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Yu S, Jia H, Ding S, Zhang M, Li F, Xu P, Tian Y, Ma L, Gong L, Feng J, Sun Z, Qian F, Li H. Efficacy and safety of intracoronary pro-urokinase combined with low-pressure balloon pre-dilatation during percutaneous coronary intervention in patients with anterior ST-segment elevation myocardial infarction. J Cardiothorac Surg 2024; 19:180. [PMID: 38580976 PMCID: PMC10996115 DOI: 10.1186/s13019-024-02699-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Accepted: 03/27/2024] [Indexed: 04/07/2024] Open
Abstract
BACKGROUND The efficacy and safety of low-pressure balloon pre-dilatation before intracoronary pro-urokinase (pro-UK) in preventing no-reflow during percutaneous coronary intervention (PCI) remains unknown. This study aimed to evaluate the clinical outcomes of intracoronary pro-UK combined with low-pressure balloon pre-dilatation in patients with anterior ST-segment-elevation myocardial infarction (STEMI). METHODS This was a randomized, single-blind, investigator-initiated trial that included 179 patients diagnosed with acute anterior STEMI. All patients were eligible for PCI and were randomized into two groups: intracoronary pro-UK combined with (ICPpD group, n = 90) or without (ICP group, n = 89) low-pressure balloon pre-dilatation. The main efficacy endpoint was complete epicardial and myocardial reperfusion. The safety endpoints were major adverse cardiovascular events (MACEs), which were analyzed at 12 months follow-up. RESULTS Patients in the ICPpD group presented significantly higher TIMI myocardial perfusion grade 3 (TMPG3) compared to those in the ICP group (77.78% versus 68.54%, P = 0.013), and STR ≥ 70% after PCI 30 min (34.44% versus 26.97%, P = 0.047) or after PCI 90 min (40.0% versus 31.46%, P = 0.044). MACEs occurred in 23 patients (25.56%) in the ICPpD group and in 32 patients (35.96%) in the ICP group. There was no difference in hemorrhagic complications during hospitalization between the groups. CONCLUSION Patients with acute anterior STEMI presented more complete epicardial and myocardial reperfusion with adjunctive low-pressure balloon pre-dilatation before intracoronary pro-UK during PCI. TRIAL REGISTRATION 2019xkj213.
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Affiliation(s)
- Shicheng Yu
- Department of Cardiology, Lu'an Hospital of Anhui Medical University, Lu'an, Anhui, 237000, People's Republic of China.
| | - Haoxuan Jia
- Graduate School of Bengbu Medical College, Bengbu, Anhui, 233004, People's Republic of China
| | - Shengkai Ding
- Department of Cardiology, Lu'an Hospital of Anhui Medical University, Lu'an, Anhui, 237000, People's Republic of China
| | - Mengda Zhang
- Department of Cardiology, Lu'an Hospital of Anhui Medical University, Lu'an, Anhui, 237000, People's Republic of China
| | - Fengyun Li
- Department of Cardiology, Lu'an Hospital of Anhui Medical University, Lu'an, Anhui, 237000, People's Republic of China
| | - Pan Xu
- Department of Cardiology, Lu'an Hospital of Anhui Medical University, Lu'an, Anhui, 237000, People's Republic of China
| | - Yuan Tian
- Department of Cardiology, Lu'an Hospital of Anhui Medical University, Lu'an, Anhui, 237000, People's Republic of China
| | - Lingling Ma
- Department of Cardiology, Lu'an Hospital of Anhui Medical University, Lu'an, Anhui, 237000, People's Republic of China
| | - Lijie Gong
- Department of Cardiology, Lu'an Hospital of Anhui Medical University, Lu'an, Anhui, 237000, People's Republic of China
| | - Jun Feng
- Department of Cardiology, Lu'an Hospital of Anhui Medical University, Lu'an, Anhui, 237000, People's Republic of China
| | - Zhaojin Sun
- Department of Cardiology, Lu'an Hospital of Anhui Medical University, Lu'an, Anhui, 237000, People's Republic of China
| | - Fudong Qian
- Department of Cardiology, Lu'an Hospital of Anhui Medical University, Lu'an, Anhui, 237000, People's Republic of China
| | - Hui Li
- Department of Cardiology, Lu'an Hospital of Anhui Medical University, Lu'an, Anhui, 237000, People's Republic of China
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2
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Pan CS, Yan L, Lin SQ, He K, Cui YC, Liu YY, Hu BH, Chang X, Zhao XR, Fan JY, Han JY. QiShenYiQi Pills Attenuates Ischemia/Reperfusion-Induced Cardiac Microvascular Hyperpermeability Implicating Src/Caveolin-1 and RhoA/ROCK/MLC Signaling. Front Physiol 2022; 12:753761. [PMID: 34975519 PMCID: PMC8718710 DOI: 10.3389/fphys.2021.753761] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 11/18/2021] [Indexed: 01/25/2023] Open
Abstract
Aims: Coronary microvascular hyperpermeability is an important contributor to ischemia or reperfusion (I/R) injury. However, the effective strategy for this insult remains limited. This study aimed to explore the protective effect of the compound Chinese medicine QiShenYiQi Pills (QSYQ) against coronary microvascular hyperpermeability after cardiac I/R with focusing on the underlying mechanism. Methods and Results: Male Sprague-Dawley rats under anesthesia were subjected to occlusion of left coronary anterior descending artery followed by reperfusion. QSYQ was administrated 90 min before ischemia initiation. Human cardiac microvascular endothelial cells (HCMECs) underwent hypoxia or reoxygenation (H/R) challenge with QSYQ administrated 1 h prior to hypoxia. QSYQ exhibited effects on attenuating microvascular damage and albumin leakage after I/R injury, showing a role in maintaining endothelial junctions, caveolae, and collagen in basement membrane (BM) of microvessels. Study using HCMECs disclosed that QSYQ protected endothelial barrier from impairment by H/R, attenuating the decline of respiratory chain complex I and ATP synthase, activation of Src/caveolin-1 and increase of RhoA/ROCK/p-MLC, MMP-9, and CTSS. PP2, a Src inhibitor, partially imitated the effect of QSYQ. Conclusions: The QSYQ was able to prevent I/R-induced cardiac microvascular hyperpermeability via a mechanism involving Src/caveolin-1 and RhoA/ROCK/MLC signaling.
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Affiliation(s)
- Chun-Shui Pan
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.,Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Li Yan
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.,Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Se-Qi Lin
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Ke He
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.,Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yuan-Chen Cui
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.,Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yu-Ying Liu
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.,Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Bai-He Hu
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.,Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Xin Chang
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.,Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Xin-Rong Zhao
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.,Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Jing-Yu Fan
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.,Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Jing-Yan Han
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.,Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.,Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China.,State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tianjin, China
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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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MG53, A Tissue Repair Protein with Broad Applications in Regenerative Medicine. Cells 2021; 10:cells10010122. [PMID: 33440658 PMCID: PMC7827922 DOI: 10.3390/cells10010122] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/22/2020] [Accepted: 12/25/2020] [Indexed: 02/06/2023] Open
Abstract
Under natural conditions, injured cells can be repaired rapidly through inherent biological processes. However, in the case of diabetes, cardiovascular disease, muscular dystrophy, and other degenerative conditions, the natural repair process is impaired. Repair of injury to the cell membrane is an important aspect of physiology. Inadequate membrane repair function is implicated in the pathophysiology of many human disorders. Recent studies show that Mitsugumin 53 (MG53), a TRIM family protein, plays a key role in repairing cell membrane damage and facilitating tissue regeneration. Clarifying the role of MG53 and its molecular mechanism are important for the application of MG53 in regenerative medicine. In this review, we analyze current research dissecting MG53′s function in cell membrane repair and tissue regeneration, and highlight the development of recombinant human MG53 protein as a potential therapeutic agent to repair multiple-organ injuries.
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Thyroid hormone postconditioning protects hearts from ischemia/reperfusion through reinforcing mitophagy. Biomed Pharmacother 2019; 118:109220. [PMID: 31357081 DOI: 10.1016/j.biopha.2019.109220] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 07/06/2019] [Accepted: 07/10/2019] [Indexed: 11/20/2022] Open
Abstract
Triiodothyronine (T3), the biologically active form of thyroid hormone, was reported to protect myocardium from ischemia/reperfusion (I/R) injury when given before sustained ischemia, but its cardioprotective effects when given at the onset of reperfusion (postconditioning), a protocol with more clinical impact is unknown. Therefore, the present study was designed to determine whether T3 postconditioning (THPostC) is able to protect the heart from reperfusion injury and its underlying mechanisms. Isolated Sprague-Dawley rat hearts were subjected to 30 min ischemia/45 min reperfusion, triiodothyronine was delivered at the first 5 min of reperfusion. Our data shown that T3 from 1 to 10 μM during the first 5-min of reperfusion concentration-dependently improved post-ischemic myocardial function. A similar protection was observed in isolated rat cardiomyocytes characterized by the alleviation of I/R-induced loss of mitochondrial membrane potential and exacerbated cell death. Moreover, mitophagy (selectively recognize and remove damaged mitochondria) was significantly stimulated by myocardial I/R, which was enhanced with THPostC. Meanwhile, we found that THPostC stimulated PINK1/Parkin pathway, a critical regulator for mitophagy. Then, adenoviral knockdown of PINK1 and Parkin conformed its roles in the THPostC-mediated cardioprotection. Our results suggest that THPostC confers cardioprotection against I/R injury at least in part by reinforcing PINK1-dependent mitophagy. These findings reveal new roles and mechanisms of triiodothyronine in the cardioprotection against I/R injury.
