytes. Finally, we discuss and analyze the related drugs that target ferroptosis to attenuate MIRI and its action targets, and point out the shortcomings of the current state of relevant research and possible future research directions. It is hoped to provide a new avenue for improving the prognosis of the acute coronary syndrome.
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Affiliation(s)
- Ke Zhao
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250000, China
| | - Xiaoshu Chen
- Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250000, China
| | - Yujing Bian
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250000, China
| | - Zhou Zhou
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250000, China
| | - Xijin Wei
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250000, China.
| | - Juan Zhang
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250000, China.
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11
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Iurova E, Rastorgueva E, Beloborodov E, Pogodina E, Fomin A, Sugak D, Viktorov D, Tumozov I, Saenko Y. Protective Effect of Peptide Calcium Channel Blocker Omega-Hexatoxin-Hv1a on Epithelial Cell during Ischemia-Reperfusion Injury. Pharmaceuticals (Basel) 2023; 16:1314. [PMID: 37765122 PMCID: PMC10538190 DOI: 10.3390/ph16091314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/25/2023] [Accepted: 09/01/2023] [Indexed: 09/29/2023] Open
Abstract
Ischemia-reperfusion injury (IRI) is a common phenomenon that develops both from natural causes and during major operations. Many intracellular processes mediated by calcium ions are involved in the development of IRI. Currently, chemical calcium channel blockers are used but they have a number of limitations. In this article, we study the effect of the omega-hexatoxin-Hv1a peptide toxin, an alternative to chemical calcium channel blockers, on the mechanisms of IRI development in epithelial cell culture. The toxin was produced using solid phase peptide synthesis. IRI was caused by deprivation of glucose, serum and oxygen. The data obtained demonstrate that the omega-hexatoxin-Hv1a toxin in nanomolar concentrations is able to prevent the development of apoptosis and necrosis in epithelial cells by reducing the concentration of calcium, sodium and potassium ions, as well as by delaying rapid normalization of the pH level, affecting the mitochondrial potential and oxidative stress. This toxin can be used as an alternative to chemical calcium channel blockers for preventing tissue and organ IRI due to its low-dose requirement and high bioavailability.
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Affiliation(s)
- Elena Iurova
- Laboratory of Research and Development of Peptide Drugs and Vaccines, S. P. Kapitsa Technological Research Institute, Ulyanovsk State University, 432017 Ulyanovsk, Russia; (E.I.); (E.R.); (E.B.); (E.P.); (A.F.); (D.S.); (D.V.); (I.T.)
| | - Eugenia Rastorgueva
- Laboratory of Research and Development of Peptide Drugs and Vaccines, S. P. Kapitsa Technological Research Institute, Ulyanovsk State University, 432017 Ulyanovsk, Russia; (E.I.); (E.R.); (E.B.); (E.P.); (A.F.); (D.S.); (D.V.); (I.T.)
- Department of General and Clinical Pharmacology and Microbiology, Faculty of Medicine, Ulyanovsk State University, 432017 Ulyanovsk, Russia
| | - Evgenii Beloborodov
- Laboratory of Research and Development of Peptide Drugs and Vaccines, S. P. Kapitsa Technological Research Institute, Ulyanovsk State University, 432017 Ulyanovsk, Russia; (E.I.); (E.R.); (E.B.); (E.P.); (A.F.); (D.S.); (D.V.); (I.T.)
| | - Evgeniya Pogodina
- Laboratory of Research and Development of Peptide Drugs and Vaccines, S. P. Kapitsa Technological Research Institute, Ulyanovsk State University, 432017 Ulyanovsk, Russia; (E.I.); (E.R.); (E.B.); (E.P.); (A.F.); (D.S.); (D.V.); (I.T.)
| | - Aleksandr Fomin
- Laboratory of Research and Development of Peptide Drugs and Vaccines, S. P. Kapitsa Technological Research Institute, Ulyanovsk State University, 432017 Ulyanovsk, Russia; (E.I.); (E.R.); (E.B.); (E.P.); (A.F.); (D.S.); (D.V.); (I.T.)
| | - Dmitrii Sugak
- Laboratory of Research and Development of Peptide Drugs and Vaccines, S. P. Kapitsa Technological Research Institute, Ulyanovsk State University, 432017 Ulyanovsk, Russia; (E.I.); (E.R.); (E.B.); (E.P.); (A.F.); (D.S.); (D.V.); (I.T.)
| | - Denis Viktorov
- Laboratory of Research and Development of Peptide Drugs and Vaccines, S. P. Kapitsa Technological Research Institute, Ulyanovsk State University, 432017 Ulyanovsk, Russia; (E.I.); (E.R.); (E.B.); (E.P.); (A.F.); (D.S.); (D.V.); (I.T.)
| | - Ivan Tumozov
- Laboratory of Research and Development of Peptide Drugs and Vaccines, S. P. Kapitsa Technological Research Institute, Ulyanovsk State University, 432017 Ulyanovsk, Russia; (E.I.); (E.R.); (E.B.); (E.P.); (A.F.); (D.S.); (D.V.); (I.T.)
| | - Yury Saenko
- Laboratory of Research and Development of Peptide Drugs and Vaccines, S. P. Kapitsa Technological Research Institute, Ulyanovsk State University, 432017 Ulyanovsk, Russia; (E.I.); (E.R.); (E.B.); (E.P.); (A.F.); (D.S.); (D.V.); (I.T.)
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12
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Koyama T. Postconditioning with Lactate-Enriched Blood for Reducing Lethal Reperfusion Injury in Humans. J Cardiovasc Transl Res 2023; 16:793-802. [PMID: 36939958 PMCID: PMC10480094 DOI: 10.1007/s12265-023-10372-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 03/08/2023] [Indexed: 03/21/2023]
Abstract
Ischemic myocardium cannot survive without reperfusion. However, reperfusion of the ischemic myocardium paradoxically induces myocyte death; this phenomenon is termed lethal reperfusion injury. To date, no effective approach has been demonstrated for ST-segment elevation myocardial infarction (STEMI) in clinical settings. Recently, we demonstrated a novel approach for cardioprotection, termed postconditioning with lactate-enriched blood (PCLeB). PCLeB comprises intermittent reperfusion and timely coronary injections of lactated Ringer's solution, which is implemented at the beginning of reperfusion. This approach is aimed at reducing lethal reperfusion injury via prolonging intracellular acidosis during the early period of reperfusion, compared with the original postconditioning protocol. Patients with STEMI treated using PCLeB have reported positive outcomes. This article represents an effort, with a perspective different from current insights, toward preventing lethal reperfusion injury, in light of the historical background of reperfusion injury research. PCLeB is considered the new approach for cardioprotection.
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Affiliation(s)
- Takashi Koyama
- Department of Cardiology, Saitama Municipal Hospital, 2460 Mimuro, Midori-Ku, Saitama City, Saitama, 336-8522, Japan.
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13
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Iurova E, Beloborodov E, Rastorgueva E, Fomin A, Saenko Y. Peptide Sodium Channels Modulator Mu-Agatoxin-Aa1a Prevents Ischemia-Reperfusion Injury of Cells. Molecules 2023; 28:molecules28073174. [PMID: 37049936 PMCID: PMC10095657 DOI: 10.3390/molecules28073174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 03/31/2023] [Accepted: 04/01/2023] [Indexed: 04/05/2023] Open
Abstract
Ischemia-reperfusion injury (IRI) is an irreversible functional and structural injury. Restoration of normal oxygen concentration exacerbates the emergence and development of deadly cells. One of the possible moments of reperfusion damage to cells is an increase in the intracellular concentration of sodium ions. In this article, we study the mu-agatoxin-Aa1a, a modulator of sodium channels, on the processes of IRI cells damage. The toxin was synthesized using an automatic peptide synthesizer. Hypoxia was induced by reducing the content of serum and oxygen in the CHO-K1 culture. The influence of the toxin on the level of apoptosis; intracellular concentration of sodium, calcium, and potassium ions; intracellular pH; totality of reactive oxygen species (ROS), nitric oxide (NO), and ATP; and changes in the mitochondrial potential were studied. The experiments performed show that mu-agatoxin-Aa1a effectively prevents IRI of cells. Toxin reduces the level of apoptosis and prevents a decrease in the intracellular concentration of sodium and calcium ions during IRI. Mu-agatoxin-Aa1a contributes to the maintenance of elevated intracellular pH, reduces the intracellular concentration of ROS, and prevents the decrease in intracellular NO concentration and mitochondrial potential under conditions of reoxygenation/reperfusion. An analysis of experimental data shows that the mu-agatoxin-Aa1a peptide has adaptogenic properties. In the future, this peptide can be used to prevent ischemia/reperfusion tissue damage different genesis.
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Affiliation(s)
- Elena Iurova
- Laboratory of Research and Development of Peptide Drugs and Vaccines, S. P. Kapitsa Technological Research Institute, Ulyanovsk State University, Ulyanovsk 432017, Russia
| | - Evgenii Beloborodov
- Laboratory of Research and Development of Peptide Drugs and Vaccines, S. P. Kapitsa Technological Research Institute, Ulyanovsk State University, Ulyanovsk 432017, Russia
| | - Eugenia Rastorgueva
- Laboratory of Research and Development of Peptide Drugs and Vaccines, S. P. Kapitsa Technological Research Institute, Ulyanovsk State University, Ulyanovsk 432017, Russia
- Department of General and Clinical Pharmacology and Microbiology, Faculty of Medicine, Ulyanovsk State University, Ulyanovsk 432017, Russia
| | - Aleksandr Fomin
- Laboratory of Research and Development of Peptide Drugs and Vaccines, S. P. Kapitsa Technological Research Institute, Ulyanovsk State University, Ulyanovsk 432017, Russia
| | - Yury Saenko
- Laboratory of Research and Development of Peptide Drugs and Vaccines, S. P. Kapitsa Technological Research Institute, Ulyanovsk State University, Ulyanovsk 432017, Russia
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14
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Milliken AS, Ciesla JH, Nadtochiy SM, Brookes PS. Distinct effects of intracellular vs. extracellular acidic pH on the cardiac metabolome during ischemia and reperfusion. J Mol Cell Cardiol 2023; 174:101-114. [PMID: 36481511 PMCID: PMC9868090 DOI: 10.1016/j.yjmcc.2022.11.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 11/22/2022] [Accepted: 11/25/2022] [Indexed: 12/10/2022]
Abstract
Tissue ischemia results in intracellular pH (pHIN) acidification, and while metabolism is a known driver of acidic pHIN, less is known about how acidic pHIN regulates metabolism. Furthermore, acidic extracellular (pHEX) during early reperfusion confers cardioprotection, but how this impacts metabolism is unclear. Herein we employed LCMS based targeted metabolomics to analyze perfused mouse hearts exposed to: (i) control perfusion, (ii) hypoxia, (iii) ischemia, (iv) enforced acidic pHIN, (v) control reperfusion, and (vi) acidic pHEX (6.8) reperfusion. Surprisingly little overlap was seen between metabolic changes induced by hypoxia, ischemia, and acidic pHIN. Acidic pHIN elevated metabolites in the top half of glycolysis, and enhanced glutathione redox state. Meanwhile, acidic pHEX reperfusion induced substantial metabolic changes in addition to those seen in control reperfusion. This included elevated metabolites in the top half of glycolysis, prevention of purine nucleotide loss, and an enhancement in glutathione redox state. These data led to hypotheses regarding potential roles for methylglyoxal inhibiting the mitochondrial permeability transition pore, and for acidic inhibition of ecto-5'-nucleotidase, as potential mediators of cardioprotection by acidic pHEX reperfusion. However, neither hypothesis was supported by subsequent experiments. In contrast, analysis of cardiac effluents revealed complex effects of pHEX on metabolite transport, suggesting that mildly acidic pHEX may enhance succinate release during reperfusion. Overall, each intervention had distinct and overlapping metabolic effects, suggesting acidic pH is an independent metabolic regulator regardless which side of the cell membrane it is imposed.
