ACBP/DBI protein neutralization confers autophagy-dependent organ protection through inhibition of cell loss, inflammation, and fibrosis.

Acyl-coenzyme A (CoA)-binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is an extracellular feedback regulator of autophagy. Here, we report that injection of a monoclonal antibody neutralizing ACBP/DBI (α-DBI) protects the murine liver against ischemia/reperfusion damage, intoxication by acetaminophen and concanavalin A, and nonalcoholic steatohepatitis caused by methionine/choline-deficient diet as well as against liver fibrosis induced by bile duct ligation or carbon tetrachloride. α-DBI downregulated proinflammatory and profibrotic genes and upregulated antioxidant defenses and fatty acid oxidation in the liver. The hepatoprotective effects of α-DBI were mimicked by the induction of ACBP/DBI-specific autoantibodies, an inducible Acbp/Dbi knockout or a constitutive Gabrg2F77I mutation that abolishes ACBP/DBI binding to the GABAA receptor. Liver-protective α-DBI effects were lost when autophagy was pharmacologically blocked or genetically inhibited by knockout of Atg4b. Of note, α-DBI also reduced myocardium infarction and lung fibrosis, supporting the contention that it mediates broad organ-protective effects against multiple insults.

SARC-F Is a Predictor of Longer LOS and Hospital Readmission in Hospitalized Patients after a Cardiovascular Event.

It is already established that sarcopenia is associated with adverse outcomes; however, few studies have focused on patients who have suffered an acute cardiovascular event. The use of SARC-F, a 5-item sarcopenia screening questionnaire, in these patients remains to be investigated. We aimed to investigate whether SARC-F can predict adverse outcomes in patients admitted to a hospital with a suspected infarction. This is a 1-year prospective cohort study. During hospitalization, patients completed the SARC-F questionnaire (scores ≥ 4 considered positive for the risk of sarcopenia). Length of hospital stay (LOS), new hospital admission, myocardial infarction, and cardiovascular mortality were collected via medical records and phone interviews. In total, 180 patients were evaluated. The median age was 60.6 years; 72.3% of the participants were men, and half of the sample had comorbidities. The median SARC-F score was 1.0 (interquartile range, 0-3.0), and 21.1% of the participants screened positive. Risk of sarcopenia was independently associated with longer LOS (odds ratio, 2.34; 95% CI, 1.09-5.04; p = 0.030) and hospital readmission (odds ratio, 3.73; 95% CI, 1.60-8.69; p = 0.002). One-fifth of post-acute cardiovascular event patients in this cohort screened positive for sarcopenia using the SARC-F screening questionnaire. Positive scores were associated with a longer LOS and hospital readmission.

Targeted trapping of endogenous endothelial progenitor cells for myocardial ischemic injury repair through neutrophil-mediated SPIO nanoparticle-conjugated CD34 antibody delivery and imaging.

