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Objective: To observe the effect of Electroacupuncture of Acupoints of the Neiguan(PC6) and Ximen(PC4) on its myocardial energy metabolism with acute myocardial ischemia rats caused by coronary artery ligation. Methods: Forty standard Spargue-Dawely(SD) rats were divided into four groups randomly, namely, group of Neiguan, group of Ximen, model group, sham group. The group of rats of myocardial ischemia were induced by coronary ligation, and the model rat of acute myocardial ischemia was prepared. The sham group had no ligation of the needle. After anesthesia was awakened, acupuncture was applied bilateral at Neiguan and Ximen of the group of Neiguan and Ximen, once a day at a fixed time for 14 days. The rats of model group and the sham group were not given acupunctured, but use the samely methods of Neiguan and Ximen groups to grap the rats at the same time everyday .After 14 days the experiment was over,observed the pathological changes of myocardial tissue by HE staining, detected the levels of free fatty acid (FFA), adenosine triphosphate (ATP) content, and the activities of Na+-K+-ATPase according to the reagents´demand. Results: Pathological results showed that acupuncuted at Neiguan and Ximen could improve the ischemic cardiomyocyte injury.Compared with the sham group, the levels of FFA in model group were increased （p

[ES] Los modelos computacionales basados en descripciones matemáticas con mucho detalle biofísico y electrofisiológico son una herramienta cada vez más utilizad para estudiar la seguridad y eficacia de fármacos y, en particular, de sus efectos en el funcionamiento del corazón. Además, la isquemia miocárdica aguda es una situación patológica del corazón en el que, tras la oclusión de una arteria coronaria, el riesgo de sufrir arritmias potencialmente mortales es elevado. En este trabajo, se utilizará la simulación computacional para estudiar la eficacia de un grupo muy numeroso de fármacos en la prevención de arritmias ventriculares en esta situación patológica. ara ello, se programarán modelos electrofisiológicamente muy detallados que permitirán establecer el efecto de dichos fármacos sobre la evolución de la concentración extracelular de potasio, uno de los biomarcadores de riesgo arrítmico más importantes., [EN] Computational models based on mathematical descriptions with a high degree of biophysical and electrophysiological detail are an increasingly used tool to study the safety and efficacy of drugs and, in particular, their effects on heart function. In addition, acute myocardial ischemia is a pathological condition of the heart in which, after the occlusion of a coronary artery, the risk of life-threatening arrhythmias is high. In this work, computer simulation will be used to study the efficacy of a very large group of drugs in the prevention of ventricular arrhythmias in this pathological situation. For this purpose, very detailed electrophysiological models will be programmed that will allow establishing the effect of these drugs on the evolution of extracellular potassium concentration, one of the most important biomarkers of arrhythmic risk.

Mitochondrial malfunction leads to the remodeling of myocardial energy metabolism during myocardial ischemia (MI). However, the alterations to the mitochondrial proteome profile during this period has not yet been clarified. An acute MI model was established by high position ligation of the left anterior descending artery in 8-week-old C57BL/6N mice. After 15 min of ligation, the animals were euthanized, and their hearts were collected. The myocardial ultrastructure was observed using transmission electron microscopy (TEM). The cardiac mitochondrial proteome profile was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analyses. TEM showed that the outer membrane of the mitochondria was dissolved, and the inner membrane (cristae) was corrupted and broken down extensively in the MI group. The mitochondrial membrane potential was decreased. More than 1,700 mitochondrial proteins were identified by LC-MS/MS analysis, and 119 were differentially expressed. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis showed that endopeptidase activity regulation, the mitochondrial inner membrane, oxidative phosphorylation, the hypoxia-inducible factor-1 signaling pathway, the pentose phosphate pathway and the peroxisome proliferator-activated receptor signaling pathway were involved in the pathophysiological process in the early stage of acute MI. Extensive and substantial changes in the mitochondrial proteins as well as mitochondrial microstructural damage occur in the early stages of acute MI. In the present study, the series of proteins crucially involved in the pathways of mitochondrial dysfunction and metabolism were identified. Further studies are needed to clarify the roles of these proteins in myocardial metabolism remodeling during acute MI injury.

Acute myocardial infarction (AMI) is one of the major leading causes of death in humans globally. Recently, increased levels of recruited macrophages and AGE-albumin were observed in the hearts of humans and animals with acute myocardial infarction. Thus, the purposes of this study were to investigate whether the elevated levels of AGE-albumin from activated macrophage cells are implicated in ischemia-induced cardiomyocyte death and to develop therapeutic strategies for AMI based on its underlying molecular mechanisms with respect to AGEs. The present study demonstrated that activated macrophages and AGE-albumin were observed in heart tissues obtained from humans and rats with AMI incidences. In the cellular model of AMI, it was found that increased expression of AGE-albumin was shown to be co-localized with macrophages, and the presence of AGE-albumin led to increased expression of RAGE through the mitogen-activated protein kinase pathway. After revealing cardiomyocyte apoptosis induced by toxicity of the AGE-RAGE system, sRAGE-secreting MSCs were generated using the CRISPR/Cas9 platform to investigate the therapeutic effects of sRAGE-MSCs in an AMI rat model. Gene-edited sRAGE-MSCs showed greater therapeutic effects against AMI pathogenesis in rat models compared to mock MSCs, and promising results of the functional improvement of stem cells could result in significant improvements in the clinical management of cardiovascular diseases.

