Are Catecholamines the crucial link between myocarditis and mRNA vaccines?

Part II: Examining Dr. Cadegiani's Hypothesis

Following the prior post which provided some background knowledge on Catecholamines, let’s take a look at the hypothesis proposed by Dr. Cadegiani.

For those not in the know, Dr. Cadegiani is a Brazilian physician who has touted Ivermectin’s effectiveness, however his field of research has primarily looked into androgens, endocrinology, and physical science. Much of this background can be found on his Cureus biography page. Of note, one study that Cadegiani is associated with is a study looking at prophylactic Ivermectin use against COVID¹.

I haven’t read this study for myself so I won’t provide my own perspective on that specific study.

However, it appears that Cadegiani’s work and practices during COVID has put him within the line of fire from critics, with one noteworthy critic being Scott Alexander. Scott Alexander has been rather critical of Ivermectin, leading to other Substack publishers such as Alexandros Marinos to pushback against said criticisms, with one notable piece written by Marinos in defense of Cadegiani’s work:

The Misportrayal of Dr. Flavio Cadegiani

One strange note made by Alexander as cited by Marinos was a little stone-tossing against Cadegiani for his looks²:

And this is at the end:

Anyway, let’s not base anything important on the results of this study, mmkay?

A defiant Flavio Cadegiani. Imagine a guy who looks like this telling you to take ultra-high-dose antiandrogens.

If only all of our detractors could criticize us for our looks…

But I digress, mostly because there’s no saving the downhill slope my looks are tumbling down.

It was within this context that I stumbled across Cadegiani. It mostly serves no relation to the examination of his hypothesis, but it at least provides some background as well as some information in case someone were to look into Cadegiani’s work and practice.

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An informal breakdown

The hypothesis in question is the one linked in my prior post³:

Let me start of by saying that this work isn’t wholly unique. It touches on many of the ideas that have been circulating around already. Concerns over Catecholamine association with the mRNA vaccines have probably been circulating around prior to the release of this post (there was a preprint of this circulating in Spring, but this one was posted on August 11, 2022 after peer-review), with the release of the autopsy report from the two adolescent males in February providing more fuel for the Catecholamine fire.

However, this hypothesis provides basis for future works to use. It helps to collect some of the information out there in a more succinct way rather than running around like a headless chickens Googling whatever we can to find a lead- I’m sure many people doing their own research have fallen into that trap.

Ironically, this is how Cadegiani framed his review of the literature:

The following terms were searched in indexed and non-indexed peer review articles and recent preprints (<12 months): agent, “SARS-CoV-2” or “COVID-19”; event, “myocarditis” or “sudden death(s)” or “myocarditis+sudden death(s)” or “cardiac event(s)”; underlying cause, “mRNA” or “spike protein” or “infection” or “vaccine”; proposed trigger, “catecholamine(s)” or “adrenaline” or “epinephrine” or “noradrenaline” or “norepinephrine” or “testosterone”; and affected population, “young male(s)” or “athlete(s).” 

Using anecdotes of young males and athletes suffering from myocarditis post-vaccination, Cadegiani looked for studies with given search terms to see what possible avenues were available to follow. Essentially, given the fact that young men and athletes were the most susceptible to mRNA vaccine-associated myocarditis risks, what about these groups made them more susceptible relative to other demographics?

It’s from here that Cadegiani provides the framework for his hypothesis (emphasis mine):

While young males and male athletes appear to be at higher risk of cardiac events as observed in a chronologically correlative manner, causality has not been established. The particularities of these populations should be prioritized as potential causes. The two major aspects hypothesized to be specific to these populations are high testosterone and high catecholamine (noradrenaline and adrenaline) levels, which alone or combined may experience interference by SARS-CoV-2 components, including the disease (COVID-19) and vaccines. In particular, there appear to be overwhelming chronological coincidences between catecholamine peaks and the incidence of the associated cardiac events. From these observations, it was hypothesized that a “hypercatecholaminergic” state, increased catecholamine levels, and enhanced sensitivity to catecholamines combined with high testosterone levels may mediate SARS-CoV-2 mRNA vaccine-induced myocarditis and related events. In the present article, a scoping review of the emerging literature was performed to substantiate or refute the proposed hypothesis. Ultimately, this article does not aim to discourage or stimulate hesitation regarding SARS-CoV-2 vaccines but to detect and propose explanations for the phenomenon, leading to more effective monitoring and prevention of further events.

