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， 其底物，主要是神经酰胺三己糖苷（GL 3）的细胞内积累，引起严重的多器官 并发症酶替代疗法（ERT）是目前法布里病患者的标准治疗方法 疾病然而，一些细胞，包括肾脏足细胞（PC），心肌细胞（CM）和血管平滑肌细胞（VSMC）， 肌细胞（VSMC）对ERT具有相对抵抗力，这在相当大比例的患者中产生了剩余风险。 ERT治疗患者的严重并发症，如中风，心脏和肾衰竭。虽然心血管 并发症是法布里病最常见的死亡原因，其次是肾脏并发症 疾病，病变的病理生理基础这些并发症是知之甚少，需要 进一步研究。此类研究需要接触大量患者和活检样本，以及详细的临床资料。 信息，这些是罕见疾病研究中常见的障碍。溶酶体疾病网络 (LDN)为研究这些罕见疾病的研究人员之间建立联系创造了一个独特的机会。 利用我们在LDN内外广泛的合作者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史和ERT治疗 法布里病心血管和肾脏并发症的关键病变的结局， 形态计量学方法。这些经过验证的具体和定量方法将 使我们能够描述这些病变与心肾功能之间的关系。我们还将研究 皮肤小动脉VSMC，包括同时进行肾活检的患者，以确定是否存在较少的 侵入性方法将提供关于这些重要细胞在不易接近的组织中的重要器官信息。 此外，我们还将研究ERT对心肌细胞和心脏、肾脏和肾脏中GL 3清除的影响。 皮肤VSMC，以确定影响ERT有效性的因素。这些研究很有可能 为未来的法布里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。此外，我们将评估心率和血压的倾斜床变异性 反应，以及心室去极化/复极化的心电图（ECG）标记，以便 检测法布里病中自主神经功能障碍的存在和严重程度，并在初步研究中， 自主神经功能障碍和ECG参数可以预测法布里病患者心脏事件/功能障碍的发生 患者这些独特的心脏和肾脏项目极有可能带来新的见解， 了解法布里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.