Heart Regeneration: Opportunities and Challenges for Drug Discovery with Novel Chemical and Therapeutic Methods or Agents

Following a heart attack, more than a billion cardiac muscle cells (cardiomyocytes) can be killed, leading to heart failure and sudden death. Much research in this area is now focused on the regeneration of heart tissue through differentiation of stem cells, proliferation of existing cardiomyocytes and cardiac progenitor cells, and reprogramming of fibroblasts into cardiomyocytes. Different chemical modalities (i.e. methods or agents), ranging from small molecules and RNA approaches (including both microRNA and anti‐microRNA) to modified peptides and proteins, are showing potential to meet this medical need. In this Review, we outline the recent advances in these areas and describe both the modality and progress, including novel screening strategies to identify hits, and the upcoming challenges and opportunities to develop these hits into pharmaceuticals, at which chemistry plays a key role.     

超声心动图联合动态心电图检查对急性心肌梗死诊断和预后评估的价值

为探讨超声心动图联合动态心电图检查在急性心肌梗死(AMI)患者诊断和预后评估中的应用价值,本研究选取2016年6月~2018年6月我院收治并确诊的100例AMI患者作为观察组,另选取同期100例非冠心病患者作为对照组。以AMI患者心源性死亡为终点事件,将观察组分为死亡组(n=15)和存活组(n=85)。所有患者均采用飞利浦IU-Elite及EPIQ5彩色多普勒超声诊断仪进行超声心动图检查,采用DMS-3004A进行标准的12导联动态心电图检查。比较各组患者心率震荡指标[震荡起始(TO)、震荡斜率(TS)]、心率变异性指标[NN间期标准差(SDNN)、QT离散度(QTd)、经心率校正的QT离散度(QTcd)]及心功能指标[左心室舒张末期内径(LVEDD)、左心室射血分数(LVEF)]水平的变化。结果显示,观察组TO、QTd、QTcd、LVEDD均明显高于对照组,TS、SDNN、LVEF均明显低于对照组,差异有统计学意义(P<0.05)。死亡组TS、SDNN均明显低于存活组,差异有统计学意义(P<0.05);死亡组TO高于存活组,QTd、QTcd、LVEF、LVEDD均低于存活组,但差异无统计学意义(P>0.05)。本研究结果表明,AMI患者心率震荡(HRT)明显减弱甚至消失,HRV、LVEF明显降低,LVEDD、QTd明显增大,QT间期明显延长。超声心动图和动态心电图联合检查对AMI患者诊断及预后评估均有重要的临床应用价值。     

Theil Entropy as a Non-Lineal Analysis for Spectral Inequality of Physiological Oscillations

Theil entropy is a statistical measure used in economics to quantify income inequalities. However, it can be applied to any data distribution including biological signals. In this work, we applied different spectral methods on heart rate variability signals and cellular calcium oscillations previously to Theil entropy analysis. The behavior of Theil entropy and its decomposable property was investigated using exponents in the range of [−1, 2], on the spectrum of synthetic and physiological signals. Our results suggest that the best spectral decomposition method to analyze the spectral inequality of physiological oscillations is the Lomb–Scargle method, followed by Theil entropy analysis. Moreover, our results showed that the exponents that provide more information to describe the spectral inequality in the tested signals were zero, one, and two. It was also observed that the intra-band component is the one that contributes the most to total inequality for the studied oscillations. More in detail, we found that in the state of mental stress, the inequality determined by the Theil entropy analysis of heart rate increases with respect to the resting state. Likewise, the same analytical approach shows that cellular calcium oscillations present on developing interneurons display greater inequality distribution when inhibition of a neurotransmitter system is in place. In conclusion, we propose that Theil entropy is useful for analyzing spectral inequality and to explore its origin in physiological signals.     

血清钙、镁和微量元素与冠心病

综述了钙、镁和微量元素在动脉粥样硬化、冠心病(包括冠状动脉痉挛)研究的相关报道,以进一步研究钙、镁和微量元素与冠状动脉痉挛的关系。     

Machine Learning Algorithm to Predict Acidemia Using Electronic Fetal Monitoring Recording Parameters

Background: Electronic fetal monitoring (EFM) is the universal method for the surveillance of fetal well-being in intrapartum. Our objective was to predict acidemia from fetal heart signal features using machine learning algorithms. Methods: A case–control 1:2 study was carried out compromising 378 infants, born in the Miguel Servet University Hospital, Spain. Neonatal acidemia was defined as pH < 7.10. Using EFM recording logistic regression, random forest and neural networks models were built to predict acidemia. Validation of models was performed by means of discrimination, calibration, and clinical utility. Results: Best performance was attained using a random forest model built with 100 trees. The discrimination ability was good, with an area under the Receiver Operating Characteristic curve (AUC) of 0.865. The calibration showed a slight overestimation of acidemia occurrence for probabilities above 0.4. The clinical utility showed that for 33% cutoff point, missing 5% of acidotic cases, 46% of unnecessary cesarean sections could be prevented. Logistic regression and neural networks showed similar discrimination ability but with worse calibration and clinical utility. Conclusions: The combination of the variables extracted from EFM recording provided a predictive model of acidemia that showed good accuracy and provides a practical tool to prevent unnecessary cesarean sections.     