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Affiliation(s)
- Alexander S Milliken
- Department of Pharmacology and Physiology, University of Rochester Medical Center, USA
| | - Jessica H Ciesla
- Department of Biochemistry, University of Rochester Medical Center, USA
| | - Sergiy M Nadtochiy
- Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center, USA
| | - Paul S Brookes
- Department of Pharmacology and Physiology, University of Rochester Medical Center, USA; Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center, USA.
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15
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Enomoto A, Ichikawa K. Research and Development of Preclinical Overhauser-Enhanced Magnetic Resonance Imaging. Antioxid Redox Signal 2022; 37:1094-1110. [PMID: 35369734 DOI: 10.1089/ars.2022.0038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Significance: Imaging free radicals, including reactive oxygen species and reactive nitrogen species, can be useful for understanding the pathology of diseases in animal disease models, as they are related to various physiological functions or diseases. Among the methods used for imaging free radicals, Overhauser-enhanced magnetic resonance imaging (OMRI) has a short image acquisition time and high spatial resolution. Therefore, OMRI is used to obtain various biological parameters. In this study, we review the methodology for improving the biological OMRI system and its applications. Recent Advances: The sensitivity of OMRI systems has been enhanced significantly to allow the visualization of various biological parameters, such as redox state, partial oxygen pressure, and pH, in different body parts of small animals, using spin probes. Furthermore, both endogenous free radicals and exogenous free radicals present in drugs can be visualized using OMRI. Critical Issues: To acquire accurate biological parameters at a high resolution, it is essential to increase the electron paramagnetic resonance (EPR) excitation efficiency and achieve a high enhancement factor. In addition, the size and magnetic field strength also need to be optimized for the measurement target. Future Directions: The advancement of in vivo OMRI techniques will be useful for understanding the pathology, diagnosis, and evaluation of therapeutic effects of drugs in various disease models. Antioxid. Redox Signal. 37, 1094-1110.
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Affiliation(s)
- Ayano Enomoto
- Department of Biophysical Chemistry, Faculty of Pharmaceutical Sciences, Nagasaki International University, Sasebo, Japan
| | - Kazuhiro Ichikawa
- Department of Biophysical Chemistry, Faculty of Pharmaceutical Sciences, Nagasaki International University, Sasebo, Japan
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16
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Penna C, Comità S, Tullio F, Alloatti G, Pagliaro P. Challenges facing the clinical translation of cardioprotection: 35 years after the discovery of ischemic preconditioning. Vascul Pharmacol 2022; 144:106995. [PMID: 35470102 DOI: 10.1016/j.vph.2022.106995] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/17/2022] [Accepted: 04/16/2022] [Indexed: 12/19/2022]
Abstract
Since coronary reperfusion was introduced into clinical practice in the late 1970s, the further translation of several successful animal experiments on cardioprotection into clinical practice has been disappointing to date. Animal experiments are often performed on young, healthy animals lacking the risk factors, co-morbidities and co-medications characteristic of acute myocardial infarction patients. Many hopes were kindled in 1986 when ischemic preconditioning was discovered. However, it is not yet known how long ischemia can last and what is the best modality for additional cardioprotection through conditioning to obtain benefits. There is a lack of experimental studies on the long-term effects of additional cardioprotection, in addition to the reduction in infarct size; in particular, there is a lack of studies on vessel protection, repair, inflammation, remodeling, and mortality. The reproducibility and robustness of experimental studies are often limited by species differences, the role of co-morbidities, vascular damage, inflammatory processes, and co-medications, which are not adequately considered. In particular, inflammatory processes, including NLRP3 inflammasome, play an important role in the long-term effects. Future studies should focus on interventions/agents with robust preclinical data and should recruit patients who truly have the potential to benefit from further cardioprotection. Here we focus on the main mechanisms and targets of cardioprotection during remote conditioning and their alteration by one of the most common co-morbidities, namely diabetes, in which microvascular lesions and inflammatory processes play extremely important roles.
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Affiliation(s)
- Claudia Penna
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano, 10043 Torino, TO, Italy; National Institute for Cardiovascular Research (INRC), Bologna, Italy
| | - Stefano Comità
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano, 10043 Torino, TO, Italy
| | - Francesca Tullio
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano, 10043 Torino, TO, Italy
| | | | - Pasquale Pagliaro
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano, 10043 Torino, TO, Italy; National Institute for Cardiovascular Research (INRC), Bologna, Italy.
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17
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An Overview of the Molecular Mechanisms Associated with Myocardial Ischemic Injury: State of the Art and Translational Perspectives. Cells 2022; 11:cells11071165. [PMID: 35406729 PMCID: PMC8998015 DOI: 10.3390/cells11071165] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 03/22/2022] [Accepted: 03/24/2022] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular disease is the leading cause of death in western countries. Among cardiovascular diseases, myocardial infarction represents a life-threatening condition predisposing to the development of heart failure. In recent decades, much effort has been invested in studying the molecular mechanisms underlying the development and progression of ischemia/reperfusion (I/R) injury and post-ischemic cardiac remodeling. These mechanisms include metabolic alterations, ROS overproduction, inflammation, autophagy deregulation and mitochondrial dysfunction. This review article discusses the most recent evidence regarding the molecular basis of myocardial ischemic injury and the new potential therapeutic interventions for boosting cardioprotection and attenuating cardiac remodeling.
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18
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Lyotropic Liquid Crystals: A Biocompatible and Safe Material for Local Cardiac Application. Pharmaceutics 2022; 14:pharmaceutics14020452. [PMID: 35214184 PMCID: PMC8879243 DOI: 10.3390/pharmaceutics14020452] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/03/2022] [Accepted: 02/17/2022] [Indexed: 02/01/2023] Open
Abstract
The regeneration of cardiac tissue is a multidisciplinary research field aiming to improve the health condition of the post-heart attack patient. Indeed, myocardial tissue has a poor ability to self-regenerate after severe damage. The scientific efforts focused on the research of a biomaterial able to adapt to heart tissue, thus guaranteeing the in situ release of active substances or growth promoters. Many types of hydrogels were proposed for this purpose, showing several limitations. The aim of this study was to suggest a new usage for glyceryl monooleate-based lyotropic liquid crystals (LLCs) as a biocompatible and inert material for a myocardial application. The main advantages of LLCs are mainly related to their easy in situ injection as lamellar phase and their instant in situ transition in the cubic phase. In vivo studies proved the biocompatibility and the inertia of LLCs after their application on the myocardial tissue of mice. In detail, the cardiac activity was monitored through 28 days, and no significant alterations were recorded in the heart anatomy and functionality. Moreover, gross anatomy showed the ability of LLCs to be bio-degraded in a suitable time frame. Overall, these results permitted us to suppose a potential use of LLCs as materials for cardiac drug delivery.
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19
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Grass M, McDougal AD, Blazeski A, Kamm RD, García-Cardeña G, Dewey CF. A computational model of cardiomyocyte metabolism predicts unique reperfusion protocols capable of reducing cell damage during ischemia/reperfusion. J Biol Chem 2022; 298:101693. [PMID: 35157851 PMCID: PMC9062261 DOI: 10.1016/j.jbc.2022.101693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/25/2022] [Accepted: 02/03/2022] [Indexed: 11/20/2022] Open
Abstract
If a coronary blood vessel is occluded and the neighboring cardiomyocytes deprived of oxygen, subsequent reperfusion of the ischemic tissue can lead to oxidative damage due to excessive generation of reactive oxygen species. Cardiomyocytes and their mitochondria are the main energy producers and consumers of the heart, and their metabolic changes during ischemia seem to be a key driver of reperfusion injury. Here, we hypothesized that tracking changes in cardiomyocyte metabolism, such as oxygen and ATP concentrations, would help in identifying points of metabolic failure during ischemia and reperfusion. To track some of these changes continuously from the onset of ischemia through reperfusion, we developed a system of differential equations representing the chemical reactions involved in the production and consumption of 67 molecular species. This model was validated and used to identify conditions present during periods of critical transition in ischemia and reperfusion that could lead to oxidative damage. These simulations identified a range of oxygen concentrations that lead to reverse mitochondrial electron transport at complex I of the respiratory chain and a spike in mitochondrial membrane potential, which are key suspects in the generation of reactive oxygen species at the onset of reperfusion. Our model predicts that a short initial reperfusion treatment with reduced oxygen content (5% of physiological levels) could reduce the cellular damage from both of these mechanisms. This model should serve as an open-source platform to test ideas for treatment of the ischemia reperfusion process by following the temporal evolution of molecular concentrations in the cardiomyocyte.
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Affiliation(s)
- Matthias Grass
- Department of Mechanical Engineering, ETH Zurich, Zurich, Switzerland; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA; Program in Human Biology and Translational Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Anthony D McDougal
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Adriana Blazeski
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA; Program in Human Biology and Translational Medicine, Harvard Medical School, Boston, Massachusetts, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Roger D Kamm
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Guillermo García-Cardeña
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA; Program in Human Biology and Translational Medicine, Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
| | - C Forbes Dewey
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
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20
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Maslov LN, Popov SV, Mukhomedzyanov AV, Naryzhnaya NV, Voronkov NS, Ryabov VV, Boshchenko AA, Khaliulin I, Prasad NR, Fu F, Pei JM, Logvinov SV, Oeltgen PR. Reperfusion Cardiac Injury: Receptors and the Signaling Mechanisms. Curr Cardiol Rev 2022; 18:63-79. [PMID: 35422224 PMCID: PMC9896422 DOI: 10.2174/1573403x18666220413121730] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 01/01/2022] [Accepted: 01/10/2022] [Indexed: 11/22/2022] Open
Abstract
It has been documented that Ca2+ overload and increased production of reactive oxygen species play a significant role in reperfusion injury (RI) of cardiomyocytes. Ischemia/reperfusion induces cell death as a result of necrosis, necroptosis, apoptosis, and possibly autophagy, pyroptosis and ferroptosis. It has also been demonstrated that the NLRP3 inflammasome is involved in RI of the heart. An increase in adrenergic system activity during the restoration of coronary perfusion negatively affected cardiac resistance to RI. Toll-like receptors are involved in RI of the heart. Angiotensin II and endothelin-1 aggravated ischemic/reperfusion injury of the heart. Activation of neutrophils, monocytes, CD4+ T-cells and platelets contributes to cardiac ischemia/reperfusion injury. Our review outlines the role of these factors in reperfusion cardiac injury.