[ES] Una mejor comprensión de los mecanismos subyacentes a las arritmias ventriculares, así como una mejora de las terapias eléctricas y farmacológicas asociadas, son un factor clave para prevenir la muerte súbita cardíaca en pacientes con cardiopatías estructurales y eléctricas. Una miocardiopatía importante que puede provocar arritmias ventriculares potencialmente mortales es la insuficiencia cardíaca (HF). Los pacientes con HF a menudo sufren también de bloqueo de rama izquierda (LBBB) que deteriora su condición. Actualmente, el tratamiento más eficaz para estos pacientes es la terapia de resincronización cardíaca (CRT). Sin embargo, no se alcanza una respuesta positiva en todos los casos, por lo que es necesario un mayor estudio para mejorar este tratamiento. Una segunda patología cardíaca que también produce arritmias letales es la isquemia miocárdica. Evidencia experimental ha demostrado que las alteraciones electrofisiológicas en el miocardio ventricular constituyen un sustrato para la generación de arritmias durante la fase aguda de isquemia. Estas alteraciones son inducidas por los tres componentes isquémicos principales: hipercalemia, hipoxia y acidosis. Sin embargo, la influencia de cada componente en los mecanismos de inicio y mantenimiento de las arritmias no se comprende aún con claridad. Una primera parte de esta tesis doctoral, se centra en la optimización de la CRT durante su aplicación en un corazón que padece HF y LBBB. Para esto, se modificó el modelo de potencial de acción (AP) de O'Hara para simular una velocidad de conducción realista tanto en condiciones sanas como patológicas. Además, se estimó e incorporó un sistema de His-Purkinje (HPS) dentro de un modelo biventricular/torso humano 3D para simular un LBBB realista. A continuación, se desarrolló un conjunto de simulaciones computacionales para diferentes configuraciones de la CRT a fin de determinar la posición y el instante de estimulación óptimo que conducen a la duración más corta del QRS. Posteriormente, los resultados se compararon con otros criterios de optimización. Los principales hallazgos de este estudio mostraron la necesidad de definir criterios de optimización mejores o complementarios, como un índice basado en el tiempo hasta alcanzar el 90% del área del QRS sugerido en este trabajo, para alcanzar la mejor sincronía eléctrica ventricular durante la aplicación de la CRT. Además, nuestros resultados también muestran que el septo superior cercano al tracto de salida es un sitio alternativo para la estimulación del ventrículo derecho, lo cual evita los problemas de perforación de la pared apical durante el procedimiento típico de la CRT. Por último, para obtener mejores resultados de la CRT se deben considerar protocolos de estimulación endocárdica en el ventrículo izquierdo. En la segunda parte de esta tesis se investigó los efectos de los tres componentes principales de la isquemia sobre la vulnerabilidad a una reentrada, así como el papel del HPS y sus mecanismos de acción en la generación y mantenimiento de arritmias ventriculares. Para lograr este objetivo, en primer lugar, se modificó el modelo AP ventricular para simular de forma realista las principales alteraciones provocadas por la isquemia miocárdica aguda. Las simulaciones se realizaron en un modelo biventricular humano 3D, acoplado en un torso virtual, que incluye una geometría realista de las zonas isquémicas central y de borde, así como un HPS detallado. Se simularon cuatro escenarios de severidad isquémica correspondientes a diferentes minutos de oclusión de la arteria coronaria para evaluar los efectos de la evolución de la isquemia en el tiempo. Luego, se evaluó la influencia individual de la hipercalemia, hipoxia y acidosis en el ancho de la ventana vulnerable (VW) a reentradas durante siete escenarios de isquemia aguda. Finalmente, se repitió este último conjunto de simulaciones isquémicas utilizando el modelo anatómico sin el HPS para evaluar el efecto de este último en la VW. Los resultados muestran que una condición isquémica moderada es el peor escenario para la generación de una reentrada. La hipoxia es el componente isquémico con el efecto más significativo en el ancho de la VW. Además, el flujo de corriente retrógrado desde el miocardio hacia el HPS en la región isquémica, los bloqueos de conducción en secciones discretas del HPS y el grado de hiperkalemia que afecta a las células de Purkinje, son sugeridos como mecanismos que podrían favorecer la aparición de arritmias ventriculares., [EN] A better understanding of the mechanisms underlying ventricular arrhythmias, as well as an improvement of the associated electrical and pharmacological therapies, are a key factor to prevent sudden cardiac death in patients with structural and electrical heart diseases. An important cardiomyopathy that can lead to life-threatening ventricular arrhythmias is heart failure (HF). Patients with HF also often suffer from left bundle branch block (LBBB), which worsens their condition. Currently, the most effective treatment to these patients is cardiac resynchronization therapy (CRT). However, many patients are non-responders, so further studies are needed to improve this treatment. A second cardiac pathology that also produces lethal arrhythmias is myocardial ischemia. Substantial experimental evidence has shown that electrophysiological alterations in the ventricular myocardium constitute a substrate for the generation of arrhythmias during the acute phase of ischemia. These alterations are induced by the three main ischemic components: hyperkalemia, hypoxia and acidosis. However, the influence of each component in the mechanisms of arrhythmia initiation and maintenance is still not completely understood. In the first section of this doctoral thesis, we focus on the optimization of CRT during its application in a heart suffering from HF and LBBB. For this purpose, we modified the O'Hara action potential (AP) model to simulate a realistic conduction velocity both in healthy and pathological conditions. In addition, a His-Purkinje system (HPS) was generated and incorporated into a 3D human biventricular/torso model to simulate realistic LBBB. A set of computational simulations were performed for different CRT configurations to determine the optimal pacing leads location and delay values leading to the shortest QRS duration. Subsequently, results were compared with other optimization criteria. The main findings of this study showed the need of better or complementary optimization criteria, such as an index based on the time to reach the 90% of the QRS area suggested in this work, to reach the best ventricular electrical synchrony during the CRT application. In addition, our results also show that the upper septum close to the outflow tract is an alternative site for the right ventricle (RV) stimulation, which avoids the perforation problems of the RV apical wall during the typical CRT procedure. Finally, protocols of left ventricle endocardial pacing should be considered to obtain better CRT results. In the second section of this thesis, we investigated the effects of the three main components of ischemia on the vulnerability to reentry, as well as the role of the HPS and its mechanisms of action in the generation and maintenance of ventricular arrhythmias. In order to achieve our goal, we first modified the ventricular AP model to realistically simulate the major alterations caused by acute myocardial ischemia. Simulations were performed in a 3D human biventricular model, embedded in a virtual torso, which includes a realistic geometry of the central and border ischemic zones, as well as a detailed HPS. Four scenarios of ischemic severity corresponding to different minutes after coronary artery occlusion were simulated to evaluate the effects of the evolution of ischemia over time. Then, the individual influence of hyperkalemia, hypoxia and acidosis in the width of the vulnerable window (VW) for reentry was assessed during seven scenarios of acute ischemia. Finally, this last set of ischemic simulations was repeated using the anatomical model without the HPS to evaluate the effect of the latter in the VW. Results show that a moderate ischemic condition is the worst scenario for reentry generation. Hypoxia is the ischemic component with the most significant effect on the width of the VW. Furthermore, the retrograde current flow from the myocardium to the HPS in the ischemic region, conduction blocks in discrete sections of the HPS, and the degree of hyperkalemia affecting the Purkinje cells, are suggested as HPS mechanisms that could favor the triggering of ventricular arrhythmias., [CA] Una millor comprensió dels mecanismes subjacents a les arrítmies ventriculars, així com una millora de les teràpies elèctriques i farmacològiques associades, són un factor clau per a previndre la mort sobtada cardíaca en pacients amb cardiopaties estructurals i elèctriques. Una miocardiopatia important que pot provocar arrítmies ventriculars potencialment mortals és la insuficiència cardíaca (HF). Els pacients amb HF sovint pateixen també de bloqueig de branca esquerra (LBBB) que deteriora la seua condició. Actualment, el tractament més eficaç per a aquests pacients és la teràpia de resincronització cardíaca (CRT). No obstant això, no s'aconsegueix una resposta positiva en tots els casos, per la qual cosa és necessari un major estudi per a millorar aquest tractament. Una segona patologia cardíaca que també produeix arrítmies letals és la isquèmia miocàrdica. Evidència experimental ha demostrat que les alteracions electrofisiològiques en el miocardi ventricular constitueixen un substrat per a la generació d'arrítmies durant la fase aguda d'isquèmia. Aquestes alteracions són induïdes pels tres components isquèmics principals: hipercalèmia, hipòxia i acidosi. No obstant això, la influència de cada component en els mecanismes d'inici i manteniment de les arrítmies no es comprén encara amb claredat. Una primera part d'aquesta tesi doctoral, se centra en l'optimització de la CRT durant la seua aplicació en un cor que pateix HF i LBBB. Per a això, es va modificar el model de potencial d'acció (AP) de O'Hara per a simular una velocitat de conducció realista tant en condicions sanes com patològiques. A més, es va estimar i es va incorporar un sistema de His-Purkinje (HPS) dins d'un model biventricular/tors humà 3D per a simular un LBBB realista. A continuació, es va desenvolupar un conjunt de simulacions computacionals per a diferents configuracions de la CRT a fi de determinar la posició i l'instant d'estimulació òptim que condueixen a la duració més curta del QRS. Posteriorment, els resultats es van comparar amb altres criteris d'optimització. Les principals troballes d'aquest estudi van mostrar la necessitat de definir millors o complementaris criteris d'optimització, com un índex basat en el temps fins a aconseguir el 90% de l'àrea del QRS suggerida en aquest treball, per a aconseguir la millor sincronia elèctrica ventricular durant l'aplicació de la CRT. A més, els nostres resultats també mostren que el septe superior pròxim al tracte d'eixida és un lloc alternatiu per a l'estimulació del ventricle dret, la cual cosa evita els problemes de perforació de la paret apical durant el procediment típic de la CRT. Finalment, per a obtindre millors resultats de la CRT s'han de considerar protocols d'estimulació endocárdica en el ventricle esquerre. En la segona part d'aquesta tesi es va investigar els efectes dels tres components principals de la isquèmia sobre la vulnerabilitat a una reentrada, així com el paper del HPS i els seus mecanismes d'acció en la generació i manteniment d'arrítmies ventriculars. Per a aconseguir aquest objectiu, en primer lloc es va modificar el model AP ventricular per a simular de manera realista les principals alteracions provocades per la isquèmia miocàrdica aguda. Les simulacions es van realitzar en un model biventricular humà 3D, acoblat en un tors virtual, que inclou una geometria realista de les zones isquèmiques central i de vora, així com un HPS detallat. Es van simular quatre escenaris de severitat isquèmica corresponents a diferents minuts d'oclusió de l'artèria coronària per a avaluar els efectes de l'evolució de la isquèmia en el temps. Després, es va avaluar la influència individual de la hipercalèmia, hipòxia i acidosi en l'ample de la finestra vulnerable (VW) a reentradas durant set escenaris d'isquèmia aguda. Finalment, es va repetir aquest últim conjunt de simulacions isquèmiques utilitzant el model anatòmic sense el HPS per a avaluar l'efecte d'aquest últim en la VW. Els resultats mostren que una condició isquèmica moderada és el pitjor escenari per a la generació d'una reentrada. La hipòxia és el component isquèmic amb l'efecte més significatiu en l'ample de la VW. A més, el flux de corrent retrògrad des del miocardi cap al HPS a la regió isquèmica, els bloquejos de conducció en seccions discretes del HPS i el grau d'hiperkalèmia que afecta les cèl·lules de Purkinje, són suggerits com a mecanismes que podrien afavorir l'aparició d'arrítmies ventriculars.

[ES] La isquemia miocárdica aguda es un patología que causa aproximadamente 7 millones de muertes al año. Durante la primera fase de esta enfermedad cardiaca se producen potenciales de acción alternantes, que son fuertemente arritmogénicos. Sin embargo, aunque se dispone de estudios donde se han observado dichos alternantes experimentalmente, sus causas son aún desconocidas. El objetivo del presente TFG es doble. Por un lado, se ha partido de una versión del modelo de O'Hara-Rudy (O’Hara et al., 2011) de potencial de acción ventricular humano desarrollado por Ana González en su TFG (Gonzalez Ascaso, 2019) programado en Matlab y se ha desarrollado una versión que permite el estudio teórico de las causas de la aparición de potenciales de acción alternantes en situaciones de isquemia aguda de miocardio. El segundo objetivo consiste en determinar las causas de estos alternantes. Para ello, se ha programado un módulo nuevo para realizar de manera sistemática un elevado número de simulaciones que permiten identificar las condiciones que dan lugar a alternantes. Además, se han realizado distintas modificaciones de esta nueva versión del modelo para el estudio de los factores isquémicos y de las corrientes y concentraciones iónicas para tratar de dilucidar las causas de los mismos, y estudiar potenciales formas terapéuticas de eliminarlos. Los resultados obtenidos sugieren que los valores que toman las concentraciones intracelulares de ATP y ADP durante la isquemia aguda son clave en la aparición de alternantes eléctricos a través de la corriente de potasio sensible a ATP. También lo es la concentración extracelular de potasio. Por otro lado, la alternancia que se produce en el ciclo del calcio también tiene efectos en el potencial de acción, al provocar una alternancia en la corriente de calcio a través de los canales de tipo L. Asimismo, la depresión de la corriente rápida de sodio también ha probado ser clave en la aparición de alternantes. Por último, la corriente rápida de potasio favorece el mantenimiento dichos potenciales de acción alternantes, aunque no constituye la causa directa de la aparición de los mismos., [EN] Acute myocardial ischemia is a disease that causes approximately 7 million deaths every year. During the first phase of this heart disease, alternans action potentials are produced, which are strongly arrhythmogenic. However, although there are studies where such alternans have been observed experimentally, their causes are still unknown. The aim of the present TFG is twofold. On the one hand, we have started from a version of the O’Hara-Rudy model (O’Hara et al., 2011) of the human ventricular action potential developed by Ana González during her TFG (Gonzalez Ascaso, 2019) programmed in Matlab and a version has been developed that allows the study, using computational models, of the causes of the appearance of alternans action potentials in situations of acute myocardial ischemia. The second objective is to determinate the causes of these alternans. A new module has then been programmed to systematically perform a large number of simulations to identify the conditions that lead to alternans. In addition, various modifications have been made to this new version of the model to study of ischemic factors and ionic currents and concentrations to try to elucidate the causes their causes and study potentials therapeutic ways of eliminating them. The results obtained suggest that the values taken by ATP, ADP and extracellular potassium during ischemia are key in the appearance of electrical alternants through the ATP-sensitive potassium current. On the other hand, the alternation that occurs in the calcium cycle also has effects on the action potentials, by causing an alternation in L-type calcium current. Likewise, depression of the fast sodium current has also been shown to be key in the occurrence of alternans. Finally, the fast potassium current favours the maintenance of these alternans action potentials, although it is not the direct cause of their appearance.

Introduction Acute myocardial ischaemia and the transition from reversible to irreversible myocardial injury are associated with abnormal metabolic patterns. Advances in metabolomics have extended our capabilities to define these metabolic perturbations on a metabolome-wide scale. Objectives This study was designed to identify cardiac metabolic changes in serum during the first 5 min following early myocardial ischaemia in humans, applying an untargeted metabolomics approach. Methods Peripheral venous samples were collected from 46 patients in a discovery study (DS) and a validation study (VS) (25 for DS, 21 for VS). Coronary sinus venous samples were collected from 7 patients (4 for DS, 3 for VS). Acute myocardial ischaemia was induced by transient coronary occlusion during percutaneous coronary intervention (PCI). Plasma samples were collected at baseline (prior to PCI) and at 1 and 5 min post-coronary occlusion. Samples were analyzed by Ultra Performance Liquid Chromatography-Mass Spectrometry in an untargeted metabolomics approach. Results The study observed changes in the circulating levels of metabolites at 1 and 5 min following transient coronary ischaemia. Both DS and VS identified 54 and 55 metabolites as significant (P Conclusion Using an untargeted metabolomics approach, the study identified important cardiac metabolic changes in peripheral and coronary sinus plasma, in a human model of controlled acute myocardial ischaemia. Distinct classes of metabolites were shown to be involved in the rapid cardiac response to ischemia and provide insights into diagnostic and interventional targets.

