Hikers descending the famed 99 switchbacks on California’s Mt. Whitney in the summers of 2017 and 2018 didn’t expect to meet an interventional cardiologist camped out at 12,000 feet, ready to chat.
Yet, Jonathan M. Tobis, MD, had made Trail Camp his home for the week. An experienced backpacker, he had already summited Mt. Whitney – the tallest peak in the continental U.S. – twice before. This time, he was here for work, hoping to recruit hikers with altitude sickness into a clinical study.
Hikers who enrolled in the study were asked to stop by the hospital in the town of Lone Pine. There, a researcher started an IV and injected a harmless saline solution containing microbubbles. Next, she fitted a transcranial doppler over their temples. The ultrasound test uses sound waves to determine if any of the microbubbles traveled through the middle cerebral artery. Bloodstream bubbles indicated a hiker with a tunnel in the heart.
That tunnel is a patent foramen ovale (PFO), a passageway between the right and left atria, the upper chambers of the heart. PFO is the most frequent congenital cardiac lesion, affecting up to 25% of the population, but most people won’t know they have one unless or until it’s implicated in a health condition.
PFO has been linked to stroke, migraines, decompression illness in scuba divers (the “bends”), low blood oxygen and sleep apnea. And the Mt. Whitney study found that hikers with acute mountain sickness were more likely to have a PFO.
“Most of the time, a PFO doesn't cause disease so you just live with it and don't worry about it,” said Dr. Tobis, a clinical professor of medicine in the department of cardiology, and director of interventional cardiology research at the David Geffen School of Medicine at UCLA. “But if it causes migraines, if it causes a stroke, if it causes low blood oxygen, then it is a disorder.”
If a PFO is deemed to be problematic, Dr. Tobis can seal it shut in a 20-minute procedure. A Teflon-coated medical device is threaded through the femoral vein – no surgery required – and acts like a clamshell on the septum dividing the atria.
Dr. Tobis, who has been researching PFO for nearly 25 years since first hearing about the condition at a conference in 1998, has treated more than 1,300 patients. Most recently, he was editor of a special issue of Cardiology Clinics dedicated to PFO.
“It seemed just fascinating to me that here was this condition that we knew about anatomically, from medical school, residency and fellowship, but had no appreciation of the multiple manifestations and clinical syndromes that were associated with it,” he said.
PFO development
Everyone starts out life with a PFO (“open oval hole” in Latin). The passageway has been preserved throughout evolution, and not just in humans, but tigers, gorillas, bats – all mammals.
Before birth, a fetus receives oxygenated blood from the mother’s placenta since its lungs are still developing. The PFO allows this oxygen-rich blood to pass from the right to left sides of the heart and then to circulate around the body. After birth, blood from the right chambers of the heart heads to the lungs for oxygen, returns to the left chambers, and is circulated. At this point, the PFO is no longer needed; fibrous tissue closes it up in most people during the first year of life.
But a PFO that does not close may allow blood – and potentially, blood clots – to pass to the left atrium and eventually into circulation. PFOs are on a spectrum, from tiny to large holes, explained Dr. Tobis.
“We also know that it’s genetically related,” he said. “If you look at an individual who has a PFO, 63% of the first-degree relatives will have one. It runs in families.”
The majority of patients referred to Dr. Tobis have experienced a stroke, the only condition for which the U.S. Food and Drug Administration approves PFO closure. The heart lesion is associated – but not always proven as the cause – with several other conditions. Running a randomized clinical trial for PFO and sleep apnea, decompression illness, and others, would cost medical device makers about $100 million for each. With such hefty costs, they must choose very carefully what studies they pursue.
Stroke
In April 2022, model Hailey Bieber posted a video to YouTube detailing her stroke-like transient ischemic attack, and thanked Dr. Tobis, who diagnosed her PFO and performed a closure procedure. She said her PFO was at the highest level on the ultrasound test. With such a large PFO, Dr. Tobis notes that the transcranial doppler reads a “shower of bubbles too numerous to count.”
Like Bieber, about 40,000 Americans, usually under age 60, experience a stroke due to PFO, accounting for about 5% of all strokes. Over the last year, Dr. Tobis has had regular joint conferences with vascular neurologist Jeffrey L. Saver, MD, and other colleagues, to collaborate on diagnosis and treatment of patients.
“In the neurologist’s view, the heart exists to supply the brain,” said Dr. Saver, vice chair and distinguished professor in the department of neurology at the David Geffen School of Medicine at UCLA. “If the heart falls down on its job in supplying the brain, then the brain suffers. So there's a very strong connection between heart and brain.”
That connection could fail if a clot passes through a PFO and blocks a cerebral artery. Dr. Saver explained that 20% of blood flow goes to the brain, corresponding with 20% of clots as well. And he noted that since the brain is “so eloquent an organ, even a very small clot going to the brain causes symptoms we recognize.”
Dr. Saver co-designed the algorithm that determines whether a PFO is the cause for a stroke and should be closed. PASCAL (PFO-Associated Stroke Causal Likelihood) looks at two sources of information: the presence of a PFO, and factors for high cardiac and/or systemic risk.
Once a stroke is attributed to PFO, Dr. Saver has two treatment options: PFO closure or medications to prevent clotting, with the former as the preferred first line of therapy in most patients. The recurrence rate of stroke is modest with both treatment options.
“The PFO story over the last two decades has been a fascinating one,” said Dr. Saver. “They are the first accepted additions to the causes of stroke that have had a substantial population impact since the 1960s. So it really has been a major advance in diagnosis and treatment.”
Migraines
Dr. Tobis speculated that his patient caseload – primarily stroke referrals – would look markedly different if the FDA approved PFO closure for migraines. Overall, about 12% of the U.S. population, 42 million people, suffers from the debilitating headaches.
However, research has yet to definitively pinpoint PFO as a cause for migraines. The associations are strong, especially for migraines with aura, a phenomenon that usually precedes the headache such as flashing lights in the visual field or changes in sensation or speech.
About half of the people with a PFO get migraines with aura, and conversely, about 50% of those who suffer from migraines with aura turn out to have a PFO. The likelihood for a PFO is even greater, 90%, for someone who has had a stroke and also migraines with aura.
“But association doesn't necessarily mean causation,” said Peony Pak, MD, a headache specialist at the UCLA Goldberg Migraine Program and an assistant professor in the department of neurology at the David Geffen School of Medicine at UCLA.
Dr. Pak said patients in her clinical practice do ask about the PFO-migraine connection. Though with the currently available evidence, she cannot support PFO closure for migraine prevention, Dr. Pak said she can sometimes take more conservative measures, such as medications to prevent clot formation and determine if they minimize migraines with aura in patients with a PFO.
“There does need to be ongoing research about PFO closure, not only in reduction of migraine days, but also in reduction of aura frequency,” said Dr. Pak. “There really is a clear association with aura, and oftentimes the auras can be as debilitating as the pain itself.”
PFO’s associations with migraines, sleep apnea and other conditions are strong. But progressing to definitive causation – as for stroke – will require continued research, clinical trials and perhaps even new technologies, as Dr. Tobis noted in the special issue of Cardiology Clinics.
“The fact that patients like these were not identified prior to the 1990s,” he wrote, “provides a lesson in the history of medical science."
