RESUMO
For >4 decades, the holy grail in the treatment of acute myocardial infarction has been the mitigation of lethal injury. Despite promising initial results and decades of investigation by the cardiology research community, the only treatment with proven efficacy is early reperfusion of the occluded coronary artery. The remarkable record of failure has led us and others to wonder if cardioprotection is dead. The path to translation, like the ascent to Everest, is certainly littered with corpses. We do, however, highlight a therapeutic principle that provides a glimmer of hope: cellular postconditioning. Administration of cardiosphere-derived cells after reperfusion limits infarct size measured acutely, while providing long-term structural and functional benefits. The recognition that cell therapy may be cardioprotective, and not just regenerative, merits further exploration before we abandon the pursuit entirely.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos/tendências , Pós-Condicionamento Isquêmico/tendências , Infarto do Miocárdio/terapia , Reperfusão Miocárdica/tendências , Miócitos Cardíacos/transplante , Animais , Terapia Baseada em Transplante de Células e Tecidos/métodos , Humanos , Pós-Condicionamento Isquêmico/métodos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/prevenção & controle , Reperfusão Miocárdica/métodosRESUMO
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.
Assuntos
Pós-Condicionamento Isquêmico/métodos , Precondicionamento Isquêmico Miocárdico/métodos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Ensaios Clínicos como Assunto/métodos , Humanos , Pós-Condicionamento Isquêmico/tendências , Precondicionamento Isquêmico Miocárdico/tendências , Isquemia Miocárdica/fisiopatologia , Isquemia Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Fatores de TempoRESUMO
Ischemia-reperfusion injury is the leading cause of acute kidney injury in a variety of clinical settings such as renal transplantation and hypovolemic and/or septic shock. Strategies to reduce ischemia-reperfusion injury are obviously clinically relevant. Ischemic conditioning is an inherent part of the renal defense mechanism against ischemia and can be triggered by short periods of intermittent ischemia and reperfusion. Understanding the signaling transduction pathways of renal ischemic conditioning can promote further clinical translation and pharmacological advancements in this era. This review summarizes research on the molecular mechanisms underlying both local and remote ischemic pre-, per- and postconditioning of the kidney. The different types of conditioning strategies in the kidney recruit similar powerful pro-survival mechanisms. Likewise, renal ischemic conditioning mobilizes many of the same protective signaling pathways as in other organs, but differences are recognized.
Assuntos
Pós-Condicionamento Isquêmico/métodos , Precondicionamento Isquêmico/métodos , Rim/irrigação sanguínea , Injúria Renal Aguda/fisiopatologia , Injúria Renal Aguda/prevenção & controle , Animais , Ensaios Clínicos como Assunto , Função Retardada do Enxerto/fisiopatologia , Função Retardada do Enxerto/prevenção & controle , Humanos , Pós-Condicionamento Isquêmico/tendências , Precondicionamento Isquêmico/tendências , Rim/fisiopatologia , Transplante de Rim , Modelos Biológicos , Traumatismo por Reperfusão/fisiopatologia , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais , Pesquisa Translacional BiomédicaRESUMO
The year 2013 was rich of new developments in cardiology, and percutaneous coronary intervention (PCI) in particular. This overview article will focus on contributions in the following areas: training for PCI, appropriateness and indications; access site selection, risk scores, peri-procedural myocardial infarction; trial results and long-term follow-up; PCI for specific patient and lesion subsets, including acute coronary syndrome and ST-segment myocardial infarction; prevention of ischemic and reperfusion injury; stent thrombosis and new coronary stents and scaffolds.