Background In the prehospital triage of patients presenting with symptoms suggestive of acute myocardial ischemia, reliable myocardial ischemia detection in the electrocardiogram (ECG) is pivotal. Due to large interindividual variability and overlap between ischemic and nonischemic ECG‐patterns, incorporation of a previous elective (reference) ECG may improve accuracy. The aim of the current study was to explore the potential value of serial ECG analysis using subtraction electrocardiography. Methods SUBTRACT is a multicenter retrospective observational study, including patients who were prehospitally evaluated for acute myocardial ischemia. For each patient, an elective previously recorded reference ECG was subtracted from the ambulance ECG. Patients were classified as myocardial ischemia cases or controls, based on the in‐hospital diagnosis. The diagnostic performance of subtraction electrocardiography was tested using logistic regression of 28 variables describing the differences between the reference and ambulance ECGs. The Uni‐G ECG Analysis Program was used for state‐of‐the‐art single‐ECG interpretation of the ambulance ECG. Results In 1,229 patients, the mean area‐under‐the‐curve of subtraction electrocardiography was 0.80 (95%CI: 0.77–0.82). The performance of our new method was comparable to single‐ECG analysis using the Uni‐G algorithm: sensitivities were 66% versus 67% (p‐value > .05), respectively; specificities were 80% versus 81% (p‐value > .05), respectively. Conclusions In our initial exploration, the diagnostic performance of subtraction electrocardiography for the detection of acute myocardial ischemia proved equal to that of state‐of‐the‐art automated single‐ECG analysis by the Uni‐G algorithm. Possibly, refinement of both algorithms, or even integration of the two, could surpass current electrocardiographic myocardial ischemia detection.

[EN] Electrophysiological alterations of the myocardium caused by acute ischemia constitute a pro-arrhythmic substrate for the generation of potentially lethal arrhythmias. Experimental evidence has shown that the main components of acute ischemia that induce these electrophysiological alterations are hyperkalemia, hypoxia (or anoxia in complete artery occlusion), and acidosis. However, the influence of each ischemic component on the likelihood of reentry is not completely established. Moreover, the role of the His-Purkinje system (HPS) in the initiation and maintenance of arrhythmias is not completely understood. In the present work, we investigate how the three components of ischemia affect the vulnerable window (VW) for reentry using computational simulations. In addition, we analyze the role of the HPS on arrhythmogenesis. A 3D biventricular/torso human model that includes a realistic geometry of the central and border ischemic zones with one of the most electrophysiologically detailed model of ischemia to date, as well as a realistic cardiac conduction system, were used to assess the VW for reentry. Four scenarios of ischemic severity corresponding to different minutes after coronary artery occlusion were simulated. Our results suggest that ischemic severity plays an important role in the generation of reentries. Indeed, this is the first 3D simulation study to show that ventricular arrhythmias could be generated under moderate ischemic conditions, but not in mild and severe ischemia. Moreover, our results show that anoxia is the ischemic component with the most significant effect on the width of the VW. Thus, a change in the level of anoxia from moderate to severe leads to a greater increment in the VW (40 ms), in comparison with the increment of 20 ms and 35 ms produced by the individual change in the level of hyperkalemia and acidosis, respectively. Finally, the HPS was a necessary element for the generation of approximately 17% of reentries obtained. The retrograde conduction from the myocardium to HPS in the ischemic region, conduction blocks in discrete sections of the HPS, and the degree of ischemia affecting Purkinje cells, are suggested as mechanisms that favor the generation of ventricular arrhythmias., This work was supported by the Secretaría de Educacion ¿ Superior, Ciencia, Tecnología e Innovacion ¿ (SENESCYT) of Ecuador CIBAE-023- 2014, by Grant PID2019-104356RB-C41 funded by MCIN/AEI/ 10.13039/501100011033, by the European Union¿s Horizon 2020 research and innovation programme under grant agreement No 101016496, by Direccion ¿ General de Política Científica de la Generalitat Valenciana (PROMETEO 2020/043), and by the ¿Programa Salvador de Madariaga 2018¿¿ of the Spanish Ministry of Science, Innovation and Universities (Grant Reference PRX18/00489).

The hippocampus is involved in the regulation of the autonomic nervous system, together with the hypothalamus and brainstem nuclei, such as the paraventricular nucleus and nucleus tractus solitarius. The vagus nerve-nucleus tractus solitarius pathway has an important role in cardiovascular reflex regulation. Myocardial ischemia has been shown to cause changes in the autonomic nervous system, affecting the dynamic equilibrium of the sympathetic and vagal nerves. However, it remains poorly understood how the hippocampus communicates with brainstem nuclei to regulate the autonomic nervous system and alleviate myocardial ischemic tissue damage. A rat model of acute myocardial ischemia (AMI) was made by ligating the left anterior descending branch of the coronary artery. Three days before ischemia, the hippocampal CA1 region was damaged. Then, 3 days after ischemia, electroacupuncture (EA) at Shenmen (HT7)-Tongli (HT5) was performed (continuous wave, 1 mA, 2 Hz, duration of 30 minutes). Cluster analysis of firing patterns showed that one type of neuron was found in rats in the sham and AMI groups. Three types of neurons were observed in the AMI + EA group. Six types of neurons were found in the AMI + EA + Lesion group. Correlation analysis showed that the frequency of vagus nerve discharge in each group was negatively correlated with heart rate (HR) (P < 0.05, r = −0.424), and positively correlated with mean arterial pressure (MAP) (P < 0.05, r = 0.40987) and the rate-pressure product (RPP) (P < 0.05, r = 0.4252). The total frequency of the nucleus tractus solitarius discharge in each group was positively correlated with vagus nerve discharge (P < 0.01, r = 0.7021), but not with hemodynamic index (HR: P > 0.05, r = −0.03263; MAP: P > 0.05, r = −0.08993; RPP: P > 0.05, r = −0.03263). Some neurons (Neuron C) were negatively correlated with vagus nerve discharge, HR, MAP and RPP in the AMI + EA group (vagus nerve discharge: P < 0.05, r = −0.87749; HR: P < 0.01, r = −0.91902; MAP: P < 0.05, r = −0.85691; RPP: P < 0.01, r = −0.91902). Some neurons (Neurons C, D and E) were positively correlated with vagus nerve discharge, HR, MAP and RPP in the AMI + EA + Lesion group (vagus nerve discharge: P < 0.01, r = 0.8905, P < 0.01, r = 0.9725, P < 0.01, r = 0.9054; HR: P < 0.01, r = 0.9347, P < 0.01, r = 0.9089, P < 0.05, r = 0.8247; MAP: P < 0.05, r = 0.8474, P < 0.01, r = 0.9691, P < 0.01, r = 0.9027; RPP: P < 0.05, r = 0.8637, P < 0.01, r = 0.9407, P < 0.01, r = 0.9027). These findings show that the hippocampus-nucleus tractus solitarius-vagus nerve pathway is involved in the cardioprotective effect of EA at the heart meridian. Some interneurons in the nucleus tractus solitarius may play a particularly important role in the cardiomodulatory process.

Sudden cardiac death (SCD) is the leading cause of death worldwide. Myocardial ischemia (MI) is the most common underlying causal disorder for SCD. Metabolic risks leading to SCD during acute MI are still not fully understood. Here, using tissue metabolomics, we aimed to investigate myocardial metabolic alterations relevant to SCD events in an acute MI rat model induced by coronary artery ligation (CAL). Thirty-four rats were successfully performed CAL, of which 13 developed lethal ventricular tachyarrhythmia (LVTA)-SCD and 7 developed severe atrioventricular block (AB)-SCD. Fourteen rats that survived within 70 min after the ligation were served as peer controls. The partial least squares-discriminant analysis plots demonstrated clear separations between the SCD rats and controls, indicating obvious differences in myocardial metabolome between these rats. The levels of isoleucine, lactate, glutamate choline, phosphorylcholine, taurine and asparagine in ischemic myocardia were positively associated with LVTA-SCD events; in contrast, the levels of alanine, urea, phenylalanine, linoleic acid, elaidic acid and stearic acid were inversely correlated with LVTA-SCD events. The levels of glutamate and urea were positively and negatively relevant to AB-SCD events, respectively. The dangerous metabolites indicated that lower levels of energy substrates, severe hypoxia, the inhibition of transamination and hyper sympathetic excitement and reactive oxygen species in myocardia were vulnerable to SCD during acute MI. The results suggest fatal metabolic alterations correlated with SCD events during acute MI, which could offer novel clues for the prevention or treatment of acute MI-related SCD.

Acute coronary syndrome (ACS) is an acute and severe manifestation of coronary artery disease (CAD); thus, timely diagnosis can save a life. Commonly, cardiac troponin T (CTnT), cardiac troponin I (CTnI) or creatine kinase muscle/brain subtype (CK-MB) have been used as cardiac biomarkers to assess ACS with certain limitations, such as increased time to rise for diagnosis and increased levels in the patients with chronic kidney disease (CKD). Recently, micro-ribonucleic acids (miRNAs) have become potential candidates as biomarkers for cardiac ischemia due to their remarkable stability and reproducibility. Certain miRNAs, for instance, miR-1, miR-133a/b, miR-208a/b, and miR-499a, strongly increase in the serum or plasma of patients with acute cardiac ischemia, making them as cardio-specific miRNAs and prospective biomarkers in ACS. This literature review gives enlightenment about the regulation of cardio-specific miRNA in acute myocardial ischemia (AMI) and correlation with common cardiac biomarkers and time at which they increase in the blood.

Emerging evidence highlights the role of gut microbiota in regulating the pathogenesis of coronary heart disease. Here, we performed 16S rRNA gene sequencing and UPLC-Q-TOF/MS-based metabolomics to investigate the gut microbiome and metabolomes of cecal contents in the isoproterenol (ISO)-induced acute myocardial ischemia (AMI) rats. As expected, considerable gut microbiota alterations were observed in the AMI rats compared with the control rats, paralleling with intestinal inflammation and apoptosis. At phylum level, the abundance of Firmicutes was significantly decreased, whereas the abundance of Bacteroidetes and Spirochaetae was strikingly enriched in the AMI group. At genus level, the significant alteration of genera Treponema 2, Rikenellaceae RC9 gut group, Prevotellaceae UCG-003, and Bacteroides may contribute to the pathogenesis of AMI. These altered microbiota might influence the intestinal permeability and subsequently impair intestinal barrier and stimulate gut inflammation. Consistently, significantly metabolic differences of cecal contents between the AMI and control groups were revealed, and threonic acid, L-urobilin and L-urobilinogen were considered the most associated cecal metabolites with AMI. These strikingly altered metabolites were mainly related to energy metabolism and oxidative stress which could lead to apoptosis and further affect gut barrier. Ultimately, we revealed the potential link of these altered gut microbiota/metabolomes and intestinal inflammatory factors and apoptotic proteins and further confirmed their intimate connections with intestinal inflammation and gut barrier. Our findings depict uncovered potential relationship among the gut microbiome, cecal metabolomes and AMI.

