POTS Research Breakthroughs | YMyHealth

In the past few years, for many of you, it was probably the first time you heard or saw the acronym “POTS.” Yet, it's a condition that has been around for decades, and now because of Long COVID shining a light on it, not only is POTS more commonly known by the general public, but the knowledge of it and speed at which it is being studied has skyrocketed.

POTS, which stands for Postural Orthostatic Tachycardia Syndrome, is a form of dysautonomia—a disorder of the autonomic nervous system. In POTS, the body’s blood flow becomes dysregulated, so that when a person stands upright blood pools in the legs and not enough blood is pumped back up to the brain and heart. This leads to lightheadedness sometimes with fainting, heart palpitations, tremors, nausea, and other symptoms.

While there currently is no cure for the condition, Sarah Diekman, MD, JD, MS, MPH, believes that given the current pace of research a cure is possible now in her lifetime, and the discovery of more effective treatments in the next few years ahead of that. She is one of the few providers in the country who specializes in treating patients with POTS and Long COVID in her practice, Diekman Dysautonomia LLC, and a fellow patient living with POTS.

Diekman shines a light on some of the interesting origins of POTS care recommendations along with some very exciting discoveries in POTS research that point to potential treatments in places the public and scientists alike would not have expected.

The surprising origins of POTS research

Before we dive into current research discoveries, we have to start with how you have to really think about where studies were conducted and who they were conducted on before being able to truly apply the results to all patients.

In POTS, exercise is known to be controversial. For some people, it can help lessen symptoms, for others it can make them extremely ill. Considering that the main mechanism behind POTS has to do with blood flow being dysregulated and blood flow is a huge part of exercise for anyone, this makes sense.

So, wouldn’t it surprise you to know that physicians came up with their protocol (or were given guidelines to follow) on how to guide patients when it comes to exercise based on research on astronauts and space travel?

Yes, it is true! Research on astronauts' bodies, which had experienced being in zero-gravity environments, led to exercise protocols for POTS patients. It was called the Levine protocol, and the concept was that “exercise fixes everything when it comes to POTS” because it did for the astronauts who returned to Earth with induced POTS from being in zero gravity.

“Back in the day, NASA was very worried about what could happen to human life up in space. So, you couldn't need eyeglasses or have one physical ailment. Astronauts had to be super healthy humans. So, these perfectly healthy people would go up to outer space and they came back and had what we now call POTS,” Diekman explained. “Physicians found that they could exercise it away, but the difference is their POTS was 100% induced by a zero-gravity environment, right?”

As she tells her patients: “For us, it comes from within.” None of them had POTS induced by a zero-gravity environment nor did the astronauts have any autoimmune stuff, which some POTS patients also have.

So, while, yes, the research can hold up for some patients, for whom exercise can help lessen POTS symptoms and does for Diekman’s case personally, for other patients they have very little exercise tolerance, and for some patients, exercise can cause symptom flares (which turns the research findings on its head).

Sarah Diekman, MD, JD, MS, MPH, is a Postural Orthostatic Tachycardia Syndrome (POTS) and Dysautonomia expert who is board-certified Preventive Medicine physician.
Diekman earned her MD and her MS in Biology/Biological Sciences from Indiana University.
She then went on to pursue and earn her JD at Florida Agricultural and Mechanical University. She did her residency in Occupational and Environmental Medicine at Johns Hopkins University, where she was Chief Resident. She earned her MPH at the John Hopkins Bloomberg School of Public Health.

The immunology revolution in POTS understanding

One of the exciting new discoveries is on the specifics of how the immune system may be one of the underlying causes of POTS.

First, multiple studies have shown that a cytokine–a chemical messenger–called interleukin-6 may be involved in the body’s pathway that leads to POTS development, and its symptoms. This not only helps better understand “the why” behind POTS, but also makes it a potential target for therapies.

Currently, there are interleukin-6 targeting drugs that are used and approved for treating rheumatologic and arthritis conditions, but until more studies are completed they will not be covered by insurance companies for treating POTS. But the fact that there are existing drugs targeting interleukin-6 specifically is exciting because they could be studied in POTS patients sooner rather than having to wait to formulate drugs from scratch. (Note: In general, new drug development can take as long as 10 years.)

Researchers have also discovered a very exciting link between fibrin (a key player in the blood clotting cascade that enables the body to form a clot, stopping bleeding), the COVID-19 spike protein, and POTS.

“There recently was a study finding that fibrin, an element of the clotting cascade, interacts with the spike protein in COVID, and this is playing a role in triggering this immunologic process,” Diekman said. The process in the immune system she is referring to could be one of the pathways that is leading people to develop POTS after COVID-19.

“What we're looking for from all these clues is something that unites the triad of diseases that we know tend to come together, like the mast cell dysfunction, the Ehlers-Danlos Syndrome and the POTS. Why are these related?” she asked. “So, when we see something like fibrin, it's really exciting because that could be the unifying factor as to why people with Ehlers Danlos also are so susceptible to POTS.”