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Affiliation(s)
- Leonid N. Maslov
- Address correspondence to this author at the Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk National Research Medical Center of the Russian Academy of Science, Kyevskskaya 111A, 634012 Tomsk, Russia; Tel. +7 3822 262174; E-mail:
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21
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Ehresman J, Cottrill E, Caplan JM, McDougall CG, Theodore N, Nyquist PA. Neuroprotective Role of Acidosis in Ischemia: Review of the Preclinical Evidence. Mol Neurobiol 2021; 58:6684-6696. [PMID: 34606050 DOI: 10.1007/s12035-021-02578-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 09/26/2021] [Indexed: 12/09/2022]
Abstract
Efforts to develop effective neuroprotective therapies for ischemic stroke have had little success to date. One promising approach to neuroprotection is ischemic postconditioning, which utilizes brief bouts of ischemia after acute ischemic stroke to elicit neuroprotection, although the mechanism is largely unknown. As the primary components of transient ischemia are local hypoxia and acidosis, and hypoxic postconditioning has had little success, it is possible that the acidosis component may be the primary driver. To address the evidence behind this, we performed a systematic review of preclinical studies focused on the neuroprotective role of transient acidosis after ischemia. Animal studies demonstrated that mild-to-moderate acidosis after ischemic events led to better functional neurologic outcomes with reduced infarct volumes, while severe acidosis often led to cerebral edema and worse functional outcomes. In vitro studies demonstrated that mild-to-moderate acidosis improves neuronal survival largely through two means: (1) inhibition of harmful superoxide formation in the excitotoxic pathway and (2) remodeling neuronal mitochondria to allow for efficient ATP production (i.e., oxidative phosphorylation), even in the absence of oxygen. Similar to the animal studies, acidotic postconditioning in humans would entail short cycles of carbon dioxide inhalation, which has already been demonstrated to be safe as part of a hypercapnic challenge when measuring cerebrovascular reactivity. Due to the preclinical efficacy of acidotic postconditioning, its relatively straightforward translation into humans, and the growing need for neuroprotective therapies, future preclinical studies should focus on filling the current knowledge gaps that are currently restricting the development of phase I/II clinical trials.
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Affiliation(s)
- Jeff Ehresman
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Phipps 416, 600 N. Wolfe St., Baltimore, MD, 21287, USA
| | - Ethan Cottrill
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Phipps 416, 600 N. Wolfe St., Baltimore, MD, 21287, USA
| | - Justin M Caplan
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Phipps 416, 600 N. Wolfe St., Baltimore, MD, 21287, USA
| | - Cameron G McDougall
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Phipps 416, 600 N. Wolfe St., Baltimore, MD, 21287, USA
| | - Nicholas Theodore
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Phipps 416, 600 N. Wolfe St., Baltimore, MD, 21287, USA
| | - Paul A Nyquist
- Department of Neurology, Johns Hopkins University School of Medicine, Phipps 416, 600 N. Wolfe St., Baltimore, MD, 21287, USA.
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22
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Fischesser DM, Bo B, Benton RP, Su H, Jahanpanah N, Haworth KJ. Controlling Reperfusion Injury With Controlled Reperfusion: Historical Perspectives and New Paradigms. J Cardiovasc Pharmacol Ther 2021; 26:504-523. [PMID: 34534022 DOI: 10.1177/10742484211046674] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Cardiac reperfusion injury is a well-established outcome following treatment of acute myocardial infarction and other types of ischemic heart conditions. Numerous cardioprotection protocols and therapies have been pursued with success in pre-clinical models. Unfortunately, there has been lack of successful large-scale clinical translation, perhaps in part due to the multiple pathways that reperfusion can contribute to cell death. The search continues for new cardioprotection protocols based on what has been learned from past results. One class of cardioprotection protocols that remain under active investigation is that of controlled reperfusion. This class consists of those approaches that modify, in a controlled manner, the content of the reperfusate or the mechanical properties of the reperfusate (e.g., pressure and flow). This review article first provides a basic overview of the primary pathways to cell death that have the potential to be addressed by various forms of controlled reperfusion, including no-reflow phenomenon, ion imbalances (particularly calcium overload), and oxidative stress. Descriptions of various controlled reperfusion approaches are described, along with summaries of both mechanistic and outcome-oriented studies at the pre-clinical and clinical phases. This review will constrain itself to approaches that modify endogenously-occurring blood components. These approaches include ischemic postconditioning, gentle reperfusion, controlled hypoxic reperfusion, controlled hyperoxic reperfusion, controlled acidotic reperfusion, and controlled ionic reperfusion. This review concludes with a discussion of the limitations of past approaches and how they point to potential directions of investigation for the future.
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Affiliation(s)
- Demetria M Fischesser
- Division of Cardiovascular Health and Disease, Department of Internal Medicine, College of Medicine, 2514University of Cincinnati, Cincinnati, OH, USA
| | - Bin Bo
- Division of Cardiovascular Health and Disease, Department of Internal Medicine, College of Medicine, 2514University of Cincinnati, Cincinnati, OH, USA
| | - Rachel P Benton
- Division of Cardiovascular Health and Disease, Department of Internal Medicine, College of Medicine, 2514University of Cincinnati, Cincinnati, OH, USA
| | - Haili Su
- Division of Cardiovascular Health and Disease, Department of Internal Medicine, College of Medicine, 2514University of Cincinnati, Cincinnati, OH, USA
| | - Newsha Jahanpanah
- Division of Cardiovascular Health and Disease, Department of Internal Medicine, College of Medicine, 2514University of Cincinnati, Cincinnati, OH, USA
| | - Kevin J Haworth
- Division of Cardiovascular Health and Disease, Department of Internal Medicine, College of Medicine, 2514University of Cincinnati, Cincinnati, OH, USA
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Role of Oxidative DNA Damage and Repair in Atrial Fibrillation and Ischemic Heart Disease. Int J Mol Sci 2021; 22:ijms22083838. [PMID: 33917194 PMCID: PMC8068079 DOI: 10.3390/ijms22083838] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/31/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023] Open
Abstract
Atrial fibrillation (AF) and ischemic heart disease (IHD) represent the two most common clinical cardiac diseases, characterized by angina, arrhythmia, myocardial damage, and cardiac dysfunction, significantly contributing to cardiovascular morbidity and mortality and posing a heavy socio-economic burden on society worldwide. Current treatments of these two diseases are mainly symptomatic and lack efficacy. There is thus an urgent need to develop novel therapies based on the underlying pathophysiological mechanisms. Emerging evidence indicates that oxidative DNA damage might be a major underlying mechanism that promotes a variety of cardiac diseases, including AF and IHD. Antioxidants, nicotinamide adenine dinucleotide (NAD+) boosters, and enzymes involved in oxidative DNA repair processes have been shown to attenuate oxidative damage to DNA, making them potential therapeutic targets for AF and IHD. In this review, we first summarize the main molecular mechanisms responsible for oxidative DNA damage and repair both in nuclei and mitochondria, then describe the effects of oxidative DNA damage on the development of AF and IHD, and finally discuss potential targets for oxidative DNA repair-based therapeutic approaches for these two cardiac diseases.
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24
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Milliken AS, Brookes PS. Amber alert: getting to the heart of succinate efflux in reperfusion injury. Cardiovasc Res 2021; 117:997-998. [PMID: 32666087 DOI: 10.1093/cvr/cvaa216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Alexander S Milliken
- Department of Pharmacology & Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Paul S Brookes
- Department of Pharmacology & Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Department of Anesthesiology & Perioperative Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
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25
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Qiu YY, Zhang HS, Tang Y, Liu FY, Pang JQ, Zhang XY, Xiong H, Liang YS, Zhao HY, Chen SJ. Mitochondrial dysfunction resulting from the down-regulation of bone morphogenetic protein 5 may cause microtia. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:418. [PMID: 33842639 PMCID: PMC8033356 DOI: 10.21037/atm-21-831] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background Bone morphogenetic protein 5 (BMP5) has been identified as one of the important risk factors for microtia; however, the link between them has yet to be clarified. In this study, we aimed to demonstrate the relationship of BMP5 with mitochondrial function and investigate the specific role of mitochondria in regulating microtia development. Methods BMP5 expression was measured in auricular cartilage tissues from patients with and without microtia. The effects of BMP5 knockdown on cellular function and mitochondrial function were also analyzed in vitro. Changes in genome-wide expression profiles were measured in BMP5-knockdown cells. Finally, the specific impact of BMP5 down-regulation on mitochondrial fat oxidation was analyzed in vitro. Results BMP5 expression was down-regulated in the auricular cartilage tissues of microtia patients. BMP5 down-regulation inhibited various cellular functions in vitro, including cell proliferation, mobility, and cytoactivity. The functional integrity of mitochondria was also damaged, accompanied by a decrease in mitochondrial membrane potential, reactive oxygen species (ROS) neutralization, and reduced adenosine triphosphate (ATP) production. Carnitine O-palmitoyltransferase 2 and diacylglycerol acyltransferase 2, two of the key regulators of mitochondrial lipid oxidation, were also found to be decreased by BMP5 down-regulation. Conclusions Down-regulation of BMP5 affects glycerolipid metabolism and fatty acid degradation, leading to mitochondrial dysfunction, reduced ATP production, and changes in cell function, and ultimately resulting in microtia. This research provides supporting evidence for an important role of BMP5 down-regulation in affecting mitochondrial metabolism in cells, and sheds new light on the mechanisms underlying the pathogenesis of microtia.
