Vascular and Skeletal Muscle Function in Gulf War Veterans Illness

描述(由申请人提供)： 海湾战争退伍军人疾病(GWVI)是海湾战争退伍军人在1991年从部署返回后不久报告的一系列症状。GWVI的临床诊断标准基于慢性多系统疾病(CMI)标准，该标准基于统计症状聚类分析，得出三类症状：疲劳、情绪/认知和肌肉骨骼症状。目前，根据这些标准，大约40%的海湾战争退伍军人(超过140万退伍军人)患有GWVI。GWVI背后的病理生理机制尚不清楚，对GWVI机制的深入了解可能导致新的概念、研究方法和治疗干预措施。我们的初步研究将评估25例GWVI患者和25例没有GWVI的退伍军人对照的血管和骨骼肌功能的三个方面。这项拟议的为期三年的先导性研究的目的是确定患有GWVI的退伍军人的下肢(腿)内皮功能、运动功能和骨骼肌线粒体基因调控是否与没有GWVI的退伍军人不同。内皮功能障碍、骨骼肌功能损伤和线粒体基因调节失调是GWVI的可能机制，因为在海湾战争期间暴露于抗胆碱酯酶抑制剂可能会影响这些功能，导致疲劳症状和其他肌肉骨骼症状。我们将从海湾战争退伍军人(德文斯堡队列)中招募受试者。在这个队列中，大约60%的海湾战争退伍军人符合明确的GWVI标准。在这些队列中，症状和接触杀虫剂、溴化吡斯的明和低水平沙林的情况都有很好的记录。患者和对照组将在心导管实验室使用多普勒血流线和血管内超声进行股动脉微血管内皮细胞功能的侵入性评估。我们将使用这项技术来测量动脉内输注内皮依赖性血管扩张剂乙酰胆碱10-6M、微血管内皮非依赖性扩张剂腺苷和大动脉扩张剂硝酸甘油的血流和动脉反应。PI在这类研究方面有很长的记录。一周后，受试者将接受广泛的骨骼肌功能评估，使用心肺运动测试来测量无氧阈值，客观的力量和疲劳评估，以及6分钟步行测试。在这项研究的一周后，受试者将接受大腿骨骼肌活组织检查。我们将对此进行分析 对于肌肉纤维类型，以及RT-PCR，以评估负责调节线粒体呼吸功能的核和线粒体基因。总体目标是评估病理生理和肌肉机制的差异，这将使我们能够设计更明确的优点审查建议，以评估这些功能的差异，并测试针对这些机制的潜在治疗方法。这项先导性研究还可能为其他以疲劳和其他肌肉骨骼症状为特征的慢性病提供见解，如外周血管疾病和充血性心力衰竭。

DESCRIPTION (provided by applicant): Gulf War Veterans Illness (GWVI) is a constellation of symptoms reported by Gulf War Veterans shortly after their return from deployment in 1991. Clinical diagnostic criteria for GWVI are based on chronic multisystem illness (CMI) criteria, which are based on statistical symptom cluster analysis resulting in three categories: fatigue, mood/ cognition, and musculoskeletal symptoms. Currently, approximately 40% of Gulf War Veterans (over 1/4 million Veterans) have GWVI by these criteria. The pathophysiological mechanisms underlying GWVI are not understood, and insights into the mechanisms of GWVI could lead to novel concepts, methodologies for study, and treatment interventions. Our Pilot study will assess three facets of vascular and skeletal muscle function in 25 cases with GWVI and 25 Veteran controls without GWVI. The purpose of the proposed three-year pilot study is to determine whether lower extremity (leg) endothelial function, exercise functions, and skeletal muscle mitochondrial gene regulation are different among Veterans with GWVI compared to Veterans' without this illness. Endothelial dysfunction, skeletal muscle functional impairment, and dysregulation of mitochondrial genes are plausible mechanisms for GWVI as exposure to anticholinesterase inhibitors during the Gulf War may affect these functions to cause symptoms of fatigue and other musculoskeletal symptoms. We will recruit subjects from a well characterized cohort of Gulf War Veterans (the Fort Devens Cohort). Approximately 60% of Gulf War Veterans in this cohort meet clear CMI criteria for GWVI. Symptoms and exposure to pesticides, pyridostigmine bromide, and low level sarin exposure are well documented in these cohorts. Cases and controls will have femoral artery microvascular endothelial function assessed invasively in the cardiac catheterization laboratory using Doppler flow wire and intravascular ultrasound. We will use this technique to measure flow and artery responses to intra-arterial infusions of the endothelium-dependent vasodilator acetylcholine 10-6M, the microvascular endothelium-independent dilator adenosine, and the large artery vasodilator nitroglycerin. The PI has a long track record in this type of research. After 1 week, subjects will have an extensive skeletal muscle functional assessment using cardiopulmonary exercise testing to measure anaerobic threshold, objective strength and fatigue assessments, and the 6-minute walk test. One week after this study, subjects will have a skeletal muscle biopsy from the thigh. This will be analyzed for muscle fiber type, and RT-PCR to assess nuclear and mitochondrial genes responsible for regulating mitochondrial respiratory function. The overall aim is to assess differences in pathophysiological and muscle mechanisms, which will allow us to design a more definitive MERIT Review proposal to assess differences in these functions and test potential treatments targeting these mechanisms. This Pilot study may also provide insights into other chronic illness characterized by fatigue and other musculoskeletal symptoms, such as peripheral vascular disease and congestive heart failure.