To note, fibrin is a part of connective tissue, which is what supports our skin, bones, and blood vessels, and it's this tissue that is weakened in Ehlers-Danlos Syndrome leading to things like hypermobile joints, bruising easily, and longer wound-healing times.

Unexpected breakthroughs

Two additional recent discoveries, Diekman says, are “jaw droppers” in POTS and Long COVID research: the use of Metformin and the potential of testosterone.

The Metformin discovery

While Metformin is a decades-old treatment for type 2 diabetes, research from a Veterans Affairs Hospital Study is now showing that it can also be an effective treatment for preventing Long COVID. This ultimately has positive implications for POTS which can result from Long COVID or be one of the forms of this post-viral illness after COVID-19.

“This was a really good study where researchers stratified by the medications study participants were taking, which is a good way of controlling for variables. This study was an absolute masterclass in why you do this. So, they were looking at diabetes and COVID-19 because COVID has worse outcomes for people who already have diabetes and can cause diabetes. That's what the point of this study was,” Diekman explained.

“But what they found was this protective signal from the people who are on Metformin. They were doing really well even compared to the controls. Then, in follow-up studies, they found that Metformin taken during an acute COVID-19 infection can prevent Long COVID by like 40%. Better than Paxlovid.”

So, Metformin is actually better than Paxlovid, and as she points out, unfortunately it's underutilized right now with few clinicians prescribing it to patients who get COVID-19. Metformin has even been found to be useful in treating some patients who have Long COVID.

Testosterone's surprising role

Another jaw-dropping discovery is the use of testosterone and Long COVID symptoms in transgender patients.

“While I'm hesitant to think that it’s just as simple as one hormone, the interesting thing is that there have been some case studies of transgender patients and another publication recently that had to do with the cytokine profiles that were happening in the setting of testosterone,” Diekman explained.

Again, this takes us back to interleukin-6, which is showing a lot of promise.

“So, the biggest clue that we're having in the research here is from transgender patients–female assigned at birth that transitioned female to male on testosterone–who are getting full resolution of their Long COVID symptoms, which is an illness where we're lucky if we can get like 80% resolution. That is really attention getting,” Diekman emphasized.

This makes testosterone have great potential for alleviating both Long COVID symptoms and the development of POTS as a result. She stresses though that there is more research needed on the use of testosterone to alleviate symptoms in patients who do not want to obtain also masculine characteristics, and to figure out the most effective dosage.

The impact of Long COVID on POTS research

Long COVID has accelerated the pace and amount of POTS research being done. A very welcomed and promising time for a condition that has long affected millions.

POTS diagnoses have doubled since the COVID-19 pandemic to approximately 6 million in the US, and many cases of Long COVID resemble or are in the form of POTS directly affecting many millennials who also happen to make up the bulk of the US workforce.

Given this, research dollars have poured in along with a race to find better treatments, as POTS symptoms can be debilitating without proper treatment. And these symptoms have made many younger members of the workforce have to change their original career path or leave the workforce altogether.

“We already knew that something like 40 to 50% of new POTS cases correlated with the virus. So, you know they are caused by a virus or is it like someone has an underlying genetic predisposition and that it takes the second hit to have the virus, or maybe, do you need one viral infection, then two, then three, and each time it's deranging the immune system, and then it's the third one, where you finally have symptoms.”

Long COVID has shown us this role of the aftermath of having a virus more and more.

Thankfully, the research funding accelerated by Long COVID has simultaneously occurred with a brighter spotlight placed on POTS by the media, all of which have led to a better understanding of POTS from those in the clinical world as well.

“When we figure out why all these things are happening, that's widely regarded as when we will be in cure territory. Why do we see these things together? Why are they all traveling together? There is the real clue,” Diekman emphasized.

Looking to the future

Her vision for the future of POTS research and what's on her ‘wish list’ as part of that is getting closer to reality of what is being worked on in the field, and that is very exciting.

There is hope now for the potential of discovering biomarkers, which she says are needed to prove things are happening inside the immune system to people, to get treatments approved, and coverage.

There is also potential for more effective and improved ways for diagnosing the disease, especially diagnostics that measure cerebral blood flow. To note, the technology for cerebral blood flow measurements already exists, it’s a matter of credentialing people to use it as a method for diagnosing POTS, Diekman told us.

All around there is great optimism about discovering more targeted and effective treatments as new findings continue to roll in at a steady pace.

“Viral illness has been underfunded for decades, essentially since Salk and Sabin invented the polio vaccines. That was the end of funding. Viral illness vaccines have been so effective that viral illness has basically been treated as secondary,” Diekman said. That has changed.

“Now is an exciting time for POTS research and treatment discovery. This is not all going to happen like next year, but in the next 10 years, yes, it will,” she said.

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Breakthrough Discoveries in POTS Research