Role of fibrinogen in the attenuation of ischemia reperfusion and remote ischemic preconditioning / El papel del fibrinógeno en la atenuación de la isquemia-reperfusión y el preacondicionamiento isquémico remoto

Abstract Background: Ischemic reperfusion injury (IRI) is a common hazard involved in many human diseases, such as cerebral stroke, myocardial infarction, solid organ transplant dysfunction or failure, and vascular diseases. Understanding the molecular bases of this injury is essential for the prevention and control of these life-threatening conditions. Ischemic and remote ischemic preconditioning techniques (IPC and RIPC, respectively) have gained increasing importance in the clinical practice to protect against the IRI; however, the exact mechanisms of these techniques are not fully understood, which renders their clinical application query. Possible effectors: Nitric oxide (NO) has been reported by multiple studies to be an important mediator of the protective effects of those techniques. While the physiological concentrations of NO and fibrinogen (FB) are known to antagonize each other, the circulating levels of both effectors increase in response to RIPC. Hypothesis: While NO has potential anti-inflammatory effects, non-soluble fibrinogen (sFB) shows pro- inflammatory effects. However, the sFB may have the potential to act synergistically rather than antagonistically with NO toward the attenuation of the IRI. Conclusion: While increased FB is considered a risk factor for cardiovascular and inflammatory conditions that is also able to decrease the efflux of NO, and increase the NO oxidative metabolits and S- nitroglutathione, the increased sFB during the acute phase reaction might have other protective aspects that should be carefully investigated.

Resumen Antecedentes: La lesión por isquemia-reperfusión (LIR) es un riesgo común involucrado en muchas enfermedades humanas tales como derrame cerebral, infarto del miocardio, disfunción o falla de trasplante de órgano sólido, y enfermedades vasculares. Una comprensión de la base molecular de esta lesión es fundamental para la prevención y el control de estas enfermedades potencialmente mortales. Las técnicas de preacondicionamiento isquémico y preacondicionamiento isquémico remoto (PIR) han cobrado una creciente importancia en la práctica clínica para la protección contra la LIR, sin embargo, los mecanismos precisos de estas técnicas no se entienden plenamente, lo cual pone en duda su aplicación clínica. Posibles efectores: El óxido nítrico (ON) ha sido reportado por varios estudios como un importante mediador de los efectos protectores de estas técnicas. Si bien se sabe que las concentraciones fisiológicas del ON y fibrinógeno son antagónicas, los niveles circulantes de ambos efectores aumentan en respuesta al PIR. Hipótesis: Aunque el ON tiene posibles efectos anti-inflamatorios, el fibrinógeno insoluble muestra efectos proinflamatorios. Sin embargo, el fibrinógeno soluble puede tener el potencial de actuar de manera sinérgica en lugar de antagónica con el ON hacia la atenuación de la LIR. Conclusión: Aunque el fibrinógeno elevado se considera un factor de riesgo para las enfermedades cardiovasculares e inflamatorias, que también puede disminuir la descarga de ON y aumentar los niveles de metabolitos oxidantes del ON y de S-nitrosoglutatión, el aumento de fibrinógeno soluble durante la reacción de fase aguda puede tener otros aspectos protectores que deben ser cuidadosamente investigados.

Interactions between remote ischemic conditioning and post-stroke sleep regulation / 医学前沿

Sleep disturbances are common in patients with stroke, and sleep quality has a critical role in the onset and outcome of stroke. Poor sleep exacerbates neurological injury, impedes nerve regeneration, and elicits serious complications. Thus, exploring a therapy suitable for patients with stroke and sleep disturbances is imperative. As a multi-targeted nonpharmacological intervention, remote ischemic conditioning can reduce the ischemic size of the brain, improve the functional outcome of stroke, and increase sleep duration. Preclinical/clinical evidence showed that this method can inhibit the inflammatory response, mediate the signal transductions of adenosine, activate the efferents of the vagal nerve, and reset the circadian clocks, all of which are involved in sleep regulation. In particular, cytokines tumor necrosis factor α (TNFα) and adenosine are sleep factors, and electrical vagal nerve stimulation can improve insomnia. On the basis of the common mechanisms of remote ischemic conditioning and sleep regulation, a causal relationship was proposed between remote ischemic conditioning and post-stroke sleep quality.