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Liu D, Xu L, Zhang X, Shi C, Qiao S, Ma Z, Yuan J. Snapshot: Implications for mTOR in Aging-related Ischemia/Reperfusion Injury. Aging Dis 2019; 10:116-133. [PMID: 30705773 PMCID: PMC6345330 DOI: 10.14336/ad.2018.0501] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Accepted: 05/01/2018] [Indexed: 12/15/2022] Open
Abstract
Aging may aggravate the damage and dysfunction of different components of multiorgan and thus increasing multiorgan ischemia/reperfusion (IR) injury. IR injury occurs in many organs and tissues, which is a major cause of morbidity and mortality worldwide. The kinase mammalian target of rapamycin (mTOR), an atypical serine/threonine protein kinase, involves in the pathophysiological process of IR injury. In this review, we first briefly introduce the molecular features of mTOR, the association between mTOR and aging, and especially its role on autophagy. Special focus is placed on the roles of mTOR during ischemic and IR injury. We then clarify the association between mTOR and conditioning phenomena. Following this background, we expand our discussion to potential future directions of research in this area. Collectively, information reviewed herein will serve as a comprehensive reference for the actions of mTOR in IR injury and may be significant for the design of future research and increase the potential of mTOR as a therapeutic target.
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Affiliation(s)
- Dong Liu
- 1State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
| | - Liqun Xu
- 1State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.,2Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China.,3Cadet group 3, School of Basic Medical Sciences, The Fourth Military Medical University, Xi'an 710032, China.,4Laboratory Animal Center, The Fourth Military Medical University, Xi'an 710032, China
| | - Xiaoyan Zhang
- 2Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China.,3Cadet group 3, School of Basic Medical Sciences, The Fourth Military Medical University, Xi'an 710032, China
| | - Changhong Shi
- 4Laboratory Animal Center, The Fourth Military Medical University, Xi'an 710032, China
| | - Shubin Qiao
- 1State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
| | - Zhiqiang Ma
- 1State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.,2Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China
| | - Jiansong Yuan
- 1State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
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van der Weg K, Prinzen FW, Gorgels AP. Editor's Choice- Reperfusion cardiac arrhythmias and their relation to reperfusion-induced cell death. EUROPEAN HEART JOURNAL-ACUTE CARDIOVASCULAR CARE 2018; 8:142-152. [PMID: 30421619 DOI: 10.1177/2048872618812148] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Reperfusion does not only salvage ischaemic myocardium but can also cause additional cell death which is called lethal reperfusion injury. The time of reperfusion is often accompanied by ventricular arrhythmias, i.e. reperfusion arrhythmias. While both conditions are seen as separate processes, recent research has shown that reperfusion arrhythmias are related to larger infarct size. The pathophysiology of fatal reperfusion injury revolves around intracellular calcium overload and reactive oxidative species inducing apoptosis by opening of the mitochondrial protein transition pore. The pathophysiological basis for reperfusion arrhythmias is the same intracellular calcium overload as that causing fatal reperfusion injury. Therefore both conditions should not be seen as separate entities but as one and the same process resulting in two different visible effects. Reperfusion arrhythmias could therefore be seen as a potential marker for fatal reperfusion injury.
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Affiliation(s)
- Kirian van der Weg
- 1 Department of Cardiology, Maastricht University Medical Center, The Netherlands
| | - Frits W Prinzen
- 2 Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands
| | - Anton Pm Gorgels
- 1 Department of Cardiology, Maastricht University Medical Center, The Netherlands.,2 Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands
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Heusch G, Gersh BJ. The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. Eur Heart J 2018; 38:774-784. [PMID: 27354052 DOI: 10.1093/eurheartj/ehw224] [Citation(s) in RCA: 302] [Impact Index Per Article: 43.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 05/12/2016] [Indexed: 12/15/2022] Open
Abstract
The incidence of ST segment elevation myocardial infarction (STEMI) has decreased over the last two decades in developed countries, but mortality from STEMI despite widespread access to reperfusion therapy is still substantial as is the development of heart failure, particularly among an expanding older population. In developing countries, the incidence of STEMI is increasing and interventional reperfusion is often not available. We here review the pathophysiology of acute myocardial infarction and reperfusion, notably the temporal and spatial evolution of ischaemic and reperfusion injury, the different modes of cell death, and the resulting coronary microvascular dysfunction. We then go on to briefly characterize the cardioprotective phenomena of ischaemic preconditioning, ischaemic postconditioning, and remote ischaemic conditioning and their underlying signal transduction pathways. We discuss in detail the attempts to translate conditioning strategies and drug therapy into the clinical setting. Most attempts have failed so far to reduce infarct size and improve clinical outcomes in STEMI patients, and we discuss potential reasons for such failure. Currently, it appears that remote ischaemic conditioning and a few drugs (atrial natriuretic peptide, exenatide, metoprolol, and esmolol) reduce infarct size, but studies with clinical outcome as primary endpoint are still underway.
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Affiliation(s)
- Gerd Heusch
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Hufelandstr. 55, 45122 Essen, Germany
| | - Bernard J Gersh
- Division of Cardiovascular Diseases, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, MN, USA
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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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10
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Andrienko TN, Pasdois P, Pereira GC, Ovens MJ, Halestrap AP. The role of succinate and ROS in reperfusion injury - A critical appraisal. J Mol Cell Cardiol 2017; 110:1-14. [PMID: 28689004 PMCID: PMC5678286 DOI: 10.1016/j.yjmcc.2017.06.016] [Citation(s) in RCA: 110] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 06/14/2017] [Accepted: 06/30/2017] [Indexed: 12/20/2022]
Abstract
We critically assess the proposal that succinate-fuelled reverse electron flow (REF) drives mitochondrial matrix superoxide production from Complex I early in reperfusion, thus acting as a key mediator of ischemia/reperfusion (IR) injury. Real-time surface fluorescence measurements of NAD(P)H and flavoprotein redox state suggest that conditions are unfavourable for REF during early reperfusion. Furthermore, rapid loss of succinate accumulated during ischemia can be explained by its efflux rather than oxidation. Moreover, succinate accumulation during ischemia is not attenuated by ischemic preconditioning (IP) despite powerful cardioprotection. In addition, measurement of intracellular reactive oxygen species (ROS) during reperfusion using surface fluorescence and mitochondrial aconitase activity detected major increases in ROS only after mitochondrial permeability transition pore (mPTP) opening was first detected. We conclude that mPTP opening is probably triggered initially by factors other than ROS, including increased mitochondrial [Ca2+]. However, IP only attenuates [Ca2+] increases later in reperfusion, again after initial mPTP opening, implying that IP regulates mPTP opening through additional mechanisms. One such is mitochondria-bound hexokinase 2 (HK2) which dissociates from mitochondria during ischemia in control hearts but not those subject to IP. Indeed, there is a strong correlation between the extent of HK2 loss from mitochondria during ischemia and infarct size on subsequent reperfusion. Mechanisms linking HK2 dissociation to mPTP sensitisation remain to be fully established but several related processes have been implicated including VDAC1 oligomerisation, the stability of contact sites between the inner and outer membranes, cristae morphology, Bcl-2 family members and mitochondrial fission proteins such as Drp1.
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Affiliation(s)
- Tatyana N Andrienko
- School of Biochemistry and The Bristol Heart Institute, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, UK
| | - Philippe Pasdois
- School of Biochemistry and The Bristol Heart Institute, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, UK
| | - Gonçalo C Pereira
- School of Biochemistry and The Bristol Heart Institute, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, UK
| | - Matthew J Ovens
- School of Biochemistry and The Bristol Heart Institute, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, UK
| | - Andrew P Halestrap
- School of Biochemistry and The Bristol Heart Institute, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
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11
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Abstract
The atherosclerotic coronary vasculature is not only the culprit but also a victim of myocardial ischemia/reperfusion injury. Manifestations of such injury are increased vascular permeability and edema, endothelial dysfunction and impaired vasomotion, microembolization of atherothrombotic debris, stasis with intravascular cell aggregates, and finally, in its most severe form, capillary destruction with hemorrhage. In animal experiments, local and remote ischemic pre- and postconditioning not only reduce infarct size but also these manifestations of coronary vascular injury, as do drugs which recruit signal transduction steps of conditioning. Clinically, no-reflow is frequently seen after interventional reperfusion, and it carries an adverse prognosis. The translation of cardioprotective interventions to clinical practice has been difficult to date. Only 4 drugs (brain natriuretic peptide, exenatide, metoprolol, and esmolol) stand unchallenged to date in reducing infarct size in patients with reperfused acute myocardial infarction; unfortunately, for these drugs, no information on their impact on the ischemic/reperfused coronary circulation is available.