Background: Acoustic cardiography is a hybrid technique that couples heart sounds recording with ECG providing insights into electrical-mechanical activity of the heart in an unsupervised, non-invasive and inexpensive manner. During myocardial ischemia hemodynamic abnormalities appear in the first minutes and we hypothesize a putative diagnostic role of acoustic cardiography for prompt detection of cardiac dysfunction for future patient management improvement. Methods and Results: Ten female Swiss large white pigs underwent permanent distal coronary occlusion as a model of acute myocardial ischemia. Acoustic cardiography analyses were performed prior, during and after coronary occlusion. Pressure-volume analysis was conducted in parallel as an invasive method of hemodynamic assessment for comparison. Similar systolic and diastolic intervals obtained with the two techniques were significantly correlated [Q to min dP/dt vs. Q to second heart sound (r2 = 0.9583, p < 0.0001), PV diastolic filling time vs. AC perfusion time (r2 = 0.9686, p < 0.0001)]. Indexes of systolic and diastolic impairment correlated with quantifiable features of heart sounds [Tau vs. fourth heart sound Display Value (r2 = 0.2721, p < 0.0001) cardiac output vs. third heart sound Display Value (r2 = 0.0791 p = 0.0023)]. Additionally, acoustic cardiography diastolic time (AUC 0.675, p = 0.008), perfusion time (AUC 0.649, p = 0.024) and third heart sound Display Value (AUC 0.654, p = 0.019) emerged as possible indicators of coronary occlusion. Finally, these three parameters, when joined with heart rate into a composite joint-index, represent the best model in our experience for ischemia detection (AUC 0.770, p < 0.001). Conclusion: In the rapidly evolving setting of acute myocardial ischemia, acoustic cardiography provided meaningful insights of mechanical dysfunction in a prompt and non-invasive manner. These findings should propel interest in resurrecting this technique for future translational studies as well as reconsidering its reintroduction in the clinical setting., Frontiers in Physiology, 10, ISSN:1664-042X

Danshen (salvia miltiorrhiza) and honghua(Carthamus tinctorius) were traditional herb pair with promoting blood circulation and removing blood stasis actions, in China. Both were widely used to treat cardiovascular diseases (CVD) for hundreds years, especially shown definite advantage in the treatment of ischemic heart disease (IHD). However, the mechanism of danshen-honghua herb pair (DHHP) in the treatment of IHD was still unclear. This study was focused on examining the effects and possible mechanisms of DHHP in rats with acute myocardial ischemia induced by isoproterenol (ISO). The results suggested that DHHP significantly ameliorated the myocardial tissue abnormalities, notablely inhibited the elevation of lactate dehydrogenase (LDH), creatine kinase (CK), aspartate aminotransferase (AST), creatinekinase isoenzyme (CK-MB) and cardiac troponin T (CTn-T) in plasma, obviously decreased the plasma levels of Tumor Necrosis Factor α (TNF-α), outstandingly inhibited the reduction of superoxide dismutase (SOD), catalase (CAT) caused by ISO, significantly inhibited the high expression of Bcl-2 assaciated X protein (Bax) and nuclear transcriptionfactor-κBP65 (NF-κBP65) protein, significantly induced the low expression of B-cell lymphoma-2 (Bcl-2) protein in acute myocardial ischemia rats. DHHP can obviously ameliorate hemodynamic parameters. In summary, DHHP can significantly improve myocardial ischemia in acute myocardial ischemia model rats caused by ISO. Anti-free radicals, anti-peroxidation, inhibition of cell apoptosis and anti- inflammation maybe are the potential mechanisms of DHHP anti-myocardial ischemia in acute myocardial ischemia rats in duced by ISO.

The effects of intravenous high mobility group box 1 (HMGB1) on myocardial ischemia/reperfusion (I/R) injury remains to be elucidated. The purpose of the present study was to investigate the effects of intravenous HMGB1 on the expression of hypoxia inducible factor-1α (HIF-1α) in the myocardium of rats following acute myocardial ischemia, and to examine the effects of intravenous HMGB1 on myocardial I/R injury. Male Wistar rats were divided into the following groups: Sham operation group (n=10), a group exposed to ischemia for 30 min and reperfusion for 4 h (I/R group) as a control (n=10), an HMGB group, in which 100 ng/kg HMGB was administered intravenously 30 min prior to ischemia (n=10), an LY group, in which LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), was administered intravenously (0.3 mg/kg) 40 min prior to ischemia (n=10), and the HMGB1+LY group, in which HMGB1 (100 ng/kg) and LY294002 (0.3 mg/kg) were administered intravenously 30 min and 40 min prior to ischemia, respectively (n=10). The serum levels of cardiac troponin I (cTnI) and tumor necrosis factor-α (TNF-α), and myocardial infarct size were measured. The expression levels of phosphorylated Akt and HIF-1α were investigated using western blot analyses. The results showed that pre-treatment with HMGB1 significantly decreased serum levels of cTnI, and TNF-α, and reduced myocardial infarct size following 4 h reperfusion (all P

Date of Conference: 2-5 May 2018 In patients with acute myocardial ischemia, chest pains together with changes in ST/T sections of ECG signal occur before the start of myocardial infarction. In this study, in order to diagnose acute myocardial ischemia, a technique which automatically detects changes in ST/T sections of ECG is developed. For this purpose, by using ECG recordings of STAFF III database, ECG features that are critical in the detection of acute myocardial ischemia are identified. By using support vector machines (SVM) operating with linear and radial basis function (RBF) kernels, classifiers that use two and four most discriminating features of ST/T sections of ECG signal are designed. As a result of implementing the developed technique on ECG recordings of STAFF III database, obtained results over a considerable number of patients indicate that the proposed technique provides highly reliable detection of acute myocardial ischemia. Therefore, by using the developed technique, early and accurate diagnosis of acute myocardial ischemia can be performed, which can lead to a significant decrease in morbidity and mortality rates.

Trichosanthes pericarpium (TP) had been widely used to cure patients of cardiovascular disease for 2,000 years in China. This study aims to extend our previous work to explore the mechanism underlying the protective effect of TP on acute myocardial ischemia (AMI). We hypothesized that TP may display its protective effect on AMI by promoting the mobilization of endothelial progenitor cells (EPC) via up-regulating the expression level of vascular endothelial growth factor (VEGF), endothelial nitric oxide syntheses (eNOS), nitric oxide (NO), and matrix metalloproteinase 9 (MMP-9) in AMI rats. To confirm this hypothesis, we treated AMI model rats with intragastrical administration of TP aqueous extract (TPAE), and examined both changes in the number of CEPC, and the expression levels of VEGF, eNOS, NO, and MMP-9 in myocardial tissue and their plasma content in these rats. Rats in each group were randomly divided into seven subgroups. From day 1 to 7 following AMI modeling, rats in these subgroups was sequentially phlebotomized from their celiac artery after being anesthetized by chloral hydrate. We found that, compared with the AMI model rats, in rats treated by TPAE, the CEPC counts, the expression of VEGF, eNOS, NO, and MMP-9 in myocardial tissue and their plasma content all increased more rapidly 7 days after AMI and remained at higher level (P < 0.05 or P < 0.01). Our results showed that, in AMI rats, the TPAE could significantly promote the mobilization of EPC and up-regulate the expression level of VEGF, eNOS, NO, and MMP-9 in myocardium and their plasma content. Therefore, our results suggest that TAPE may regulate EPC mobilization through up-regulating the expression level of VEGF, eNOS, NO and MMP-9 in the myocardium of AMI rats.

Hydrogen sulfide (H2S) is believed to be involved in numerous physiological and pathophysiological processes, and now it is recognized as the third endogenous signaling gasotransmitter, following nitric oxide and carbon monoxide; however, the effects of H2S on inflammatory factors in acute myocardial ischemia injury in rats have not been clarified. In the present study, sodium hydrosulfide (NaHS) was used as the H2S donor. Thirty-six male Sprague Dawley rats were randomly divided into five groups: Sham, ischemia, ischemia + low-dose (0.78 mg/kg) NaHS, ischemia + medium-dose (1.56 mg/kg) NaHS, ischemia + high-dose (3.12 mg/kg) NaHS and ischemia + propargylglycine (PPG) (30 mg/kg). The rats in each group were sacrificed 6 h after the surgery for sample collection. Compared with the ischemia group, the cardiac damage in the rats in the ischemia + NaHS groups was significantly reduced, particularly in the high-dose group; in the ischemia + PPG group, the myocardial injury was aggravated compared with that in the ischemia group. Compared with the ischemia group, the levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) in the serum of rats in the ischemia + medium- and high-dose NaHS groups were significantly reduced, and the expression of intercellular adhesion molecule-1 (ICAM-1) mRNA and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) protein in the myocardial tissues of rats was significantly reduced. In the ischemia + PPG group, the TNF-α, IL-1β and IL-6 levels in the serum were significantly increased, the expression of ICAM-1 mRNA was increased, although without a significant difference, and the expression of NF-κB was increased. The findings of the present study provide novel evidence for the dual effects of H2S on acute myocardial ischemia injury via the modulation of inflammatory factors.

Abstact Background To evaluate the left ventricular (LV) longitudinal function changes in rabbits after acute occlusion of the left anterior descending artery (LAD) by two-dimensional speckle tracking imaging (2D–STI). Methods Forty-eight New Zealand white rabbits underwent echocardiography examination. EchoPAC was used to measure LV peak systolic longitudinal strain (LS) of the endocardium, middle myocardium, and epicardium, peak longitudinal strain rate (LSr), segmental and global longitudinal rotation (LR) degrees. Ligated the LAD and repeated all measurements after 10 min. Results Peak LS and LSr were significantly different between the preoperative and postoperative rabbits among most LV walls (P

Objective A new cardiac “electrical” biomarker (CEB) for detection of 12-lead electrocardiogram (ECG) changes indicative of acute myocardial ischemic injury has been identified. Objective was to test CEB diagnostic accuracy. Methods This is a blinded, observational retrospective case-control, noninferiority study. A total of 508 ECGs obtained from archived digital databases were interpreted by cardiologist and emergency physician (EP) blinded reference standards for presence of acute myocardial ischemic injury. CEB was constructed from three ECG cardiac monitoring leads using nonlinear modeling. Comparative active controls included ST voltage changes (J-point, ST area under curve) and a computerized ECG interpretive algorithm (ECGI). Training set of 141 ECGs identified CEB cutoffs by receiver-operating-characteristic (ROC) analysis. Test set of 367 ECGs was analyzed for validation. Poor-quality ECGs were excluded. Sensitivity, specificity, and negative and positive predictive values were calculated with 95% confidence intervals. Adjudication was performed by consensus. Results CEB demonstrated noninferiority to all active controls by hypothesis testing. CEB adjudication demonstrated 85.3–94.4% sensitivity, 92.5–93.0% specificity, 93.8–98.6% negative predictive value, and 74.6–83.5% positive predictive value. CEB was superior against all active controls in EP analysis, and against ST area under curve and ECGI by cardiologist. Conclusion CEB detects acute myocardial ischemic injury with high diagnostic accuracy. CEB is instantly constructed from three ECG leads on the cardiac monitor and displayed instantly allowing immediate cost-effective identification of patients with acute ischemic injury during cardiac rhythm monitoring.

