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: 8298799
• 负责人: Wolfgang Singer
• 金额: $ 16.56万
• 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/8298799
• 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. PUBLIC HEALTH RELEVANCE: The Postural Tachycardia Syndrome (POTS) is a frequently encountered and disabling condition that is characterized by an excessive rise in heart rate and symptoms of lightheadedness and faintness when standing. In spite of years of intensive research, our understanding of this condition remains poor and treatment options are less than optimal. With this proposal the investigator plans to test the well- supported hypothesis that POTS is not a single condition as previously assumed, but a syndrome that consists of distinctly different subtypes with different underlying mechanisms, and that these subtypes can be identified using routine clinical tests.

描述（由申请人提供）：体位性心动过速综合征（POTS）是一种立位耐受性障碍，其特征为过度心动过速以及采取直立姿势时的头晕和昏厥症状。它通常会影响年轻的健康男性和女性，导致经常致残的慢性症状，并导致高度的社会经济影响。尽管经过多年的深入研究，这种常见综合征的病理生理学仍然知之甚少。POTS并不存在普遍接受的病理生理学概念，但有科学证据的概念包括存在有限的自主神经病变、肾上腺素能亢进状态、再适应和慢性血容量不足。主要学术中心提出的证据和研究结果令患者和研究人员感到沮丧，不仅因为我们对疾病的病理生理学理解缺乏进展，而且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确定了不同的表型模式，表明不同的潜在病理生理学，即神经病，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，并且可以很好地解释以前的困难， 不可复制和相互矛盾的结果。POTS作为异质实体的概念已经被该领域的成熟研究者讨论过，并且已经描述了不同亚型之间自主测试的差异，但这个概念尚未得到科学验证，大多数研究人员继续研究和治疗POTS作为一个单一的实体。因此，该候选人提议测试这样的假设：POTS不是一个单一实体，而是一组由明显不同的潜在病理生理学组成的异质性疾病。他建议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，研究一组POTS患者。然后，他为每个患者推导出一组平衡的变量，反映不同的病理机制，目的是使用聚类分析识别不同的亚型。方法将包括显微神经造影术，血容量估计，运动试验，神经纤维密度和血浆儿茶酚胺的测量。候选人还提议检验以下假设：这些不同的病理生理学导致临床自主测试的不同表型模式，允许常规识别和未来治疗分层。拟议的一系列研究应提供重要的步骤，以提高我们的能力，了解和充分治疗POTS患者。同样重要的是，他们将培养候选人作为临床研究员的职业发展。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指导培训将成为候选人发展为独立研究者的基石。该计划的成功将由一些重要因素保证：1）候选人作为自主神经学家的强大临床背景和先前在自主神经疾病患者的病理生理学和治疗方面的研究经验。 2)导师和共同导师的科学指导和培训支持，他们是备受推崇的研究者，并完全致力于本提案的成功和候选人作为独立研究者的发展，即菲利普低，迈克乔伊纳，罗伊弗里曼和杰伊曼德雷卡。 3)对该主题的多学科方法，以及多学科培训经验，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合作。 4)通过马约的转化科学活动中心的临床和转化科学证书课程，以及生物统计学和试验设计方面的指导经验，进行有效和充分的临床研究方法培训。 5)在临床相关临床研究方面拥有卓越记录并具有悠久历史的机构的全力支持 自主神经科学通过本项目中提出的额外技能和培训，沿着优秀的导师团队和充分的机构支持，候选人将在本奖项的时间范围内实现成为独立临床研究者的职业发展目标。 公共卫生相关性：体位性心动过速综合征（POTS）是一种常见的致残性疾病，其特征是心率过度升高，站立时出现头晕和昏厥症状。尽管经过多年的深入研究，我们对这种情况的了解仍然很差，治疗方案也不是最佳的。根据这一提议，研究者计划检验得到充分支持的假设，即POTS不是先前假设的单一病症，而是由具有不同潜在机制的明显不同亚型组成的综合征，并且这些亚型可以使用常规临床试验来识别。