Remote ischemic conditioning enhances heart and brain antioxidant defense / Condicionamento isquêmico remoto melhora a defesa antioxidante do coração e do cérebro

Abstract Background Ischemia-reperfusion injury contributes to morbidity after revascularization procedures. Along with early reperfusion, tissue conditioning by alternating intervals of brief ischemia-reperfusion episodes is considered the best approach to limit tissue damage. Remote ischemic conditioning is conducted remotely, in tissues other than those under ischemia. Despite this, remote ischemic conditioning protection mechanisms are poorly understood, which can lead to misapplication. Objectives To assess whether remote ischemic conditioning works in the heart and brain through enhancement of cells' antioxidant defenses and whether the response is sustained or temporary. Methods Twenty-one male Wistar rats were assigned to three groups (n = 7): SHAM: same procedure as the other groups, but no remote ischemic conditioning was carried out. RIC 10: heart and brain were harvested 10 minutes after the remote ischemic conditioning protocol. RIC 60: heart and brain were harvested 60 minutes after the remote ischemic conditioning protocol. The remote ischemic conditioning protocol consisted of 3 cycles of 5 min left hindlimb ischemia followed by 5 min left hindlimb perfusion, lasting 30 min in total. Heart and brain samples were used to measure the tissue antioxidant capacity. Results Remote ischemic conditioning increased heart and brain antioxidant capacity after 10 minutes (0.746 ± 0.160/0.801 ± 0.227 mM/L) when compared to SHAM (0.523 ± 0.078/0.404 ± 0.124 mM/L). No enhancement of heart or brain antioxidant capacity was detected 60 minutes after remote ischemic conditioning (0.551 ± 0.073/0.455 ± 0.107 mM/L). Conclusions Remote ischemic conditioning temporarily enhances heart and brain antioxidant defenses in male Wistar rats.

Resumo Contexto A lesão de isquemia e reperfusão contribui para a morbidade após procedimentos de revascularização. Juntamente com a reperfusão precoce, o condicionamento tecidual através de breves episódios de isquemia e reperfusão é considerado a melhor abordagem para limitar o dano tecidual. Apesar disso, os mecanismos do condicionamento isquêmico remoto são pouco compreendidos, o que pode levar a uma aplicação incorreta. Objetivos Avaliar se o condicionamento isquêmico remoto funciona no coração e no cérebro através do aprimoramento da defesa antioxidante das células e se é uma resposta sustentada ou temporária. Métodos Vinte e um ratos Wistar foram divididos em três grupos (n = 7): SHAM, no qual não foi realizado condicionamento isquêmico; RIC 10, no qual 10 minutos após o protocolo de condicionamento isquêmico, foi realizada a coleta dos órgãos; e RIC 60, no qual 60 minutos após o protocolo de condicionamento isquêmico, foi realizada a coleta dos órgãos. O protocolo de condicionamento isquêmico remoto consistiu em três ciclos de 5 minutos de isquemia, seguidos de 5 minutos de perfusão no membro posterior esquerdo, com duração total de 30 minutos. Amostras foram usadas para medir a capacidade antioxidante do tecido. Resultados O condicionamento isquêmico remoto aumentou a capacidade antioxidante do coração e do cérebro após 10 minutos (0,746 ± 0,160/0,801 ± 0,227 mM/L) quando comparado ao SHAM (0,523 ± 0,078/0,404 ± 0,124 mM/L) . Sessenta minutos após o condicionamento isquêmico remoto, não foi detectado aumento da capacidade antioxidante do coração ou do cérebro (0,551 ± 0,073/0,455 ± 0,107 mM/L). Conclusões O condicionamento isquêmico remoto melhora temporariamente as defesas antioxidantes do coração e do cérebro em ratos Wistar.