The potential of nitric oxide (NO) as a rapid assay biomarker, one that could provide a quantum leap in acute care, remains largely untapped. NO plays a crucial role as bronchodilator, vasodilator and inflammatory mediator. The main objective of this review is to demonstrate how NO is a molecule of heavy interest in various acute disease states along the emergency department and critical care spectrum: respiratory infections, central nervous system infections, asthma, acute kidney injury, sepsis, septic shock, and myocardial ischemia, to name just a few. We discuss how NO and its oxidative metabolites, nitrite and nitrate, are readily detectable in several body compartments and fluids, and as such they are associated with many of the pathophysiological processes mentioned above. With methods such as high performance liquid chromatography and chemiluminescence these entities are relatively easy and inexpensive to analyze. Emphasis is placed on diagnostic rapidity, as this relates directly to quality of care in acute care situations. Further, a rationale is provided for more bench, translational and clinical research in the field of NO biomarkers for such settings. Developing standard protocols for the aforementioned disease states, centered on concentrations of NO and its metabolites, can prove to revolutionize diagnostics and prognostication along a spectrum of clinical care. We present a strong case for developing these biomarkers more as point-of-care assays with potential of color gradient test strips for rapid screening of disease entities in acute care and beyond. This will be relevant to global health.

У статті представлені дані сучасних джерел літератури про методи визначення гострої ішемії міокарда. Описано їх діагностичні можливості, переваги та недоліки при проведенні судово-медичних експертиз для діагностики причини настання смерті., В статье представлены данные современных литературных источников о методах определения острой ишемии миокарда. Описаны их диагностические возможности, преимущества и недостатки при проведении судебно-медицинских экспертиз для диагностики причины наступления смерти., This article presents modern literature sources on methods for determining acute myocardial ischemia. The diagnostic capabilities as well as the advantages and disadvantages when performing forensic medical examinations for cause of death have been highlighted.

Background: The aim of the study was to evaluate the impact of different plasma glucose levels on heart rate (HR) in experimental rats with acute myocardial infarction (AMI). Methods: One hundred and twenty-one male Wistar rats were randomly divided into AMI group (n = 70) and sham-operation group (n = 51). Both groups had low, normal and high glucose levels, respectively. In the former group, hypertonic glucose was injected into the rats to make their blood glucose levels above 16 mmol/L and insulin below 3.3 mmol/L; then, the left anterior descending artery was ligated. In the later group, the models of different blood glucose levels were the same as the former ones, but false operations, thread without ligating, were given to the rats. Electrocardiogram and troponin I (TnI) confirmed that the models were prepared successfully. Electrocardiogram expression of AMI was the formation of Q-wave in over three adjacent leads and abnormal elevation of TnI. Results: The HR of the rats in the hypoglycemic group is higher than that of the hyperglycemic group and normal blood glucose group before AMI (P < 0.05). The HR of the hyperglycemic rats is higher than that of the hypoglycemic group and normal blood glucose group after AMI (P < 0.05). In the hypoglycemic group, the HR of the rats who suffered from AMI was lower than that of the rats of the sham group (P < 0.05). Conclusion: Hypoglycemia allows faster HR and the HR in the rats with hyperglycemia is higher than that in the rats with hypoglycemia among the AMI rats. Cardiol Res. 2016;7(4):146-151 doi: http://dx.doi.org/10.14740/cr488w

The present study aimed to determine the effects of high mobility group box 1 protein (HMGB1) on myocardial ischemia reperfusion (I/R) injury in rats following acute myocardial ischemia and investigate the underlying molecular mechanisms of these effects. Male Wistar rats were randomly divided into the following groups (n=10/group): Sham operation; I/R; HMGB50 (50 ng/kg HMGB1 before I/R); HMGB100 (100 ng/kg HMGB1 before I/R); and HMGB200 (200 ng/kg HMGB1 before I/R). Serum cardiac troponin I (cTnI), interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels were subsequently measured. Myocardial levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were also determined. Myocardial infarction size (IS) was determined by 2,3,5-triphenyltetrazolium chloride staining. Myocardial expression of hypoxia inducible factor (HIF)-1α and phosphorylated p38 mitogen-activated protein kinase (P-p38 MAPK) protein was measured using western blotting. The results demonstrated that HMGB1 significantly decreased serum levels of cTnI, IL-6 and TNF-α and myocardial IS in I/R rats compared with the sham group (all P

The purpose of this review was to provide a critical evaluation of medical literature on so-called “cardiac cephalgia” or “cardiac cephalalgia”. The 2004 International Classification of Headache Disorders codes cardiac cephalgia to 10.6 in the group of secondary headaches attributed to disorder of homoeostasis. This headache is hardly recognizable and is associated to an ischaemic cardiovascular event, of which it may be the only manifestation in 27% of cases. It usually occurs after exertion. Sometimes routine examinations, cardiac enzymes, ECG and even exercise stress test prove negative. In such cases, only a coronary angiogram can provide sufficient evidence for diagnosis. Cardiac cephalgia manifests itself without a specific pattern of clinical features: indeed, in this headache subtype there is a high variability of clinical manifestations between different patients and also within the same patient. It “mimics” sometimes a form of migraine either accompanied or not by autonomic symptoms, sometimes a form of tension-type headache; on other occasions, it exhibits characteristics that can hardly be interpreted as typical of primary headache. Pain location is highly variable. When the headache occurs as the only manifestation of an acute coronary event, the clues for suspicion are a) older age at onset, b) no past medical history of headache, c) presence of risk factors for vascular disorders and d) onset of headache under stress. Knowledge of cardiac cephalgia is scarce, due to its rare clinical occurrence and to the scant importance given to headache as a symptom concomitantly with an ischaemic cardiac event.

The endogenous signaling gasotransmitter, hydrosulfide (H2S), has been shown to exert cardioprotective effects against acute myocardial infarction (AMI) due to ischemic injury. However, the mechanisms responsible for these effects are not yet fully understood. In this study, we investigated whether sodium hydrogen sulfide (NaHS), an H2S donor, attenuates acute myocardial ischemic injury through glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling. For this purpose, we utilized an in vivo rat model of AMI by occluding the left anterior descending coronary artery. NaHS (0.39, 0.78 or 1.56 mg/kg, intraperitoneally), the GSK-3β inhibitor, SB216763 (0.6 mg/kg, intravenously), or 1% dimethylsulfoxide (2 ml/kg, intravenously) were administered to the rats. The results demonstrated that the administration of medium- and high-dose NaHS and SB216763 significantly improved rat cardiac function, as evidenced by an increase in the mean arterial pressure, left ventricular developed pressure, contraction and relaxation rates, as well as a decrease in left ventricular end-diastolic pressure. In addition, the administration of NaHS and SB216763 attenuated myocardial injury as reflected by a decrease in apoptotic cell death and in the serum lactate dehydrogenase concentrations, and prevented myocardial structural changes. The administration of NaHS and SB216763 increased the concentrations of phosphorylated (p-)GSK-3β, the p-GSK-3β/t-GSK-3β ratio and downstream protein β-catenin. Moreover, western blot and immunohistochemical analyses of apoptotic signaling pathway proteins further established the cardioprotective potential of NaHS, as reflected by the upregulation of Bcl-2 expression, the downregulation of Bax expression, and a decrease in the number of TUNEL-positive stained cells. These findings suggest that hydrosulfide exerts cardioprotective effects against AMI-induced apoptosis through the GSK-3β/β-catenin signaling pathway.

Ventricular fibrillation (VF) is most frequent in the very early phase in acute coronary occlusion, and is triggered by the re-entrant mechanism in this phase. An inhomogeneous conduction in the ischemic myocardium would be substrates for re-entry. The aim of this study was to examine the relationship between the severity of irregularities of the QRS complex and VF. Eleven pigs were analyzed, and the heart was fixed in the pericardial cradle. Ag-AgCI bipolar electrodes were fixed on the epicardium in ischemic and non-ischemic regions. The proximal portion of the left anterior descending coronary artery was occluded for one hour. Electrocardiograms (ECGs) were continuously recorded on a magnetic tape, and wavelet analysis was performed on signal-averaged ECG (25 beats) every 60 sec after the experiment. The number of local maxima (N) and the duration between the first and the last local maximum (D) were automatically measured. Nand D significantly increased in the ischemic area, but not in the non-ischemic area. Nand D increased approximately twofold just before the occurrence of VF in 8 fibrillated pigs (p < 0.01, each). There were significant positive linear relationships between the rate of increase in Nand D to VF and basal heart rate before coronary occlusion (r = 0.90, P < 0.01 in N, r = 0.84, P < 0.01 in D at 160 Hz). These results suggest that there would be a threshold inhomogeneous conduction for the occurrence of VF and an increase in heart rate would accelerate the inhomogeneous conduction in acute myocardial ischemia.

Mortality rates associated with off‑pump coronary artery bypass (CAB) are relatively high, as the majority of patients requiring CAB are at a high risk for cardiac events. The present study aimed to establish porcine models of acute myocardial ischemia, and evaluate the protective role of shunt and active perfusion. A total of 30 pigs were randomly assigned to five groups, as follows: i) Sham (control); ii) A1 (shunt; stenosis rate, 55%); iii) A2 (shunt; stenosis rate, 75%); iv) B1 (active perfusion; stenosis rate, 55%); and v) B2 (active perfusion; stenosis rate, 75%) groups. Aortic pressure (P0), left anterior descending coronary pressure (P1), and coronary effective perfusion pressure (P1/P0) were measured. The expression levels of tumor necrosis factor‑α (TNF‑α), cardiac troponin (cTnI), creatine kinase‑myocardial band (CK‑MB), interleukin (IL)‑6, IL‑10, B‑cell lymphoma 2 (Bcl‑2), and caspase‑3 were detected using enzyme‑linked immunosorbent assay or western blotting. The myocardial apoptosis rate was determined using the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Ischemia models with stenosis rates of 55 and 75% were successfully constructed following suturing of the descending artery. Compared with the control, the 55 and 75% stenosis groups demonstrated significantly decreased P1/P0, increased expression levels of TNF‑α, cTnI, CK‑MB, IL‑6, IL‑10 and caspase‑3, an increased rate of myocardial apoptosis, and a decreased expression level of anti‑apoptotic protein, Bcl‑2. At 30 min following successful establishment of the model (ST segment elevation to 1 mm), group B demonstrated significantly increased P1/P0, decreased expression levels of TNF‑α, cTnI, CK‑MB, IL‑6, IL‑10 and caspase‑3, a decreased rate of myocardial apoptosis, and an increased expression level of anti-apoptotic protein, Bcl‑2. Furthermore, the current study indicated that active perfusion was more efficacious in maintaining myocardial perfusion and alleviating ischemic injury when compared with traditional shunt perfusion.