Endothelia progenitor cell (EPC)-based revascularization therapies have shown promise for the treatment of myocardial ischemic injury. However, applications and efficacy are limited by the relatively inefficient recruitment of endogenous EPCs to the ischemic area, while implantation of exogenous EPCs carries the risk of tumorigenicity. In this study, we developed a therapeutic protocol that relies on the capacity of neutrophils (NEs) to target lesions and release preloaded EPC-binding molecules for high efficiency capture. Neutrophils were loaded with superparamagnetic iron oxide nanoparticles conjugated to an antibody against the EPC surface marker CD34 (SPIO-antiCD34/NEs), and the therapeutic efficacy in ischemic mouse heart following SPIO-antiCD34/NEs injection was monitored by SPIO-enhanced magnetic resonance imaging (MRI). These SPIO-antiCD34/NEs exhibited unimpaired cell viability, superoxide generation, and chemotaxis in vitro as well as satisfactory biocompatibility in vivo. In a mouse model of acute myocardial infarction (MI), SPIO-antiCD34 accumulation could be observed 0.5 h after intravenous injection of SPIO-antiCD34/NEs. Moreover, the degree of CD133+ EPC accumulation at MI sites was three-fold higher than in control MI model mice, while ensuing microvessel density was roughly two-fold higher than controls and left ventricular ejection fraction was > 50%. Therapeutic cell biodistribution, MI site targeting, and treatment effects were confirmed by SPIO-enhanced MRI. This study offers a new strategy to improve the endogenous EPC-based myocardial ischemic injury repair through NEs mediated SPIO nanoparticle conjugated CD34 antibody delivery and imaging. STATEMENT OF SIGNIFICANCE: The efficacy of endogenous endothelial progenitor cell (EPC)-based cardiovascular repair therapy for ischemic heart damage is limited by relatively low EPC accumulation at the target site. We have developed a method to improve EPC capture by exploiting the strong targeting ability of neutrophils (NEs) to ischemic inflammatory foci and the capacity of these treated cells to release of preloaded cargo with EPC-binding affinity. Briefly, NEs were loaded with superparamagnetic iron oxide nanoparticles conjugated to an antibody against the EPC surface protein CD34 (SPIO-antiCD34). Thus, we explored sites targeting with nanocomposites cargo for non-invasive EPCs interception and therapy tracking. We demonstrate that SPIO-antiCD34 released from NEs can effectively capture endogenous EPCs and thereby promote heart revascularization and functional recovery in mice. Moreover, the entire process can be monitored by SPIO-enhanced magnetic resonance imaging including therapeutic cell biodistribution, myocardial infarction site targeting, and tissue repair.

Cholesterol metabolic enzyme Ggpps regulates epicardium development and ventricular wall architecture integrity in mice.

During embryonic heart development, the progenitor cells in the epicardium would migrate and differentiate into noncardiomyocytes in myocardium and affect the integrity of ventricular wall, but the underlying mechanism has not been well studied. We have found that myocardium geranylgeranyl diphosphate synthase (Ggpps), a metabolic enzyme for cholesterol biosynthesis, is critical for cardiac cytoarchitecture remodelling during heart development. Here, we further reveal that epicardial Ggpps could also regulate ventricular wall architecture integrity. Epicardium-specific deletion of Ggpps before embryonic day 10.5 (E10.5) is embryonic lethal, whereas after E13.5 is survival but with defects in the epicardium and ventricular wall structure. Ggpps deficiency in the epicardium enhances the proliferation of epicardial cells and disrupts cell‒cell contact, which makes epicardial cells easier to invade into ventricular wall. Thus, the fibroblast proliferation and coronary formation in myocardium were found enhanced that might disturb the coronary vasculature remodelling and ventricular wall integrity. These processes might be associated with the activation of YAP signalling, whose nuclear distribution is blocked by Ggpps deletion. In conclusion, our findings reveal a potential link between the cholesterol metabolism and heart epicardium and myocardium development in mammals, which might provide a new view of the cause for congenital heart diseases and potential therapeutic target in pathological cardiac conditions.

Comparison of Left Ventricular Global Strain in Anterior and Non-anterior Wall Myocardial Infarction With CMR Tissue Tracking.

Left ventricular (LV) myocardial dysfunction occurs after myocardial infarction (MI) is associated with the location, infarct size, and transmurality degrees of MI. The myocardial strain is a sensitive index used for the quantification of myocardium dysfunction. This study used Tissue-Tracking to evaluate whether the different location of MI would result in different myocardial dysfunction. One hundred patients diagnosed with MI who underwent cardiovascular magnetic resonance examination were included. The tissue-tracking indices, LV global radial strain (GRS), global circumferential strain (GCS), global longitudinal strain (GLS), and the infarct size (IS,% of LV mass) were quantified. There were 42 cases of anterior wall MI (AWMI) and 58 cases of non-anterior wall MI (NAWMI). The GCS of AWMI was significantly lower than that of NAWMI (P = 0.036). In the same level of infarct size, the myocardial strain of AWMI was not significantly different from NAWMI group (P > 0.05). The GRS and GCS were significantly different between transmurality > 50% group with transmurality ≤ 50% group (P < 0.05). The present study demonstrated that LV MI is associated with reduced myocardial strain, and the infarct size and degrees of transmurality were both related to the decline of myocardial strain in patients with MI.