Assuntos
Cardiologia/tendências , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea/tendências , Cardiologia/educação , Trombose Coronária/terapia , Stents Farmacológicos/tendências , Feminino , Oclusão de Enxerto Vascular/etiologia , Humanos , Balão Intra-Aórtico/métodos , Pós-Condicionamento Isquêmico/tendências , Precondicionamento Isquêmico Miocárdico/tendências , Masculino , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Intervenção Coronária Percutânea/educação , Intervenção Coronária Percutânea/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Stents , Alicerces TeciduaisRESUMO
BACKGROUND: Although extensive reports have demonstrated the neuroprotection of sevoflurane postconditioning in cases of focal and global cerebral ischemia/reperfusion, the underlying mechanisms are not completely elucidated. This study investigated whether this effect is related to endothelial nitric oxide synthase (eNOS) and mediated by the phosphoinositide-3-kinase pathway in a rat model of hemorrhagic shock and resuscitation. METHODS: Adult male Sprague Dawley rats were subjected to hemorrhagic shock for 60 minutes and then resuscitation for 30 minutes in experimental groups. Sevoflurane postconditioning was performed at the beginning of resuscitation to completion. At 24 hours after resuscitation, the brain infarct volume was evaluated by 2,3,5-triphenyltetrazolium chloride staining. The neuronal morphological changes and apoptosis were determined by hematoxylin and eosin staining and immunohistochemistry analysis, respectively. The activity of phosphorylated Akt and eNOS was evaluated by Western blot analysis. RESULTS: Brain injuries such as the cerebral infarct volume and pathological neuronal changes as well as cell apoptosis were observed in the hippocampus after hemorrhagic shock and resuscitation. Postconditioning with 2.4% sevoflurane significantly attenuated brain injuries. Wortmannin prevented the improvements of neuronal characteristics elicited by sevoflurane postconditioning as well as the hyperactivity of eNOS and phosphorylated Akt. CONCLUSIONS: Sevoflurane postconditioning could attenuate brain injury induced by hemorrhagic shock and resuscitation, and this neuroprotective effect may be partly by upregulation of eNOS through the phosphoinositide-3-kinase/Akt signaling pathway.
Assuntos
Fármacos Neuroprotetores/administração & dosagem , Óxido Nítrico Sintase Tipo III/biossíntese , Fosfatidilinositol 3-Quinase/biossíntese , Proteínas Proto-Oncogênicas c-akt/biossíntese , Sevoflurano/administração & dosagem , Choque Hemorrágico/metabolismo , Anestésicos Inalatórios/administração & dosagem , Animais , Modelos Animais de Doenças , Pós-Condicionamento Isquêmico/tendências , Masculino , Ratos , Ratos Sprague-Dawley , Ressuscitação/tendências , Choque Hemorrágico/prevenção & controle , Choque Hemorrágico/terapia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Ischemic postconditioning (PCON) appears as a potentially beneficial tool in ST-segment elevation myocardial infarction (STEMI). We evaluated the effect of PCON on microvascular obstruction (MVO) in STEMI patients and in an experimental swine model. METHODS: A prospective randomized study in patients and an experimental study in swine were carried out in two university hospitals in Spain. 101 consecutive STEMI patients were randomized to undergo primary angioplasty followed by PCON or primary angioplasty alone (non-PCON). Using late gadolinium enhancement cardiovascular magnetic resonance, infarct size and MVO were quantified (% of left ventricular mass). In swine, using an angioplasty balloon-induced anterior STEMI model, MVO was defined as the % of area at risk without thioflavin-S staining. RESULTS: In patients, PCON (n=49) in comparison with non-PCON (n=52) did not significantly reduce MVO (0 [0-1.02]% vs. 0 [0-2.1]% p=0.2) or IS (18 ± 13% vs. 21 ± 14%, p=0.2). MVO (>1 segment in the 17-segment model) occurred in 12/49 (25%) PCON and in 18/52 (35%) non-PCON patients, p=0.3. No significant differences were observed between PCON and non-PCON patients in left ventricular volumes, ejection fraction or the extent of hemorrhage. In the swine model, MVO occurred in 4/6 (67%) PCON and in 4/6 (67%) non-PCON pigs, p=0.9. The extent of MVO (10 ± 7% vs. 10 ± 8%, p=0.9) and infarct size (23 ± 14% vs. 24 ± 10%, p=0.8) was not reduced in PCON compared with non-PCON pigs. CONCLUSIONS: Ischemic postconditioning does not significantly reduce microvascular obstruction in ST-segment elevation myocardial infarction. Clinical Trial Registration http://www.clinicaltrials.gov. Unique identifier: NCT01898546.