Beneficios perioperatorios por condicionamiento isquémico a distancia en la revascularización coronaria / Perioperative benefits of distant ischemic conditioning in coronary revascularization

Introducción: Una serie de breves periodos de isquemias a distancia pueden limitar el daño miocárdico producido por la isquemia/reperfusión. Objetivo: Analizar las diferencias entre los dos grupos (control y estudio) teniendo en cuanta el consumo de inotrópicos y/o vasopresores durante los períodos intra y posoperatorio, así como, incidencia de eventos adversos cardiacos mayores y mortalidad en el postoperatorio. Métodos: Se realizó un estudio cuasiexperimental, explicativo, comparativo con control histórico, en dos grupos de 247 pacientes, propuestos para revascularización coronaria. Se colocó un torniquete en el brazo derecho, en el grupo estudio, alternando 3 insuflaciones con 3 desinsuflaciones con una presión de 200 mmHg, manteniéndola 5 min cada una. Este proceder se realizó previo, durante y después del evento isquémico mayor, provocado por el pinzamiento de la arteria coronaria. Resultados: Se logró una disminución significativa del consumo de drogas inotrópicas y vasoactivas. Se comprobó además, la disminución en la incidencia de bajo gasto cardiaco reversible, fibrilación ventricular, nuevo infarto agudo de miocardio. Conclusiones: El condicionamiento isquémico a distancia es una importante herramienta a tener en cuenta para la protección cardiaca perioperatoria en la revascularización coronaria(AU)

Introduction: A series of brief distant ischemia periods can limit myocardial damage produced by ischemia or reperfusion. Objective: To analyze the differences between the two groups (control and study) taking into account the consumption of inotropics and/or vasopressors during the intraoperative and postoperative periods, as well as the incidence of major cardiac adverse events and mortality in the postoperative period. Methods: A quasiexperimental, explanatory and comparative study with historical control was conducted on two groups of 247 patients proposed for coronary revascularization. A tourniquet was placed to the right arm, in the study group, alternating three insufflations with three dessufflations with a pressure of 200 mmHg, keeping each for five minutes. This procedure was performed before, during and after the major ischemic event, caused by pinching of the coronary artery. Results: A significant decrease in the consumption of inotropic and vasoactive drugs was achieved. The decrease in the incidence of low reversible cardiac output, ventricular fibrillation, and new acute myocardial infarction was also proven. Conclusions: Distant ischemic conditioning is an important tool to be taken into account for perioperative cardiac protection in coronary revascularization(AU)

Angioplastia primaria en el infarto agudo de miocardio: ¿es beneficioso el condicionamiento isquémico remoto?

El paradigma de la reapertura precoz de la arteria ocluida ha representado un hito en el tratamiento del infarto agudo de miocardio y su aplicación universal en la práctica cardiológica se tradujo en una reducción significativa de la magnitud del daño miocárdico y de la mortalidad por esta causa. Sin embargo, la oclusión coronaria aguda continúa siendo una causa prevalente de muerte y discapacidad de origen cardíaco, por lo cual persiste la búsqueda de nuevos procedimientos, fármacos o estrategias que contribuyan a una mayor preservación del tejido miocárdico en este contexto. El precondicionamiento isquémico cardíaco, en sus diferentes modalidades, a pesar de haber sido objeto de diversos estudios tanto a nivel clínico como experimental, no forma parte de la práctica habitual en los laboratorios de cateterismo cardíaco, servicios de cardiología crítica o unidades de emergencia móvil donde se lleva a cabo la reperfusión miocárdica. En esta controversia, los autores presentan argumentos a favor y en contra de la utilización del precondicionamiento isquémico remoto como adjunto a la angioplastia primaria en un escenario clínico concreto, brindando al lector el estado de la evidencia sobre un procedimiento cuyo margen de utilidad aguarda aún una clara definición.

Summary: Early reopening of the occluded artery paradigm has represented a milestone in the treatment of acute myocardial infarction, and its universal application in cardiological practice lead to a significant reduction in the extension of myocardial injury and mortality from this cause. However, acute coronary occlusion is still a prevalent cause of death and disability; therefore, a lively interest in identificating new procedures, drugs or strategies that contribute to a greater preservation of myocardial tissue persists in this context. Cardiac ischemic preconditioning in its various forms, despite having been object of several studies, both at clinical and experimental levels, is not part of the usual practice of catheterization laboratories, critical cardiology services or mobile emergency units, where myocardial reperfusion is carried out. In this controversy, the authors present arguments for and against the use of remote cardiac ischemic preconditioning as an adjunct to primary angioplasty in a particular clinical stage, providing the reader the status of evidence about a procedure whose profit margin still awaits a clear definition.

