Effect of Atorvastatin on Endothelial Function and Raynaud in Diffuse Scleroderma

阿托伐他汀对弥漫性硬皮病内皮功能和雷诺氏的影响

• 批准号: 8832216
• 负责人: Robyn Therese Domsic
• 金额: $ 20.16万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8832216
• 关键词: Affect; Age; Autoimmune Diseases; Autoimmune Process; Blood Vessels; Blood capillaries; Cell Adhesion Molecules; Clinical; Clinical Trials; Complex; Complication; Conflict (Psychology); Connective Tissue Diseases; Cutaneous; Data; Diffuse Scleroderma; Disease; Disease Progression; Early Diagnosis; Early Intervention; Early treatment; Endothelial Cells; Event; FDA approved; Fibrosis; Fingers; Functional disorder; Gangrene; Gender; Image; Imaging Techniques; Immune system; Immunologics; Individual; Injury; Intervention; Ischemia; Lasers; Lymphocyte; Measurement; Measures; Mediating; Microcirculation; Microvascular Dysfunction; Modality; Nitric Oxide; Oral; Organ; Outcome; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Pilot Projects; Placebos; Process; Production; Publishing; Pulmonary Hypertension; Race; Raynaud Disease; Reperfusion Therapy; Risk; Skin; Surrogate Markers; Symptoms; Systemic Scleroderma; Testing; Toes; Ulcer; Vascular Diseases; Work; atorvastatin; brachial artery; capillary; cell injury; cohort; contrast imaging; design; digital; endothelial dysfunction; experience; imaging modality; improved; migration; mortality; novel therapeutics; pleiotropism; prevent; public health relevance; response; targeted treatment; theories; vascular abnormality; vascular smooth muscle cell proliferation

 DESCRIPTION: Systemic sclerosis (SSc) is a multisystem autoimmune illness characterized by vasculopathy, immune system activation and fibrosis of the skin and internal organs. SSc affects approximately 240 people per million in the US, but is a disease for which there is no FDA approved medication. Current hypothesis of pathogenesis suggest that a vascular injury with endothelial dysfunction may be an inciting event contributing to immunologic activation and fibrosis in the pathogenesis of the disease. More than 90% of individuals with SSc have vascular complications including Raynaud phenomenon, digital ulcers or gangrene and pulmonary hypertension, with microvascular abnormalities felt to contribute to Raynaud and digital ulcerations. Statin medications are well-recognized to have pleiotropic effects which may modify all aspects of SSc pathogenesis. A few preliminary statin studies have found conflicting results, but have used patients with overall longstanding disease, when the vasculopathy may have not been amenable to treatment. In our preliminary work we have found evidence that statins may mediate microvascular endothelial dysfunction in patients with very early systemic sclerosis. Laser speckle contrast imaging (LSCI) is a newer imaging modality that assesses microcirculation and has been proposed as a surrogate marker for systemic microvascular function. Our preliminary data showed a distinct pattern of microcirculatory flow as measured by LSCI compared to healthy age, gender and race-matched controls and holds promise as a functional assessment of microvascular function in SSc patients. Our hypothesis are that treatment with atorvastatin in a well-defined cohort of early diffuse SSc will improve microvascular endothelial function as measured by EndoPAT and thereby improve related Raynaud symptoms. We propose to apply LSCI imaging as a modality to assess microvascular endothelial function response to statins and hypothesize that this modality will allow us to predict responders to statins.

 描述：系统性硬化症(SSC)是一种以血管病变、免疫系统激活和皮肤和内脏纤维化为特征的多系统自身免疫性疾病。在美国，每百万人中约有240人受到SSc的影响，但这是一种没有FDA批准的药物治疗的疾病。目前的发病机制假说表明，血管损伤伴内皮细胞功能障碍可能是在疾病发病机制中导致免疫激活和纤维化的激发事件。超过90%的SSc患者有血管并发症，包括雷诺现象、指端溃疡或坏疽和肺动脉高压，微血管异常可导致雷诺现象和指端溃疡。他汀类药物被公认为具有多效性，可以改变SSC发病的方方面面。一些他汀类药物的初步研究发现了相互矛盾的结果，但他们使用的是所有长期存在疾病的患者，当血管病变可能无法治疗时。在我们的初步工作中，我们发现了他汀类药物可能介导极早期系统性硬化症患者微血管内皮细胞功能障碍的证据。激光散斑对比成像(LSCI)是一种评估微循环的较新的成像手段，已被认为是全身微血管功能的替代标志物。我们的初步数据显示，与健康的年龄、性别和种族匹配的对照组相比，LSCI测量的微循环血流具有明显的模式，有望作为SSC患者微血管功能的功能评估。我们的假设是，在定义明确的早期弥漫性SSc队列中使用阿托伐他汀治疗将改善Entopat测量的微血管内皮功能，从而改善相关的雷诺症状。我们建议应用LSCI成像作为一种评估微血管内皮功能对他汀类药物的反应的方法，并假设这种方法将使我们能够预测他汀类药物的反应者。