Background: Plasma proBNP levels are increased in patients with acute myocardial infarction. Previous studies have shown conflicting data on the effect of transient myocardial ischemia on plasma BNP levels. We designed the current study to examine plasma proBNP levels in patients with transient myocardial ischemia during a percutaneous coronary intervention (PCI). This study was to study plasma proBNP as a marker of transient myocardial ischemia. Methods: We enrolled 49 consecutive patients with a history of angina or abnormal stress test who presented for cardiac catheterization. We obtained plasma proBNP levels in all patients at 1) arterial access (proBNP-1), 2) the end of the procedure (proBNP-2) and 3) 4 hours after procedure (proBNP-3). Hotelling’s T-squared test was used to evaluate the equality of means. Log transforms of proBNP were used to impart data normality. Results: Twenty-two patients underwent diagnostic catheterization (DCA group) and 27 underwent PCI (PCI group). Both groups had normal left ventricular function and a baseline creatinine < 2 mg/dL. Baseline log (proBNP) was 4.7 + 0.99 (units) and rose significantly at 4 hours in both groups (P < 0.02), with no difference in rate of change. Conclusions: Plasma proBNP was increased in both DCA and PCI groups which limits its utility to identify transient myocardial ischemia. The etiology of increase in proBNP in both groups is speculative and may be related to injection of radiographic contrast media into the coronary artery which leads to microcirculatory impairment resulting in myocardial tissue hypoxia and transient increase in left ventricular pressure; however, further evaluation is required. J Clin Med Res. 2015;7(7):506-510 doi: http://dx.doi.org/10.14740/jocmr2024w

Background In patients with symptoms compatible with acute myocardial infarction (MI), early triage by ECG in the pre-hospital phase by ST-segment elevation myocardial infarction (STEMI) criteria is important for direct transport of these patients to a regional center for primary percutaneous coronary intervention (pPCI). The time from first medical contact to pPCI should, due to present guidelines, be no longer than two hours. One main determinant of final infarct size (IS), in addition to myocardium at risk (MaR) and time to treatment, is the severity of ischemia, which relates to the rate of progression of the infarction wavefront. Presently, no assessment of severity is made. Patients with severe ischemia may have changes within the QRS complex in addition to ST-T changes, making it possible to identify these high-risk patients. QRS changes are, however more difficult to determine and to quantify correctly as compared to the changes within the ST segment. Aims and methods The overall objective was to increase the understanding of depolarization changes during myocardial ischemia and to evaluate whether these changes have possible clinical implications in patients with acute MI. Different QRS methods are applied in patients during ischemia produced by elective, prolonged PCI as well as during STEMI, and comparisons are made with conventional ECG parameters as well as single-photon emission computed tomography (SPECT) images. Results and conclusions Study I compared the computer-derived high-frequency QRS components (HF-QRS) in patients with and without standard ECG changes indicative of old MI. In contrast to previous findings we found that HF-QRS cannot differentiate between patients with and without old MI. Study II tested the ability of HF-QRS versus conventional ST-segment measurements to detect and quantify myocardial ischemia, as determined by SPECT, in a group of patients undergoing elective balloon PCI. We showed that HF-QRS can provide valuable information both for detecting acute ischemia and for quantifying MaR and its severity. Study III evaluated a potentially more readily available (compared with HF-QRS) new marker of ventricular depolarization distortion, which is based on calculation of up- and downslope within the QRS complex, in patients undergoing coronary intervention that includes temporary occlusion of a coronary artery. We found that in particular the downward slope between R and S waves better correlates with ischemia than conventional QRS parameters, as quantified by SPECT, and thus can be of value in risk stratification of patients with ischemia in addition to conventional ST-segment analysis. Study IV, in a large cohort of STEMI patients, assessed the value of the conventional Sclarovsky-Birnbaum ischemia grading system that includes terminal QRS distortion in addition to ST elevation, on pre-hospital ECG and its dynamic behavior during transport time to the PCI center for prediction of final infarct size and salvage, as estimated by SPECT imaging. The study explored the temporal behavior of the ischemia grading and showed the strong association of ischemia grade assessed from pre-hospital ECG, as well as the dynamic patterns, with infarct size, independent of ST-segment analysis. It also demonstrated the importance of early intervention, which was found to be particularly important in patients who had advanced, QRS-based ischemia grade. Bakgrund Den medicinska utvecklingen har varit stark under de senaste åren vad gäller akut omhändertagande av patienter med misstänkt hjärtinfarkt. Snabb teknisk utveckling inom området för kateterburen koronarkärlsintervention (PCI) och framsteg inom farmakologisk behandling har bidragit till allt bättre vårdresultat. Omedelbar och korrekt beslutsprocess har kommit att bli alltmer avgörande för att rädda hotad hjärtmuskelvävnad, och därmed avsevärt påverka patientens framtida liv. Beslut bör tas redan prehospitalt, för triagering av patienterna antingen till lokalt sjukhus eller till regionalt PCI-center. Detta ställer mycket höga krav på tillförlitlig diagnostisk. Den undersökning som ger mest information i den akuta situationen är 12-avlednings EKG, som är ett enkelt, lättillgängligt och icke-invasivt diagnosredskap vid sidan om patientens sjukdomshistoria och aktuella symtom. I den akuta situationen ses vanligen ingen diagnostiskt värdefull information i hjärtspecifika blodprover. Den förhärskande metoden att upptäcka akut hjärtinfarkt är att studera förändringar under repolarisationen (ST-T-sträckan) på EKG. Om vissa EKG-kriterier uppfylls för ST-sträckan (sk STEMI-kriterier), bör patienten helst så snart som möjligt behandlas med primär PCI. Detta kan ofta innebära lång transport av patienten till ett sjukhus där PCI kan utföras. I enlighet med både amerikanska och europeiska riktlinjer bör man eftersträva att patienterna får sådan behandling inom 2 timmar från första EKG där STEMI-kriterier verifierats. Telemedicin med digital överföring av akuta EKG tagna i patientens hem, i ambulansen alternativt på lokalt sjukhus underlättar för att effektivisera denna process. Idag ges alla patienter liknande avlastande behandling under transporten. Vissa patienter har emellertid mera allvarlig syrebrist (ischemi) i hjärtat än andra, vilket får till följd att en större andel av hjärtmuskelvävnaden utsatt för syrebrist kommer att gå under (infarcera) per tidsenhet innan man kommer till PCI-behandlingen. Genom att även analysera andra delar av hjärtcykeln med EKG (depolarisationen, dvs QRS komplexet), finns det möjligheter att identifiera dessa högriskpatienter och i framtiden eventuellt kunna skräddarsy mera intensiv, kompletterande behandling redan under transporten. Denna kunskap skulle kunna nyttjas i stor omfattning och adderas till utvecklingen av akut hjärtinfarktbehandling globalt. Övergripande syfte och ingående patientgrupper Avhandlingens övergripande mål var att utvärdera metoder för att extrahera mer information från EKG-signalen under depolarisationen (QRS-komplexet), som additivt diagnostiskt hjälpmedel till dagens repolarisationsanalys (ST-T sträckan). I de olika delarbetena studerades patienter med olika typer av akut ischemi, dels i en mindre population under planerad och kontrollerad ballongvidgning av ett kranskärl (Studie II och III), dels i en betydligt större patientgrupp med akut pågående hjärtinfarkt (STEMI) i Studie IV. I dessa populationer fanns multipla kliniska variabler liksom kvantifiering av graden av ischemi med myokardscintigrafi (SPECT). I Studie I analyserades patienter dessutom under vilobetingelser avseende olika typer av QRS-förändringar som tyder på äldre hjärtinfarkt. Generellt sett är QRS-förändringar svårare att karakterisera och mäta än de som ses under ST-sträckan. Inom QRS-komplexet i ett standard-EKG kan man mäta skillnader i amplitud av ingående komponenter samt deras durationer. Båda, men i synnerhet den sistnämnda har felkällor, varför det finns behov av ett mera övergripande och tillförlitligt QRS-mått. I denna avhandling har QRS-komplexet analyserats utifrån både konventionellt, standard-EKG, samt de två mer tekniskt avancerade analysmetoderna högfrekvens-EKG (HF-QRS) och QRS-slope metoden. Dessa metoder värderades under akut ischemi, pågående och tidigare infarkt. Den förstnämnda, standard-EKG baserade metoden, sk Sclarovsky-Birnbaum (S-B) graderingen av ischemi, värderar allvarlighetsgraden av ischemi under ett akut hjärtinfarktskede. Denna metod är sedan tidigare beskriven, men har ännu inte kommit att användas i klinisk praxis. Specifika mål Delarbete I: Studera om man med hjälp av HF-QRS metoden han differentiera mellan patienter med en tidigare genomgången hjärtinfarkt och de som inte haft någon infarkt, där själva infarktdiagnosen verifierats med vanligt standard-EKG. Delarbete II: Värdera om förändringar av HF-QRS vid akut ischemi är associerade till dess utbredning och allvarlighetsgrad. Delarbete III: Studera hur den, jämfört med HF-QRS- metoden, mindre bruskänsliga och mera kliniskt lättillgängliga QRS-slope- metoden, kan användas för att värdera utbredning och allvarlighetsgrad av akut ischemi. Delarbete IV: Undersöka hur depolarisationförändringarna som ingår i S-B graderingen av ischemi varierar över tid (från ambulans-EKG till EKG taget senare på mottagande sjukhus just innan PCI behandlingen). Vidare studera det kliniska värdet av tidig hjärtinfarktgradering, dels utifrån ambulans-EKG, men även värdet av själva dynamiken under transporten fram till PCI behandlingen. Testa om denna EKG-information relaterar till faktisk allvarlighetsgrad, dvs hastighet av infarktutveckling och behandlingsresultatet av akut PCI inklusive slutlig infarktstorlek. Fynd och sammanfattning Studie I visade att vid värdering av en större patientpopulation och med fler EKG- avledningar jämfört med tidigare, liknande studier, kunde vi, till skillnad från tidigare resultat, med hjälp av HF-QRS inte differentiera mellan patienter med och utan tecken till tidigare hjärtinfarkt. I Studie II fann vi att högfrekvenskomponenter inom QRS komplexet sjunker vid ischemi. Graden av förändringen visar signifikant korrelation med både utbredning och svårighetsgrad av ischemin kvantifierad med SPECT med högre korrelationskoefficient än konventionella ST-förändringar. Med den betydligt mera bruståliga och därmed mera kliniskt lättillgängliga QRS-slope metoden, kunde vi i Studie III konstatera att förändringar i synnerhet vad gäller nedåtgående lutningen av R vågen uppvisar signifikant korrelation med både utbredning och svårighetsgrad av ischemin kvantifierad med SPECT, som är starkare än för övriga, konventionella QRS parametrar i standard-EKG och adderar information till ST-analys. Studie IV visade att “QRS distortion”, som ingår i den allvarligaste grad 3 i S-B ischemigradering, uppvisar en dynamik mellan ambulans-EKG och EKG precis innan PCI-behandlingen. Patienter med grad 3-ischemi redan vid tidig EKG värdering i ambulansen, liksom de som uppvisade en dynamik där de bibehöll eller utvecklade denna grad under transporten, utvecklade större infarkter än de som inte hade dessa EKG-förändringar. Detta trots motsvarande storlek av det ischemiska området och samma tid från symtomdebut till PCI behandling. Vidare kunde vi konstatera att det är avhängigt graden av ischemi hur snabbt infarkten utvecklar sig, och hur stor del av det hotade hjärtmuskelområdet man därigenom kan rädda med hjälp av att öppna det stängda kranskärlet med PCI. Patienter som behandlades inom 2.5 timmar från symtomdebut uppvisade samma behandlingseffekt av PCI oavsett ischemigrad. Vid behandling senare än 2.5 timmar såg vi däremot sämre resultat för den grupp av patienter som hade grad 3 ischemi på ambulans EKG jämfört med patienter som hade grad 2 ischemi. Avhandlingen visar att uttalad akut ischemi ger förändringar under själva depolarisationen som kan kvantifieras. Då analysmetoden för HF-QRS är relativt bruskänslig och därmed kräver avancerad medelvärdesberäkning, testades en nyutvecklad QRS-slopemetod, som vi bedömer kunna ge likvärdig information på ett mera lättillgängligt och tillförlitligt sätt. Den lämpar sig främst för att följa förändringar under pågående EKG-monitorering, men kan även nyttjas i bedömning av ett enskilt EKG om det finns ett tidigare, jämförande EKG. Resultaten från Studie IV indikerar att grad 3-ischemi som noteras tidigt kan indikera allvarlig ischemi med snabb infarktutveckling. Fler studier behövs både för att vidare applicera QRS-slope metoden i ett mera kliniskt sammanhang och för att få ytterligare förståelse för hur förändringar i den senare delen av QRS-komplexet bäst kan nyttjas för riskvärdering av patienter med akut hjärtinfarkt.

