肥厚型心肌病患者在心肺运动中核心指标的特征性研究*

目的: 肥厚型心肌病（HCM）,以心肌肥厚为主要特征的心肌疾病,猝死率高。临床症状表现为呼吸困难、乏力、胸痛等。症状限制性极限运动心肺运动试验（CPET）在整体整合生理和医学（HIPM）理论指导下是唯一评估人体整体功能状态检查,肥厚型心肌病患者在心肺运动中核心数据变化值得进一步探讨。方法: 选择2017年4月至2020年1月在阜外医院就诊签署知情同意书后完成CPET受试者244例为研究对象,其中219例肥厚型心肌病（肥厚心组）和无诊断疾病健康人25例（正常组）,观察两组CPET核心指标的异同。结果: ①肥厚心组男163女56例,正常组11男14女;肥厚心组年龄（46.7±12.8,16.0~71.0）岁;正常组年龄（43.7±10.4,26.0~61.0）岁。②肥厚心组CPET核心指标的峰值摄氧量（Peak VO₂）为（65.2±13.8,22.8~103.4）%pred;无氧阈（AT）为（66.4±13.0,33.7~103.5）%pred;峰值氧脉搏（Peak O₂ pulse）为（84.3±19.0,90.9~126.0）%pred;摄氧效率平台（OUEP）为（99.2±13.4,69.1~155.5）%pred;分钟通气量和二氧化碳排出量比值最小值（Lowest VE/VCO₂）为（108.0±13.2,70.4~154.0）%pred;分钟通气量和二氧化碳排出量比值斜率（VE/VCO₂ Slope）为（108.5±17.9,66.9~164.9）%pred, 肥厚心组较正常组在峰值摄氧量,无氧阈,峰值氧脉搏,摄氧效率平台等百分预计值（%pred）等指标均显著降低（P<0.01或P<0.05）;而Lowest VE/VCO₂和VE/VCO₂ Slope（%pred）显著升高（P<0.05）,差异均有统计学意义。个体而言,部分患者就诊时整体功能状态尚在正常范围内。③CPET中Peak VO₂与其他核心指标AT、OUEP、Peak O₂ pulse、峰值收缩压呈正相关;与Lowest VE/VCO₂ 和VE/VCO₂ Slope呈负相关。结论: 肥厚型心肌病患者能安全完成CPET,CPET指标具有特异性,不仅可用于整体功能评测、疾病诊断与鉴别诊断、危险分层、疗效评估和精准预后预测,并可用于整体论指导下的个体化整体方案慢病有效管理,值得进一步深入研究和临床推广应用。     

肥厚型心肌病患者运动血压反应异常的两类表现及其相关因素分析*

目的: 运动血压反应不足及运动后恢复期血压降低是肥厚型心肌病（HCM）患者常见的异常表现,本研究的目的是分析HCM患者这两类异常血压反应表现的相关因素及其与心肺运动功能的关系。方法: 回顾性研究2018年4月至2020年1月期间在阜外医院功能检测中心行心肺运动试验（CPET）的HCM患者219例。111例行CPET的性别、年龄匹配的正常体检者作为正常对照组。比较正常对照组与HCM组的CPET运动血压反应。将HCM患者分为运动血压反应正常组及运动血压反应不足组,以及运动后血压正常组及运动后恢复期血压降低组,分别比较上述两类运动血压反应异常者的临床情况及CPET功能指标。结果: 与正常对照组相比,HCM患者运动血压反应不足（8.7%比1.8%,P=0.016）及运动后恢复期血压降低（6.8%比0.0%,P=0.003）的发生率显著升高。在HCM患者中,与运动血压反应正常者相比,运动血压反应不足的HCM患者更多合并冠心病（P=0.029）、肺动脉高压（P=0.002）及房颤/房扑（P=0.036）;与运动后血压正常者相比,运动后恢复期血压下降的HCM患者静息流出道压差（P=0.017）更高,合并流出道梗阻比例（P=0.015）、合并收缩期二尖瓣前移现象（P=0.022）及左室射血分数（P=0.043）更高。经过Logistic多元回归分析,运动血压反应不足的独立相关因素为冠心病（β=1.519,P=0.013）、肺动脉高压（β=2.292, P=0.000）。而运动后恢复期血压下降仅与左室流出道压差有独立的相关性（β=0.018, P=0.005）。运动血压反应不足的HCM患者峰值摄氧量（P=0.003）、峰值心率（P=0.014）及心率储备（P=0.003）更低,NT末端B型脑钠肽前体（P=0.019）及二氧化碳通气当量斜率（P=0.000）更高。运动后恢复期血压下降与各种心肺功能指标均无相关性。结论: HCM运动血压反应不足及运动后恢复期血压降低的发生率均较正常人群显著升高。HCM患者运动血压反应不足与合并冠心病和肺动脉高压有显著的独立相关性,而运动后血压下降仅与左室流出道压差独立相关。运动血压反应不足的HCM患者心肺运动功能降低,而运动后恢复期血压降低与心肺运动功能无显著相关性。     