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Affiliation(s)
- Gerd Heusch
- From the Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, University of Essen, Essen, Germany.
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12
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Berbamine postconditioning protects the heart from ischemia/reperfusion injury through modulation of autophagy. Cell Death Dis 2017; 8:e2577. [PMID: 28151484 PMCID: PMC5386498 DOI: 10.1038/cddis.2017.7] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 12/17/2016] [Accepted: 12/27/2016] [Indexed: 12/22/2022]
Abstract
Pretreatment of berbamine protects the heart from ischemia/reperfusion (I/R) injury. However it is unknown whether it has cardioprotection when given at the onset of reperfusion (postconditioning (PoC)), a protocol with more clinical impact. Autophagy is upregulated in I/R myocardium and exacerbates cardiomyocyte death during reperfusion. However, it is unknown whether the autophagy during reperfusion is regulated by berbamine. Here we investigated whether berbamine PoC (BMPoC) protects the heart through regulation of autophagy by analyzing the effects of BMPoC on infarct size and/or cell death, functional recovery and autophagy in perfused rat hearts and isolated cardiomyocytes subjected to I/R. Berbamine from 10 to 100 nM given during the first 5 min of reperfusion concentration-dependently improved post-ischemic myocardial function and attenuated cell death. Similar protections were observed in cardiomyocytes subjected to simulated I/R. Meanwhile, BMPoC prevented I/R-induced impairment of autophagosome processing in cardiomyocytes, characterized by increased LC3-II level and GFP-LC3 puncta, and decreased p62 degradation. Besides, lysosomal inhibitor chloroquine did not induce additional increase of LC3-II and P62 abundance after I/R but it reversed the effects of BMPoC in those parameters in cardiomyocytes, suggesting that I/R-impaired autophagic flux is restored by BMPoC. Moreover, I/R injury was accompanied by enhanced expression of Beclin 1, which was significantly inhibited by BMPoC. In vitro and in vivo adenovirus-mediated knockdown of Beclin 1 in myocardium and cardiomyocytes restored I/R-impaired autophagosome processing, associated with an improvement of post-ischemic recovery of myocardial contractile function and a reduction of cell death, but it did not have additive effects to BMPoC. Conversely, overexpression of Beclin 1 abolished the cardioprotection of BMPoC as did by overexpression of an essential autophagy gene Atg5. Furthermore, BMPoC-mediated cardioprotection was abolished by a specific Akt1/2 inhibitor A6730. Our results demonstrate that BMPoC confers cardioprotection by modulating autophagy during reperfusion through the activation of PI3K/Akt signaling pathway.
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Elshaer SL, El-Remessy AB. Implication of the neurotrophin receptor p75 NTR in vascular diseases: beyond the eye. EXPERT REVIEW OF OPHTHALMOLOGY 2016; 12:149-158. [PMID: 28979360 DOI: 10.1080/17469899.2017.1269602] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
INTRODUCTION The p75 neurotrophin receptor (p75NTR) is a member of TNF-α receptor superfamily that bind all neurotrophins, mainly regulating their pro-apoptotic actions. Ischemia is a common pathology in different cardiovascular diseases affecting multiple organs, however the contribution of p75NTR remains not fully addressed. The aim of this work is to review the current evidence through published literature studying the impact of p75NTR receptor in ischemic vascular diseases. AREAS COVERED In the eye, several ischemic ocular diseases are associated with enhanced p75NTR expression. Ischemic retinopathy including diabetic retinopathy, retinopathy of prematurity and retinal vein occlusion are characterized initially by ischemia followed by excessive neovascularization. Beyond the eye, cerebral ischemia, myocardial infarction and critical limb ischemia are ischemic cardiovascular diseases that are characterized by altered expression of neurotrophins and p75NTR expression. We surveyed both clinical and experimental studies that examined the impact of p75NTR receptor in ischemic diseases of eye, heart, brain and peripheral limbs. EXPERT COMMENTARY p75NTR receptor is a major player in multiple ischemic vascular diseases affecting the eye, brain, heart and peripheral limbs with significant increases in its expression accompanying neuro-vascular injury. This has been addressed in the current review along with the beneficial vascular outcomes of p75NTR inhibition.
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Affiliation(s)
- Sally L Elshaer
- Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, USA.,Research Service, Charlie Norwood VA Medical Center, Augusta, GA
| | - Azza B El-Remessy
- Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, USA.,Research Service, Charlie Norwood VA Medical Center, Augusta, GA.,Augusta Biomedical Research Corporation, Augusta, GA, USA
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14
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Understanding pacing postconditioning-mediated cardiac protection: a role of oxidative stress and a synergistic effect of adenosine. J Physiol Biochem 2016; 73:175-185. [PMID: 27864790 DOI: 10.1007/s13105-016-0535-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 10/24/2016] [Indexed: 12/13/2022]
Abstract
We and others have demonstrated a protective role for pacing postconditioning (PPC) against ischemia/reperfusion (I/R) injury in the heart; however, the underlying mechanisms behind these protective effects are not completely understood. In this study, we wanted to further characterize PPC-mediated cardiac protection, specifically identify optimal pacing sites; examine the role of oxidative stress; and test the existence of a potential synergistic effect between PPC and adenosine. Isolated rat hearts were subjected to coronary occlusion followed by reperfusion. PPC involved three, 30 s, episodes of alternating left ventricular (LV) and right atrial (RA) pacing. Multiple pacing protocols with different pacing electrode locations were used. To test the involvement of oxidative stress, target-specific agonists or antagonists were infused at the beginning of reperfusion. Hemodynamic data were digitally recorded, and cardiac enzymes, oxidant, and antioxidant status were chemically measured. Pacing at the LV or RV but not at the heart apex or base significantly (P < 0.001) protected against ischemia-reperfusion injury. PPC-mediated protection was completely abrogated in the presence of reactive oxygen species (ROS) scavenger, ebselen; peroxynitrite (ONOO-) scavenger, uric acid; and nitric oxide synthase inhibitor, L-NAME. Nitric oxide (NO) donor, snap, however significantly (P < 0.05) protected the heart against I/R injury in the absence of PPC. The protective effects of PPC were significantly improved by adenosine. PPC-stimulated protection can be achieved by alternating LV and RA pacing applied at the beginning of reperfusion. NO, ROS, and the product of their interaction ONOO- play a significant role in PPC-induced cardiac protection. Finally, the protective effects of PPC can be synergized with adenosine.
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15
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Abstract
The mortality from acute myocardial infarction (AMI) remains significant, and the prevalence of post-myocardial infarction heart failure is increasing. Therefore, cardioprotection beyond timely reperfusion is needed. Conditioning procedures are the most powerful cardioprotective interventions in animal experiments. However, ischemic preconditioning cannot be used to reduce infarct size in patients with AMI because its occurrence is not predictable; several studies in patients undergoing surgical coronary revascularization report reduced release of creatine kinase and troponin. Ischemic postconditioning reduces infarct size in most, but not all, studies in patients undergoing interventional reperfusion of AMI, but may require direct stenting and exclusion of patients with >6 hours of symptom onset to protect. Remote ischemic conditioning reduces infarct size in patients undergoing interventional reperfusion of AMI, elective percutaneous or surgical coronary revascularization, and other cardiovascular surgery in many, but not in all, studies. Adequate dose-finding phase II studies do not exist. There are only 2 phase III trials, both on remote ischemic conditioning in patients undergoing cardiovascular surgery, both with neutral results in terms of infarct size and clinical outcome, but also both with major problems in trial design. We discuss the difficulties in translation of cardioprotection from animal experiments and proof-of-concept trials to clinical practice. Given that most studies on ischemic postconditioning and all studies on remote ischemic preconditioning in patients with AMI reported reduced infarct size, it would be premature to give up on cardioprotection.