It’s rather striking that Cadegiani is being maligned, especially considering the last sentence suggests that readers take a cautionary approach with this hypothesis- something that many vaccine critics may not take too kindly towards if one were to insinuate not being explicitly against the vaccines⁴.

Now, it’s at this point we may have to address a key fault in this hypothesis- most notably that this hypothesis focused solely on mRNA vaccines. We know that the adenoviral vector vaccines carry risks of myocarditis, and the recent warnings about Novavax also provides evidence in support of the spike being the main culprit for myocarditis:

All Roads Lead to Spike (Protein)

Given these explanations, one may wonder why this hypothesis was an mRNA-driven hypothesis. Keep in mind that not much was known about Novavax until recently, and so if Cadegiani’s hypothesis was in preprint form by early spring it likely missed out on Novavax. More importantly, this may be an unfortunate circumstance in which the COVID literature may bias results in favor of mRNA studies, as much of the research and case reports of myocarditis have come from mRNA vaccinees. This may be a case of the literature weeding out other leads due to saturation.

Keep these circumstances in mind when viewing this hypothesis.

Now, one reason this paper should be given some attention is not due to the hypothesis alone, but due to the way that Cadegiani outlines the formation of his hypothesis.

Heather Heying has raised great consternations against scientists who treat science more as an assembly line rather than an endeavor that’s hypothesis-driven. If anyone’s familiar with her work, you’ll note that she is highly critical of scientists who can’t even be bothered to understand what a hypothesis is, or how to even form one. Some of these criticisms can be seen in her recent post:

On Fraud

Because of this I do find it significant that Cadegiani outlines his process and provides an explanation as to how he formulated his hypothesis.

Cadegiani draws from 3 pillars needed to construct his hypothesis:

To build the hypothesis, the following pillars for the hypothesis must be characterized: detection of the risk of the event (myocarditis and related outcomes) (pillar 1) (for detecting the phenomenon), and potential alterations and abnormalities identified after SARS-CoV-2 mRNA vaccination or COVID-19 infection and consequent events (pillar 2) and physiological characteristics specific to the population likely most affected by myocarditis and the related outcomes (pillar 3) (for searching for the etiology of the phenomenon).

It’s a rather straightforward formulation, and one that many of us have informally considered when wondering why young men are the most susceptible to myocarditis post-vaccination sans any consideration for Catecholamines.

Cadegiani provides a very good outline for his hypothesis and his 3 pillars, which can be seen below. It breaks down each pillar and asks questions that should be answered somewhere within the literature. Remember that Cadegiani’s research should provide evidence for each pillar, eventually tying them all together into a hypothesis.

Dr. Cadegiani’s flowchart for his construction of his Catecholamine hypothesis. Pillars below outline the flow of thought from one idea, through pertinent questions, to the prevailing evidence in support of each pillar. Taken together, the evidence should work to provide the basis of the hypothesis.

Case reports of post-vaccination deaths

Bolstering his hypothesis and searching through the literature Cadegiani added a few case reports of deaths which occurred after vaccination.

Two examples should be familiar at this point; the autopsy reports of the two adolescent males showed signs of catecholamine-induced stress and contraction band necrosis (CBN).

What’s interesting is that a few deaths showed signs of CBN, and Cadegiani makes note of a 22-year old male who had damage localized predominately to the left ventricle:

Conversely, cardiomyocyte necrosis and scattered single-cell necrosis, degeneration, and adjacent inflammatory infiltrate were noted. The most remarkable characteristic was multiple scattered foci of CBN throughout the myocardium predominantly in the left ventricle, which is the most muscular heart chamber.

Remember the remarks in the prior post about takotsubo cardiomyopathy (TCM) and the ballooning of the left ventricle. The evidence from this 22-year old male would appear to correlate with presentations of TCM, and would strengthen the association between Catecholamines and myocarditis. However, Cadegiani makes references to pheochromocytoma rather than TCM.