On the Variability of Heart Rate Variability—Evidence from Prospective Study of Healthy Young College Students

Heart rate variability (HRV) has been widely used as indices for autonomic regulation, including linear analyses, entropy and multi-scale entropy based nonlinear analyses, and however, it is strongly influenced by the conditions under which the signal is being recorded. To investigate the variability of healthy HRV under different settings, we recorded electrocardiograph (ECG) signals from 56 healthy young college students (20 h for each participant) at campus using wearable single-lead ECG device. Accurate R peak to R peak (RR) intervals were extracted by combing the advantages of five commonly used R-peak detection algorithms to eliminate data quality influence. Thorough and detailed linear and nonlinear HRV analyses were performed. Variability of HRV metrics were evaluated from five categories: (1) different states of daily activities; (2) different recording time period in the same day during free-running daily activities; (3) body postures of sitting and lying; (4) lying on the left, right and back; and (5) gender influence. For most of the analyzed HRV metrics, significant differences (p < 0.05) were found among different recording conditions within the five categories except lying on different positions. Results suggested that the standardization of ECG data collection and HRV analysis should be implemented in HRV related studies, especially for entropy and multi-scale entropy based analyses. Furthermore, this preliminary study provides reference values of HRV indices under various recording conditions of healthy young subjects that could be useful information for different applications (e.g., health monitoring and management).     

心衰标志物可视化联合检测方法研究

基于夹心免疫原理和表面免疫吸附模型,采用Image Pro Plus软件对硅片表面磁颗粒分布图像进行定量化处理,建立了硅片表面心衰标志物可视化联合检测方法。研究表明,该方法从抗体包被到获得检测结果不超过1 ｈ,操作简单,在单张硅片上可实现心衰标志物NT-proBNP和cTnI的联合检测。NT-proBNP和cTnI的最低检出限分别为21.8 pg/mL和0.034 ng/mL,检测范围分别为21.8~40000 pg/mL和0.034~50 ng/mL。83例不同程度心血管疾病患者的血清样本的检测结果与商品化免疫分析仪检测结果一致,相关系数r>0.98。因此,该快速免疫检测方法可以满足临床检测心衰标志物的需要。     

Magnetic resonance imaging of coronary arteries and heart valves in a living mouse: techniques and preliminary results

New investigations in MRI of a mouse heart showed high-contrast cardiac images and thereby the possibility of doing functional cardiac studies of in vivo mice. But is MRI, in addition, capable of visualizing microstructures such as the coronary arteries and the heart valves of a living mouse? To answer this question, 2D and 3D gradient echo sequences with and without flow compensation were used to image the coronary arteries. To increase signal-to-noise ratio, a birdcage resonator was optimized for mouse heart imaging. Contrast between blood and myocardium was achieved through the inflow effect. A segmented three-dimensional FLASH sequence acquired with a multiple overlap thin slab technique showed the best results. With this technique an isotropic resolution of 100 microm was achieved. The left coronary artery could be visualized up to the apex of the heart. This is demonstrated with short axis views and 3D surface reconstructions of the mouse heart. The four cardiac valves were also visible with the 3D method.     

单个心肌细胞内钙波的微观动力学研究

利用基于近场光学原理构建的全内反射荧光显微镜研究了大鼠单个心肌细胞中的钙信号. 利用这种显微镜的快速成像和高信噪比的特点，观察到单个细胞中复杂的二维钙波斑图. 分析了单个钙信号释放事件在钙波形成、运动过程中的作用. 建立在fire-diffuse-fire模型基础上的模拟显示，由基本钙释放事件组成的钙波可以在心肌细胞中稳定存在. 此研究对进一步认识活体可激发系统的微观动力学行为有指导意义. 关键词： 近场光学 全内反射荧光显微镜 心肌细胞 钙波     

Mechanism of interaction of pressure waves at a discrete partial blockage

This paper analyses the mechanism of interaction between an incident pressure wave and blockages of different geometrical characteristics (i.e., a butterfly and a ball valves, two short stretches of pipe with a reduced diameter, and a device simulating a longitudinal body blockage) by means of laboratory and numerical tests. Experiments have shown that the mechanism of interaction with pressure waves is influenced by their path through the device: sinuous because of the device body for partially closed in-line valves (type I mechanism), and straight for the small bore pipe devices (type II mechanism). Type I mechanism is characterized by a rise followed by an almost constant value whereas in type II one a drop occurs after the rise. To complete the investigation the effect of the pre-transient condition is discussed.