Differential Approach to the Postural Tachycardia Syndrome

体位性心动过速综合征的鉴别诊断方法

• 批准号: 8454414
• 负责人: Wolfgang Singer
• 金额: $ 17.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8454414
• 关键词: Address; Adrenergic Agents; Affect; Agreement; Autonomic Denervation; Autonomic nervous system disorders; Award; Biometry; Blood Plasma Volume; Blood Volume; Cardiovascular system; Catecholamines; Categories; Center for Translational Science Activities; Chronic; Clinical; Clinical Investigator; Clinical Research; Clinical Sciences; Clinical Trials Design; Cluster Analysis; Collaborations; Commit; Conflict (Psychology); Data; Development; Diagnostic; Disease; Distal; Equilibrium; Evaluation; Exercise; Exercise Physiology; Exercise stress test; Failure; Functional disorder; Future; Goals; Heart Rate; Hypovolemia; Individual; Institution; Laboratories; Left; Lightheadedness; Measurement; Mentors; Mentorship; Methods; Muscle; Nerve; Nerve Fibers; Neurologist; Neurology; Neuropathy; Neurosciences; Outcome Study; Oxygen Consumption; Pathologic; Pathology; Patients; Pattern; Phenotype; Plasma; Positioning Attribute; Prospective Studies; Recording of previous events; Research; Research Methodology; Research Personnel; Research Technics; Stratification; Stress; Subcategory; Subgroup; Symptoms; Syndrome; Tachycardia; Testing; Therapeutic; Time; Training; Training Support; Translational Research; Woman; adrenergic; autonomic nerve; autonomic neuropathy; base; career development; clinically relevant; density; experience; improved; interdisciplinary approach; men; multidisciplinary; novel therapeutic intervention; programs; skills; skills training; socioeconomics; statistics; success; trafficking; treatment response

DESCRIPTION (provided by applicant): The Postural Tachycardia Syndrome (POTS) is a disorder of orthostatic tolerance, characterized by excessive tachycardia and symptoms of lightheadedness and faintness when assuming the upright position. It typically affects young, otherwise healthy men and women, causes often disabling chronic symptoms, and results in high socioeconomic impact. In spite of years of intensive research, the pathophysiology of this frequently encountered syndrome remains poorly understood. A commonly accepted pathophysiologic concept of POTS does not exist, but concepts with scientific evidence include the presence of a limited autonomic neuropathy, a hyperadrenergic state, reconditioning, and chronic hypovolemia. Conflicting evidence and study outcomes brought forward by major academic centers has left patients and researchers frustrated, not only in terms of lack of progression of our pathophysiologic understanding of the disorder, but also in terms of lack of improvement of therapeutic approaches. We and others have started to recognize that autonomic testing in patients with POTS identifies different phenotypic patterns suggesting different underlying pathophysiologies, namely a neuropathic, hyperadrenergic, and reconditioned subtype. The conventional approach of investigating POTS as a single entity would therefore appear to be a setup for failure, and could well explain previous difficulties with non-reproducible and conflicting findings. The concept of POTS as heterogeneous entity has been discussed by well-established investigators in the field, and differences in autonomic testing between different subtypes have been described, but this concept has not been scientifically validated and most researchers continue to study and treat POTS as a single entity. The candidate therefore proposes to test the hypothesis that POTS is not a single entity but a heterogeneous group of disorders comprised of distinctly different underlying pathophysiologies. He proposes to study an unselected group of patients with POTS applying state-of-the art research techniques to assess underlying pathology and pathophysiology. He then derives a balanced set of variables for each patient reflecting different pathomechanisms with the goal to identify distinct subtypes using cluster analysis. Methods will include microneurography, blood volume estimation, exercise testing, and measurements of nerve fiber density and plasma catecholamine's. The candidate furthermore proposes to test the hypothesis that these distinct pathophysiologies result in distinct phenotypic patterns on clinical autonomic testing allowing for routine identification and future treatment stratification. The proposed serie of studies should provide important steps towards improving our ability to understand and adequately treat patients with POTS. Equally important, they will nurture the career development of the candidate as clinician-investigator. The mentored research experience, acquisition of important additional skills in autonomic research, and a mentored training in clinical research methods, trial design, and statistics will be cornerstones in the candidate's development as independent investigator. Success of this plan will be guaranteed by a number of important factors: 1) the candidate's strong clinical background as autonomic neurologist and previous experience in research on pathophysiology and therapy of patients with autonomic disorders. 2) Scientific guidance and training support by mentors and co-mentors who are highly regarded investigators and fully committed to the success of this proposal and the candidate's development as independent investigator, namely Phillip Low, Mike Joyner, Roy Freeman, and Jay Mandrekar. 3) A multidisciplinary approach to the topic but also a multidisciplinary training experience and collaborations with experts in the fields of autonomic neurology and pathology, exercise physiology, and biostatistics and trial design. 4) Training in efficient and adequate clinical research methods through a Certificate program in Clinical and Translational Science through Mayo's Center for Translational Science Activities, and a mentored experience in biostatistics and trial design. 5) Full support from an institution with a record of excellence in clinically relevant clinical research and with a long history of excellence in Autonomic Neuroscience. With the additional skills and training as proposed in this project, along with the outstanding mentorship team and full institutional support, the candidate will have achieved his career development goal of becoming an independent clinical investigator within the time frame of this award.