不同剂量链脲佐菌素腹腔注射制备大鼠糖尿病心肌病模型的病理学观察

建立糖尿病性心肌病（DCM）大鼠模型,观察不同剂量链脲佐菌素（STZ）单次腹腔注射后大鼠心肌和胰腺的病理学变化。用STZ 50 mg/kg、55 mg/kg、60 mg/kg 3种剂量单次腹腔注射,制备糖尿病大鼠模型;以柠檬酸三钠-柠檬酸缓冲液腹腔注射,作为对照。72 h后,测空腹血糖及做口服葡萄糖耐量实验（OGTT）;3周后,HE染色观察各组大鼠胰腺和心肌形态学变化,Masson三色染色观察心肌纤维化改变。OGTT和空腹血糖显示3组存活大鼠糖尿病均成模;3周末,50 mg/kg和55 mg/kg剂量死亡率为25%;60 mg/kg剂量高,达到75%;HE染色显示55 mg/kg剂量组大鼠胰岛明显萎缩,轮廓不清晰,胰岛细胞数量少,心肌细胞肥大、排列紊乱,细胞间隙增大,并有炎症细胞浸润;50 mg/kg组胰岛和心肌也有变化,但无55 mg/kg组明显。心肌Masson染色显示55 mg/kg组心肌内胶原组织明显增多,排列紊乱,分布不均。55 mg/kg剂量的STZ单次注射大鼠腹腔,造模3周可以建立较明显的DCM模型,可为DCM的组织病理学和实验研究提供一个较好的动物模型。     

Effect of spatial inlet velocity profiles on the vortex formation pattern in a dilated left ventricle

Despite the advancement of cardiac imaging technologies, these have traditionally been limited to global geometrical measurements. Computational fluid dynamics (CFD) has emerged as a reliable tool that provides flow ?eld information and other variables essential for the assessment of the cardiac function. Extensive studies have shown that vortex formation and propagation during the filling phase acts as a promising indicator for the diagnosis of the cardiac health condition. Proper setting of the boundary conditions is crucial in a CFD study as they are important determinants, that affect the simulation results. In this article, the effect of different transmitral velocity profiles (parabolic and uniform profile) on the vortex formation patterns during diastole was studied in a ventricle with dilated cardiomyopathy (DCM). The resulting vortex evolution pattern using the uniform inlet velocity profile agreed with that reported in the literature, which revealed an increase in thrombus risk in a ventricle with DCM. However the application of a parabolic velocity profile at the inlet yields a deviated vortical flow pattern and overestimates the propagation velocity of the vortex ring towards the apex of the ventricle. This study highlighted that uniform inlet velocity profile should be applied in the study of the filling dynamics in a left ventricle because it produces results closer to that observed experimentally.     