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Affiliation(s)
- Yin-Yi Qiu
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hua-Song Zhang
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Otolaryngology, Longgang E.N.T Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T Shenzhen, Shenzhen, China
| | - Yuan Tang
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Fei-Yi Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen, University, Guangzhou, China
| | - Jia-Qi Pang
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xue-Yuan Zhang
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hao Xiong
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yu-Shuang Liang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen, University, Guangzhou, China
| | - Hui-Ying Zhao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen, University, Guangzhou, China
| | - Sui-Jun Chen
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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26
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de Miranda DC, de Oliveira Faria G, Hermidorff MM, Dos Santos Silva FC, de Assis LVM, Isoldi MC. Pre- and Post-Conditioning of the Heart: An Overview of Cardioprotective Signaling Pathways. Curr Vasc Pharmacol 2020; 19:499-524. [PMID: 33222675 DOI: 10.2174/1570161119666201120160619] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 11/02/2020] [Accepted: 11/02/2020] [Indexed: 11/22/2022]
Abstract
Since the discovery of ischemic pre- and post-conditioning, more than 30 years ago, the knowledge about the mechanisms and signaling pathways involved in these processes has significantly increased. In clinical practice, on the other hand, such advancement has yet to be seen. This article provides an overview of ischemic pre-, post-, remote, and pharmacological conditioning related to the heart. In addition, we reviewed the cardioprotective signaling pathways and therapeutic agents involved in the above-mentioned processes, aiming to provide a comprehensive evaluation of the advancements in the field. The advancements made over the last decades cannot be ignored and with the exponential growth in techniques and applications. The future of pre- and post-conditioning is promising.
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Affiliation(s)
- Denise Coutinho de Miranda
- Laboratory of Cell Signaling, Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Gabriela de Oliveira Faria
- Laboratory of Cell Signaling, Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Milla Marques Hermidorff
- Laboratory of Cell Signaling, Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Fernanda Cacilda Dos Santos Silva
- Laboratory of Cardiovascular Physiology, Department of Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Leonardo Vinícius Monteiro de Assis
- Laboratory of Comparative Physiology of Pigmentation, Department of Physiology, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Mauro César Isoldi
- Laboratory of Cell Signaling, Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
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27
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Topal DG, Engstrøm T, Nepper-Christensen L, Holmvang L, Køber L, Kelbæk H, Lønborg J. Degree of ST-segment elevation in patients with STEMI reflects the acute ischemic burden and the salvage potential. J Electrocardiol 2020; 63:28-34. [PMID: 33070031 DOI: 10.1016/j.jelectrocard.2020.09.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 08/20/2020] [Accepted: 09/27/2020] [Indexed: 11/30/2022]
Abstract
BACKGROUND ST-segment elevation myocardial infarction (STEMI) is clinically diagnosed by significant ST-segment elevation (STE) in the electrocardiogram (ECG). The importance of the sum of significant ST-segment elevation (∑STE) before primary percutaneous coronary intervention (PPCI) - considered an indicator of the degree of ischemia - is sparse. We evaluated the association of ∑STE before PPCI with respect to area at risk, infarct size and myocardial salvage. METHODS A total of 503 patients with STEMI and available cardiac magnetic resonance (CMR) were included. CMR was performed at day 1 (interquartile range [IQR], 1-1) and at follow-up at day 92 (IQR, 88-96). The ECG before PPCI with the most prominent STE was used for analysis. RESULTS ∑STE divided into quartiles were progressive linearly associated with area at risk (p < 0.001), final infarct size (p < 0.001) and extent of microvascular obstruction (p < 0.001) and inverse linearly associated with final myocardial salvage (p < 0.001). Similar results were found for linear regression analyses. However, ∑STE was not associated with final myocardial salvage in patients with pre-PCI TIMI (thrombolysis in myocardial infarction) flow 0/1 (p = 0.24) in contrast to patients with pre-PCI TIMI flow 2/3 (p ≤ 0.001). CONCLUSION In patients with STEMI presenting within 12 h of symptom onset, the degree of STE in the ECG before PPCI is a marker of the extent of myocardium at risk that in turn affects the infarct size in patients with pre-PCI TIMI flow 0/1, whereas the degree of STE in patients with pre-PCI TIMI flow 2/3 is a marker of the extent of the myocardium at risk as well as myocardial salvage - both affecting the myocardial damage.
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Affiliation(s)
- Divan Gabriel Topal
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark.
| | - Thomas Engstrøm
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark; Department of Cardiology, Lund University Hospital, Lund, Sweden
| | | | - Lene Holmvang
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Lars Køber
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Henning Kelbæk
- Department of Cardiology, Zealand University Hospital, Denmark
| | - Jacob Lønborg
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark
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28
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Milliken AS, Kulkarni CA, Brookes PS. Acid enhancement of ROS generation by complex-I reverse electron transport is balanced by acid inhibition of complex-II: Relevance for tissue reperfusion injury. Redox Biol 2020; 37:101733. [PMID: 33007502 PMCID: PMC7527751 DOI: 10.1016/j.redox.2020.101733] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/11/2020] [Accepted: 09/13/2020] [Indexed: 02/02/2023] Open
Abstract
Generation of mitochondrial reactive oxygen species (ROS) is an important process in triggering cellular necrosis and tissue infarction during ischemia-reperfusion (IR) injury. Ischemia results in accumulation of the metabolite succinate. Rapid oxidation of this succinate by mitochondrial complex II (Cx-II) during reperfusion reduces the co-enzyme Q (Co-Q) pool, thereby driving electrons backward into complex-I (Cx-I), a process known as reverse electron transport (RET), which is thought to be a major source of ROS. During ischemia, enhanced glycolysis results in an acidic cellular pH at the onset of reperfusion. While the process of RsET within Cx-I is known to be enhanced by a high mitochondrial trans-membrane ΔpH, the impact of pH itself on the integrated process of Cx-II to Cx-I RET has not been fully studied. Using isolated mouse heart and liver mitochondria under conditions which mimic the onset of reperfusion (i.e., high [ADP]), we show that mitochondrial respiration (state 2 and state 3) as well as isolated Cx-II activity are impaired at acidic pH, whereas the overall generation of ROS by Cx-II to Cx-I RET was insensitive to pH. Together these data indicate that the acceleration of Cx-I RET ROS by ΔpH appears to be cancelled out by the impact of pH on the source of electrons, i.e. Cx-II. Implications for the role of Cx-II to Cx-I RET derived ROS in IR injury are discussed.
ROS from complex I (Cx-I) reverse electron transport (RET) is enhanced at acidic pH. Mitochondrial complex II (Cx-II) activity is inhibited at acidic pH. These effects cancel out, yielding no net pH response of Cx-II to Cx-I RET ROS.
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Affiliation(s)
- Alexander S Milliken
- Department of Pharmacology and Physiology, University of Rochester Medical Center, USA
| | - Chaitanya A Kulkarni
- Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center, USA
| | - Paul S Brookes
- Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center, USA.
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29
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Zuurbier CJ, Bertrand L, Beauloye CR, Andreadou I, Ruiz‐Meana M, Jespersen NR, Kula‐Alwar D, Prag HA, Eric Botker H, Dambrova M, Montessuit C, Kaambre T, Liepinsh E, Brookes PS, Krieg T. Cardiac metabolism as a driver and therapeutic target of myocardial infarction. J Cell Mol Med 2020; 24:5937-5954. [PMID: 32384583 PMCID: PMC7294140 DOI: 10.1111/jcmm.15180] [Citation(s) in RCA: 121] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 02/13/2020] [Accepted: 03/08/2020] [Indexed: 12/11/2022] Open
Abstract
Reducing infarct size during a cardiac ischaemic-reperfusion episode is still of paramount importance, because the extension of myocardial necrosis is an important risk factor for developing heart failure. Cardiac ischaemia-reperfusion injury (IRI) is in principle a metabolic pathology as it is caused by abruptly halted metabolism during the ischaemic episode and exacerbated by sudden restart of specific metabolic pathways at reperfusion. It should therefore not come as a surprise that therapy directed at metabolic pathways can modulate IRI. Here, we summarize the current knowledge of important metabolic pathways as therapeutic targets to combat cardiac IRI. Activating metabolic pathways such as glycolysis (eg AMPK activators), glucose oxidation (activating pyruvate dehydrogenase complex), ketone oxidation (increasing ketone plasma levels), hexosamine biosynthesis pathway (O-GlcNAcylation; administration of glucosamine/glutamine) and deacetylation (activating sirtuins 1 or 3; administration of NAD+ -boosting compounds) all seem to hold promise to reduce acute IRI. In contrast, some metabolic pathways may offer protection through diminished activity. These pathways comprise the malate-aspartate shuttle (in need of novel specific reversible inhibitors), mitochondrial oxygen consumption, fatty acid oxidation (CD36 inhibitors, malonyl-CoA decarboxylase inhibitors) and mitochondrial succinate metabolism (malonate). Additionally, protecting the cristae structure of the mitochondria during IR, by maintaining the association of hexokinase II or creatine kinase with mitochondria, or inhibiting destabilization of FO F1 -ATPase dimers, prevents mitochondrial damage and thereby reduces cardiac IRI. Currently, the most promising and druggable metabolic therapy against cardiac IRI seems to be the singular or combined targeting of glycolysis, O-GlcNAcylation and metabolism of ketones, fatty acids and succinate.
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Affiliation(s)
- Coert J. Zuurbier
- Department of AnesthesiologyLaboratory of Experimental Intensive Care and AnesthesiologyAmsterdam Infection & ImmunityAmsterdam Cardiovascular SciencesAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Luc Bertrand
- Institut de Recherche Expérimentale et CliniquePole of Cardiovascular ResearchUniversité catholique de LouvainBrusselsBelgium
| | - Christoph R. Beauloye
- Institut de Recherche Expérimentale et CliniquePole of Cardiovascular ResearchUniversité catholique de LouvainBrusselsBelgium
- Cliniques Universitaires Saint‐LucBrusselsBelgium
| | - Ioanna Andreadou
- Laboratory of PharmacologyFaculty of PharmacyNational and Kapodistrian University of AthensAthensGreece
| | - Marisol Ruiz‐Meana
- Department of CardiologyHospital Universitari Vall d’HebronVall d’Hebron Institut de Recerca (VHIR)CIBER‐CVUniversitat Autonoma de Barcelona and Centro de Investigación Biomédica en Red‐CVMadridSpain
| | | | | | - Hiran A. Prag
- Department of MedicineUniversity of CambridgeCambridgeUK
| | - Hans Eric Botker
- Department of CardiologyAarhus University HospitalAarhus NDenmark
| | - Maija Dambrova
- Pharmaceutical PharmacologyLatvian Institute of Organic SynthesisRigaLatvia
| | - Christophe Montessuit
- Department of Pathology and ImmunologyUniversity of Geneva School of MedicineGenevaSwitzerland
| | - Tuuli Kaambre
- Laboratory of Chemical BiologyNational Institute of Chemical Physics and BiophysicsTallinnEstonia
| | - Edgars Liepinsh
- Pharmaceutical PharmacologyLatvian Institute of Organic SynthesisRigaLatvia
| | - Paul S. Brookes
- Department of AnesthesiologyUniversity of Rochester Medical CenterRochesterNYUSA
| | - Thomas Krieg
- Department of MedicineUniversity of CambridgeCambridgeUK
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30
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Penna C, Alloatti G, Crisafulli A. Mechanisms Involved in Cardioprotection Induced by Physical Exercise. Antioxid Redox Signal 2020; 32:1115-1134. [PMID: 31892282 DOI: 10.1089/ars.2019.8009] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Significance: Regular exercise training can reduce myocardial damage caused by acute ischemia/reperfusion (I/R). Exercise can reproduce the phenomenon of ischemic preconditioning, due to the capacity of brief periods of ischemia to reduce myocardial damage caused by acute I/R. In addition, exercise may also activate the multiple kinase cascade responsible for cardioprotection even in the absence of ischemia. Recent Advances: Animal and human studies highlighted the fact that, besides to reduce risk factors related to cardiovascular disease, the beneficial effects of exercise are also due to its ability to induce conditioning of the heart. Exercise behaves as a physiological stress that triggers beneficial adaptive cellular responses, inducing a protective phenotype in the heart. The factors contributing to the exercise-induced heart preconditioning include stimulation of the anti-radical defense system and nitric oxide production, opioids, myokines, and adenosine-5'-triphosphate (ATP) dependent potassium channels. They appear to be also involved in the protective effect exerted by exercise against cardiotoxicity related to chemotherapy. Critical Issues and Future Directions: Although several experimental evidences on the protective effect of exercise have been obtained, the mechanisms underlying this phenomenon have not yet been fully clarified. Further studies are warranted to define precise exercise prescriptions in patients at risk of myocardial infarction or undergoing chemotherapy.