Ischemic cardiopathies are a major cause of cardiovascular mortality potentially leading tosudden death by ventricular fibrillation (VF). In patients with coronary disease, onetherapeutic goal is to reduce oxygen requirements via slowing of heart rate (SHR). Severalmedicinal drugs, such as beta-blockers and calcium inhibitors can achieve this goal, but canresult in altered cardiac contractility and various adverse effects, which restricts their use. Wefocused our interest on the effects of a selective inhibitor of the pacemaker current If, namelyivabradine (IVA), which can reduce sinusal heart rate. The aim of the present work was toevaluate the impact of SHR on the propensity to VF and to better understand thephysiological and metabolism mechanisms involved. The first study was performed on a pigmodel of acute myocardial ischemia leading to VF. In the second study, the impact of SHRwas evaluated using a mouse model of isolated perfused working heart. Our resultsdemonstrated that IVA induced SHR in both models and this was associated in vivo withenhanced coronary flow, conservation of mitochondrial structure and myocardial energeticstatus, thus reducing the risk of triggering ischemia-induced VF. Moreover, ex vivo, theobserved SHR did not change the selection of substrates for energy production. From atherapeutic point of view, it is critical to improve the conditions within tissues and to reducethe loss of substrates during myocardial ischemia. IVA apparently met this goal. Indeed, viaspecific effects on sinusal automaticity, it can act both preventively and curatively, Les cardiopathies ischémiques sont une cause majeure de mortalité cardiovasculaire pouvantaboutir à la mort subite par fibrillation ventriculaire (FV). Un des objectifs thérapeutiqueschez les coronariens est de diminuer la demande en O2 par réduction de la fréquencecardiaque (RFC). Plusieurs médicaments dont les bêta-bloquants et inhibiteurs calciquesrépondent à cet objectif, mais peuvent être responsable d’altération de la contractilitécardiaque et d’effets secondaires limitant leur utilisation. Nous nous sommes intéressés auxeffets d’un inhibiteur sélectif du courant pacemaker If, l’ivabradine (IVA) dontl’administration induit une RFC sinusale. L’objectif de ce travail a été d’évaluer l’impact dela RFC sur la propension à la FV et de comprendre les mécanismes fonctionnels etmétaboliques impliqués. Un premier travail a été réalisé sur un modèle d’ischémiemyocardique aigue. Dans un second travail l’impact de la RFC sur la sélection des substratspour la production d’énergie a été évalué sur coeur isolé et perfusé en mode travaillant. Nosrésultats démontrent que l’IVA dans les deux modèles a induit une RFC qui était associée invivo à une amélioration de la perfusion coronaire, une préservation de la structuremitochondriale et du statut énergétique myocardique, réduisant la propension à la FV. Exvivo, la RFC n’a pas modifié la sélection des substrats et le statut énergétique. Enthérapeutique, il est important d’améliorer les conditions tissulaires et de réduire la perte desubstrats lors d’ischémie myocardique, l’IVA semble répondre à cette attente. Son effetspécifique sur l’automaticité sinusale lui confère la possibilité d’agir en préventif et en curatif

Ischemic cardiopathies are a major cause of cardiovascular mortality potentially leading tosudden death by ventricular fibrillation (VF). In patients with coronary disease, onetherapeutic goal is to reduce oxygen requirements via slowing of heart rate (SHR). Severalmedicinal drugs, such as beta-blockers and calcium inhibitors can achieve this goal, but canresult in altered cardiac contractility and various adverse effects, which restricts their use. Wefocused our interest on the effects of a selective inhibitor of the pacemaker current If, namelyivabradine (IVA), which can reduce sinusal heart rate. The aim of the present work was toevaluate the impact of SHR on the propensity to VF and to better understand thephysiological and metabolism mechanisms involved. The first study was performed on a pigmodel of acute myocardial ischemia leading to VF. In the second study, the impact of SHRwas evaluated using a mouse model of isolated perfused working heart. Our resultsdemonstrated that IVA induced SHR in both models and this was associated in vivo withenhanced coronary flow, conservation of mitochondrial structure and myocardial energeticstatus, thus reducing the risk of triggering ischemia-induced VF. Moreover, ex vivo, theobserved SHR did not change the selection of substrates for energy production. From atherapeutic point of view, it is critical to improve the conditions within tissues and to reducethe loss of substrates during myocardial ischemia. IVA apparently met this goal. Indeed, viaspecific effects on sinusal automaticity, it can act both preventively and curatively, Les cardiopathies ischémiques sont une cause majeure de mortalité cardiovasculaire pouvantaboutir à la mort subite par fibrillation ventriculaire (FV). Un des objectifs thérapeutiqueschez les coronariens est de diminuer la demande en O2 par réduction de la fréquencecardiaque (RFC). Plusieurs médicaments dont les bêta-bloquants et inhibiteurs calciquesrépondent à cet objectif, mais peuvent être responsable d’altération de la contractilitécardiaque et d’effets secondaires limitant leur utilisation. Nous nous sommes intéressés auxeffets d’un inhibiteur sélectif du courant pacemaker If, l’ivabradine (IVA) dontl’administration induit une RFC sinusale. L’objectif de ce travail a été d’évaluer l’impact dela RFC sur la propension à la FV et de comprendre les mécanismes fonctionnels etmétaboliques impliqués. Un premier travail a été réalisé sur un modèle d’ischémiemyocardique aigue. Dans un second travail l’impact de la RFC sur la sélection des substratspour la production d’énergie a été évalué sur coeur isolé et perfusé en mode travaillant. Nosrésultats démontrent que l’IVA dans les deux modèles a induit une RFC qui était associée invivo à une amélioration de la perfusion coronaire, une préservation de la structuremitochondriale et du statut énergétique myocardique, réduisant la propension à la FV. Exvivo, la RFC n’a pas modifié la sélection des substrats et le statut énergétique. Enthérapeutique, il est important d’améliorer les conditions tissulaires et de réduire la perte desubstrats lors d’ischémie myocardique, l’IVA semble répondre à cette attente. Son effetspécifique sur l’automaticité sinusale lui confère la possibilité d’agir en préventif et en curatif

A study was performed on anesthetized dogs to investigate the changes in hemodynamics, plasma catecholamine concentrations and catecholamine stores in the heart muscle during experimental acute myocardial ischemia and reperfusion. Ligation of the left anterior descending coronary artery produced a decrease in cardiac output (CO) and rises in pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP). Obstruction and reperfusion of the coronary artery did not alter mean aortic blood pressure (ABP) or heart rate (HR) in the course of the experiment. Catecholamine stores in the heart muscle were significantly lower in the ischemic zone than in the non-ischemic zone of the reperfused and non-reperfused heart. Marked increases in noradrenaline and adrenaline concentrations in aortic and coronary sinus blood after ligation were observed, with the degree of increase in noradrenaline concentration higher in coronary sinus blood than in aortic blood. The elevated noradrenaline and adrenaline concentrations in coronary sinus blood persisted after reperfusion, while noradrenaline and adrenaline concentrations in the aortic blood tended to decline to the original levels. The decline in catecholamine stores in the ischemic tissue is suspected to be due mainly to degeneration of the sympathetic nerve fibers distributed in the heart muscle. This release of catecholamines from the nerve fibers may account for the increase of catecholamines in coronary sinus blood and hemodynamic changes.

Among the many cardiopulmonary reflexes, this review specifically examines the roles of the arterial baroreflex during the Bezold-Jarisch reflex (BJR). Activation of cardiopulmonary vagal afferent C-fibers induces hypotension, bradycardia, and apnea, which are known collectively as the BJR; myocardial ischemia and infarction might induce the BJR. Arterial baroreflex has been established as an important negative feedback system that stabilizes arterial blood pressure against exogenous pressure perturbations. Therefore, understanding the functions of the arterial baroreflex during the BJR is crucial for elucidating its pathophysiological implications. The main central pathways of the BJR and the baroreflex are outlined herein, particularly addressing the common pathway between the reflexes. Furthermore, the pathophysiological roles of the arterial baroreflex during the BJR are described along with a brief discussion of pathophysiological merits and shortcomings of the reflexes.