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Affiliation(s)
- Gerd Heusch
- From the Institute for Pathophysiology (G.H.) and Clinic for Cardiology (T.R.), West German Heart and Vascular Center, University School of Medicine Essen, Essen, Germany
| | - Tienush Rassaf
- From the Institute for Pathophysiology (G.H.) and Clinic for Cardiology (T.R.), West German Heart and Vascular Center, University School of Medicine Essen, Essen, Germany
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The Role of Mitochondrial Reactive Oxygen Species in Cardiovascular Injury and Protective Strategies. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:8254942. [PMID: 27200148 PMCID: PMC4856919 DOI: 10.1155/2016/8254942] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Revised: 03/29/2016] [Accepted: 03/30/2016] [Indexed: 12/14/2022]
Abstract
Ischaemia/reperfusion (I/R) injury of the heart represents a major health burden mainly associated with acute coronary syndromes. While timely coronary reperfusion has become the established routine therapy in patients with ST-elevation myocardial infarction, the restoration of blood flow into the previously ischaemic area is always accompanied by myocardial injury. The central mechanism involved in this phenomenon is represented by the excessive generation of reactive oxygen species (ROS). Besides their harmful role when highly generated during early reperfusion, minimal ROS formation during ischaemia and/or at reperfusion is critical for the redox signaling of cardioprotection. In the past decades, mitochondria have emerged as the major source of ROS as well as a critical target for cardioprotective strategies at reperfusion. Mitochondria dysfunction associated with I/R myocardial injury is further described and ultimately analyzed with respect to its role as source of both deleterious and beneficial ROS. Furthermore, the contribution of ROS in the highly investigated field of conditioning strategies is analyzed. In the end, the vascular sources of mitochondria-derived ROS are briefly reviewed.
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Heusch G. Treatment of Myocardial Ischemia/Reperfusion Injury by Ischemic and Pharmacological Postconditioning. Compr Physiol 2016; 5:1123-45. [PMID: 26140711 DOI: 10.1002/cphy.c140075] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Timely reperfusion is the only way to salvage ischemic myocardium from impending infarction. However, reperfusion also adds a further component to myocardial injury such that the ultimate infarct size is the result of both ischemia- and reperfusion-induced injury. Modification of reperfusion can attenuate reperfusion injury and thus reduce infarct size. Ischemic postconditioning is a maneuver of repeated brief interruption of reperfusion by short-lasting coronary occlusions which results in reduced infarct size. Cardioprotection by ischemic postconditioning is mediated through delayed reversal of acidosis and the activation of a complex signal transduction cascade, including triggers such as adenosine, bradykinin, and opioids, mediators such as protein kinases and, notably, mitochondrial function as effector. Inhibition of the mitochondrial permeability transition pore appears to be a final signaling step of ischemic postconditioning. Several drugs which recruit in part such signaling steps of ischemic postconditioning can induce cardioprotection, even when the drug is only administered at reperfusion, that is, there is also pharmacological postconditioning. Ischemic and pharmacological postconditioning have been translated to patients with acute myocardial infarction in proof-of-concept studies, but further mechanistic insight is needed to optimize the conditions and algorithms of cardioprotection by postconditioning.
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Affiliation(s)
- Gerd Heusch
- Institut für Pathophysiologie, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany
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18
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19
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Ferrera R, Benhabbouche S, Da Silva CC, Alam MR, Ovize M. Delayed low pressure at reperfusion: A new approach for cardioprotection. J Thorac Cardiovasc Surg 2015; 150:1641-8.e2. [PMID: 26384749 DOI: 10.1016/j.jtcvs.2015.08.053] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 08/13/2015] [Accepted: 08/19/2015] [Indexed: 11/19/2022]
Abstract
OBJECTIVES The aims of this study were to evaluate whether the delayed application of low-pressure reperfusion could reduce lethal reperfusion injury and whether the inhibition of the opening of the mitochondrial permeability transition pore is involved in this protection. METHODS Isolated rat hearts (n = 120) underwent 40 minutes of global ischemia followed by 60 minutes of reperfusion. Hearts were randomly assigned to the following groups: control, postconditioning (comprising 2 episodes of 30 seconds of ischemia and 30 seconds of reperfusion), and low-pressure reperfusion (using a reduction of perfusion pressure at 70 cm H2O for 10 minutes). In additional groups, postconditioning and low-pressure reperfusion were applied after a delay of 3, 10, and 20 minutes after the initial 40-minute ischemic insult. RESULTS As expected, infarct size (triphenyltetrazolium chloride staining) and lactate dehydrogenase release were significantly reduced in low-pressure reperfusion and postconditioning versus controls (P < .01), whereas functional parameters (coronary flow, rate pressure product) were improved (P < .01). Although delaying postconditioning by more than 3 minutes resulted in a loss of protection, low-pressure reperfusion still significantly reduced infarct size when applied as late as 20 minutes after reperfusion. This delayed low-pressure reperfusion protection was associated with an improved mitochondrial respiration, lower reactive oxygen species production, and enhanced calcium retention capacity, related to inhibition of permeability transition pore opening. CONCLUSIONS We demonstrated for the first time that low-pressure reperfusion can reduce lethal myocardial reperfusion injury even when performed 10 to 20 minutes after the initiation of reperfusion.
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Affiliation(s)
| | | | | | | | - Michel Ovize
- Université Lyon 1, Lyon, France; IHU OPERA and Service d'Explorations Fonctionnelles Cardiovasculaires and CIC de Lyon, Groupement Hospitalier Est, Hospices Civils of Lyon, Lyon, France
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20
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Abstract
Reperfusion is mandatory to salvage ischemic myocardium from infarction, but reperfusion per se contributes to injury and ultimate infarct size. Therefore, cardioprotection beyond that by timely reperfusion is needed to reduce infarct size and improve the prognosis of patients with acute myocardial infarction. The conditioning phenomena provide such cardioprotection, insofar as brief episodes of coronary occlusion/reperfusion preceding (ischemic preconditioning) or following (ischemic postconditioning) sustained myocardial ischemia with reperfusion reduce infarct size. Even ischemia/reperfusion in organs remote from the heart provides cardioprotection (remote ischemic conditioning). The present review characterizes the signal transduction underlying the conditioning phenomena, including their physical and chemical triggers, intracellular signal transduction, and effector mechanisms, notably in the mitochondria. Cardioprotective signal transduction appears as a highly concerted spatiotemporal program. Although the translation of ischemic postconditioning and remote ischemic conditioning protocols to patients with acute myocardial infarction has been fairly successful, the pharmacological recruitment of cardioprotective signaling has been largely disappointing to date.
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Affiliation(s)
- Gerd Heusch
- From the Institute for Pathophysiology, West German Heart and Vascular Centre, University of Essen Medical School, Essen, Germany.
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21
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Ibáñez B, Heusch G, Ovize M, Van de Werf F. Evolving Therapies for Myocardial Ischemia/Reperfusion Injury. J Am Coll Cardiol 2015; 65:1454-71. [DOI: 10.1016/j.jacc.2015.02.032] [Citation(s) in RCA: 527] [Impact Index Per Article: 52.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 02/22/2015] [Indexed: 12/28/2022]
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22
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Jivraj N, Liew F, Marber M. Ischaemic postconditioning: cardiac protection after the event. Anaesthesia 2015; 70:598-612. [DOI: 10.1111/anae.12974] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/05/2014] [Indexed: 12/11/2022]
Affiliation(s)
- N. Jivraj
- School of Medicine and BHF Centre of Excellence; Cardiovascular Division; King's College London; London UK
| | - F. Liew
- School of Medicine; University College London; London UK
| | - M. Marber
- School of Medicine and BHF Centre of Excellence; Cardiovascular Division; King's College London; London UK
- NIHR Biomedical Research Centre; Guy's and St Thomas' NHS Foundation Trust; London UK
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23
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Kleinbongard P, Heusch G. Extracellular signalling molecules in the ischaemic/reperfused heart - druggable and translatable for cardioprotection? Br J Pharmacol 2014; 172:2010-25. [PMID: 25204973 DOI: 10.1111/bph.12902] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 08/21/2014] [Accepted: 08/29/2014] [Indexed: 12/28/2022] Open
Abstract
In patients with acute myocardial infarction, timely reperfusion is essential to limit infarct size. However, reperfusion also adds to myocardial injury. Brief episodes of ischaemia/reperfusion in the myocardium or on organ remote from the heart, before or shortly after sustained myocardial ischaemia effectively reduce infarct size, provided there is eventual reperfusion. Such conditioning phenomena have been established in many experimental studies and also translated to humans. The underlying signal transduction, that is the molecular identity of triggers, mediators and effectors, is not clear yet in detail, but several extracellular signalling molecules, such as adenosine, bradykinin and opioids, have been identified to contribute to cardioprotection by conditioning manoeuvres. Several trials have attempted the translation of cardioprotection by such autacoids into a clinical scenario of myocardial ischaemia and reperfusion. Adenosine and its selective agonists reduced infarct size in a few studies, but this benefit was not translated into improved clinical outcome. All studies with bradykinin or drugs which increase bradykinin's bioavailability reported reduced infarct size and some of them also improved clinical outcome. Synthetic opioid agonists did not result in a robust infarct size reduction, but this failure of translation may relate to the cardioprotective properties of the underlying anaesthesia per se or of the comparator drugs. The translation of findings in healthy, young animals with acute coronary occlusion/reperfusion to patients of older age, with a variety of co-morbidities and co-medications, suffering from different scenarios of myocardial ischaemia/reperfusion remains a challenge.
