Differential Approach to the Postural Tachycardia Syndrome

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.