Subcellular Localization of Dystrophin Isoforms in Cardiomyocytes and Phenotypic Analysis of Dystrophin-deficient Mice Reveal Cardiac Myopathy is Predominantly Caused by a Deficiency in Full-length Dystrophin

Duchenne muscular dystrophy (DMD) is an X-linked recessive progressive muscle degenerative disorder that causes dilated cardiomyopathy in the second decade of life in affected males. Dystrophin, the gene responsible for DMD, encodes full-length dystrophin and various short dystrophin isoforms. In the mouse heart, full-length dystrophin Dp427 and a short dystrophin isoform, Dp71, are expressed. In this study, we intended to clarify the functions of these dystrophin isoforms in DMD-related cardiomyopathy. We used two strains of mice: mdx mice, in which Dp427 was absent but Dp71 was present, and DMD-null mice, in which both were absent. By immunohistochemical staining and density-gradient centrifugation, we found that Dp427 was located in the cardiac sarcolemma and also at the T-tubules, whereas Dp71 was specifically located at the T-tubules. In order to determine whether T tubule-associated Dp71 was involved in DMD-related cardiac disruption, we compared the cardiac phenotypes between DMD-null mice and mdx mice. Both DMD-null mice and mdx mice exhibited severe necrosis, which was followed by fibrosis in cardiac muscle. However, we could not detect a significant difference in myocardial fibrosis between mdx mice and DMD-null mice. Based on the present results, we have shown that cardiac myopathy is caused predominantly by a deficiency of full-length dystrophin Dp427.     

Acute exacerbations in patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing interstitial lung disease that primarily affects older adults. Median survival after diagnosis is 2–3 years. The clinical course of IPF may include periods of acute deterioration in respiratory function, which are termed acute exacerbations of IPF (AEx-IPF) when a cause cannot be identified. AEx-IPF may represent a sudden acceleration of the underlying disease process of IPF, or a biologically distinct pathological process that is clinically undiagnosed. An AEx-IPF can occur at any time during the course of IPF and may be the presenting manifestation. The incidence of AEx-IPF is hard to establish due to variation in the methodology used to assess AEx-IPF in different studies, but AEx-IPF are believed to occur in between 5 and 10% of patients with IPF every year. Risk factors for AEx-IPF are unclear, but there is evidence that poorer lung function increases the risk of an AEx-IPF and reduces the chances of a patient surviving an AEx-IPF. The presence of comorbidities such as gastroesophageal reflux disease (GERD) and pulmonary hypertension may also increase the risk of an AEx-IPF. AEx-IPF are associated with high morbidity and mortality. Patients who experience an AEx-IPF show a worsened prognosis and AEx-IPF are believed to reflect disease progression in IPF. Current treatments for AEx-IPF have only limited data to support their effectiveness. The latest international treatment guidelines state that supportive care remains the mainstay of treatment for AEx-IPF, but also give a weak recommendation for the treatment of the majority of patients with AEx-IPF with corticosteroids. There is emerging evidence from clinical trials of investigational therapies that chronic treatment of IPF may reduce the incidence of AEx-IPF. Additional clinical trials investigating this are underway.     

Desmosomes in the Heart: A Review of Clinical and Mechanistic Analyses

Abstract

Desmosomes have long been appreciated as intercellular junctions that are vital for maintaining the structural integrity of stratified epithelia. More recent clinical investigations of patients with diseases such as arrhythmogenic cardiomyopathy have further highlighted the importance of desmosomes in cardiac tissue, where they help to maintain coordination of cardiac myocytes. Here, we review clinical and mechanistic studies that provide insight into the functions of desmosomal proteins in skin and heart during homeostasis and in disease. While intercellular junctions are organized differently in cardiac and epithelial tissues, studies conducted in epithelial systems may inform our understanding of cardiac desmosomes. We explore traditional and non-traditional roles of desmosomal proteins, ranging from adhesive capacities to nuclear functions. Finally, we discuss how these studies can guide future investigations focused on determining the molecular mechanisms by which desmosomal mutations promote the development of cardiac diseases.     

Highlights from Special Issue: Junctional Targets of Skin and Heart Diseases

Abstract

In this issue, guest editors Kathy Green and Mario Delmar, who are leaders in the fields of epidermal desmosomes and heart intercalated discs respectively, have joined forces to collate a two-part series of reviews focused on junctional proteins and genes that are targets of skin and heart diseases.