[The social economic indices of regions and population morbidity of myocardium infarction].

In Russia, in recent decades, there were regional gapping in terms of social inequality and high level of morbidity and mortality in comparison with European countries. The high morbidity and mortality of population in the Russian Federation from diseases of circulatory system on one hand, and regional differences in terms of social economic status on the other hand, determined the purpose of the study. In order to evaluate relationship between social economic status of regions of the Russian Federation and incidence rate of myocardial infarction, the analysis was applied to standardized data of adult morbidity in classes of acute myocardial infarction and repeated myocardial infarction. Also was evaluated a number of social economic indices that reflect state and conditions of life of population. The statistical analysis was applied using MS Excel and Statistica 6 software. The critical significance level of null statistical hypothesis was established as p=0.05. When analyzing morbidity of adult population of Russia with acute and repeated myocardial infarction, significant regional differences were established. The seven factors were identified that statistically significantly affect morbidity rate of the adult population with myocardial infarction, which made it possible to divide the regions into four clusters, between which differences in morbidity rate of acute myocardial infarction were revealed. The analysis of morbidity of acute and repeated myocardial infarction established significant regional differences such as in 2017 7.7 times for acute myocardium infarction and 61 times for repeated myocardium infarction. The allocation of regional clusters depending on their social economic status allows to supplement regional and federal projects with risk-oriented technologies with purpose of decreasing morbidity of diseases of circulatory system.

ACSL1 affects Triglyceride Levels through the PPARγ Pathway.

In clinical cohort studies, high expression of long-chain acyl-coenzyme A synthetases 1 (ACSL1 gene) in peripheral white blood cells of patients with acute myocardial infarction (AMI) has been utilized as molecular markers of myocardial infarction diagnosis. The plasma triglyceride level of AMI patients is significantly higher than that of healthy individuals. We hypothesized that the high expression of ACSL1 increases the level of triglyceride, which is one of the pathogenesis of AMI promoted by ACSL1. In this report, cell culture based methods were adopted to test the hypothesis and further investigate the effect and mechanism of ACSL1 on lipid metabolism. In this study, liver cells of healthy individuals were cultured, the overexpression and the knockdown vectors of ACSL1 were constructed and transfected into liver cells. The transfection was verified at the mRNA and protein level. Intracellular triglyceride content was quantitatively analyzed using ELISA. Changes of genes related to lipid metabolism were subsequently measured through PCR array. Overexpression of ACSL1 led to higher gene expression and protein levels compared to control and the triglyceride content was significantly increased in overexpressing cells. The expression level of fatty acid oxidation pathway PPARγ was significantly down-regulated compared with the control group, as were genes associated with fatty acid synthesis pathways: SREBP1, ACC, FAS, and SCD1. ACSL1 knockdown decreased the content of triglyceride whereas PPARγ was up-regulated and SREBP1, ACC, FAS, and SCD1 were down-regulated compared with the control group. In summary, high expression of ACSL1 reduced fatty acid ß-oxidation through the PPARγ pathway, thereby increasing triglyceride levels.

Vitamin D-binding protein (rs4588) T/T genotype is associated with anteroseptal myocardial infarction in coronary artery disease patients.