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Affiliation(s)
- P Kleinbongard
- Institute for Pathophysiology, West German Heart and Vascular Center, University School of Medicine Essen, Essen, Germany
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24
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Ostadal B, Ostadal P. Sex-based differences in cardiac ischaemic injury and protection: therapeutic implications. Br J Pharmacol 2014; 171:541-54. [PMID: 23750471 DOI: 10.1111/bph.12270] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Revised: 05/21/2013] [Accepted: 05/30/2013] [Indexed: 12/22/2022] Open
Abstract
Ischaemic heart disease (IHD) is the most frequent cause of mortality among men and women. Many epidemiological studies have demonstrated that premenopausal women have a reduced risk for IHD compared with their male counterparts. The incidence of IHD in women increases after menopause, suggesting that IHD is related to declining oestrogen levels. Experimental observations have confirmed the results of epidemiological studies investigating sex-specific differences in cardiac tolerance to ischaemia. Female sex appears also to favourably influence cardiac remodelling after ischaemia/reperfusion injury. Furthermore, sex-related differences in ischaemic tolerance of the adult myocardium can be influenced by interventions during the early phases of ontogenetic development. Detailed mechanisms of these sex-related differences remain unknown; however, they involve the genomic and non-genomic effects of sex steroid hormones, particularly the oestrogens, which have been the most extensively studied. Although the protective effects of oestrogen have many potential therapeutic implications, clinical trials have shown that oestrogen replacement in postmenopausal women may actually increase the incidence of IHD. The results of these trials have illustrated the complexity underlying the mechanisms involved in sex-related differences in cardiac tolerance to ischaemia. Sex-related differences in cardiac sensitivity to ischaemia/reperfusion injury may also influence therapeutic strategies in women with acute coronary syndrome. Women undergo coronary intervention less frequently and a lower proportion of women receive evidence-based therapy compared with men. Although our understanding of this important topic has increased in recent years, there is an urgent need for intensive experimental and clinical research to develop female-specific therapeutic strategies. Only then we will be able to offer patients better evidence-based treatment, a better quality of life and lower mortality.
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Affiliation(s)
- B Ostadal
- Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
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25
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Ferdinandy P, Hausenloy DJ, Heusch G, Baxter GF, Schulz R. Interaction of risk factors, comorbidities, and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev 2014; 66:1142-74. [PMID: 25261534 DOI: 10.1124/pr.113.008300] [Citation(s) in RCA: 461] [Impact Index Per Article: 41.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Pre-, post-, and remote conditioning of the myocardium are well described adaptive responses that markedly enhance the ability of the heart to withstand a prolonged ischemia/reperfusion insult and provide therapeutic paradigms for cardioprotection. Nevertheless, more than 25 years after the discovery of ischemic preconditioning, we still do not have established cardioprotective drugs on the market. Most experimental studies on cardioprotection are still undertaken in animal models, in which ischemia/reperfusion is imposed in the absence of cardiovascular risk factors. However, ischemic heart disease in humans is a complex disorder caused by, or associated with, cardiovascular risk factors and comorbidities, including hypertension, hyperlipidemia, diabetes, insulin resistance, heart failure, altered coronary circulation, and aging. These risk factors induce fundamental alterations in cellular signaling cascades that affect the development of ischemia/reperfusion injury per se and responses to cardioprotective interventions. Moreover, some of the medications used to treat these risk factors, including statins, nitrates, and antidiabetic drugs, may impact cardioprotection by modifying cellular signaling. The aim of this article is to review the recent evidence that cardiovascular risk factors and their medication may modify the response to cardioprotective interventions. We emphasize the critical need to take into account the presence of cardiovascular risk factors and concomitant medications when designing preclinical studies for the identification and validation of cardioprotective drug targets and clinical studies. This will hopefully maximize the success rate of developing rational approaches to effective cardioprotective therapies for the majority of patients with multiple risk factors.
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Affiliation(s)
- Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged and Pharmahungary Group, Szeged, Hungary (P.F.); The Hatter Cardiovascular Institute, University College London, London, United Kingdom (D.J.H.); Institute for Pathophysiology, University of Essen Medical School, Essen, Germany (G.H.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom (G.F.B.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
| | - Derek J Hausenloy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged and Pharmahungary Group, Szeged, Hungary (P.F.); The Hatter Cardiovascular Institute, University College London, London, United Kingdom (D.J.H.); Institute for Pathophysiology, University of Essen Medical School, Essen, Germany (G.H.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom (G.F.B.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
| | - Gerd Heusch
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged and Pharmahungary Group, Szeged, Hungary (P.F.); The Hatter Cardiovascular Institute, University College London, London, United Kingdom (D.J.H.); Institute for Pathophysiology, University of Essen Medical School, Essen, Germany (G.H.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom (G.F.B.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
| | - Gary F Baxter
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged and Pharmahungary Group, Szeged, Hungary (P.F.); The Hatter Cardiovascular Institute, University College London, London, United Kingdom (D.J.H.); Institute for Pathophysiology, University of Essen Medical School, Essen, Germany (G.H.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom (G.F.B.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
| | - Rainer Schulz
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged and Pharmahungary Group, Szeged, Hungary (P.F.); The Hatter Cardiovascular Institute, University College London, London, United Kingdom (D.J.H.); Institute for Pathophysiology, University of Essen Medical School, Essen, Germany (G.H.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom (G.F.B.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
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Adjuvant cardioprotection in cardiac surgery: update. BIOMED RESEARCH INTERNATIONAL 2014; 2014:808096. [PMID: 25215293 PMCID: PMC4151827 DOI: 10.1155/2014/808096] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 07/16/2014] [Indexed: 01/14/2023]
Abstract
Cardiac surgery patients are now more risky in terms of age, comorbidities, and the need for complex procedures. It brings about reperfusion injury, which leads to dysfunction and/or loss of part of the myocardium. These groups of patients have a higher incidence of postoperative complications and mortality. One way of augmenting intraoperative myocardial protection is the phenomenon of myocardial conditioning, elicited with brief nonlethal episodes of ischaemia-reperfusion. In addition, drugs are being tested that mimic ischaemic conditioning. Such cardioprotective techniques are mainly focused on reperfusion injury, a complex response of the organism to the restoration of coronary blood flow in ischaemic tissue, which can lead to cell death. Extensive research over the last three decades has revealed the basic mechanisms of reperfusion injury and myocardial conditioning, suggesting its therapeutic potential. But despite the enormous efforts that have been expended in preclinical studies, almost all cardioprotective therapies have failed in the third phase of clinical trials. One reason is that evolutionary young cellular mechanisms of protection against oxygen handling are not very robust. Ischaemic conditioning, which is among these, is also limited by this. At present, the prevailing belief is that such options of treatment exist, but their full employment will not occur until subquestions and methodological issues with the transfer into clinical practice have been resolved.
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Khalili H, Patel VG, Mayo HG, de Lemos JA, Brilakis ES, Banerjee S, Bavry AA, Bhatt DL, Kumbhani DJ. Surrogate and clinical outcomes following ischemic postconditioning during primary percutaneous coronary intervention of ST--segment elevation myocardial infarction: a meta-analysis of 15 randomized trials. Catheter Cardiovasc Interv 2014; 84:978-86. [PMID: 24948465 DOI: 10.1002/ccd.25581] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Revised: 06/05/2014] [Accepted: 06/14/2014] [Indexed: 12/23/2022]
Abstract
OBJECTIVES To conduct a meta-analysis on surrogate and clinical outcomes with myocardial ischemic postconditioning (IPoC) following revascularization with primary percutaneous intervention (PPCI) for ST-segment myocardial infarction (STEMI) compared with PPCI alone. BACKGROUND Reperfusion injury remains an important problem following PPCI for STEMI. Trials of IPoC have mainly focused on cardiac biomarkers; the impact on clinical outcomes is unknown. METHODS Clinical trials that randomized STEMI patients to IPoC as compared with conventional PPCI were included for analysis. RESULTS A total of 15 randomized trials with 1,545 patients met our selection criteria (785 underwent IPoC + PPCI, 760 PPCI alone). Mean follow-up for clinical outcomes was 4.7 months. The mean ischemic time was 225 min. ST-segment resolution (Relative Risk [RR] = 0.98; 95% Confidence Intervals [CI] 0.85-1.13; P = 0.75) and infarct size (Weighted mean difference [WMD] = -2.53%, 95% CI -6.10 to 1.05; P = 0.17) were similar between the IPoC + PPCI vs. PPCI arms. Left ventricular ejection fraction at follow-up was marginally higher in the IPoC (WMD = 4.15%, 95% CI 0.19-8.12%, P = 0.04). No differences were noted in any of the clinical outcomes studied, including mortality (RR = 1.52; 95% CI 0.77-2.99; P = 0.23), recurrent MI (RR = 3.04; 95% CI 0.74-12.54; P = 0.12); stent thrombosis (RR = 1.24, 95% CI 0.51-3.04; P = 0.83) or the composite MACE outcome (RR = 1.53; 95% CI 0.89-2.63; P = 0.13). CONCLUSIONS IPoC following PPCI is not associated with improvements in surrogate or clinical outcomes at 5 months as compared with PPCI alone. Our findings indicate no role for IPoC in the routine management of patients with STEMI.
