Cardiac Manifestations of MCAS with Dr. Andrew Maxwell
(interviewed by Tanya Dempsey, transcript here. Dr. Maxwell is a board-certified pediatric cardiologist and pediatrician. He received his medical degree from Johns Hopkins Medical School and a residency in pediatrics at the University of California at San Francisco, followed by clinical and research fellowships in pediatric cardiology at Lucille Salter Packard in Stanford Hospitals and Children's Hospital of Philadelphia)
"Dr. Maxwell walks us through his thinking and how MCAS is linked to POTS and Long COVID. This episode is a must-listen for patients and practitioners alike." He says this connection is more important than ever because " in the age of COVID where we're seeing more POTS, Kounis syndrome, myocarditis and even inappropriate sinus tachycardia, which I see a lot of, which is probably a localized version of myocarditis."
Mast cells can cause dysautonomia and POTS, and this is often connected with Ehlers-Danlos Syndrome (EDS). He says the major issue underlying MCAS is an environmental exposure which can be a pathogen (like a virus) or a toxic substance. In the case of Long COVID and COVID vaccine injury, he says it's probably the spike protein that is the toxic element activating mast cells because that's what the virus and the vaccine have in common. He says that "mast cells are doing a lot of the things that we are seeing in these patients causing post COVID long haul syndrome leading to POTS with or without the post COVID long haul. I mean, it could be very specifically POTS, it could be very specifically Kounis syndrome. It could be very specifically myocarditis, could be very specifically inappropriate sinus tachycardia. But I believe mast cells are very frequently the underlying mediator of that inflammation. Now, it could be where it’s partly a mediator and something more direct or some other thing as being a mediator as well. But I see time and time again a pretty good response to full mast cell suppression. So that, that again informs us that very commonly it’s mast cells doing the mediation."
"Kounis syndrome is basically an allergic spasm of the coronary arteries. And so when you have a spasm of the coronary arteries, you have essentially all the signs and symptoms of the angina that might lead one to believe they’re having problems with coronary perfusion. And you are. But it is reversible with, with mast cell medications." He says he doesn't think his colleagues are making the connection that this chest pain is related to mast cell activation and therefore can be treated with mast cell meds effectively. He also believes that Kounis Syndrome is much more common than previously thought, so it's important to get the word out and inform more doctors about it.
He says he identifies MCAS patients by taking a close look at their clinical picture, really looking at their symptoms across body systems, and taking a thorough medical history. This shows if a viral infection seems to have been the trigger. He points out that some patients have never had a positive test for COVID but were known to have been exposed and developed "long haul" symptoms following the exposure at the right time, so they were just asymptomatic. "What I kind of look, try to look for is the food sensitivities, the GI distresses that are a little bit different with mast cell activation. And then the one particular feature, what I call rushes of flushes, which is sure there’s tachycardia and palpitations, burst of racing heart palpitations, but you can find that in both the straightforward dysautonomia and mast cell activation. So how do you tell the difference between the two? You get the flushing and the rashiness with rushes of flushes. And that’s kind of how I say, okay, this is definitely a mast cell phenomenon going on."