BACKGROUND: Cardiovascular diseases (CVD) are among leading causes of death worldwide and amongst CVD, coronary artery disease (CAD) accounts for almost half of all cardiovascular deaths as the most common cause of death in the developed world. Vitamin D and the vitamin D-binding protein (VDBP) have been studied as possible CAD pathogenesis factors but literature data provide opposing evidence on their role in CAD. Herein we aimed to present novel evidence on the association of two VDBP polymorphisms (rs4588) and (rs7041) with CAD in patients after acute myocardial infarction and study possible correlations of these polymorphisms with 25-hydroxyvitamin D [25(OH)D] serum levels. METHODS: The cross-section genotyping study included 155 subjects with CAD upon acute myocardial infarct and 104 control subjects. All patients and control group were Caucasians of European descent. VDBP polymorphisms (rs4588) and (rs7041) were studied by use of RT-PCR. Liquid chromatography, tandem mass spectrometry (LC-MS/MS) method was used for measurement of vitamin D in the serum. RESULTS: Association of the VDBP (rs4588) T/T genotype with CAD patients after acute MI and correlation of VDBP (rs4588) genotype G/G with higher levels of total vitamin D were found. No correlation of 25(OH)D serum levels with CAD were established but the multivariate logistic regression modelling enabled association of total vitamin D level and VDBP (rs4588) T/T genotype with CAD and anteroseptal myocardial infarction (ASMI) CAD occurrence. CONCLUSIONS: Obtained data speak in favor to the VDBP (rs4588) T/T genotype as a susceptibility factor for anteroseptal myocardial infarction where the same genotype showed to be generally more prevalent in smokers.

Antibody-Armed Platelets for the Regenerative Targeting of Endogenous Stem Cells.

Stem cell therapies have shown promise in treating acute and chronic ischemic heart disease. However, current therapies are limited by the low retention and poor integration of injected cells in the injured tissue. Taking advantage of the natural infarct-homing ability of platelets, we engineered CD34 antibody-linked platelets (P-CD34) to capture circulating CD34-positive endogenous stem cells and direct them to the injured heart. In vitro, P-CD34 could bind to damaged aortas and capture endogenous stem cells in whole blood. In a mouse model of acute myocardial infarction, P-CD34 accumulated in the injured heart after intravenous administration, leading to a concentration of endogenous CD34 stem cells in the injured heart for effective heart repair. This represents a new technology for endogenous stem cell therapy.

Fluorescence properties of curcumin-loaded nanoparticles for cell tracking.

BACKGROUND: Posttransplant cell tracking, via stem cell labeling, is a crucial strategy for monitoring and maximizing benefits of cell-based therapies. The structures and functionalities of polysaccharides, proteins, and lipids allow their utilization in nanotechnology systems. MATERIALS AND METHODS: In the present study, we analyzed the potential benefit of curcumin-loaded nanoparticles (NPC) using Vero cells (in vitro) and NPC-labeled adipose-derived mesenchymal stem cells (NPC-ADMSCs) (in vivo) in myocardial infarction and sciatic nerve crush preclinical models. Thereafter, transplantation, histological examination, real time imaging, and assessment of tissue regeneration were done. RESULTS: Transplanted NPC-ADMSCs were clearly identified and revealed potential benefit when used in cell tracking. CONCLUSION: This approach may have broad applications in modeling labeled transplanted cells and in developing improved stem cell therapeutic strategies.

[The Occupational, Housing and Family Risk Factors in Prognostication of Myocardium Infarction Morbidity].

The results of prevalence and prognostic significance of occupational, housing and family risk factors for myocardial infarction are presented. The significance of the analyzed risk factors for predicting development of myocardial infarction is established. The myocardial infarction (MI) have to do with global social and medical evidential problems. The MI morbidity results in significant economic and social damage. The loss of the gross domestic product as a result of MI mortality in able-bodied age prevails in the structure of economic damage in the Russian Federation and makes up to more than 49 billion rubles per year. In MI patients such risk factors as tense psychological relationships at work, duration of workday more than 8 hours are highly spread. This is especially true for tensed psychological relationships at work, which are 5.6 times more likely to be detected in patients with MI as compared with other groups of patients. The study demonstrated considerable prevalence and significant role of particular professional, housing and family risk factors in the MI development. It is proved that physical overloads, unsatisfactory housing conditions and lack of one's own housing are of highest prevalence and prognostic significance. The study data permits to prognosticate possibility of MI development and to implement preventive and curative measures prior to onset of disease resulting in decreasing of MI morbidity, various complications and mortality.

Coronary Artery Fistula Causing Acute Myocardial Infarction and Right Ventricle Thrombus.