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Affiliation(s)
- Houman Khalili
- Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, Texas
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Schmidt MR, Pryds K, Bøtker HE. Novel adjunctive treatments of myocardial infarction. World J Cardiol 2014; 6:434-443. [PMID: 24976915 PMCID: PMC4072833 DOI: 10.4330/wjc.v6.i6.434] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Revised: 01/23/2014] [Accepted: 04/17/2014] [Indexed: 02/06/2023] Open
Abstract
Myocardial infarction is a major cause of death and disability worldwide and myocardial infarct size is a major determinant of prognosis. Early and successful restoration of myocardial reperfusion following an ischemic event is the most effective strategy to reduce final infarct size and improve clinical outcome, but reperfusion may induce further myocardial damage itself. Development of adjunctive therapies to limit myocardial reperfusion injury beyond opening of the coronary artery gains increasing attention. A vast number of experimental studies have shown cardioprotective effects of ischemic and pharmacological conditioning, but despite decades of research, the translation into clinical effects has been challenging. Recently published clinical studies, however, prompt optimism as novel techniques allow for improved clinical applicability. Cyclosporine A, the GLP-1 analogue exenatide and rapid cooling by endovascular infusion of cold saline all reduce infarct size and may confer clinical benefit for patients admitted with acute myocardial infarcts. Equally promising, three follow-up studies of the effect of remote ischemic conditioning (RIC) show clinical prognostic benefit in patients undergoing coronary surgery and percutaneous coronary intervention. The discovery that RIC can be performed noninvasively using a blood pressure cuff on the upper arm to induce brief episodes of limb ischemia and reperfusion has facilitated the translation of RIC into the clinical arena. This review focus on novel advances in adjunctive therapies in relation to acute and elective coronary procedures.
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Brooks MJ, Andrews DT. Molecular mechanisms of ischemic conditioning: translation into patient outcomes. Future Cardiol 2014; 9:549-68. [PMID: 23834695 DOI: 10.2217/fca.13.30] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Following the initiation of an ischemic insult, reperfusion injury (RI) can result in numerous deleterious cardiac effects, including cardiomyocyte death. Experimental data have suggested that ischemic conditioning, when delivered either before or after the ischemic event, can provide considerable cardioprotection against RI. Ischemic conditioning involves delivering brief repetitive cycles of ischemia to the myocardium (local) or to another distal organ or structure (remote). This review will discuss recent advances in the molecular mechanisms involved in RI, the signaling pathways recruited by ischemic conditioning and conclude with an appraisal of the evidence for the use of ischemic conditioning in current clinical practice.
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Affiliation(s)
- Matthew J Brooks
- Department of Cardiology, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia
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Roubille F, Mewton N, Elbaz M, Roth O, Prunier F, Cung TT, Piot C, Roncalli J, Rioufol G, Bonnefoy-Cudraz E, Wiedemann JY, Furber A, Jacquemin L, Willoteaux S, Abi-Khallil W, Sanchez I, Finet G, Sibellas F, Ranc S, Boussaha I, Croisille P, Ovize M. No post-conditioning in the human heart with thrombolysis in myocardial infarction flow 2-3 on admission. Eur Heart J 2014; 35:1675-82. [DOI: 10.1093/eurheartj/ehu054] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
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Abstract
Myocardial conditioning is an endogenous cardioprotective phenomenon that profoundly limits infarct size in experimental models. The current challenge is to translate this paradigm from the laboratory to the clinic. Accordingly, our goal in this review is to provide a critical summary of the progress toward, opportunities for, and caveats to, the successful clinical translation of postconditioning and remote conditioning, the 2 conditioning strategies considered to have the broadest applicability for real-world patient care. In the majority of phase II studies published to date, postconditioning evoked a ≈35% reduction of infarct size in ST-segment-elevation myocardial infarction patients. Essential criteria for the successful implementation of postconditioning include the appropriate choice of patients (ie, those with large risk regions and negligible collateral flow), timely application of the postconditioning stimulus (immediately on reperfusion), together with proper choice of end points (infarct size, with concomitant assessment of risk region). Remote conditioning has been applied in planned ischemic events (including cardiac surgery and elective percutaneous coronary intervention) and in ST-segment-elevation myocardial infarction patients during hospital transport. Controversies with regard to efficacy have emerged, particularly among surgical trials. These disparate outcomes in all likelihood reflect the remarkable heterogeneity within and among studies, together with a deficit in our understanding of the impact of these variations on the infarct-sparing effect of remote conditioning. Ongoing phase III trials will provide critical insight into the future role of postconditioning and remote conditioning as clinically relevant cardioprotective strategies.
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Affiliation(s)
- Michel Ovize
- Centre d'Investigation Clinique de Lyon, Service d’Explorations Fonctionnelles Cardiovasculaires, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
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Sadat U, Walsh SR, Varty K. Cardioprotection by ischemic postconditioning during surgical procedures. Expert Rev Cardiovasc Ther 2014; 6:999-1006. [DOI: 10.1586/14779072.6.7.999] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Baars T, Skyschally A, Klein-Hitpass L, Cario E, Erbel R, Heusch G, Kleinbongard P. microRNA expression and its potential role in cardioprotection by ischemic postconditioning in pigs. Pflugers Arch 2014; 466:1953-61. [DOI: 10.1007/s00424-013-1429-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 12/19/2013] [Indexed: 12/22/2022]
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Gedik N, Heusch G, Skyschally A. Infarct size reduction by cyclosporine A at reperfusion involves inhibition of the mitochondrial permeability transition pore but does not improve mitochondrial respiration. Arch Med Sci 2013; 9:968-75. [PMID: 24482638 PMCID: PMC3902704 DOI: 10.5114/aoms.2013.38175] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Revised: 07/29/2013] [Accepted: 09/02/2013] [Indexed: 12/31/2022] Open
Abstract
INTRODUCTION Ischemic postconditioning (PoCo) and cyclosporine A (CysA) given prior to reperfusion reduce myocardial infarct size after ischemia/reperfusion. Ischemic postconditioning's protection is characterized by better preservation of mitochondrial respiration and calcium retention capacity. Protection by CysA is not entirely clear. Cyclosporine A inhibits not only mitochondrial permeability transition pore (mPTP) opening but also the phosphatase calcineurin. We have investigated whether CysA mediates protection not only by mPTP inhibition but also through a more upstream inhibition of calcineurin with subsequently better preserved mitochondrial respiration. MATERIAL AND METHODS Anesthetized pigs were subjected to 90 min ischemia and 10 min reperfusion initiated with either PoCo (6 × 20 s reperfusion/re-occlusion; n = 9), CysA infusion (5 mg/kg i.v.; 5 min before reperfusion; n = 4), or immediate full reperfusion (IFR; n = 8). Mitochondria were isolated from myocardial tissue for measurement of respiration and calcium retention capacity. RESULTS In mitochondria from ischemic/reperfused myocardium, ADP-stimulated complex I respiration was similar between CysA (116 ±11 nmol O2/min/mg protein) and IFR (117 ±8), but better preserved with PoCo (160 ±9; p < 0.05). Calcium retention capacity was greater with both PoCo and CysA (1096 ±45 and 1287 ±128 nmol Ca(2+)/mg protein) than with IFR (756 ±103; p < 0.05). CONCLUSIONS Cyclosporine A's protection is not associated with improved mitochondrial respiration. Protection is unlikely related to an upstream calcineurin inhibition, but is indeed secondary to mPTP inhibition.