It’s likely here that Cadegiani makes a bit of a faulty assumption, in that he remarks that Catecholamines-induced stress is a feature unique to the mRNA vaccines:

Unlike cases of post-SARS-CoV-2 mRNA vaccine myocarditis, the autopsies from deaths due to cardiovascular events after COVID-19 infection and other types of SARS-CoV-2 vaccine did not demonstrate contraction bands in the cardiomyocytes or any other indication of damage caused by excessive catecholaminergic activity in any tissue [33], demonstrating the specificness of the damage caused by SARS-CoV-2 mRNA vaccines.

We can’t speak much about what happens with adenoviral vaccines or Novavax’s in regards to a hypercatecholaminergic response, but there is evidence of TCM occurring in those infected with COVID. For instance, a 2020 case report published in the BMJ shows evidence of TCM in a 57-year old woman who had COVID and presented with acute left ventricle dysfunction and balloning⁵.

In short, there is clear evidence of Catecholamine-related heart damage and death noted within several case reports, and this would at least support the argument that the mRNA vaccines may be associated with excess release of Catecholamines. However, this effect may not be limited to mRNA vaccines alone, and may point to other mechanisms that should be worth examining.

The hyperadrenergic state

Here I think Cadegiani’s association is a bit tenuous, although it can’t be blamed on his assessment alone. The hyperadrenergic state is a state of excessive Catecholamine release, and it’s here where the associations between the vaccines and the hyperadrenergic state are lacking.

Essentially, it takes a bit of a transitive property approach.

• There’s evidence of the virus reaching the adrenal glands and adrenal medulla.

• High levels of SARS-COV2 mRNA has been associated with medullary dysfunction and overexpression of DOPA decarboxylase, which converts L-DOPA into Dopamine, furthering the production of Epi/NE and the production of a hyperadrenergic state.

• Spike mRNA from the vaccines have been found in the adrenal glands.

  • Therefore

• The vaccines may cause a hyperadrenergic state.

And so it’s the last two that I have a bit of an issue with, mainly because there isn’t any definitive association between the virus and the vaccine that can allow us to make that leap, unless we argue that the production of the spike is what’s important. It’s worth noting that Cadegiani does include such remarks about spike protein production, and so this may implicate the spike protein as playing a role rather than the mRNA itself:

The adrenal glands have been repeatedly demonstrated to be a major site of SARS-CoV-2 mRNA accumulation and SARS-CoV-2 spike protein production, indicating that both the adrenal cortex and medulla were affected. A report evaluating spike protein production after COVID-19 mRNA vaccination determined that the adrenal glands were one of the highest SARS-CoV-2 spike protein-producing tissues, demonstrating that the spike protein production in these glands increased with time [36]. Furthermore, notable, robust, and dense SARS-CoV-2 RNA expression and spike protein presence were detected in the adrenal medulla of animal models and the overall adrenal glands in humans [37]. Although focal or diffuse inflammation and swollen and necrotic chromaffin cells were noted in the adrenal medulla, the adrenal cortex might also have been affected [38].

Also, Cadegiani does remark that there are no direct comparisons between the presence of viral RNA and vaccine spike mRNA, so there is some precaution needed when making these associations.

Overall, all of this is very interesting, but it does require a bit of a leap and should be examined with a bit of skepticism.

Additional context- specific demographic features

If we argue that Catecholamines are associated with myocarditis caused by the mRNA vaccines, we may wonder if demographics who generally have higher levels of Catecholamines are at higher risk.

In short, young men and athletes are generally associated with higher levels of Catecholamines. It’s argued that for young men this may be indicative of puberty and release of androgens. With athletes the stress induced by extreme physical activity may be a culprit as well.

Cadegiani provides his own context:

Age, sex, and athletic-level physical activity present pronounced differences in the physiology of catecholamine metabolism. Athletes, particularly male athletes, had significantly higher accumulated levels of active catecholamines, even at rest, compared to non-athletes. This observation was based on measuring 12-hour nocturnal urinary catecholamines, which refers to the accumulated release of these hormones throughout the night. While athletes had higher catecholamine levels than sex-, age-, and comorbidity-matched non-athletes, the catecholamine metabolite metanephrine remained unchanged, suggesting unaltered catecholamine clearance that led to a chronic physiological increase in exposure [41-43].

