As directed by the Senate Committee on Appropriations, the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Neurological Disorders and Stroke (NINDS), with participation from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Institutes within the National Institutes of Health (NIH), jointly convened a workshop on July 29, 2019, to discuss the state of the science and gaps in the current understanding of postural orthostatic tachycardia syndrome (POTS). The workshop included presentations by leading experts in POTS research and care, officials from the three sponsoring Institutes, and patient advocates, all of whom provided their individual perspectives on this timely and important topic.
When a person moves from lying down to sitting or standing upright (called orthostasis), nearly a half-liter of blood moves to the lower extremities, causing a temporary reduction in blood flow to the brain. Normally, these changes activate the involuntary (autonomic) nervous system leading to a temporary increase in heart rate. But in people with postural orthostatic tachycardia syndrome (POTS), something goes wrong with the body’s response to upright posture. People with POTS suffer from an excessive increase in heart rate (tachycardia) and other symptoms that worsen upon standing or sitting up, such as light-headedness, shortness of breath, chest pain, and palpitations. In July 2019, the NIH convened a multi-stakeholder meeting to define the current state of POTS research, and to identify knowledge gaps and future research opportunities.
POTS can be a debilitating condition that affects routine activities such as working or attending school. POTS primarily affects women of child-bearing age, with most studies reporting >80-90% female predominance. The peak incidence is at age 14 years, but half of all individuals with POTS develop it in adulthood. While there are no precise data on the prevalence of POTS, it is estimated to affect 0.2-1% of the U.S. population.
In addition to cardiovascular symptoms, common additional symptoms include profound fatigue, insomnia, headache, neurocognitive impairments, problems with body temperature regulation, nausea, abdominal pains, diarrhea or constipation, and dark red-blue discoloration of the legs. Individuals with POTS also tend to have one or more associated conditions, or comorbidities. Common comorbidities with POTS include migraine, irritable bowel syndrome, and joint hypermobility syndrome. Many people with POTS also have a personal or family history of autoimmune disease, in which the immune system attacks the body’s own tissues.
Potential Causes of POTS
It is likely that POTS has multiple underlying mechanisms that vary from person to person. There is evidence that POTS can arise from abnormalities in autonomic nervous system function, immune system function including autoimmunity, regulation of blood volume and blood flow, or a combination of these factors. Genetic factors probably also affect susceptibility to POTS. Many people with POTS report a preceding medical or life-changing event such as viral infection, concussion, surgery, pregnancy, or puberty. Due to the highly variable symptoms and signs of POTS across different people, it is unclear whether POTS is best defined as a single syndrome or as a syndrome with several subtypes that have distinct underlying causes.
Current State of POTS Care and Treatment
Leading medical organizations have developed the following working diagnostic criteria for POTS:
- Excessive increase in heart rate within 10 minutes of upright posture (≥30 bpm in adults or ≥40 bpm in adolescents); and
- Absence of orthostatic hypotension (defined as a drop in blood pressure ≥20/10 mm Hg within the first 3 minutes of upright posture); and
- Other symptoms that develop or worsen with upright posture, and that improve or resolve with recumbence; and
- Symptoms lasting at least three months; and
- Absence of other obvious illness or circumstance that could cause orthostatic tachycardia such as dehydration, anemia, or recent blood loss.
Yet, the wide range of symptoms and comorbidities associated with POTS can still make diagnosis challenging, especially for physicians who are unfamiliar with it. Many POTS specialists have lengthy waiting lists (ranging from 6 months to >2 years). One patient survey found that more than half of POTS patients traveled more than 100 miles from home, and >20% of patients travelled >500 miles from home, for POTS-related medical care. In the same survey, patients reported seeing an average of 7 physicians before receiving a POTS diagnosis, and an average diagnostic delay of almost 5 years.
There is no cure and no standardized therapy for POTS, and current treatment options focus on addressing symptoms rather than underlying disease processes. Many patients benefit acutely from dietary salt and volume expansion, although there are no data on the long-term effects of such therapy. Drug therapies focused on increasing blood pressure, expanding blood volume, and lowering heart rate can also be helpful. Exercise training, with a primary focus on aerobic reconditioning, has also been shown to help. In the case of non-cardiovascular symptoms, these may also benefit from symptomatic treatment with non-pharmacological and pharmacological approaches.
Challenges with POTS Research
There are several challenges to research in POTS. First, despite working diagnostic criteria, there are limited diagnostic tests and tools available to physicians. For example, there are no POTS biomarkers (defined as biological or chemical signs of a disease like blood sugar measurements in diabetes mellitus). Second, because POTS patients have symptoms and complications that involve many organ systems (and therefore many medical specialties), it can be difficult for any one clinician or scientist to become a comprehensive expert in all aspects of POTS. Advances in POTS treatment are limited by fundamental gaps in understanding of its underlying cause(s) and mechanisms, as well as a lack of high-quality evidence for efficacy of potential therapies. While the gold standard for efficacy is the controlled randomized trial (in which participants are randomly assigned to receive the experimental therapy or a placebo), most POTS trials are uncontrolled or non-randomized, or if randomized, are of very short duration. Most published trials also involved participants from a single academic medical center, rather than recruiting a larger, more nationally representative group of patients.