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Affiliation(s)
- Nilguen Gedik
- Institut für Pathophysiologie, Universitätsklinikum Essen, Essen, Germany
| | - Gerd Heusch
- Institut für Pathophysiologie, Universitätsklinikum Essen, Essen, Germany
| | - Andreas Skyschally
- Institut für Pathophysiologie, Universitätsklinikum Essen, Essen, Germany
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Brown DA, Sabbah HN, Shaikh SR. Mitochondrial inner membrane lipids and proteins as targets for decreasing cardiac ischemia/reperfusion injury. Pharmacol Ther 2013; 140:258-66. [DOI: 10.1016/j.pharmthera.2013.07.005] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Accepted: 07/09/2013] [Indexed: 01/06/2023]
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36
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Myocardial infarction and coronary microvascular obstruction: an intimate, but complicated relationship. Basic Res Cardiol 2013; 108:380. [DOI: 10.1007/s00395-013-0380-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Mewton N, Thibault H, Roubille F, Lairez O, Rioufol G, Sportouch C, Sanchez I, Bergerot C, Cung TT, Finet G, Angoulvant D, Revel D, Bonnefoy-Cudraz E, Elbaz M, Piot C, Sahraoui I, Croisille P, Ovize M. Postconditioning attenuates no-reflow in STEMI patients. Basic Res Cardiol 2013; 108:383. [DOI: 10.1007/s00395-013-0383-8] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 08/23/2013] [Accepted: 08/26/2013] [Indexed: 02/06/2023]
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Affiliation(s)
- Alex Schevchuck
- From the Division of Cardiology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM
| | - Warren K. Laskey
- From the Division of Cardiology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM
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Diazoxide postconditioning induces mitochondrial protein S-Nitrosylation and a redox-sensitive mitochondrial phosphorylation/translocation of RISK elements: no role for SAFE. Basic Res Cardiol 2013; 108:371. [DOI: 10.1007/s00395-013-0371-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Revised: 06/28/2013] [Accepted: 07/05/2013] [Indexed: 02/07/2023]
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Simkhovich BZ, Przyklenk K, Kloner RA. Role of Protein Kinase C in Ischemic “Conditioning”. J Cardiovasc Pharmacol Ther 2013; 18:525-32. [DOI: 10.1177/1074248413494814] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Since the discovery of ischemic preconditioning (IPC) 26 years ago, numerous studies attempted to determine the mechanism of this powerful form of cardioprotection. One of the first proposed pathways of IPC suggested that the preconditioning stimulus activated phospholipase C via G-protein, and diacylglycerol released from phospholipid moieties activated protein kinase C (PKC) by translocating it from the cytosol to the sarcolemmal membranes. The major protective isoform of PKC was found to be the PKC-∊. Despite some contradictions and controversies, today even the most skeptical opponents acknowledge that PKC plays a significant role in the mechanism of IPC. During recent years, both the role and the place of PKC-∊ in the mechanism of IPC have been revised. The current review presents the evolution of the “PKC theory” and summarizes the most recent data regarding the role of PKC in IPC. In addition to classical IPC, PKC appears to play a role in the mechanisms of newer conditioning protocols, that is, remote IPC and ischemic postconditioning.
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Affiliation(s)
- Boris Z. Simkhovich
- Heart Institute, Good Samaritan Hospital, Los Angeles, CA, USA
- Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Karin Przyklenk
- Department of Physiology, Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI, USA
- Department of Emergency Medicine, Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI, USA
| | - Robert A. Kloner
- Heart Institute, Good Samaritan Hospital, Los Angeles, CA, USA
- Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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Fröhlich GM, Meier P, White SK, Yellon DM, Hausenloy DJ. Myocardial reperfusion injury: looking beyond primary PCI. Eur Heart J 2013; 34:1714-22. [PMID: 23536610 DOI: 10.1093/eurheartj/eht090] [Citation(s) in RCA: 304] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Coronary heart disease (CHD) is the leading cause of death and disability in Europe. For patients presenting with an acute ST-segment elevation myocardial infarction (STEMI), timely myocardial reperfusion using either thrombolytic therapy or primary percutaneous coronary intervention (PPCI) is the most effective therapy for limiting myocardial infarct (MI) size, preserving left-ventricular systolic function and reducing the onset of heart failure. Despite this, the morbidity and mortality of STEMI patients remain significant, and novel therapeutic interventions are required to improve clinical outcomes in this patient group. Paradoxically, the process of myocardial reperfusion can itself induce cardiomyocyte death-a phenomenon which has been termed 'myocardial reperfusion injury' (RI), the irreversible consequences of which include microvascular obstruction and myocardial infarction. Unfortunately, there is currently no effective therapy for preventing myocardial RI in STEMI patients making it an important residual target for cardioprotection. Previous attempts to translate cardioprotective therapies (antioxidants, calcium-channel blockers, and anti-inflammatory agents) for reducing RI into the clinic, have been unsuccessful. An improved understanding of the pathophysiological mechanisms underlying RI has resulted in the identification of several promising mechanical (ischaemic post-conditioning, remote ischaemic pre-conditioning, therapeutic hypothermia, and hyperoxaemia), and pharmacological (atrial natriuretic peptide, cyclosporin-A, and exenatide) therapeutic strategies, for preventing myocardial RI, many of which have shown promise in initial proof-of-principle clinical studies. In this article, we review the pathophysiology underlying myocardial RI, and highlight the potential therapeutic interventions which may be used in the future to prevent RI and improve clinical outcomes in patients with CHD.
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Affiliation(s)
- Georg M Fröhlich
- The Heart Hospital, University College London Hospitals, 16-18 Westmoreland Street, W1G 8PH, London, UK
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Penna C, Perrelli MG, Pagliaro P. Mitochondrial pathways, permeability transition pore, and redox signaling in cardioprotection: therapeutic implications. Antioxid Redox Signal 2013; 18:556-99. [PMID: 22668069 DOI: 10.1089/ars.2011.4459] [Citation(s) in RCA: 125] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Reperfusion therapy is the indispensable treatment of acute myocardial infarction (AMI) and must be applied as soon as possible to attenuate the ischemic insult. However, reperfusion is responsible for additional myocardial damage likely involving opening of the mitochondrial permeability transition pore (mPTP). A great part of reperfusion injury occurs during the first minute of reperfusion. The prolonged opening of mPTP is considered one of the endpoints of the cascade to myocardial damage, causing loss of cardiomyocyte function and viability. Opening of mPTP and the consequent oxidative stress due to reactive oxygen and nitrogen species (ROS/RNS) are considered among the major mechanisms of mitochondrial and myocardial dysfunction. Kinases and mitochondrial components constitute an intricate network of signaling molecules and mitochondrial proteins, which interact in response to stressors. Cardioprotective pathways are activated by stimuli such as preconditioning and postconditioning (PostC), obtained with brief intermittent ischemia or with pharmacological agents, which drastically reduce the lethal ischemia/reperfusion injury. The protective pathways converging on mitochondria may preserve their function. Protection involves kinases, adenosine triphosphate-dependent potassium channels, ROS signaling, and the mPTP modulation. Some clinical studies using ischemic PostC during angioplasty support its protective effects, and an interesting alternative is pharmacological PostC. In fact, the mPTP desensitizer, cyclosporine A, has been shown to induce appreciable protections in AMI patients. Several factors and comorbidities that might interfere with cardioprotective signaling are considered. Hence, treatments adapted to the characteristics of the patient (i.e., phenotype oriented) might be feasible in the future.
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Affiliation(s)
- Claudia Penna
- Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy
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Skyschally A, Walter B, Schultz Hansen R, Heusch G. The antiarrhythmic dipeptide ZP1609 (danegaptide) when given at reperfusion reduces myocardial infarct size in pigs. Naunyn Schmiedebergs Arch Pharmacol 2013; 386:383-91. [PMID: 23397587 DOI: 10.1007/s00210-013-0840-9] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Accepted: 01/28/2013] [Indexed: 12/12/2022]
Abstract
Connexin 43 is located in the cardiomyocyte sarcolemma and in the mitochondrial membrane. Sarcolemmal connexin 43 contributes to the spread of myocardial ischemia/reperfusion injury, whereas mitochondrial connexin 43 contributes to cardioprotection. We have now investigated the antiarrhythmic dipeptide ZP1609 (danegaptide), which is an analog of the connexin 43 targeting antiarrhythmic peptide rotigaptide (ZP123), in an established and clinically relevant experimental model of ischemia/reperfusion in pigs. Pigs were subjected to 60 min coronary occlusion and 3 h reperfusion. ZP1609 (n = 10) was given 10 min prior to reperfusion (75 μg/kg b.w. bolus i.v. + 57 μg/kg/min i.v. infusion for 3 h). Immediate full reperfusion (IFR, n = 9) served as control. Ischemic postconditioning (PoCo, n = 9; 1 min LAD reocclusion after 1 min reperfusion; four repetitions) was used as a positive control of cardioprotection. Infarct size (TTC) was determined as the end point of cardioprotection. Systemic hemodynamics and regional myocardial blood flow during ischemia were not different between groups. PoCo and ZP1609 reduced infarct size vs. IFR (IFR, 46 ± 4 % of area at risk; mean ± SEM; PoCo, 31 ± 4 %; ZP1609, 25 ± 5 %; both p < 0.05 vs. IFR; ANOVA). There were only few arrhythmias during reperfusion such that no antiarrhythmic action of ZP1609 was observed. ZP1609 when given before reperfusion reduces infarct size to a similar extent as ischemic postconditioning. Further studies are necessary to define the mechanism/action of ZP1609 on connexin 43 in cardiomyocytes.