Coronary artery fistula (CAF) is a rare congenital anomaly, which is most commonly asymptomatic. In symptomatic cases, aneurysms can occur with complications of thromboembolic events. This report describes a rare case of CAF presenting with complications of inferior acute myocardial infarction and thrombus formation in the right ventricle.

[The Morbidity of Myocardium Infarction in the Russian Federation, the Siberian Federal District and the Omsk Region].

The study was organized to analyze myocardium infarction morbidity in the Russian Federation, the Siberian Federal District and the Omsk Region of the Russian Federation. In the Omsk Region, in 2014 myocardium infarction morbidity amounted to 175.6 cases per 100 000 of population that is 1.4 times higher tan in the Siberian Federal District and in the Russian Federation. The morbidity of recurrent myocardium infarction amounted to 56.9 cases per 100 000 of population. During thirteenth years period, in Russia, level of acute myocardium infarction morbidity decreased up to 12%, in the Siberian Federal District up to 10% and in the Omsk Region up to 25%. The morbidity of recurrent myocardium infarction in Russia increased up to 32%, in the Omsk Region up to 68%. The increasing of morbidity of recurrent myocardium infarction in Russia resulted in increasing of percentage of recurrent myocardium infarction up to 1.3 times, in the Siberian Federal District up to 1.4 times and in the Omsk Region up to 1.8 times. The high myocardium infarction morbidity in the Omsk Region is determined by high social and economic losses in the Region. The Regional health care has an important task of optimization of activities targeted to achievement of the all-Russian level of myocardium infarction morbidity.

[The prognostication of acute myocardium infarction according biochemical indices of blood.]

In actual conditions, the acute myocardium infarction is a main cause of population mortality factually in all countries. The purpose of study is to establish a prognostic significance of biochemical cardio-markers of blood and to develop prognostic models for acute myocardium infarction. The sampling included 157 patients with acute myocardium infarction and 138 healthy individuals. The cardio-markers in blood were analyzed using immune chromatographic and spectrometric techniques and also applying portable biochemical analyzer MultiCareIn (Italy). It is demonstrated that the highest prognostic value for development of acute myocardium infarction is increasing of level of creatine kinase in blood more than 25 ME/l, troponin - more than 0.5 mkg/l, lactate dehydrogenase 1 - more than 200 ME/l and lactate dehydrogenase 2 - more than 180 ME/l. The developed regression model for prognosis of acute myocardium infarction according the indices mentioned above has a high sensitivity and specificity. Conclusion. The application of prognostically significant cardio-markers of blood and developed regression model permits to forecast development of acute myocardium infarction and to implement prevention and treatment in earlier period.

Prediction of myocardial infarction by assessing regional cardiac wall in CMR images through active mesh modeling.

Myocardial infarction is a leading cause of morbidity and mortality. In this study, using Cine MRI images, the infarct region was precisely determined by examining the local migration path length of critical points on myocardium borders and the fractional thickening effects. First, MRI Cine images of Epi/Endocardium were processed in 3D for all slices, and then incorporated in all frames to build a dynamic model. Epi/Endocardium images were segmented using Heiberg algorithm, and then by a robust restricted block matching algorithm, the sparse points were tracked. Finally, by fitting a 3D active mesh model to the sparse point displacements, a dense motion field was obtained, and some useful local parameters of left ventricle in patients with myocardial infarction were estimated. The local parameters are path length, fractional thickening, and strain. Using this process, the cardiac wall motion was quantized to determine the region and extent of infarct lesion. The process was implemented, and the results were examined and modified against the cardiac perfusion scan. Data were acquired from 10 healthy individuals and 20 patients with the myocardial infarction. The findings also reveal that the infarct region can be determined by locating less than 20% in the wall thickening. In all the patients, the process was able to precisely determine the affected region. The cardiac wall kinesis in damaged regions was properly evaluated by normalized path length and presented in standard bull's-eye format. The above approach is promising and can be extended in prognosis of acute heart infraction by prediction of prone to the wall kinesis regions in the patients close to MI by examining the local indexes of the myocardium in the cardiac MRI images.