描述(申请人提供)：体位性心动过速综合征(POTS)是一种立位耐力障碍，特征是过度心动过速，立位时出现头晕目眩的症状。它通常影响年轻的、原本健康的男性和女性，导致通常使人丧失能力的慢性症状，并导致高度的社会经济影响。尽管进行了多年的深入研究，但这种常见综合征的病理生理学仍知之甚少。目前尚不存在公认的POTS的病理生理学概念，但有科学证据的概念包括局限性自主神经病变、高肾上腺素能状态、修复和慢性低血容量。主要学术中心提出的相互矛盾的证据和研究结果让患者和研究人员感到沮丧，不仅是因为我们对这种疾病的病理生理了解缺乏进展，也是因为治疗方法缺乏改进。我们和其他人已经开始认识到，POTS患者的自主神经测试识别出不同的表型模式，暗示着不同的潜在病理生理，即神经病变、肾上腺素能亢进和修复亚型。因此，将POTS作为一个单一实体进行调查的传统方法似乎是一种失败的设置，可以很好地解释以前在以下方面的困难 不可重现和相互矛盾的发现。POTS作为异质实体的概念已经被该领域的知名研究人员讨论过，并描述了不同亚型之间自主神经测试的差异，但这一概念尚未得到科学验证，大多数研究人员继续将POTS作为一个单一实体进行研究和处理。因此，候选人建议检验这一假设，即POTS不是一个单一实体，而是由截然不同的潜在病理生理学组成的一组不同的疾病。他建议对一组未选定的POTS患者进行研究，应用最先进的研究技术来评估潜在的病理学和病理生理学。然后，他为每个患者得出了一组反映不同病理机制的平衡变量，目的是使用聚类分析来识别不同的亚型。方法将包括显微神经学、血容量估计、运动测试以及神经纤维密度和血浆儿茶酚胺的测量。候选人进一步建议检验这样的假设，即这些不同的病理生理导致临床自主神经测试中不同的表型模式，从而允许常规识别和未来的治疗分层。拟议一系列研究应为提高我们理解和适当治疗POTS患者的能力提供重要步骤。同样重要的是，他们将促进应聘者作为临床医生-研究员的职业发展。有指导的研究经验，在自主研究中获得重要的额外技能，以及在临床研究方法、试验设计和统计学方面的有指导的培训将是候选人作为独立研究员发展的基石。这项计划的成功将得到一些重要因素的保证：1)候选人作为自主神经学家的强大临床背景，以及之前在自主神经障碍患者的病理生理学和治疗方面的研究经验。2)由导师和联合导师提供科学指导和培训支持，这些导师和合作导师是高度重视调查人员并完全致力于本提案的成功和候选人作为独立调查人员的发展，他们是Phillip Low、Mike Joyner、Roy Freeman和Jay Mandrekar。3)针对这一主题的多学科方法，以及与自主神经学和病理学、运动生理学、生物统计学和试验设计领域的专家的多学科培训经验和合作。4)通过梅奥翻译科学活动中心的临床和翻译科学证书计划，以及生物统计学和试验设计方面的指导经验，培训有效和适当的临床研究方法。5)来自一家在临床相关临床研究方面拥有卓越记录并具有长期卓越历史的机构的全力支持 自主神经科学。有了这个项目建议的额外技能和培训，再加上杰出的指导团队和充分的机构支持，候选人将在该奖项的时间框架内实现他的职业发展目标，成为一名独立的临床研究员。