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Affiliation(s)
- Andreas Skyschally
- Institut für Pathophysiologie, Universitätsklinikum Essen, Hufelandstr. 55, 45122 Essen, Germany
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Tian YS, Rong TZ, Hong YL, Min L, Jian PG. Pharmacological postconditioning with diazoxide attenuates ischemia/reperfusion-induced injury in rat liver. Exp Ther Med 2013; 5:1169-1173. [PMID: 23596486 PMCID: PMC3627466 DOI: 10.3892/etm.2013.941] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Accepted: 10/11/2012] [Indexed: 11/25/2022] Open
Abstract
It has been demonstrated that ischemic postconditioning (IPO) is capable of attenuating ischemia/reperfusion (I/R) injury in the heart. However, the novel role of pharmacological postconditioning in the liver remains unclear. In this study, the hypothesis that diazoxide postconditioning reduces I/R-induced injury in rat liver was tested. Rats were assigned randomly to the sham-operated control, I/R (occlusion of the porta hepatis for 60 min, followed by a persistent reperfusion for 120 min), diazoxide ischemic postconditioning (DIPO; occlusion of the porta hepatis for 60 min, then treatment with diazoxide for 10 min reperfusion, followed by a persistent reperfusion for 110 min) or 5-hydroxydecanoate (5-HD)+DIPO (occlusion of the porta hepatis for 60 min, then treatment with diazoxide and 5-HD for 10 min reperfusion, followed by a persistent reperfusion for 110 min) groups. The alanine aminotransferase (ALT) and aspartate transaminase (AST) levels were assayed. The expression levels of protein kinase c-ε (pkc-ε), cytochrome c (cyt-c), caspase-3 and bcl-2 protein were determined by western blotting. The serum levels of ALT and AST and expression levels of cyt-c and caspase-3 were significantly lower in the DIPO group (P<0.05). However, the protein expression levels of pkc-ε and bcl-2 were markedly increased in the DIPO group (P<0.05). 5-HD abrogated the protective effects of DIPO. The data of the present study provide the first evidence that DIPO protects the liver from I/R injury by opening the mitochondrial KATP channels, activating and upregulating pkc-ε and inhibiting the activation of the apoptotic pathway by decreasing the release of cyt-c and the expression of caspase-3 and increasing bcl-2 expression.
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Affiliation(s)
- Y S Tian
- Chongqing Key Laboratory of Hepatobiliary Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China
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Hausenloy DJ, Erik Bøtker H, Condorelli G, Ferdinandy P, Garcia-Dorado D, Heusch G, Lecour S, van Laake LW, Madonna R, Ruiz-Meana M, Schulz R, Sluijter JPG, Yellon DM, Ovize M. Translating cardioprotection for patient benefit: position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res 2013; 98:7-27. [PMID: 23334258 DOI: 10.1093/cvr/cvt004] [Citation(s) in RCA: 183] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Coronary heart disease (CHD) is the leading cause of death and disability worldwide. Despite current therapy, the morbidity and mortality for patients with CHD remains significant. The most important manifestations of CHD arise from acute myocardial ischaemia-reperfusion injury (IRI) in terms of cardiomyocyte death and its long-term consequences. As such, new therapeutic interventions are required to protect the heart against the detrimental effects of acute IRI and improve clinical outcomes. Although a large number of cardioprotective therapies discovered in pre-clinical studies have been investigated in CHD patients, few have been translated into the clinical setting, and a significant number of these have failed to show any benefit in terms of reduced myocardial infarction and improved clinical outcomes. Because of this, there is currently no effective therapy for protecting the heart against the detrimental effects of acute IRI in patients with CHD. One major factor for this lack of success in translating cardioprotective therapies into the clinical setting can be attributed to problems with the clinical study design. Many of these clinical studies have not taken into consideration the important data provided from previously published pre-clinical and clinical studies. The overall aim of this ESC Working Group Cellular Biology of the Heart Position Paper is to provide recommendations for optimizing the design of clinical cardioprotection studies, which should hopefully result in new and effective therapeutic interventions for the future benefit of CHD patients.
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Affiliation(s)
- Derek J Hausenloy
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK.
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Abstract
Myocardial infarct size is a major determinant of prognosis. Ischaemic preconditioning with brief coronary occlusion and reperfusion before a sustained period of coronary occlusion with reperfusion delays infarct development. Ischaemic postconditioning uses repetitive brief coronary occlusion during early reperfusion of myocardial infarction and reduces infarct size. Remote ischaemic preconditioning uses brief ischaemia and reperfusion of a distant organ to protect the myocardium. These conditioning protocols recruit a complex signal cascade of sarcolemmal receptor activation, intracellular enzyme activation, and ultimately mitochondrial stabilisation and inhibition of death signalling. Conditioning protocols have been successfully used in patients undergoing elective coronary revascularisation and reperfusion after acute myocardial infarction. Pharmacological recruitment of cardioprotective signalling has also been used to reduce infarct size, but so far without prognostic benefit. Outcomes of cardioprotection are affected by age, sex, comorbidities, and drugs, but also by technical issues related to determination of infarct size and revascularisation procedure.
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Affiliation(s)
- Gerd Heusch
- Institut für Pathophysiologie, Universitätsklinikum Essen, Essen, Germany.
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Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest 2013; 123:92-100. [PMID: 23281415 DOI: 10.1172/jci62874] [Citation(s) in RCA: 1659] [Impact Index Per Article: 138.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Acute myocardial infarction (MI) is a major cause of death and disability worldwide. In patients with MI, the treatment of choice for reducing acute myocardial ischemic injury and limiting MI size is timely and effective myocardial reperfusion using either thombolytic therapy or primary percutaneous coronary intervention (PPCI). However, the process of reperfusion can itself induce cardiomyocyte death, known as myocardial reperfusion injury, for which there is still no effective therapy. A number of new therapeutic strategies currently under investigation for preventing myocardial reperfusion injury have the potential to improve clinical outcomes in patients with acute MI treated with PPCI.
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Affiliation(s)
- Derek J Hausenloy
- Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, United Kingdom
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Vilahur G, Cubedo J, Casani L, Padro T, Sabate-Tenas M, Badimon JJ, Badimon L. Reperfusion-triggered stress protein response in the myocardium is blocked by post-conditioning. Systems biology pathway analysis highlights the key role of the canonical aryl-hydrocarbon receptor pathway. Eur Heart J 2012; 34:2082-93. [PMID: 22851653 DOI: 10.1093/eurheartj/ehs211] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
AIMS Ischaemic post-conditioning (IPost-Co) exerts cardioprotection by diminishing ischaemia/reperfusion injury. Yet, the mechanisms involved in such protection remain largely unknown. We have investigated the effects of IPost-Co in cardiac cells and in heart performance using molecular, proteomic and functional approaches. METHODS AND RESULTS Pigs underwent 1.5 h mid-left anterior descending balloon occlusion and then were sacrificed without reperfusion (ischaemia; n= 7), subjected to 2.5 h of cardiac reperfusion and sacrificed (n= 5); or subjected to IPost-Co before reperfusion and sacrificed 0.5 h (n= 4) and 2.5 h (n= 5) afterwards. A sham-operated group was included (n= 4). Ischaemic and non-ischaemic myocardium was obtained for molecular/histological analysis. Proteomic analysis was performed by two-dimensional electrophoresis followed by matrix-assisted laser desorption/ionization-time-of-flight identification. Potential protein networks involved were identified by bioinformatics and Ingenuity Pathway Analysis (IPA). Cardiac function was assessed by echocardiography. IPost-Co diminished (up to 2.5 h) reperfusion-induced apoptosis of both the intrinsic and extrinsic pathways whereas it did not affect reperfusion-induced Akt/mammalian target of rapamycin (mTOR)/P70S6K activation. Proteomic studies showed that IPost-Co reverted 43% of cardiac cytoplasmic protein changes observed during ischaemia and ischaemia + reperfusion. Systems biology assessment revealed significant changes in the aryl-hydrocarbon receptor (AhR) pathway (cell damage related). Bioinformatic data were confirmed since the expression of HSP90, AhR, ANRT, and β-tubulin (involved in AhR-signalling transduction) were accordingly modified after IPost-Co. IPost-Co rescued 52% of the left ventricle-at-risk compared with reperfusion alone and resulted in a ≈30% relative improvement in left ventricular ejection fraction (P <0.05). CONCLUSION IPost-Co improves cardiac function post-myocardial infarction and reduces reperfusion-induced cell damage by down-regulation of the AhR-signalling transduction pathway ultimately leading to infarct size reduction.
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Affiliation(s)
- Gemma Vilahur
- Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau and CIBEROBN-Pathophysiology of Obesity and Nutrition, c/Sant Antoni MªClaret 167, 08025 Barcelona, Spain
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