Gaps in Current Knowledge
- Longitudinal Natural History of POTS – There is a need to better understand the natural history of POTS. This issue could be investigated both in a broad sense, but also by following patients with certain features to determine if there are distinct subtypes of POTS with different prognoses and responses to treatment. One branch of this research could include an autopsy study, which would allow detailed pathology studies that are too invasive to perform on patients—for example, looking for structural damage to the nerves or parts of the brain and spinal cord that help control heart rate.
- Genetics and Epigenetics – Case series have found two gene mutations associated with POTS in some affected families, but most individuals with POTS do not appear to harbor these mutations. However, there have not been any large genetic or epigenetic studies to better understand why POTS seems to cluster in families and has such a strong female predominance.
- Studies to Understand Causes and Mechanisms of POTS – While there is evidence for several causes and mechanisms underlying POTS, there are also many knowledge gaps that would benefit from investigation to better understand the following aspects of POTS:
- Cardiovascular structure and function
- Neurocognitive function
- Imaging Biomarker Studies – These studies could utilize new and emerging biological imaging techniques, including functional MRI of the brain, as well as PET and SPECT scans to examine sympathetic neuronal function in the heart.
- Clinical Trials of POTS Treatments – Robust clinical trials are needed to test potential therapies for the complex manifestations of POTS, including cardiovascular, neurological, and other symptoms. The emphasis of clinical trials at this time is on using drugs that have been marketed for other indications and assessing their efficacy in the treatment of POTS. New mechanistic insights into POTS would enable development and testing of therapies specifically targeted to it. In order for clinical studies to be meaningful to patient care, recruitment of participants should occur at multiple clinical sites and have rigorous trial design that includes a sufficient duration of treatment and evaluation, and standardized outcome measures.
- The NIH could develop infrastructure to better coordinate POTS research across different institutes and centers, and to help address the priorities described above. Such efforts could also help young investigators to find a path to early career and independent funding for POTS-based research.
This state-of-POTS update represents an important milestone for progress in the field as of 2019. Workshop participants discussed the utility of another State of POTS meeting to be held in five years to review the progress made, and current needs at that time, and novel strategies for moving forward.
Cheryl L. McDonald, MD; Division of Cardiovascular Sciences, NHLBI
Codrin Lungu, MD; Division of Clinical Research, NINDS
Karen C. Lee, MD, MPH; Director, Behavioral Pediatrics and Health Promotion Program, NICHD
Satish R. Raj, MD, MSci; University of Calgary
Steven A. Vernino, MD, PhD; UT Southwestern Medical Center
Hasan Abdallah, MD; Children’s Heart Institute
Amy C. Arnold, PhD; Penn State College of Medicine
Jonas Axelsson, MD, PhD; Karolinska University Hospital
Jeffrey R. Boris, MD; Pediatric Cardiologist, Media, Pennsylvania
Italo Biaggioni, MD; Vanderbilt University Medical Center
Kamal R. Chémali, MD; Eastern Virginia Medical School
Tae Chung, MD; Johns Hopkins University
Glen A. Cook, MD, LCDR; Uniformed Services University
Melissa Cortez, DO; University of Utah
Anil Darbari, MD, MBA; Washington School of Medical Health Sciences
André Diedrich, MD, PhD; Vanderbilt University Medical Center
Taylor Doherty, MD; University of California, San Diego
Artur Fedorowski, MD; Skåne University Hospital
Roy Freeman, MD; Harvard Medical School
David S. Goldstein, MD, PhD; Autonomic Medicine Section, NINDS
Brent P. Goodman, MD; Mayo Clinic Arizona
Blair P. Grubb, MD; The University of Toledo Medical Center
Mitchell Miglis, MD; Stanford University
Amanda J. Miller, PhD; Penn State College of Medicine
Jeffrey Moak, MD; Children’s National Health System
Laura A. Pace, MD, PhD; University of Utah
Peter C. Rowe, MD; Johns Hopkins University School of Medicine
Robert S. Sheldon, MD, PhD; University of Calgary
Cyndya A. Shibao, MD, MSci; Vanderbilt University Medical Center
Julian M. Stewart, MD, PhD; New York Medical College
Lauren Stiles, JD; Stony Brook University School of Medicine; Dysautonomia International
David M. Systrom, MD; Harvard Medical School
Government and Organizational Participants
Joanna Derksen Bare; Office of Management, NHLBI
Jean Bérubé, JD; Office of Science Policy, Engagement, Education, and Communications, NHLBI
Andrew Breeden, PhD; Division of Neuroscience, NINDS
Marc Charette, PhD; Division of Cardiovascular Sciences, NHLBI
Shara Grant, PhD; Postdoctoral Fellow, NCCIH
Jacqueline Rutter Gully; Dysautonomia International
Christy Jagdfeld, CPA; Dysautonomia International
Walter Koroshetz, MD; Director, NINDS
Barbara McMakin; Office of Communications and Public Liaison, NINDS
Gail D. Pearson, MD, ScD; Associate Director, Division of Cardiovascular Sciences, Director, Office of Clinical Research, NHLBI
Allison Ramiller, Solve ME/CFS Initiative
Daniel Stimson, PhD, JD; Office of Science Policy, Engagement, Education, and Communications, NHLBI
Christine Torborg, PhD; Office of Science Policy and Planning, NINDS
Elizabeth R. Unger, MD, PhD; Centers for Disease Control and Prevention
Vicky Whittemore, PhD; Channels, Synapses, and Circuits Cluster, NINDS