O paradigma da reabertura precoce da artéria ocluída representou um marco histórico no tratamento do infarto agudo do miocárdio, e sua aplicação universal na prática cardiológica resultou em uma redução significativa da extensão da lesão miocárdica e da mortalidade por essa causa. No entanto, a oclusão coronariana aguda continua sendo uma causa prevalente de morte e incapacidade de origem cardíaca, persistindo, portanto, a busca de novos métodos, drogas ou estratégias que contribuam para uma maior preservação do tecido miocárdico nesse contexto. Pré-condicionamento cardíaco isquêmico, em suas diversas modalidades, que apesar de ter sido objeto de vários estudos, tanto clínicos como experimentais, não faz parte da prática usual no laboratório de cateterismo cardíaco, nos serviços de cardiologia crítica ou nas unidades móveis de emergência, onde a reperfusão miocárdica é realizada. Nesta controvérsia, os autores apresentam argumentos a favor e contra o uso do pré-condicionamento isquêmico remoto como adjuvante da angioplastia primária em um ambiente clínico específico, proporcionando ao leitor com o estado da evidência em um procedimento cuja margem de utilidade ainda aguarda uma definição clara.

Protección miocárdica por condicionamiento isquémico a distancia en la revascularización coronaria / Myocardial protection by ischemic remote conditioning in coronary revascularization

Introducción: Una serie de breves períodos de isquemias a distancia, previo al evento isquémico mayor, pueden limitar el daño miocárdico producido por la isquemia/reperfusión. Objetivo: Evaluar la utilidad del condicionamiento isquémico a distancia, en pacientes programados para procedimientos quirúrgicos de revascularización coronaria. Métodos: Se realizó un estudio cuasiexperimental, explicativo, comparativo con control histórico, en dos grupos de 247 pacientes, propuestos para revascularización coronaria. Se colocó un torniquete en el brazo derecho, en el grupo estudio, alternando 3 insuflaciones con 3 desinsuflaciones con una presión de 200 mmHg, manteniéndola 5 min cada una. Este proceder se realizó previo, durante y después del evento isquémico mayor, provocado por el pinzamiento de la arteria coronaria. Resultados: Se logró una disminución significativa de los parámetros enzimáticos. No se encontraron diferencias significativas (p>0,05) según un conjunto de variables que representan el estado inicial de los pacientes(AU)

Introduction: A series of short periods of distant ischemia, prior to the major ischemic event, can limit the myocardial damage produced by ischemia or reperfusion. Objective: To evaluate the usefulness of remote ischemic conditioning in patients scheduled for surgical procedures of coronary revascularization. Methods: A quasi-experimental, explanatory, comparative study with historical control was conducted in two groups of 247 patients proposed for coronary revascularization. A tourniquet was placed in the right arm in the study group, alternating 3 insufflations with 3 dessufflations with a pressure of 200 mmHg, keeping each for 5 minutes. This procedure was performed before, during and after the major ischemic event, caused by the impingement of the coronary artery. Results: A significant decrease in enzymatic parameters was achieved. No significant differences were found (p>0.05) according to a set of variables that represent the initial state of the patients(AU)

Reperfusing the myocardium - a damocles Sword

Return of blood flow after periodic ischemia is often accompanied by myocardial injury, commonly known as lethal reperfusion injury (RI). Experimental studies have shown that 50% of muscle die of ischemia and another 50% die because of reperfusion. It is characterized by myocardial, vascular, or electrophysiological dysfunction that is induced by the restoration of blood flow to previously ischemic tissue. This phenomenon reduces the efficiency of the present modalities used to combat the ischemic myocardium. Moreover, despite an improved understanding of the pathophysiology of this process and encouraging preclinical trials of multiple agents, most of the clinical trials to prevent RI have been disappointing and leaves us at ground zero to explore newer approaches.