Técnica de reperfusão miocárdica retrógrada: resgate histórico: [revisión] / Retrograde coronary perfusion technique: hostorical rescue: [review]

Artigo de revisão, numa perpectiva histórica, de trabalho experimental realizado em cães, em 1962, sobre técnica de reperfusão miocárdica retrógrada pelo seio coronariano. Esta técnica pioneira, apresentada neste artigo como um resgate histórico, representa um legado importante pela atual repercussão internacional da sua utilização no tratamento da doença coronariana com células-tronco.

Paper presenting a historical review of an experimental study conducted with dogs in 1962, exploring a retrograde myocardial retroperfusion technique for the coronary sinus. This pioneering approach is presented in this paper in order to preserve this historic feat,constituting an important legacy due to current international repercussions prompted by its use for treating acute myocardial infarction and stem celltreatment of coronary disease.

Tolerância à dor no infarto do miocárdio / Pain tolerance during myocardium infarction / Tolerancia al dolor en infarto del miocárdio

Objetivo: Analisar a tolerância à dor como sintoma prodrômico do infarto do miocárdio na perspectiva dos gêneros masculino e feminino em pacientes que vivenciaram esse evento cardiovascular. Métodos: Estudo exploratório de natureza quanti-qualitativa. Entrevistou-se 43 mulheres e 54 homens em hospital público. Os dados sóciodemográficos foram analisados em percentuais e os qualitativos com base na análise de conteúdo e da categoria gênero. Resultados: A mediana de idade para homens foi 55,3 e mulheres de 61,5 anos. Predominou para os gêneros a baixa escolaridade e inatividade profissional. Os homens tinham renda familiar maior e viviam mais em companhia de alguém. Evidenciou-se que homens e mulheres demonstraram igualmente enfrentamento e resistência à dor, visando manter o controle da própria existência e reproduzindo construções sociais sobre o masculino e o feminino em suas vidas cotidianas. Conclusão: O desafio profissional é atuar no plano simbólico dos gêneros para reduzir o retardo na decisão de buscar atenção médica e possibilitar os benefícios imediatos das terapias de reperfusão coronária.

Purpose: To evaluate pain tolerance as a prodromic symptom in men and women who had a myocardium infarction. Methods: This was a quantitative-qualitative exploratory study with 43 women and 54 men from a public hospital. Demographic data were analyzed with percentages and qualitative data were analyzed with content analysis according to gender. RESULTS: The men's mean age was 55.3 years. The women's mean age was 61.5 years. Both genders had low educational level and professional inactivity. Men lived with a significant other and had higher family income than women. There was no difference regarding pain tolerance between men and women. Both men and women tried to maintain control over their life and to reproduce social constructions in daily life regarding being male and female. Conclusion: Heath care professional actions for the prevention of delaying seeking medical care for coronary perfusion by both male and female is challenging.

Objetivo: Analizar la tolerancia al dolor como síntoma prodrómico del infarto del miocardio en la perspectiva de los géneros masculino y femenino en pacientes que experimentaron ese evento cardiovascular. Métodos: Estudio exploratorio de naturaleza cuantitativa cualitativa. Se entrevistaron 43 mujeres y 54 hombres en un hospital público. Los datos sociodemográficos fueron analizados en porcentajes y los cualitativos con base en el análisis de contenido y de la categoría género. Resultados: El promedio de edad para hombres fue 55,3 y mujeres de 61,5 años. Predominó para los dos géneros la baja escolaridad e inactividad profesional. Los hombres tenían renta familiar mayor y vivían más en compañía de alguien. Se evidenció que los hombres y mujeres demostraron igualmente enfrentamiento y resistencia al dolor, con el objetivo de mantener el control de la propia existencia y reproduciendo construcciones sociales sobre lo masculino y lo femenino en sus vidas cotidianas. Conclusión: El desafío profesional es actuar en el plano simbólico de los géneros para reducir el atraso en la decisión de buscar atención médica y posibilitar los beneficios inmediatos de las terapias de reperfusión coronaria.