In diagnosing and treating mast cell disease, he doesn't rely much on lab testing. He feels it doesn't add much to his understanding of the patient or how he will treat them, which is driven by their symptom presentation "we might start with that type of therapy including fludrocortisone, midodrine, corlanor, beta blockers, pyridostigmine, that type of medication directed toward dysautonomia slash POTS." After that, he will employ what he calls his "bicycle tire management strategy" which means:
"What I mean by the bicycle tire management strategy is you gotta consider mast cell activation like a bicycle tire with about seven holes in it. And those holes are you know, excessive histamine consumption in the diet. The GI tract as being a source of additional mast cell activation, so having the GI tract in order, and then mast cell action itself, both systemically and within the GI tract. And then those particular receptors of histamine, H1 and H2. So therapy would be an H1 blocker, an H2 blocker, mast cell suppression systemically with usually a lukast. Zafirlukast is what I prefer. I usually avoid montelukast and with a cromolyn substance in the gut. So Gastrocrom here in the US. Finally, quercetin is a natural version of the systemic mast cell stabilizer. So I usually have patients on quercetin. I consider it kind of a freebie that not really being exposed to a med is very safe, so why not? And then making sure the GI motility is working well, making sure that there’s no evidence of what we call SIBO, small intestinal bacterial overgrowth, doesn’t necessarily mean I work them up for that in any way. I just mean I put ’em on probiotics. Make sure if they have any evidence of slow GI motility, put ’em on a burra, gass or ginger root extract (not sure what "burra" or "gass" refer to). Rarely have to go something more extensive medication-wise with that. And then of course, put them on a low histamine diet, make sure they’re not adding histamine to their system. That’s usually the, the, in my view, patching all seven holes of that bicycle tire. And when you have all seven holes patched, You can expect a change."
When asked why he prefers Zafirlukast over Monteleukast, he says it is primarily because he sees Monteleukast cause a lot of depression in his patients. He attributes this to mast cells releasing elastases, that breakdown the blood-brain-barrier (and also the gut barrier and the endothelial layer in capillaries) by breaking down small proteins called cadherins that hold these things together, making them "leaky". He says he sees similar results with a lot of the dopamine agonist antagonists like Reglan. He speculates that this scenario may be more common in children. Dr Dempsey points out that she sees better responses to Monteleukast (and other meds) when they are compounded, so the excipients used in the standard formulations may be the problem.
(This is his complete quote from above, included because it may be of particular interest to some readers "Mast cells not only secrete histamine, but they secrete elastases and elastases breakdown the little proteins that hold things together, what are called cadherins and maybe other proteins too. But I really focus on the cadherins. Cadherins hold together, the GI epithelium, that’s the E-cadherin. So that’s where your leaky gut comes from and it holds together what are called VE-cadherins hold together, the capillaries, the endothelium within capillaries. And so if they break down, you get increased leaky capillary in general, but blood-brain barrier. And we see that with not only montelukast, we see it with a lot of the dopamine agonist antagonists like Reglan where patients will much more commonly have extra pyraminal effects being put on Reglan and other types of dopamine modifying agents.")
They go on to discuss the idea of grouping together conditions like MCAS, POTS, and other commonly comorbid conditions because it's clear that these conditions frequently occur together. At first, doctors referred to "the triad" which included MCAS, EDS, and dysautonomia. It then expanded to "the pentad" when GI dysmotility (GI involvement in general) and autoimmunity were added. The direction of causality is unclear- which condition came first? Did the leaky gut become an "auto-antibody generator over time"? Did the autoimmunity start this whole progression? The idea of identifying the 5 main pieces is that a patient would then need to set up a team of 5 doctors to manage these conditions, although in reality that is often not possible to do. Then the next two conditions were added, bringing it to "the septad"- many patients had underlying infections, such as Lyme Disease, and they also had what is often called "ME/CFS" which is now generally recognized to be mitochondrial dysfunction. Dr Dempsey than added 3 more things to bring it up to a "decad" including small fiber neuropathy, cervical instability and tethered cord, and autoimmune encephalopathy (such as PANDAS/PANS). This last component acknowledges the brain fog and cognitive issues, the neuropsychiatric issues, and endocrine issues especially thyroid, adrenal, and sex hormone issues. Dr Maxwell adds that he sees many of these additional pathologies that are being added to the list as sub-forms of things already on the list, so it may not make much difference how much you expand the list or keep it short in terms of making sure that you recognize and treat the patient's whole picture.