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Affiliation(s)
- Claudia Penna
- National Institute for Cardiovascular Research (INRC), Bologna, Italy.,Department of Clinical and Biological Sciences, University of Turin, Torino, Italy
| | | | - Antonio Crisafulli
- Department of Medical Sciences and Public Health, Sports Physiology Lab., University of Cagliari, Cagliari, Italy
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31
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Hong W, Mo F, Zhang Z, Huang M, Wei X. Nicotinamide Mononucleotide: A Promising Molecule for Therapy of Diverse Diseases by Targeting NAD+ Metabolism. Front Cell Dev Biol 2020; 8:246. [PMID: 32411700 PMCID: PMC7198709 DOI: 10.3389/fcell.2020.00246] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 03/24/2020] [Indexed: 02/05/2023] Open
Abstract
NAD+, a co-enzyme involved in a great deal of biochemical reactions, has been found to be a network node of diverse biological processes. In mammalian cells, NAD+ is synthetized, predominantly through NMN, to replenish the consumption by NADase participating in physiologic processes including DNA repair, metabolism, and cell death. Correspondingly, aberrant NAD+ metabolism is observed in many diseases. In this review, we discuss how the homeostasis of NAD+ is maintained in healthy condition and provide several age-related pathological examples related with NAD+ unbalance. The sirtuins family, whose functions are NAD-dependent, is also reviewed. Administration of NMN surprisingly demonstrated amelioration of the pathological conditions in some age-related disease mouse models. Further clinical trials have been launched to investigate the safety and benefits of NMN. The NAD+ production and consumption pathways including NMN are essential for more precise understanding and therapy of age-related pathological processes such as diabetes, ischemia–reperfusion injury, heart failure, Alzheimer’s disease, and retinal degeneration.
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Affiliation(s)
- Weiqi Hong
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Fei Mo
- West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Department of Biotherapy, Chengdu, China
| | - Ziqi Zhang
- West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Department of Biotherapy, Chengdu, China
| | - Mengyuan Huang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
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32
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Stiermaier T, Jensen JO, Rommel KP, de Waha-Thiele S, Fuernau G, Desch S, Thiele H, Eitel I. Combined Intrahospital Remote Ischemic Perconditioning and Postconditioning Improves Clinical Outcome in ST-Elevation Myocardial Infarction. Circ Res 2020; 124:1482-1491. [PMID: 30929570 DOI: 10.1161/circresaha.118.314500] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
RATIONALE Remote ischemic conditioning (RIC) or ischemic postconditioning (PostC) may protect the myocardium from ischemia-reperfusion injury in patients with ST-segment-elevation myocardial infarction. OBJECTIVE To determine whether combined intrahospital RIC and PostC or PostC alone in addition to primary percutaneous coronary intervention (PCI) reduce long-term clinical events after ST-segment-elevation myocardial infarction. METHODS AND RESULTS The present study is a post hoc analysis of a prospective trial which randomized 696 ST-segment-elevation myocardial infarction patients with symptoms <12 hours 1:1:1 to either combined RIC and PostC in addition to primary PCI, PostC alone in addition to primary PCI, or conventional PCI (control). Three cycles of RIC were performed by inflation of an upper arm blood pressure cuff for 5 minutes followed by deflation for 5 minutes. PostC was performed after primary PCI via 4 cycles of 30 seconds balloon occlusions followed by 30 seconds of reperfusion. Major adverse cardiac events consisting of cardiac death, reinfarction, and new congestive heart failure were assessed during long-term follow-up. Follow-up data were obtained in 97% of patients in median 3.6 years after the index event (interquartile range, 2.9-4.2 years). Major adverse cardiac events occurred in 10.2% of patients in the combined RIC and PostC group and in 16.9% in the control group (odds ratio, 0.56; 95% CI, 0.32-0.97; P=0.04). The difference was driven by a significantly reduced rate of new congestive heart failure in the RIC and PostC group (2.7% versus 7.8%; odds ratio, 0.32; 95% CI, 0.13-0.84; P=0.02). In contrast, PostC alone did not reduce major adverse cardiac events compared with controls (14.1% versus 16.9%; odds ratio, 0.81; 95% CI, 0.48-1.35; P=0.41), and the reduction of new congestive heart failure was not statistically significant (3.5% versus 7.8%; odds ratio, 0.43; 95% CI, 0.18-1.03; P=0.05). CONCLUSIONS Cardioprotection by combined intrahospital RIC and PostC in addition to primary PCI significantly reduced the rate of major adverse cardiac events and new congestive heart failure after ST-segment-elevation myocardial infarction. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov . Unique identifier: NCT02158468.
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Affiliation(s)
- Thomas Stiermaier
- From the University Heart Center Lübeck, Medical Clinic II (Cardiology/Angiology/Intensive Care Medicine), Germany (T.S., J.-O.J., S.d.W.-T., G.F., I.E.).,German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany (T.S., J.-O.J., S.d.W.-T., G.F., S.D., I.E.)
| | - Jan-Oluf Jensen
- From the University Heart Center Lübeck, Medical Clinic II (Cardiology/Angiology/Intensive Care Medicine), Germany (T.S., J.-O.J., S.d.W.-T., G.F., I.E.).,German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany (T.S., J.-O.J., S.d.W.-T., G.F., S.D., I.E.)
| | - Karl-Philipp Rommel
- Heart Center Leipzig, University Hospital, Department of Internal Medicine/Cardiology, Germany (K.-P.R., S.D., H.T.)
| | - Suzanne de Waha-Thiele
- From the University Heart Center Lübeck, Medical Clinic II (Cardiology/Angiology/Intensive Care Medicine), Germany (T.S., J.-O.J., S.d.W.-T., G.F., I.E.).,German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany (T.S., J.-O.J., S.d.W.-T., G.F., S.D., I.E.)
| | - Georg Fuernau
- From the University Heart Center Lübeck, Medical Clinic II (Cardiology/Angiology/Intensive Care Medicine), Germany (T.S., J.-O.J., S.d.W.-T., G.F., I.E.).,German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany (T.S., J.-O.J., S.d.W.-T., G.F., S.D., I.E.)
| | - Steffen Desch
- German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany (T.S., J.-O.J., S.d.W.-T., G.F., S.D., I.E.).,Heart Center Leipzig, University Hospital, Department of Internal Medicine/Cardiology, Germany (K.-P.R., S.D., H.T.)
| | - Holger Thiele
- Heart Center Leipzig, University Hospital, Department of Internal Medicine/Cardiology, Germany (K.-P.R., S.D., H.T.)
| | - Ingo Eitel
- From the University Heart Center Lübeck, Medical Clinic II (Cardiology/Angiology/Intensive Care Medicine), Germany (T.S., J.-O.J., S.d.W.-T., G.F., I.E.).,German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany (T.S., J.-O.J., S.d.W.-T., G.F., S.D., I.E.)
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33
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Del Re DP, Amgalan D, Linkermann A, Liu Q, Kitsis RN. Fundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease. Physiol Rev 2019; 99:1765-1817. [PMID: 31364924 DOI: 10.1152/physrev.00022.2018] [Citation(s) in RCA: 650] [Impact Index Per Article: 108.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Twelve regulated cell death programs have been described. We review in detail the basic biology of nine including death receptor-mediated apoptosis, death receptor-mediated necrosis (necroptosis), mitochondrial-mediated apoptosis, mitochondrial-mediated necrosis, autophagy-dependent cell death, ferroptosis, pyroptosis, parthanatos, and immunogenic cell death. This is followed by a dissection of the roles of these cell death programs in the major cardiac syndromes: myocardial infarction and heart failure. The most important conclusion relevant to heart disease is that regulated forms of cardiomyocyte death play important roles in both myocardial infarction with reperfusion (ischemia/reperfusion) and heart failure. While a role for apoptosis in ischemia/reperfusion cannot be excluded, regulated forms of necrosis, through both death receptor and mitochondrial pathways, are critical. Ferroptosis and parthanatos are also likely important in ischemia/reperfusion, although it is unclear if these entities are functioning as independent death programs or as amplification mechanisms for necrotic cell death. Pyroptosis may also contribute to ischemia/reperfusion injury, but potentially through effects in non-cardiomyocytes. Cardiomyocyte loss through apoptosis and necrosis is also an important component in the pathogenesis of heart failure and is mediated by both death receptor and mitochondrial signaling. Roles for immunogenic cell death in cardiac disease remain to be defined but merit study in this era of immune checkpoint cancer therapy. Biology-based approaches to inhibit cell death in the various cardiac syndromes are also discussed.