[…]

It is well-established that males present higher catecholamine responses to various stress types than females [48-50]. Moreover, both catecholamine release and beta-2 adrenergic receptor responsiveness in the cardiomyocytes are more pronounced in males than in females [51].

However, the remarks of reduced catecholamine release with age is contradicted by the diagnoses of TCM, which predominately occurs in postmenopausal women and likely due to elevated sympathetic nervous system responses. This means that there may be more to the Catecholamine story than just being young, being male, and being athletic (note that two women are included as part of Cadegiani’s case report assessment).

An incomplete starting point

I’ll leave a bit of the last assessments of this hypothesis to readers. However, I will include Cadegiani’s figure which provides his train of thought leading him to his final hypothesis, essentially replacing his questions with evidence from the literature.

There’s no doubt that Cadegiani’s hypothesis is an example of an arduous journey to collect available research and to tie things in a manner that provides us a clear line between mRNA vaccine and myocarditis. Unfortunately, even with Cadegiani’s work there’s a bit of me left wanting, and a few tenuous associations that are left to be elucidated.

Given the examples outlined in Cadegiani’s hypothesis one may assume that the spike protein may be a more suitable target to use in the hypothesis rather than the mRNA vaccines alone, and the concerns of myocarditis across all vaccine platforms would more broadly implicate the spike protein.

In Cadegiani’s Discussion he does provide some caveats to his hypothesis, which may add to the broader picture that is adverse reactions associated with the vaccines:

It is unlikely that the enhanced catecholamine release, response, receptor sensitivity, and overall activity acted alone to provoke the vaccine-induced, catecholamine-triggered myocardial complications. The catecholamines possibly acted synergistically with other dysfunctions, including abnormal immunological and inflammatory responses, as they alone may cause myocarditis only during extreme catecholamine exposure.

It remains unclear whether the proteins transcribed by SARS-CoV-2 mRNA or SARS-CoV-2 spike protein or both trigger the hypercatecholaminergic state that eventually causes myocarditis after SARS-CoV-2 mRNA vaccination. However, this should be explored in further study after the proposed hypothesis has been confirmed.

As this hypothesis stands, there are a few issues with some of the evidence provided by Dr. Cadegiani, but it nonetheless provides a good outline in how to construct a hypothesis. It lays out several thoughts and what pertinent questions to ask when trying to find evidence in support of a hypothesis- something that all of us should keep in mind when looking for evidence.

We’ll explore the first paragraph detailing synergistic possibilities even further in the next post, in which we examine what other factors may be associated with elevated Catecholamines levels and how those can provide us some additional context.

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1. Kerr L, Cadegiani F A, Baldi F, et al. (January 15, 2022) Ivermectin Prophylaxis Used for COVID-19: A Citywide, Prospective, Observational Study of 223,128 Subjects Using Propensity Score Matching. Cureus 14(1): e21272. doi:10.7759/cureus.21272

2. The irony that was (supposedly) intended with Alexander’s comments is that Cadegiani clearly works out (sans any euphemisms), and so it seems ironic that he would provide anti-androgenic medications to COVID patients. The real irony is that androgens are associated with elevated expression of ACEII receptors, and the use of antiandrogens are intended to reduce said expression. Several researchers have looked into using antiandrogens in their treatment regimen, including the FLCCC so such aspersions would probably lack context and proper understanding as to why antiandrogens may be used to combat COVID.

3. Cadegiani F A (August 11, 2022) Catecholamines Are the Key Trigger of COVID-19 mRNA Vaccine-Induced Myocarditis: A Compelling Hypothesis Supported by Epidemiological, Anatomopathological, Molecular, and Physiological Findings. Cureus 14(8): e27883. doi:10.7759/cureus.27883

4. There are a plenty of reasons as to why Cadegiani did not outright condemn the vaccines, but regardless we shouldn’t use such remarks to criticize the work. It’s the evidence that supports his hypothesis that should be under scrutiny here.

5. Gomez JMD, Nair G, Nanavaty P, et al. COVID-19-associated takotsubo cardiomyopathy. BMJ Case Reports CP 2020;13:e236811.