Cardiac and Arteriolar Lesions in Fabry Disease and Dysautonomia

摘要 法布里病是一种罕见的疾病，由溶酶体酶α-半乳糖苷酶A缺乏引起，导致 其底物，主要是球状三糖神经酰胺(GL3)在细胞内积累，导致严重的多器官 并发症。酶替代疗法(Ert)是目前治疗法布里综合征的标准疗法。 疾病。然而，一些细胞，包括肾足细胞(PC)、心肌细胞(CM)和血管 肌肉细胞(VSMC)对ERT相对耐受，这在相当大比例的 ERT治疗严重并发症的患者，如中风、心脏和肾功能衰竭。而心血管疾病 并发症是法布里最常见的死因，肾脏并发症次之。 这些并发症背后的病变的病理生理学还不是很清楚，需要 进一步的研究。这样的研究需要大量的患者和活组织检查以及详细的临床 信息，这些都是罕见疾病研究中的常见障碍。溶酶体疾病网络 (LDN)为研究这种罕见疾病的研究人员创造了一个独特的联网机会。 利用我们在LDN内外的广泛合作网络以及我们自己丰富的心脏、肾脏、 和皮肤活检收集，我们非常准备研究自然历史和ERT治疗 Fabry病心血管和肾脏并发症的关键病变通过新的治疗方案的结果 我们开发的形态测量方法。这些经过验证的具体和定量方法将 请允许我们描述这些损害与心脏和肾功能之间的关系。我们还将研究 皮肤小动脉VSMC包括同期肾活检患者，以确定是否较少 侵入性方法将在较难接触到的组织中提供有关这些重要细胞的重要器官信息。 此外，我们还将研究ERT对心肌细胞和心脏、肾脏和心脏的GL3清除的影响。 以确定影响ERT疗效的因素。这些研究极有可能 为未来的Fabry病临床试验提供可重复和敏感的结构终点，探索新的 治疗方法正在接近。此外，我们还将评估心率和血压的倾斜表变异性 以及心室除极/复极的心电图标记物，以便 检测Fabry病自主神经障碍的存在和严重程度，并在试点研究中测试这些 自主神经紊乱和心电参数可预测法布里患者心脏事件/功能障碍的发展 病人。这些独特的心脏和肾脏项目极有可能带来新的见解，进一步推动我们的 了解Fabry病和新的临床试验策略。

Abstract Fabry disease, an uncommon disease caused by deficiency of lysosomal enzyme α-galactosidase A, leads to intracellular accumulation of its substrates, mainly globotriaosylceramide (GL3), causing severe multi-organ complications. Enzyme replacement therapy (ERT) is the current standard treatment for patients with Fabry disease. However, some cells, including kidney podocytes (PC), cardiac myocytes (CM) and vascular smooth muscle cells (VSMC), are relatively resistant to ERT, this creating residual risks in a substantial proportion of ERT treated patients for serious complications, such as stroke, heart and renal failure. While cardiovascular complications are the most common, and renal complications the next most common, cause of death in Fabry disease, the pathophysiology of the lesions underlying these complications is poorly understood and requires further studies. Such studies need access to large number of patients and biopsies and detailed clinical information, these being common roadblocks in the study of rare diseases. The Lysosomal Disease Network (LDN) has created a unique opportunity of networking among the investigators studying such rare diseases. Using our extensive network of collaborators inside and outside of LDN as well as our own rich cardiac, renal, and skin biopsy collections, we are extremely well poised to study the natural history and ERT treatment outcomes of the key lesions of cardiovascular and renal complications of Fabry disease through novel morphometric approaches that we have developed. These validated specific and quantitative approaches will allow us to describe the relationships between these lesions and cardiac and renal function. We will also study skin arteriolar VSMC including in patients with concomitant renal biopsies in order to determine if a less invasive approach will provide vital organ information regarding these important cells in less accessible tissues. In addition, we will study the effect of ERT on GL3 clearance from cardiac myocytes and cardiac, renal and skin VSMC so as to determine factors influencing the effectiveness of ERT. These studies are highly likely to provide reproducible and sensitive structural endpoints for future Fabry disease clinical trials exploring new treatment approaches. In addition, we will assess tilt table variability of heart rate and blood pressure response, as well as electrocardiographic (ECG) markers of ventricular depolarization/repolarization in order to detect the presence and severity of dysautonomia in Fabry disease and, in pilot studies, to test whether these dysautonomia and ECG parameters can predict the development of cardiac events/dysfunction in Fabry patients. These unique cardiac and renal projects are highly likely to lead to new insights furthering our understanding of Fabry disease and to new clinical trial strategies.