It's worth noting that in the above discussion, Dr Maxwell puts forth the idea that there can be localized expressions of some of these conditions that may not meet full criteria, that were caused by a localized environmental exposure. For example, a person who was exposed to "something that’s aerosolized and breathed in, and what happens is you have a localized nasal pharyngeal mast cell activation that then causes havoc in the nasal pharyngeal region, specifically CCI, TMJ issues, and then loss of airway. So the airway becomes floppy for different reasons. And so you see these particular patients and they’re kind of a setup for this phenomenon I see and call "spiky leaky syndrome." (CCI is cranial cervical instability, meaning the vertebrae in the neck are unstable).
Dr Maxwell is then asked if how he sees the patient picture changes how he treats the mast cells and he says generally, no, that he pretty much starts everyone on his usual mast cell protocol. If a patient seems to need more than that, he says "another strategy I have are IV infusions of mast cell meds... getting saline along with Benadryl, Toradol, Ativan, and famotidine and IV form, and oftentimes on ondansetron as well. And so that often works much more effectively than the oral forms." He may also increase the dose of LDN (Low Dose Naltrexone). He also adds that if a patient is really "POTSie" and has "angina type symptoms and you’re thinking the mast cell meds aren’t gonna work fast enough for that, you might try some antianginal type strategy, something like a nitric oxide releaser to open up their coronaries as quick as possible."
They then go on to discuss how mast cells are related to and can cause Dysautonomia and POTS, and specifically how the COVID virus and the COVID vaccines have both been shown in research to contribute to the onset of both Dysautonomia and POTS specifically. This discussion begins at [00:26:26] in the interview- if this is very interesting to you, I suggest going to the interview and reading the entire very long quote. This is my summary of what Dr Maxwell is saying:
POTS is basically what happens when the person's venous system becomes "saggy" and "stretchy" rather than as rigid as it needs to be to appropriately control blood flow throughout the body as the body moves around and changes position. When the person stands up, the venous system is too "saggy" to bring the full amount of blood up to the heart to fill it when ti pumps so it pumps partially empty, resulting in low cardiac output. This causes the heart to beat faster, as tachycardia, in an attempt to increase cardiac output. One of the reasons that MCAS more broadly and COVID or COVID vaccine injury more specifically can cause this situation is that the spike protein activates mast cells, which then release mediators that break down the connective tissue of the venous system itself, causing it to become too "saggy" to function properly.
He says there are also several ways that mast cell activity can affect the functioning of the autonomic nervous system directly, which is the branch of the nervous system that regulates things like circulation, heart rate, and blood pressure. "(M)ast cells activated in the gut can then cause inflammation of the sensory portion of the Vagus nerve. It’s the information heading back to the brain. And so if it’s irritating and inflaming the sensory portion of the Vagus nerve, it’s as I consider it like almost like a CPU u you know, computer system with information going into the CPU, if it’s garbage in, it’s gonna be garbage back out. And so, it affects how the motor portion of the Vagus nerve works. And so you have a dysautonomia of the motor portion of the Vagus nerve that results from a inflammation of the sensory portion of the Vagus."
He outlines another way that mast cell activation can lead directly to dysfunction of the Vagus nerve as well as several other cranial nerves, which could also be leading to POTS and Dysautonomia in patients following a COVID infection or vaccine injury. Mast cells in the neck becoming activated could be releasing the mediators mentioned above that can "tenderize" connective tissues, in this case ligaments in the neck that hold the cervical vertebrae in place. This could in theory result in a situation very similar to what is called CCI (Cranial Cervical Instability) and is often seen in EDS patients (Ehlers-Danlos Syndrome, which is often comorbid with MCAS). He sees this as essentially "carpal tunnel syndrome" of the neck but says that because it acquired by mast cell activation, it is more of a clinical diagnosis and may not show up on the radiology and other types of testing used to identify CCI in EDS patients, that is more structural. In this scenario, the C1 vertebra (aka the atlas) becomes loose and unstable, and gets pushed forward, which compresses the cranial nerves 9, 10 (the Vagus nerve), and 11 that are exiting the spine at that spot. Those nerves are then compressed against the jugular vein, which is then compressed against the stylo hyoid ligament. If this situation becomes chronic, these nerves can become damaged, which can then lead to dysfunction of the parasympathetic nervous system by way of a little bit of CCI.