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Affiliation(s)
- Dominic P Del Re
- Departments of Medicine and Cell Biology, Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, and Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York; Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, New Jersey; Department of Internal Medicine 3, Division of Nephrology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and Department of Physiology and Biophysics, University of Washington, Seattle, Washington
| | - Dulguun Amgalan
- Departments of Medicine and Cell Biology, Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, and Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York; Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, New Jersey; Department of Internal Medicine 3, Division of Nephrology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and Department of Physiology and Biophysics, University of Washington, Seattle, Washington
| | - Andreas Linkermann
- Departments of Medicine and Cell Biology, Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, and Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York; Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, New Jersey; Department of Internal Medicine 3, Division of Nephrology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and Department of Physiology and Biophysics, University of Washington, Seattle, Washington
| | - Qinghang Liu
- Departments of Medicine and Cell Biology, Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, and Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York; Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, New Jersey; Department of Internal Medicine 3, Division of Nephrology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and Department of Physiology and Biophysics, University of Washington, Seattle, Washington
| | - Richard N Kitsis
- Departments of Medicine and Cell Biology, Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, and Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York; Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, New Jersey; Department of Internal Medicine 3, Division of Nephrology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and Department of Physiology and Biophysics, University of Washington, Seattle, Washington
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Nepper-Christensen L, Høfsten DE, Helqvist S, Lassen JF, Tilsted HH, Holmvang L, Pedersen F, Joshi F, Sørensen R, Bang L, Bøtker HE, Terkelsen CJ, Maeng M, Jensen LO, Aarøe J, Kelbæk H, Køber L, Engstrøm T, Lønborg J. Interaction of ischaemic postconditioning and thrombectomy in patients with ST-elevation myocardial infarction. Heart 2019; 106:24-32. [PMID: 31315939 DOI: 10.1136/heartjnl-2019-314952] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 05/24/2019] [Accepted: 06/21/2019] [Indexed: 02/01/2023] Open
Abstract
OBJECTIVE The Third Danish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction - Ischaemic Postconditioning (DANAMI-3-iPOST) did not show improved clinical outcome in patients with ST-segment elevation myocardial infarction (STEMI) treated with ischaemic postconditioning. However, the use of thrombectomy was frequent and thrombectomy may in itself diminish the effect of ischaemic postconditioning. We evaluated the effect of ischaemic postconditioning in patients included in DANAMI-3-iPOST stratified by the use of thrombectomy. METHODS Patients with STEMI were randomised to conventional primary percutaneous coronary intervention (PCI) or ischaemic postconditioning plus primary PCI. The primary endpoint was a combination of all-cause mortality and hospitalisation for heart failure. RESULTS From March 2011 until February 2014, 1234 patients were included with a median follow-up period of 35 (interquartile range 28 to 42) months. There was a significant interaction between ischaemic postconditioning and thrombectomy on the primary endpoint (p=0.004). In patients not treated with thrombectomy (n=520), the primary endpoint occurred in 33 patients (10%) who underwent ischaemic postconditioning (n=326) and in 35 patients (18%) who underwent conventional treatment (n=194) (adjusted hazard ratio (HR) 0.55 (95%confidence interval (CI) 0.34 to 0.89), p=0.016). In patients treated with thrombectomy (n=714), there was no significant difference between patients treated with ischaemic postconditioning (n=291) and conventional PCI (n=423) on the primary endpoint (adjusted HR 1.18 (95% CI 0.62 to 2.28), p=0.62). CONCLUSIONS In this post-hoc study of DANAMI-3-iPOST, ischaemic postconditioning, in addition to primary PCI, was associated with reduced risk of all-cause mortality and hospitalisation for heart failure in patients with STEMI not treated with thrombectomy. TRIAL REGISTRATION NUMBER NCT01435408.
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Affiliation(s)
- Lars Nepper-Christensen
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Dan Eik Høfsten
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Steffen Helqvist
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Jens Flensted Lassen
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Hans-Henrik Tilsted
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Lene Holmvang
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Frants Pedersen
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Francis Joshi
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Rikke Sørensen
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Lia Bang
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Hans Erik Bøtker
- Department of Cardiology, Aarhus University Hospital Skejby, Aarhus, Denmark
| | | | - Michael Maeng
- Department of Cardiology, Aarhus University Hospital Skejby, Aarhus, Denmark
| | - Lisette Okkels Jensen
- Department of Cardiology, Catheterisation Lab, Odense University Hospital, Odense, Denmark
| | - Jens Aarøe
- Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
| | - Henning Kelbæk
- Department of Cardiology, Roskilde University Hospital, Roskilde, Denmark
| | - Lars Køber
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Thomas Engstrøm
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Jacob Lønborg
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
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Protection of Myocardial Ischemia-Reperfusion by Therapeutic Hypercapnia: a Mechanism Involving Improvements in Mitochondrial Biogenesis and Function. J Cardiovasc Transl Res 2019; 12:467-477. [PMID: 30980235 DOI: 10.1007/s12265-019-09886-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Accepted: 03/26/2019] [Indexed: 12/14/2022]
Abstract
Previous studies proposed that acidic reperfusion may be a protective strategy for myocardial ischemia-reperfusion therapy with potential of clinical transformation. In this study, we investigated whether therapeutic hypercapnia could mimic acidosis postconditioning in isolated hearts with a 30-min left coronary artery ligation-reperfusion model in rats. Therapeutic hypercapnia (inhalation 20% CO2 for 10 min) is cardioprotective with a strict therapeutic time window and acidity: it reduced the infarct ratio and serum myocardial enzyme and increased the myocardial ATP content. Furthermore, mitochondrial morphology damage, the loss of mitochondrial membrane potential, and the formation of mitochondrial permeability transition pore were effectively inhibited, indicating the improvements in mitochondrial function. The expression of the mitochondrial biogenesis regulators was upregulated simultaneously. These findings indicated therapeutic hypercapnia in animals can mimic ex vivo acidosis postconditioning to alleviate myocardial ischemia-reperfusion injury. The effect is related to improvement in mitochondrial function and regulation of the mitochondrial biogenesis pathway.
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Muscle-derived autologous mitochondrial transplantation: A novel strategy for treating cerebral ischemic injury. Behav Brain Res 2018; 356:322-331. [PMID: 30213662 DOI: 10.1016/j.bbr.2018.09.005] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/07/2018] [Accepted: 09/07/2018] [Indexed: 12/18/2022]
Abstract
The available evidence showed that mitochondrial transfer by releasing the extracellular vesicles containing mitochondria from astrocytes to neurons exerted a neuroprotective effect after stroke. Whether extracellular mitochondrial replenishment could rescue the tissues from cerebral ischemic injury still needs to be explored completely. It was hypothesized that the augmentation of mitochondrial damage after cerebral ischemia could be resolved by timely replenishment of exogenous mitochondria. A stroke model of middle cerebral artery occlusion (MCAO) was used in this study to verify this hypothesis. This study found that the number of extracellular mitochondria increased in rat cerebrospinal fluid after MCAO, and a higher proportion of mitochondria were associated with good neurological outcomes. Following 90-min ischemia, autologously derived mitochondria (isolated from autologous pectoralis major) or vehicle alone was infused directly into the lateral ventricles, and the rats were allowed to recover for 4 weeks. A plenty of infused mitochondria were found to be distributed in the boundary and ischemic penumbra areas. Furthermore, the transplantation of mitochondria reduced cellular oxidative stress and apoptosis, attenuated reactive astrogliosis, and promoted neurogenesis after stroke. Moreover, the transplantation of mitochondria decreased brain infarct volume and reversed neurological deficits. The findings suggested that the delivery of mitochondria through the lateral ventricles resulted in their widespread distribution throughout the brain and exerted a neuroprotective effect after ischemia-reperfusion injury.
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Cardioprotection by nicotinamide mononucleotide (NMN): Involvement of glycolysis and acidic pH. J Mol Cell Cardiol 2018; 121:155-162. [PMID: 29958828 DOI: 10.1016/j.yjmcc.2018.06.007] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 06/23/2018] [Accepted: 06/25/2018] [Indexed: 12/25/2022]
Abstract
Stimulation of the cytosolic NAD+ dependent deacetylase SIRT1 is cardioprotective against ischemia-reperfusion (IR) injury. NAD+ precursors including nicotinamide mononucleotide (NMN) are thought to induce cardioprotection via SIRT1. Herein, while NMN protected perfused hearts against IR (functional recovery: NMN 42 ± 7% vs. vehicle 11 ± 3%), this protection was insensitive to the SIRT1 inhibitor splitomicin (recovery 47 ± 8%). Although NMN-induced cardioprotection was absent in Sirt3-/- hearts (recovery 9 ± 5%), this was likely due to enhanced baseline injury in Sirt3-/- (recovery 6 ± 2%), since similar injury levels in WT hearts also blunted the protective efficacy of NMN. Considering alternative cardiac effects of NMN, and the requirement of glycolysis for NAD+, we hypothesized NMN may confer protection in part via direct stimulation of cardiac glycolysis. In primary cardiomyocytes, NMN induced cytosolic and extracellular acidification and elevated lactate. In addition, [U-13C]glucose tracing in intact hearts revealed that NMN stimulated glycolytic flux. Consistent with a role for glycolysis in NMN-induced protection, hearts perfused without glucose (palmitate as fuel source), or hearts perfused with galactose (no ATP from glycolysis) exhibited no benefit from NMN (recovery 11 ± 4% and 15 ± 2% respectively). Acidosis during early reperfusion is known to be cardioprotective (i.e., acid post-conditioning), and we also found that NMN was cardioprotective when delivered acutely at reperfusion (recovery 39 ± 8%). This effect of NMN was not additive with acidosis, suggesting overlapping mechanisms. We conclude that the acute cardioprotective benefits of NMN are mediated in part via glycolytic stimulation, with the downstream protective mechanism involving enhanced ATP synthesis during ischemia and/or enhanced acidosis during reperfusion.
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Higuchi S, Suzuki M, Horiuchi Y, Tanaka H, Saji M, Yoshino H, Nagao K, Yamamoto T, Takayama M. Clinical impact of thrombus aspiration on in-hospital mortality in each culprit lesion in the setting of ST-segment elevation myocardial infarction. Heart Vessels 2018; 33:1168-1174. [PMID: 29704101 DOI: 10.1007/s00380-018-1171-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Accepted: 04/20/2018] [Indexed: 10/17/2022]
Abstract
Recent randomized clinical trials have questioned the clinical benefits of thrombus aspiration (TA) in ST-segment elevation myocardial infarction (STEMI). Real-world data on TA and the efficacy of TA for various culprit lesions have not been sufficiently evaluated. This study mainly aimed to evaluate whether the clinical impact of TA depends on culprit lesions in the setting of STEMI. We surveyed the Tokyo Coronary Care Unit Network Registry, a prospective cohort study, between 2010 and 2014, which included 10,232 patients with STEMI. In-hospital deaths occurred in 538 patients (5.3%). Improved Thrombolysis in Myocardial Infarction flow was more frequently observed in patients who underwent TA than in those who did not (87 vs. 80%; p < 0.001). Univariate logistic regression analysis revealed that TA was associated with a lower in-hospital mortality rate [odds ratio (OR), 0.80; 95% confidential interval (CI), 0.66-0.96; p = 0.016]. However, the difference was not significant after multivariate logistic regression analysis (OR 0.95; 95% CI 0.71-1.17; p = 0.355). Only TA for the left circumflex (LCx) lesions was associated with a better prognosis (OR 0.38; 95% CI 0.21-0.72; p = 0.003). The effect persisted after adjustment (OR 0.50; 95% CI 0.25-0.99; p = 0.049) but was attenuated after analysis using inverse probability weighting (OR 0.97; 95% CI 0.93-0.99; p = 0.048). On the basis of the findings in a large Japanese cohort, a prognostic benefit of TA on in-hospital mortality was not observed. The effect of TA on the LCx lesions was marginally significant and limited. Therefore, TA is not recommended in Japanese patients with STEMI.