It is well known that anesthetics have various effects on hemodynamics and the autonomic nervous system. Pentobarbital （PB） and morphineurethane-α-chloralose （M-U-C） have been widely used as anesthetics in acute cardiovascular experiments in animal models and their effects on the cardiovascular system have been studied. In this study, we investigated the differences between PB and M-U-C anesthesias on hemodynamics and myocardial metabolism by using an enzymatic method in the acute ischemic myocardium of dogs. Thirty mg/kg of pentobarbital was injected intravenously as the PB anesthesia, and as the M-U-C anesthesia, 30 min after intramuscular injection of morphine hydrochloride （1.5mg/kg）, a mixture of urethane and α-chloralose （450:45mg/ml） was injected 1 ml/kg intravenously. As for hemodynamics, only heart rate under PB anesthesia significantly increased more than under M-U-C anesthesia （P

The accumulation of intermediates subsequent to impaired β-oxidation of free fatty acid (FFA) has been suggested as a cause of cellular damage in ischemic myocardium. ^ We investigated the effects of propranolol and diltiazem on carnitine metabolism in ischemic myocardium. Propranolol (0.2 mg/kg/min, i.v.) and diltiazem (0.1 mg/kg/min, i.v.) were administered for 5 min, the administration started 10 min before coronary occlusion. ECGs were continuously recorded throughout the experiment. Myocardial samples were prepared from both the non-ischemic and ischemic areas 40 min after coronary ligation. Adenosine triphosphate (ATP), free carnitine, long chain acyl carnitine and long chain acyl CoA were assayed. Propranolol reduced the decrease of ATP and the accumulation of long chain acyl CoA, induced by myocardial ischemia. Diltiazem reduced the decrease of ATP and free carnitine, and the accumulation of long chain acyl carnitine in the ischemic area. Propranolol and diltiazem significantly reduced the grade of ventricular arrhythmia. These results suggest that the protective mechanisms of propranolol and diltiazem on myocardium are based, at least in part, on their beneficial effects upon myocardial carnitine metabolism

Despite considerable progress in the management of ischemic heart disease, a high incidence of sudden prehospital death, probably caused by early ventricular arrhythmia （EVA） associated with acute myocardial infarction, still persists. On the other hand, the role of collateral circulation in EVA during the early phase of acute myocardial ischemia is not well known, although regional blood flow in the ischemic area seems to depend on coronary collateral flow. This study was designed to evaluate the functional significance of coronary collaterals in the occurrence of EVA during acute myocardial ischemia and its metabolic basis. The left anterior descending coronary artery （LAD） was cannulated and perfused from the left carotid artery in 20 anesthetized open chest dogs. In order to create two kinds of ischemic situations with or without collateral flow in the same area at risk in the same dog, the following procedures were performed: （a） LAD occlusion of 6 minutes （LADOCL）, （b） LADOCL with retrograde drainage of collateral flow from the distal segment of LAD. In 13 out of 20 dogs, myocardial tissue biopsies were performed at the end of each ischemic period on the ischemic and non-ischemic zones for measurement of the concentrations of adenosine triphosphate （ATP）, creatine phosphate （CP） and lactate in the inner and outer layers of myocardium. The severity of EVA during ischemia was estimated as EVA score; grade 0=no premature ventricular contractions （PVC）, grade 1=less than 10 uniform PVCs/min, grade 2=10 or more PVCs/min, grade 3=multiform PVCs, grade 4=ventricular tachycardia, and grade 5=ventricular fibrillation. The results were as follows: 1） No significant difference was found in heart rate, mean blood pressure and rate pressure product （RPP） between the dogs with and without retrograde drainage of collateral flow in the control ?and ischemic periods, respectively. However, LADOCL without collateral flow showed a significant increase of heart rate and decreases of mean blood pressure and RPP when compared with the pre-ischemic state. 2） The diversion of collateral flow during ischemia apparently increased the number of premature ventricular contraction and the incidence of EVA including the fatal arrhythmias, ventricular tachycardia and/or fibrillation （VTVF）. 3） LADOCL induced the reduction of the contents of ATP and CP and the accumulation of lactate at both inner and outer myocardia in the ischemic zones. Moreover, deprivation of collateral flow during LADOCL further augmented the CP depletion and lactate accumulation. However, no significant difference was obtained in the myocardial concentrations of ATP and CP between the inner and the outer layers. 4） The severity of EVA significantly correlated with the extents of CP depletion and lactate accumulation in both layers in the ischemic myocardium. 5） In the group with VTVF, a significant increase of heart rate and decreases of mean blood pressure and RPP were observed during LADOCL without collateral flow in spite of no differece in coronary blood flow, coronary collateral flow and metabolic changes when compared to the group without VTVF. These findings suggest that （1）coronary collateral flow is one of the most important factors to regulate the incidence and severity of EVA independent of the size of area at risk; （2）myocardial ischemic changes representing marked CP depletion and lactate accumulation caused by deprivation of coronary collateral flow were important as a metabolic basis of exacerbation of EVA; and （3）the hemodynamic alteration might be an additional influential factor to provoke the fatal arrhythmias （VTVF）.

The effects of L-carnitine on ventricular arrhythmias were evaluated in dogs with acute myocardial ischemia and a supplement of excess free fatty acids (FFA). Acute myocardial ischemia was induced by ligation of left anterior descending coronary artery. After 80 minutes of coronary occlusion, high plasma FFA was induced by intravenous injection of heparin 200 mu/kg and Intralipid 5 ml/kg as a bolus. After additional 60 minutes, beating hearts were removed from animals and tissue levels of free carnitine, short and long chain acyl carnitine, FFA and adenosine triphosphate (ATP) were determined. L-carnitine 100 mg/kg was administered intravenously 5 minutes before coronary artery ligation. Electrocardiograms were recorded continuously by a Holter electrocardiographic recorder during the experiment and ventricular arrhythmias were quantified by an arbitrary scoring system. In ischemic and excess FFA supplemented myocardium, free carnitine and ATP decreased, whereas long chain acyl carnitine and FFA increased. And these metabolic changes tended to be reduced by L-carnitine. Pretreatment of L-carnitine also reduced the grade of ventricular arrhythmias induced both by acute myocardial ischemia and by supplemented of excess FFA. These results suggest that the administration of L-carnitine may be beneficial to prevent serious arrhythmias in ischemic heart disease, presumably by restoring the imparied FFA oxidation.

It is well known that coronary collateral flow is one of the important determinants of myocardial infarct size, lethal arrhythmia, cardiac function and prognosis after coronary occlusion, and that improved coronary collateral flow is a meritorious therapeutic goal. However, a paucity of data have been reported regarding the influences of hemodynamic and neural factors on collateral flow in situ. Therefore, this study was designed to evaluate the quantitative effects of heart rate （HR）, systemic blood pressure （BP）, left ventricular end-diastolic pressure （LVEDP） and cardiac sympathetic nerve stimulation （SNSt） on coronary collateral flow. The left anterior descending coronary artery （LAD） was cannulated and perfused from the left carotid artery in 23 anesthetized open-chest dogs. A side branch went into a small graduated cylinder for measurement of retrograde flowing blood （RF） from the distal LAD. A polyethylene T type tube connected with a reservoir was inserted into the thoracic aorta to change and/or stabilize the BP for desired levels. Twenty minutes after completion of the preparation, ECG, BP, LVEDP, coronary blood flow and coronary arterial pressure were recorded under the control perfused condition. And then, the perfusion line from the left carotid artery was clamped on, and after measuring peripheral coronary pressure （PCP）, the side branch was clamped off for collecting the RF. Coronary collateral flow （CCF） was measured using modified load line analysis, CCF=RF （1.61?mPCP/0.8mBP）. After complete recovery, the above protocol was repeated with a change of HR, BP, LVEDP and cardiac sympathetic tone, independently. In 8 dogs, HR was decreased from 145.0±3.3 to 111.3±3.9 bpm by electrical vagal stimulation, and increased to 195.7±6.4 bpm by right atrial pacing. CCF was not significantly affected by the change in HR. Pentobarbital sodium was infused into the left main coronary artery to elevate a desired LVEDP in 7 dogs. The mean LVEDP value was 5.9±1.3 mmHg before infusion and 10.8±1.5 mmHg after pentobarbital sodium administration. CCF significantly decreased after pentobarbital sodium, and had a negative correlation with LVEDP. In 8 dogs, blood pressure was reduced by lowering the blood reservoir level, and elevated by raising it. CCF decreased parallel with lowering BP, and increased with rising BP. A positive relationship was observed between BP and CCF. The anterior ansa of left stellate ganglion was electrically stimulated by 4Hz, 10V, 2msec duration （SNSt） to reveal the effect of cardiac sympathetic tone on coronary collateral circulation in 8 dogs. SNSt significantly increased CCF independent of the change of HR, BP and LVEDP. From these results, it is suggested that coronary collateral circulation, in situ, is affected by change in BP. LVEDP and sympathetic tone in acute coronary occlusion.

ObjectivesThis study was designed to determine whether imaging myocardial edema would identify acute myocardial ischemia before irreversible injury takes place.BackgroundEarly identification of acute myocardial ischemia is a diagnostic challenge.MethodsWe studied 15 dogs with serial T2-weighted and cine imaging at baseline, during transient coronary occlusion of up to 35 min, and after reperfusion in a 1.5-T magnetic resonance imaging system. Late gadolinium enhancement and troponin measurements were used to assess for the presence of irreversible injury. Myocardial water content was measured to assess myocardial edema.ResultsWe consistently observed a transmural area of high T2signal intensity matching areas with new onset regional akinesia 28 ± 4 min after experimental coronary artery occlusion. At this time, the contrast-to-noise ratio between the ischemic and remote myocardium had significantly increased from 1.0 ± 2.0 to 12.8 ± 9.6 (p < 0.003), which further increased after reperfusion to 15.8 ± 10.3 (p < 0.004 compared with baseline). Neither myocardial late gadolinium enhancement nor troponin elevation were noted at this time window. Myocardial water content of the ischemic segments was consistently higher (68.9 ± 2% vs. 67.0 ± 2%; p < 0.004) than in remote segments and the difference correlated significantly to the contrast-to-noise ratio in T2images (p < 0.04).ConclusionsWe provide the first evidence that T2-weighted cardiovascular magnetic resonance imaging of edema detects acute ischemic myocyte injury before the onset of irreversible injury. T2-weighted cardiovascular magnetic resonance imaging may serve as a very useful diagnostic marker in clinical settings such as unstable angina or evolving infarction.

Acute coronary syndrome; Coronary heart disease; Sick leave Síndrome Coronario Agudo; Enfermedad Coronaria; Ausencia por enfermedad Síndrome coronari agut; Malaltia coronària; Absència per malaltia BACKGROUND The prevalence of ischemic heart disease is high. Few recent studies have investigated the periods of sick leave of these patients. Our aim is to determine the length of sick leave after an acute coronary syndrome, its costs, associated factors and to assess the use of antidepressants and/or anxiolytics. METHODS An observational study of a retrospective cohort of patients on sick leave due to ischemic heart disease in a health region between 2008-2011, with follow-up until the first return to work, death, or end of the study (31/12/2012). MEASUREMENTS length of sick leave, sociodemographic variables and medical prescriptions. RESULTS Four hundred and ninety-seven patients (mean age 53 years, 90.7% male), diagnosed with acute myocardial infarction (60%), angina pectoris (20.7%) or chronic form of ischemic heart disease (19.1%). Thirty-seven per cent of patients took anxiolytics the year after diagnosis and 15% took antidepressants. The average duration of sick leave was 177 days (95% CI: 163-191 days). Patients diagnosed with acute myocardial infarction returned to work after a mean of 192 days, compared to 128 days in cases with angina pectoris. Patients who took antidepressants during the year after diagnosis returned to work after a mean of 240 days. The mean work productivity loss was estimated to be 9,673 euros/person. CONCLUSIONS The mean duration of sick leave due to ischemic heart disease was almost six months. Consumption of psychotropic medication doubled after the event. Older age, suffering an acute myocardial infarction and taking antidepressants were associated with a longer sick leave period.