More evidence that this happening is that you’re also seeing cranial nerve 9 and cranial nerve 11 dysfunction, which can present as tinnitus, phonophobia (sensitivity to and/or fear of certain sounds) and hyperacusis (an abnormally strong reaction to sound, occurring within the auditory pathways), vertigo, and what’s called globus feeling of a mass in the back of the throat. Dr Maxwell says he also sometimes sees "what’s called eagle syndrome type symptoms with turning the head and having pain upon turning your head. From side to side, sharp stabbing pains in the neck or pain at the base of the tongue. Those are all glossopharyngeal nerve findings. And then the cranial nerve 11 is a motor nerve to the trapezius and it innervates the trapezius. So when it’s injured, oftentimes will cause a knottiness something beyond coat hanger pain in the trapezius, but rather a knottiness in the trapezius. So when you hear these patients complaining of all these symptoms, that it sounds almost crazy that they’re related. No, there’s one place in the body where these three nerves are together and they happen to run right in front of the lateral process of c1. So when that slips forward and chronically does so, I think it causes this, this list of symptoms together."
When Dr Maxwell is asked how he manages and treats this situation with the slipped C1 vertebra if he suspects it, he responds "I will get the physical therapist involved. And I’ll often assess their airway as well, because if they have that going on, they may have a floppy airway as well, and they may be losing it at night and showing what we call upper airway resistance syndrome, which is a subtle form of sleep apnea. So we oftentimes, I get sleep studies to look at that. Oftentimes I’ll get ENT and the oral airway doctors including oral surgeons involved to make sure that they’re not losing their airway, myofunctional therapists to help strengthen the musculature of the airway. And then there’s a class of physical therapists that are geared entirely toward CCI. So I will get them and get them involved. One of the things that I’ve found useful as a test of concept in these patients is what happens if they were to get some what’s called NUCCA therapy, NUCCA. And that’s a particular form of chiropractic therapy that focuses on the Atlas. And so these NUCCA chiropractors have been very, very helpful in putting C1 back in place. And these patients can respond right away to their POTS like symptoms. Their dysautonomia improves right away." He says this is a test of concept because while the NUCCA therapy is very effective, the improvements don't last long. He discusses prolotherapy as an option and says that he encourages the therapist to inject platelet-rich plasma (from the patient in order to avoid MCAS being triggered by something foreign).
He sees this therapy, like he does the POTS therapies, as "band-aid" therapies to help as the longer-term stabilization of the mast cells and treatment of any residual COVID is taking effect. This may include the body clearing residual spike protein, treating a lingering COVID infection, or treating another infection that was latent and reactivated from the immune suppression of the COVID or vaccine (such as HHV6, EBV, or Lyme). He says he will treat with anti-virals if "the PCRs are positive or if the IGMs for those viruses are positive".
They discuss this paper Apparent risks of postural orthostatic tachycardia syndrome diagnoses after COVID-19 vaccination and SARS-Cov-2 Infection, which found a significantly higher risk of developing certain conditions associated with POTS after both COVID infection and COVID vaccines, including Dysautonomia, POTS, and MCAS, as well as some other conditions including UTIs, lower back pain, and symptoms like dizziness, fatigue, and anxiety. They go on to talk about how complicated it is to weigh the costs and benefits of vaccination for the population of people who already have any of these conditions or who are at higher risk for developing them, especially given that the nature of COVID infection has changed.