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Affiliation(s)
- Satoshi Higuchi
- Department of Cardiology, Kyorin University School of Medicine, Kyorin University Hospital, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-0004, Japan. .,Tokyo CCU Network Scientific Committee, Tokyo, Japan.
| | - Makoto Suzuki
- Tokyo CCU Network Scientific Committee, Tokyo, Japan
| | - Yu Horiuchi
- Tokyo CCU Network Scientific Committee, Tokyo, Japan
| | | | - Mike Saji
- Tokyo CCU Network Scientific Committee, Tokyo, Japan
| | | | - Ken Nagao
- Tokyo CCU Network Scientific Committee, Tokyo, Japan
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White CW, Messer SJ, Large SR, Conway J, Kim DH, Kutsogiannis DJ, Nagendran J, Freed DH. Transplantation of Hearts Donated after Circulatory Death. Front Cardiovasc Med 2018; 5:8. [PMID: 29487855 PMCID: PMC5816942 DOI: 10.3389/fcvm.2018.00008] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 01/19/2018] [Indexed: 12/17/2022] Open
Abstract
Cardiac transplantation has become limited by a critical shortage of suitable organs from brain-dead donors. Reports describing the successful clinical transplantation of hearts donated after circulatory death (DCD) have recently emerged. Hearts from DCD donors suffer significant ischemic injury prior to organ procurement; therefore, the traditional approach to the transplantation of hearts from brain-dead donors is not applicable to the DCD context. Advances in our understanding of ischemic post-conditioning have facilitated the development of DCD heart resuscitation strategies that can be used to minimize ischemia-reperfusion injury at the time of organ procurement. The availability of a clinically approved ex situ heart perfusion device now allows DCD heart preservation in a normothermic beating state and minimizes exposure to incremental cold ischemia. This technology also facilitates assessments of organ viability to be undertaken prior to transplantation, thereby minimizing the risk of primary graft dysfunction. The application of a tailored approach to DCD heart transplantation that focuses on organ resuscitation at the time of procurement, ex situ preservation, and pre-transplant assessments of organ viability has facilitated the successful clinical application of DCD heart transplantation. The transplantation of hearts from DCD donors is now a clinical reality. Investigating ways to optimize the resuscitation, preservation, evaluation, and long-term outcomes is vital to ensure a broader application of DCD heart transplantation in the future.
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Affiliation(s)
| | - Simon J Messer
- Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
| | - Stephen R Large
- Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
| | | | - Daniel H Kim
- Cardiology, University of Alberta, Edmonton, AB, Canada
| | | | - Jayan Nagendran
- Cardiac Surgery, University of Alberta, Edmonton, AB, Canada
| | - Darren H Freed
- Cardiac Surgery, University of Alberta, Edmonton, AB, Canada.,Department of Physiology, University of Alberta, Edmonton, AB, Canada.,Department of Biomedical Engineering, University of Alberta, Edmonton, AB, Canada
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McGarvey M, Ali O, Iqbal MB, Ilsley C, Wong J, Di Mario C, Redwood S, Patterson T, Pennell DJ, Rogers P, Dalby M. A feasibility and safety study of intracoronary hemodilution during primary coronary angioplasty in order to reduce reperfusion injury in myocardial infarction. Catheter Cardiovasc Interv 2018. [PMID: 28636165 DOI: 10.1002/ccd.27136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVES We designed a pilot study to evaluate safety and feasibility of an inexpensive and simple approach to intracoronary hemodilution during primary angioplasty (PPCI) to reduce reperfusion injury. INTRODUCTION Early revascularization in acute myocardial infarction decreases infarct size and improves outcomes. However, abrupt restoration of coronary flow results in myocardial reperfusion injury and increased final infarct size. Dilution of coronary blood during revascularization may help reduce this damage. If proved effective, such an approach would need to be simple and suitable for widespread adoption. METHODS Ten patients presenting with STEMI underwent intracoronary dilution with room temperature Hartmann's solution delivered through the guiding catheter during primary angioplasty (PPCI). Infusion of perfusate began prior to crossing the occluded artery with the guidewire, continuing until 10 min after completion of the balloon and stenting procedure. Infusion was briefly interrupted for contrast injection and pressure monitoring. The outcome measures were safety, including intracoronary temperature reduction and volume of intracoronary perfusate infused, and technical feasibility. RESULTS There were no significant symptomatic, hemodynamic, ECG ST/T segment or rhythm changes observed during perfusate administration. The median (interquartile range) volume of perfusate administered was 550 mL (350-725 mL) and the median intracoronary temperature reduction observed was 3.4°Celsius. Myocardial salvage was 0.54 (0.43-0.65). CONCLUSIONS Transcatheter intracoronary hemodilution with room temperature perfusate during PPCI is feasible and appears safe. Such a strategy is simple and inexpensive, with potential to be widely applied. Further mechanistic and subsequent outcome powered studies are required to evaluate whether this strategy can reduce reperfusion injury in STEMI.
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Affiliation(s)
- Michael McGarvey
- Department of Cardiology, NIHR Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, and Imperial College London, United Kingdom
| | - Omar Ali
- Department of Cardiology, NIHR Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, and Imperial College London, United Kingdom
| | - M Bilal Iqbal
- Department of Cardiology, NIHR Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, and Imperial College London, United Kingdom
| | - Charles Ilsley
- Department of Cardiology, NIHR Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, and Imperial College London, United Kingdom
| | - Joyce Wong
- Department of Cardiology, NIHR Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, and Imperial College London, United Kingdom
| | - Carlo Di Mario
- Department of Cardiology, NIHR Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, and Imperial College London, United Kingdom
| | - Simon Redwood
- Department of Cardiology, Guy's and St Thomas' Hospital, London, United Kingdom
| | - Tiffany Patterson
- Department of Cardiology, Guy's and St Thomas' Hospital, London, United Kingdom
| | - Dudley J Pennell
- Department of Cardiology, NIHR Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, and Imperial College London, United Kingdom
| | - Paula Rogers
- Department of Cardiology, NIHR Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, and Imperial College London, United Kingdom
| | - Miles Dalby
- Department of Cardiology, NIHR Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, and Imperial College London, United Kingdom
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Krylatov AV, Maslov LN, Voronkov NS, Boshchenko AA, Popov SV, Gomez L, Wang H, Jaggi AS, Downey JM. Reactive Oxygen Species as Intracellular Signaling Molecules in the Cardiovascular System. Curr Cardiol Rev 2018; 14:290-300. [PMID: 29962348 PMCID: PMC6300799 DOI: 10.2174/1573403x14666180702152436] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 06/13/2018] [Accepted: 06/20/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Redox signaling plays an important role in the lives of cells. This signaling not only becomes apparent in pathologies but is also thought to be involved in maintaining physiological homeostasis. Reactive Oxygen Species (ROS) can activate protein kinases: CaMKII, PKG, PKA, ERK, PI3K, Akt, PKC, PDK, JNK, p38. It is unclear whether it is a direct interaction of ROS with these kinases or whether their activation is a consequence of inhibition of phosphatases. ROS have a biphasic effect on the transport of Ca2+ in the cell: on one hand, they activate the sarcoplasmic reticulum Ca2+-ATPase, which can reduce the level of Ca2+ in the cell, and on the other hand, they can inactivate Ca2+-ATPase of the plasma membrane and open the cation channels TRPM2, which promote Ca2+-loading and subsequent apoptosis. ROS inhibit the enzyme PHD2, which leads to the stabilization of HIF-α and the formation of the active transcription factor HIF. CONCLUSION Activation of STAT3 and STAT5, induced by cytokines or growth factors, may include activation of NADPH oxidase and enhancement of ROS production. Normal physiological production of ROS under the action of cytokines activates the JAK/STAT while excessive ROS production leads to their inhibition. ROS cause the activation of the transcription factor NF-κB. Physiological levels of ROS control cell proliferation and angiogenesis. ROS signaling is also involved in beneficial adaptations to survive ischemia and hypoxia, while further increases in ROS can trigger programmed cell death by the mechanism of apoptosis or autophagy. ROS formation in the myocardium can be reduced by moderate exercise.
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Affiliation(s)
| | - Leonid N. Maslov
- Address correspondence to this author at the Cardiology Research Institute, Tomsk National Research Medical Center of the Russian Academy of
Science, Tomsk, Russia; Tel: 3822 262174; Fax: 3822 555057;
E-mail:
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Parks RJ, Murphy E, Liu JC. Mitochondrial Permeability Transition Pore and Calcium Handling. Methods Mol Biol 2018; 1782:187-196. [PMID: 29851001 DOI: 10.1007/978-1-4939-7831-1_11] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The opening of a large conductance channel in the inner mitochondrial membrane, known as the mitochondrial permeability transition pore (PTP), has been shown to be a primary mediator of cell death in the heart subjected to ischemia-reperfusion injury. Inhibitors of the PTP have been shown to reduce cardiac ischemia-reperfusion injury in many animal models. Furthermore, most cardioprotective strategies appear to reduce ischemic cell death either by reducing the triggers for the opening of the PTP, such as reducing calcium overload or reactive oxygen species, or by inhibiting PTP modulators. This chapter will focus on key issues in the study of the PTP and provide some methods for measuring PTP opening in isolated mitochondria.
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Affiliation(s)
- Randi J Parks
- Systems Biology Center, NHLBI, NIH, Bethesda, MD, 20892, USA
| | | | - Julia C Liu
- Systems Biology Center, NHLBI, NIH, Bethesda, MD, 20892, USA.
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Shin B, Cowan DB, Emani SM, Del Nido PJ, McCully JD. Mitochondrial Transplantation in Myocardial Ischemia and Reperfusion Injury. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 982:595-619. [PMID: 28551809 DOI: 10.1007/978-3-319-55330-6_31] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Ischemic heart disease remains the leading cause of death worldwide. Mitochondria are the power plant of the cardiomyocyte, generating more than 95% of the cardiac ATP. Complex cellular responses to myocardial ischemia converge on mitochondrial malfunction which persists and increases after reperfusion, determining the extent of cellular viability and post-ischemic functional recovery. In a quest to ameliorate various points in pathways from mitochondrial damage to myocardial necrosis, exhaustive pharmacologic and genetic tools have targeted various mediators of ischemia and reperfusion injury and procedural techniques without applicable success. The new concept of replacing damaged mitochondria with healthy mitochondria at the onset of reperfusion by auto-transplantation is emerging not only as potential therapy of myocardial rescue, but as gateway to a deeper understanding of mitochondrial metabolism and function. In this chapter, we explore the mechanisms of mitochondrial dysfunction during ischemia and reperfusion, current developments in the methodology of mitochondrial transplantation, mechanisms of cardioprotection and their clinical implications.
