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.
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.
|Loavenbruck, Adam J; Singer, Wolfgang; Mauermann, Michelle L et al. (2016) Transthyretin amyloid neuropathy has earlier neural involvement but better prognosis than primary amyloid counterpart: an answer to the paradox? Ann Neurol 80:401-11|
|LabbÃ©, Catherine; Heckman, Michael G; Lorenzo-Betancor, Oswaldo et al. (2016) MAPT haplotype diversity in multiple system atrophy. Parkinsonism Relat Disord 30:40-5|
|Coon, Elizabeth A; Sletten, David M; Suarez, Mariana D et al. (2015) Clinical features and autonomic testing predict survival in multiple system atrophy. Brain 138:3623-31|
|Loavenbruck, A; Iturrino, J; Singer, W et al. (2015) Disturbances of gastrointestinal transit and autonomic functions in postural orthostatic tachycardia syndrome. Neurogastroenterol Motil 27:92-8|
|Singer, Wolfgang; Low, Phillip A (2015) Optimizing clinical trial design for multiple system atrophy: lessons from the rifampicin study. Clin Auton Res 25:47-52|
|Low, Phillip A; Reich, Stephen G; Jankovic, Joseph et al. (2015) Natural history of multiple system atrophy in the USA: a prospective cohort study. Lancet Neurol 14:710-9|
|Figueroa, Juan J; Singer, Wolfgang; Sandroni, Paola et al. (2015) Effects of patient-controlled abdominal compression on standing systolic blood pressure in adults with orthostatic hypotension. Arch Phys Med Rehabil 96:505-10|
|Low, Phillip A; Singer, Wolfgang (2015) Treatment-induced neuropathy of diabetes: an energy crisis? Brain 138:2-3|
|Figueroa, Juan J; Singer, Wolfgang; Parsaik, Ajay et al. (2014) Multiple system atrophy: prognostic indicators of survival. Mov Disord 29:1151-7|
|Low, Phillip A; Robertson, David; Gilman, Sid et al. (2014) Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 13:268-75|
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