Dr Maxwell's last message for patients "for the patients seeking help, you know, find the right provider that works with you. Don’t let someone dismiss you. I hear again and again being told, you know, there’s no point in managing anything. You’re gonna get better with your long COVID. And you know, we’ve seen long COVID patients two years out who were just struggling, not everybody. And it’s great to see some patients getting better even on their own. But you never know who thoses are gonna be, and so you’re gonna want to try to modify what could be a very long road. And so you know, make sure you’re finding someone who’s addressing your issues that has a a pretty good handle on the underlying causes that can do it in a systematic way. And I think you’ll have some success."
Further information on the topics discussed in this interview:
Mast cells in the autonomic nervous system and potential role in disorders with dysautonomia and neuroinflammation
"Mast cells... having potential involvement in the pathophysiology of
dysautonomias and neuroinflammatory disorders. MC are located
perivascularly close to nerve endings and sites such as the carotid
bodies, heart, hypothalamus, the pineal gland, and the adrenal gland
that would allow them not only to regulate but also to be affected by
the autonomic nervous system (ANS). MC are stimulated not only by
allergens but also many other triggers including some from the ANS that
can affect MC release of neurosensitizing, proinflammatory, and
vasoactive mediators. Hence, MC may be able to regulate homeostatic
functions that seem to be dysfunctional in many conditions, such as
postural orthostatic tachycardia syndrome, autism spectrum disorder,
myalgic encephalomyelitis/chronic fatigue syndrome, and Long-COVID
syndrome."
Phonophobia and Hyperacusis: Practical Points from a Case Report
POTS association with COVID-19 vaccination and COVID-19 infection
"Although any comparison of post-exposure rates should be interpreted
cautiously, given the baseline differences in POTS incidence in the two
mutually exclusive populations, these results indicate that POTS might
be occurring at a higher-than-expected frequency following COVID-19
vaccination, although at an overall rate lower than the frequency of
POTS occurring following SARS-CoV-2 infection."
Apparent risks of postural orthostatic tachycardia syndrome diagnoses after COVID-19 vaccination and SARS-Cov-2 Infection
"POTS-related diagnoses appear to be acquired with increased frequency
after, compared to before, COVID-19 vaccination, particularly when
compared to more commonly diagnosed conditions"
"For new diagnoses made after vaccination, we found that the five conditions with the highest post-vaccination odds of new diagnoses were myocarditis, dysautonomia, POTS, mast cell activation syndrome and urinary tract infection (UTI). Two POTS-associated conditions had lower odds, with fatigue demonstrating a moderate ratio and Ehlers–Danlos syndrome (EDS) having the second from the lowest ratio."
"There is biological plausibility for the association between POTS and COVID-19 vaccination in particular. Before the pandemic, mRNA vaccination had been administered in small trials predominantly involving cancer therapy, demonstrating rare off-target neurological effects such as Bell’s palsy, which has also been seen with COVID-19 vaccination25,26. In SARS-CoV-2 infection, multiple reports of post-infection POTS invoke the possibility of an immune-mediated mechanism triggered by an antigenic component of the spike protein shared with vaccination13,24,27. Given the broad expression of ACE2 preceptors, inflammasome activation by synthetic spike protein could result in multi-systemic effects, including neurocardiogenic targets and potential induction of variable types of autoimmunity28,29,30. Additionally, the lipid nanoparticle coating in mRNA vaccine formulations is known to be highly inflammatory, although effects related to the lipid coating appear less likely contributors than spike-protein-mediated effects31. Further research is needed to clarify potential mechanisms related to either vaccine formulation or vaccine target."
Postural orthostatic tachycardia syndrome after COVID-19 vaccination
"Ten patients (3.9%) at a quaternary-care POTS clinic reported new or
worse POTS symptoms after the mRNA COVID-19 vaccine. All patients had
pre-existing comorbidities, suggesting a potential group of patients to
monitor for post-vaccine POTS. Symptoms responded to guideline-directed
POTS therapy." (Pre-existing conditions included previous COVID-19 infection, Hypermobile EDS, MCAS, and auto-immune cardiac, neurological, and gastrointestinal symptoms)
