Unraveling the pathophysiology of feline hypertrophic cardiomyopathy - an interdisciplinary approch

猫肥厚性心肌病(HCM)是一种常见的自发性成年猫疾病，主要发生在公猫身上。已有遗传原因的报道，但猫可能有突变而不会患上这种疾病，而没有突变的猫可能会表现出疾病特征。此外，到目前为止，影响这种疾病的其他因素尚不清楚。肥厚性心肌病的特点是左心腔壁增厚，结构和功能改变。这会导致心脏僵硬和功能障碍的增加，并可能导致心律失常、血栓形成和心力衰竭。然而，该病的临床症状和进展是高度可变的，关于临床和病理疾病参数几乎没有一致意见。*在我的领导下，我的研究团队发现猫心脏炎症和重塑介质的表达谱与年龄、性别和HCM有关。我们还观察到一种我们怀疑是侵入心脏或在那里生长的干细胞(SC)的细胞类型的增加。因此，我们假设HCM是由心肌细胞变性引起炎症和SC介导的代偿性修复过程引起的重塑机制驱动的。*我的研究计划的长期目标是获得猫肥厚性肥厚症疾病过程的动态、机械的图景。我的目标是进一步研究年龄、肥胖、性别和非心脏疾病等因素对心脏结构和功能的影响，并将这些方法应用于其他物种，以期在圭尔夫大学建立一个国际知名的心血管研究最先进的研究中心。未来5年的短期目标是应用新的(RNA测序、microRNA分析、RNA原位杂交)和成熟的(实时聚合酶链式反应、组织学、免疫组织学、透射电子显微镜)技术来获得有关基因、心脏和血液中调节相关蛋白质产生的成分的信息，确认这些蛋白质的产生和细胞来源，并表征去细胞和再生过程，以及SC在这些过程中的潜在参与。我的目标是应用先进的成像技术(先进的超声心动图，MRI)来研究结构变化对心功能的影响。所获得的结果将被用于随后比较猫不同的HCM表现形式(即有血栓和无血栓)，并前瞻性地研究HCM的进展。*拟议的项目将大大加深对HCM相关机制的了解，以及这些过程对心脏功能和体循环的影响。这种跨学科、最先进的方法在小动物心脏病学中是独一无二的，并将对兽医科学的基础研究领域产生重大影响。

Feline hypertrophic cardiomyopathy (HCM) is a common, spontaneous disease of adult, predominantly male cats. A genetic cause is reported, but cats can have a mutation and not develop the disease and cats without mutation can present with disease characteristics. Also, other factors that influence the disease are so far not known. HCM is characterized by thickening of the left cardiac chamber wall, with structural and functional changes. This results in increased stiffness and dysfunction of the heart and can cause arrhythmia, thrombus formation and heart failure. However, the clinical signs and progression of the disease are highly variable, and little agreement exists about the clinical and pathological disease parameter. ***Under my leadership, my research team has identified variations in the expression profiles of inflammatory and remodeling mediators in the heart of cats in association with age, gender and HCM. We also observed an increase in cells of a type that we suspect to be stem cells (SC) that invade the heart or grow there. Hence we hypothesize that HCM is driven by remodeling mechanisms resulting from heart muscle cell degeneration causing inflammation and SC mediated compensatory repair processes. ***The long-term objective of my research program is to obtain a dynamic, mechanistic picture of the disease processes in feline HCM. I aim further to investigate factors such as age, obesity, gender and non-cardiac diseases on the structure and function of the heart and to apply these methodologies to other species, with the aim to establish an internationally renowned state-of-the-art research center for cardiovascular research at the University of Guelph. The short term objectives for the next 5 years are to apply novel (RNA sequencing, microRNA analysis, RNA-in situ hybridization) and established (real-time PCR, histology, immunohistology, transmission electron microscopy) techniques to obtain information on genes involved, components in the heart and blood that regulate production of relevant proteins, confirm the production and cellular sources of these proteins, and to characterize de- and regenerative processes, and the potential involvement of SC in these processes. I aim to apply advanced imaging techniques (advanced echocardiography, MRI) to investigate the influence of structural changes on cardiac function. The results obtained will be used to subsequently compare different HCM presentations of cats (i.e with and without thrombi) and investigate prospectively the progression of HCM.***The proposed project will add substantially to the understanding of relevant mechanisms involved in HCM and the influence of these processes on the function of the heart and thereby the systemic circulation. This interdisciplinary, state-of-the-art approach is unique in small animal cardiology and will have a significant impact on an area of fundamental research in veterinary sciences.