Impact of Remote Ischemic Conditioning on Circulating miR-208b Level and Cardiac Function in Patients With ST Segment Elevation Myocardial Infarction Undergoing Primary Angioplasty / 中国循环杂志

Objectives: To investigate whether remote ischemic conditioning (RIC) applied to patients with ST-segment elevation myocardial infarction (STEMI) before percutaneous coronary intervention (PCI) could affect circulating miR-208b level or not. Methods:Patients diagnosed with STEMI undergoing PCI from January 2016 to July 2017 were enrolled from the Department of Cardiology, Affiliated Zhongshan Hospital of Dalian University.The patients were randomly allocated to two groups: (1) control group (n=25), PCI alone; (2) RIC group (n=50), PCI combined with RIC (three cycles of 5 min inflation and 5 min deflation of the right lower limb with blood pressure cuff performed before reperfusion). Serum miR-208b was measured before and immediately, at 24 h, and 48 h after PCI with real-time quantitative polymerase chain reaction. Results: The expression of miR-208b was significantly higher immediately post PCI than that before operation in the control group (84.1±9.0 vs 77.8±9.4; P=0.032), while it was significantly lower immediately post PCI than that before operationin RIC group (71.0±9.3 vs 77.4±8.8; P=0.028).miR-208b level was similar before PCI between the control and RIC groups (P=0.874), which was significantly reduced immediately post PCI in RIC group as compared with the control group (P=0.021).The peak value of creatine kinase isoenzyme (CK-MB) in the limb RIC group was significantly lower than that in the control group ([135.2±18.6] U/L vs [167.7±17.2] U/L; P=0.038).The area under the CK-MB curve of the RIC group was significantly smaller than that of the control group ([3 060.7±17.1] U/L vs [3 635.9±15.1] U/L); P=0.047]. The left ventricular ejection fraction (LVEF) in RIC group was significantly higher than that in the control group ([57.8±7.8]% vs [51.9±7.9]%; P=0.003) post PCI. The expression level of serum miR-208b was positively correlated with CK-MB AUC in RIC group (r=0.498, P<0.001). Conclusions: RIC of the lower limb prior to PCI could reduce miR-208b level and improve cardiac functionin STEMI patients.

Research progress on the protection of ischemic conditioning against retinal ischemic diseases / 中华实验眼科杂志

Retinal ischemic diseases,such as retinal vascular obstruction,diabetic retinopathy,glaucoma,and retinopathy of prematurity,are one of the common causes of visual loss.However,there are no safe and effective treatments at present.Ischemic conditioning is an endogenous protective measure,of which protection in the prevention of cardiovascular and cerebrovascular diseases has been confirmed.Ischemic conditioning can initiate endogenous neuroprotective mechanisms to reduce retinal ischemia-reperfusion injury,improve retinal tolerance to ischemia,protect retinal ganglion cells,optic disc structure and function from glaucoma,and prevent the progress of diabetic retinopathy in a variety of ways.This article summarized the research from the aspects of the conception,the protective effect on retinal and related mechanism of ischemic conditioning,which provide basic research transferring to clinical research of ischemic conditioning on retinal ischemic diseases in future for the theoretical and experimental proofs.

Remote Ischemic Conditioning by Effluent Collected from a Novel Isolated Hindlimb Model Reduces Infarct Size in an Isolated Heart Model

BACKGROUND AND OBJECTIVES: Experimental protocols for remote ischemic conditioning (RIC) utilize models in which a tourniquet is placed around the hindlimb or effluent is collected from an isolated heart. In analyzing the humoral factors that act as signal transducers in these models, sampled blood can be influenced by systemic responses, while the effluent from an isolated heart might differ from that of the hindlimb. Thus, we designed a new isolated hindlimb model for RIC and tested whether the effluent from this model could affect ischemia/reperfusion (IR) injury and if the reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways are involved in RIC. MATERIALS AND METHODS: After positioning needles into the right iliac artery and vein of rats, Krebs-Henseleit buffer was perfused using a Langendorff apparatus, and effluent was collected. The RIC protocol consisted of 3 cycles of IR for 5 minutes. In the RIC effluent group, collected effluent was perfused in an isolated heart for 10 minutes before initiating IR injury. RESULTS: Compared with the control group, the infarct area in the RIC effluent group was significantly smaller (31.2%±3.8% vs. 20.6%±1.8%, p<0.050), while phosphorylation of signal transducer and activation of transcription-3 (STAT-3) was significantly increased. However, there was a trend of increased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in this group. CONCLUSION: This is the first study to investigate the effect of effluent from a new isolated hindlimb model after RIC on IR injury in an isolated heart model. The RIC effluent was effective in reducing the IR injury, and the cardioprotective effect was associated with activation of the SAFE pathway.