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Affiliation(s)
- Borami Shin
- Department of Cardiac Surgery, Boston Children's Hospital, Boston, MA, USA
| | - Douglas B Cowan
- Department of Anesthesiology, Division of Cardiac Anesthesia Research, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Sitaram M Emani
- Division of Cardiovascular Critical Care, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Pedro J Del Nido
- Department of Cardiac Surgery, William E. Ladd Professor of Child Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - James D McCully
- Department of Cardiac Surgery, Harvard Medical School, Boston Children's Hospital, Boston, USA.
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Gohbara M, Hayakawa A, Akazawa Y, Furihata S, Kondo A, Fukushima Y, Tomari S, Endo T, Kimura K, Tamura K. Association Between Acidosis Soon After Reperfusion and Contrast-Induced Nephropathy in Patients With a First-Time ST-Segment Elevation Myocardial Infarction. J Am Heart Assoc 2017; 6:JAHA.117.006380. [PMID: 28835362 PMCID: PMC5586466 DOI: 10.1161/jaha.117.006380] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Background Contrast‐induced nephropathy (CIN) is associated with poor outcomes in patients with acute myocardial infarction. However, the predictors of CIN have yet to be fully elucidated. Methods and Results The study included 273 consecutive patients with a first‐time ST‐segment elevation myocardial infarction who underwent reperfusion within 12 hours of symptom onset. The exclusion criteria were hemodialysis, mechanical ventilation, or previous coronary artery bypass grafting. All patients underwent arterial blood gas analysis soon after reperfusion. CIN was defined as an increase of 0.5 mg/dL in serum creatinine or a 25% increase from baseline between 48 and 72 hours after contrast medium exposure. Acidosis was defined as an arterial blood pH <7.35. CIN was observed in 35 patients (12.8%). Multivariable logistic regression analysis with forward stepwise algorithm revealed a significant association between CIN and the following: reperfusion time, the prevalence of hypertension, peak creatine kinase‐MB, high‐sensitivity C‐reactive protein on admission, and the incidence of acidosis (P<0.05). Multivariable logistic regression analysis revealed that the incidence of acidosis was associated with CIN when adjusted for age, male sex, body mass index, amount of contrast medium used, estimated glomerular filtration rate on admission, glucose level on admission, high‐sensitivity C‐reactive protein on admission, and left ventricular ejection fraction (P<0.05). Moreover, the incidence of acidosis was associated with CIN when adjusted for the Mehran CIN risk score (odds ratio: 2.229, P=0.049). Conclusions The incidence of acidosis soon after reperfusion was associated with CIN in patients with a first‐time ST‐segment elevation myocardial infarction.
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Affiliation(s)
- Masaomi Gohbara
- Division of Cardiology, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Japan
| | - Azusa Hayakawa
- Division of Cardiology, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Japan
| | - Yusuke Akazawa
- Division of Cardiology, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Japan
| | - Shuta Furihata
- Division of Cardiology, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Japan
| | - Ai Kondo
- Division of Cardiology, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Japan
| | - Yusuke Fukushima
- Division of Cardiology, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Japan
| | - Sakie Tomari
- Division of Cardiology, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Japan
| | - Tsutomu Endo
- Division of Cardiology, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Japan
| | - Kazuo Kimura
- Division of Cardiology, Yokohama City University Medical Center, Yokohama, Japan
| | - Kouichi Tamura
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Seara FDAC, Barbosa RAQ, de Oliveira DF, Gran da Silva DLS, Carvalho AB, Freitas Ferreira AC, Matheus Nascimento JH, Olivares EL. Administration of anabolic steroid during adolescence induces long-term cardiac hypertrophy and increases susceptibility to ischemia/reperfusion injury in adult Wistar rats. J Steroid Biochem Mol Biol 2017; 171:34-42. [PMID: 28179209 DOI: 10.1016/j.jsbmb.2017.01.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Revised: 01/09/2017] [Accepted: 01/19/2017] [Indexed: 01/27/2023]
Abstract
Chronic administration of anabolic androgenic steroids (AAS) in adult rats results in cardiac hypertrophy and increased susceptibility to myocardial ischemia/reperfusion (IR) injury. Molecular analyses demonstrated that hyperactivation of type 1 angiotensin II (AT1) receptor mediates cardiac hypertrophy induced by AAS and also induces down-regulation of myocardial ATP-sensitive potassium channel (KATP), resulting in loss of exercise-induced cardioprotection. Exposure to AAS during adolescence promoted long-term cardiovascular dysfunctions, such as dysautonomia. We tested the hypothesis that chronic AAS exposure in the pre/pubertal phase increases the susceptibility to myocardial ischemia/reperfusion (IR) injury in adult rats. Male Wistar rats (26day old) were treated with vehicle (Control, n=12) or testosterone propionate (TP) (AAS, 5mgkg-1 n=12) 5 times/week during 5 weeks. At the end of AAS exposure, rats underwent 23days of washout period and were submitted to euthanasia. Langendorff-perfused hearts were submitted to IR injury and evaluated for mechanical dysfunctions and infarct size. Molecular analysis was performed by mRNA levels of α-myosin heavy chain (MHC), βMHC and brain-derived natriuretic peptide (BNP), ryanodine receptor (RyR2) and sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) by quantitative RT-PCR (qRT-PCR). The expression of AT1 receptor and KATP channel subunits (Kir6.1 and SURa) was analyzed by qRT-PCR and Western Blot. NADPH oxidase (Nox)-related reactive oxygen species generation was assessed by spectrofluorimetry. The expression of antioxidant enzymes was measured by qRT-PCR in order to address a potential role of redox unbalance. AAS exposure promoted long-term cardiac hypertrophy characterized by increased expression of βMHC and βMHC/αMHC ratio. Baseline derivative of pressure (dP/dt) was impaired by AAS exposure. Postischemic recovery of mechanical properties was impaired (decreased left ventricle [LV] developed pressure and maximal dP/dt; increased LV end-diastolic pressure and minimal dP/dt) and infarct size was larger in the AAS group. Catalase mRNA expression was significantly decreased in the AAS group. In conclusion, chronic administration of AAS during adolescence promoted long-term pathological cardiac hypertrophy and persistent increase in the susceptibility to myocardial IR injury possible due to disturbances on catalase expression.
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Affiliation(s)
- Fernando de Azevedo Cruz Seara
- Laboratory of Cardiovascular Physiology and Pharmacology, Department of Physiological Sciences, Institute of Biology, Federal Rural University of Rio de Janeiro, 23890-000 Seropedica, RJ, Brazil; Laboratory of Cardiac Electrophysiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-902 RJ, Brazil
| | - Raiana Andrade Quintanilha Barbosa
- Laboratory of Cellular and Molecular Cardiology, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-902 RJ, Brazil
| | - Dahienne Ferreira de Oliveira
- Laboratory of Cardiac Electrophysiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-902 RJ, Brazil
| | - Diorney Luiz Souza Gran da Silva
- Laboratory of Endocrine Physiology, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-902 RJ, Brazil
| | - Adriana Bastos Carvalho
- Laboratory of Cellular and Molecular Cardiology, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-902 RJ, Brazil
| | - Andrea Claudia Freitas Ferreira
- Laboratory of Endocrine Physiology, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-902 RJ, Brazil; NUMPEX-Bio, Pólo de Xerém, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-902 RJ, Brazil
| | - José Hamilton Matheus Nascimento
- Laboratory of Cardiac Electrophysiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-902 RJ, Brazil
| | - Emerson Lopes Olivares
- Laboratory of Cardiovascular Physiology and Pharmacology, Department of Physiological Sciences, Institute of Biology, Federal Rural University of Rio de Janeiro, 23890-000 Seropedica, RJ, Brazil.
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Postconditioning-induced neuroprotection, mechanisms and applications in cerebral ischemia. Neurochem Int 2017; 107:43-56. [DOI: 10.1016/j.neuint.2017.01.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 01/04/2017] [Accepted: 01/08/2017] [Indexed: 02/07/2023]
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Ding YP, Zhang JY, Feng DX, Kong Y, Xu Z, Chen G. Advances in molecular mechanism of cardioprotection induced by helium. Med Gas Res 2017; 7:124-132. [PMID: 28744366 PMCID: PMC5510294 DOI: 10.4103/2045-9912.208519] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Helium has been classified as a kind of inert gas that is not effortless to spark chemical reactions with other substances in the past decades. Nevertheless, the cognition of scientists has gradually changed accompanied with a variety of studies revealing the potential molecular mechanism underlying organ-protection induced by helium. Especially, as a non-anesthetic gas which is deficient of relevant cardiopulmonary side effects, helium conditioning is recognized as an emerging and promising approach to exert favorable effects by mimicking the cardioprotection of anesthetic gases or xenon. In this review we will summarize advances in the underlying biological mechanisms and clinical applicability with regards to the cardioprotective effects of helium.
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Affiliation(s)
- Yi-Ping Ding
- Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Ju-Yi Zhang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Dong-Xia Feng
- Department of Scott &White Clinic-Temple, Temple, TX, USA
| | - Yan Kong
- Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Zhuan Xu
- Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
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Abstract
Three aspects of cardioprotection are discussed in this article. The first is myocyte death as a function of the duration and severity of ischemia in experimental acute myocardial infarction in the dog heart. The short period of time during which reperfusion with arterial blood will salvage myocytes is demonstrated along with data showing that this period diminishes significantly if collateral flow is very low or absent. The second topic is a discussion of potential mechanisms underlying postconditioning. It begins with a review of the changes that lead to irreversible injury during acute ischemia in the dog heart along with a discussion of the genesis of contraction band necrosis and no reflow when myocardium is salvaged by unrestricted reperfusion with arterial blood in order to provide a basis to discuss the potential mechanisms underlying postconditioning, a situation in which reflow is intermittent and restricted. Postconditioning is reported to achieve greater myocyte salvage than unrestricted reflow. Potential explanations for this beneficial effect include: first, sufficient sarcolemmal repair occurring during the intermittent reflow (reoxygenation) to prevent cell death by explosive cell swelling, and second, prevention of the opening of the mitochondrial permeability transition pore, thereby preventing mitochondrial failure and cell death in the reperfused tissue. Since there is no way available to identify and specifically study the myocytes that would have died if not protected by postconditioning, direct demonstration of mechanisms is difficult or impossible. Finally, the third topic in this commentary is an analysis of the obstacles faced by investigators using small rodent hearts to establish cardioprotective mechanisms. Such studies provide valid data but the relationship of the changes and the proposed mechanisms underlying these changes are not necessarily directly transferable to ischemic large animal hearts including the heart of man.
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Affiliation(s)
- Robert B. Jennings
- Department of Pathology, Duke University Medical Center, Durham, NC, USA
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A novel combination technique of cold crystalloid perfusion but not cold storage facilitates transplantation of canine hearts donated after circulatory death. J Heart Lung Transplant 2016; 35:1358-1364. [DOI: 10.1016/j.healun.2016.03.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 02/17/2016] [Accepted: 03/18/2016] [Indexed: 11/18/2022] Open
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