Catecholamines Are the Key Trigger of COVID-19 mRNA Vaccine-Induced Myocarditis

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Coronavirus disease 2019 (COVID-19), a multisystemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first detected in Wuhan, China, at the end of 2019.

COVID-19 led to the first pandemic of the 21st century, causing more than six million deaths and 800 million cases until June 2022.

The peculiarities of SARS-CoV-2 caused a disease characterized by complex pathophysiology that has not been fully elucidated and changes across its variants, leading to widely varying disease presentation and severity. This indicates that COVID-19 depends more on the host (humans) than on the virus itself.

This particularity of COVID-19 also implies that the monitoring of COVID-19 effects should be age-, sex-, and comorbidity-specific for a more precise understanding of the risk factors not only for COVID-19 directly related outcomes but also for further complications.

As the large variability in presentation, severity, and complications observed in COVID-19 is likely attributed to the specificities of SARS-CoV-2 mRNA and spike protein, it should be expected and therefore presumed that SARS-CoV-2 vaccines of any type, which expose individuals to these proteins, should also be monitored in a characteristic-specific manner.

Surveillance of long-term effects of COVID-19 and SARS-CoV-2 vaccines

Efforts to mitigate the COVID-19 pandemic have been tremendous and included multiple public health recommendations and mandates, pharmacological treatments, and vaccine development. Vaccines of different types, including attenuated virus, viral vector, and SARS-CoV-2 mRNA vaccines, were developed at record speed to protect humans against COVID-19 and its outcomes.

Despite regional disparities, the massive worldwide vaccination for COVID-19 achieved in <1 year may have contributed to an overall reduction in COVID-19 cases and, to a greater extent, COVID-19 deaths.

However, neither the characterization of COVID-19’s long-term effects, including post-COVID-19 or long COVID-19 or increased complications after COVID-19, nor the long-term safety profile and less common adverse effects of SARS-CoV-2 vaccines is well established.

Ethically, collective thorough surveillance of complications after COVID-19 and SARS-CoV-2 vaccination is mandatory. Correspondingly, every event chronologically related to COVID-19 infection or SARS-CoV-2 vaccination should be presumably considered as being related until proved otherwise.

When the incidence of a certain event is apparently higher after COVID-19 infection or SARS-CoV-2 vaccination within a population of a specific sex and age range when compared to the incidence of this event in the same population before the COVID-19 pandemic or the start of COVID-19 vaccination or to the same population without exposure to SARS-CoV-2 or SARS-CoV-2 vaccines, further investigations must be conducted to fully elucidate the event. Active surveillance and investigations should be equally used for events related to COVID-19 infection and SARS-CoV-2 vaccines non-discriminatorily.

Despite insufficient surveillance, some post-SARS-CoV-2 infection and post-SARS-CoV-2 vaccination effects have been identified. An increased number of reports of myocarditis in young males and sudden deaths in male athletes chronologically following SARS-CoV-2 mRNA vaccination raised concern and led to initial investigations regarding the correlation and causality between these events and this specific type of SARS-CoV-2 vaccine.

The evidence indicating that cardiac risks are specific to SARS-CoV-2 mRNA vaccines rather than to COVID-19 or post-COVID is compelling, as multiple independent groups and data from different regions demonstrated not only similar findings but also similar patterns that the second SARS-CoV-2 mRNA vaccine dose presents a stronger risk of myocarditis and pericarditis than the first dose and that the young population, particularly males, are at the highest risk.

Conversely, despite the overwhelming increase in reports of sudden deaths in male athletes and young males, there remains a lack of more robust literature to support this claim.

Myocarditis and sudden death after COVID-19 mRNA vaccination

Myocarditis induced by SARS-CoV-2 mRNA vaccines is an indisputable complication observed particularly in young males [1-4] as demonstrated by multiple studies in different populations [1-11]. Indeed, two studies reported that COVID-19 mRNA vaccine-induced myocarditis disproportionately affected adolescents (reporting odds ratio (ROR): 22.3; 95% confidence interval (CI): 19.2-25.9), 18-29-year-olds (ROR: 6.6; 95% CI: 5.9-7.5), and males (ROR: 9.4; 95% CI: 8.3-10.6) [5,6].

These findings were supported by another large registry study that identified increased myocarditis risk following SARS-CoV-2 mRNA vaccination, with the highest risk detected in people aged 18-24 years, particularly after the second dose, where 8.1-fold increased risk after the BNT162b2 SARS-CoV-2 mRNA vaccine (95% CI: 6.7-9.9) and 30-fold increased risk after the mRNA-1273 SARS-CoV-2 vaccine (95% CI: 21-43) were reported [7].

An Israeli government dataset demonstrated 13.6-fold increased myocarditis risk (95% CI: 9.3-19.2) among males aged between 16 and 19 years compared to the expected following historical data, while a ninefold increased myocarditis risk (95% CI: 4.5-17.8) was recorded when compared to unvaccinated people of similar age and sex during the same period [8].

In a 23 million-resident area, the myocarditis risk after SARS-CoV-2 mRNA vaccination was increased across all populations but was particularly high among males aged 16-24 years after the second dose of BNT162b2 and mRNA-1273, where 5.3-fold (95% CI: 3.7-7.7) and 13.8-fold (95% CI: 8.1-23.7) increased myocarditis risk was recorded, respectively [9].

Among all population studies that universally detected increased myocarditis risk after SARS-CoV-2 mRNA vaccination, a nationwide fully controlled Israeli dataset identified a strict correlation between both first and second SARS-CoV-2 mRNA vaccine doses and an increase in emergency calls, particularly in those between the ages of 16 and 39 years, after adjustments for confounders [10]. The fact that two peaks were observed chronologically following the two SARS-CoV-2 mRNA vaccine doses strongly reinforced the correlation.

Not only were myocarditis risks identified, but a great burden following these cardiac events was also described [7]. Indeed, young males with comorbidities may experience dramatic cardiac remodeling following SARS-CoV-2 mRNA vaccination [11].

Although preliminary comparisons between COVID-19 infection and SARS-CoV-2 mRNA vaccines demonstrated similar increased myocarditis risk in athletes and people aged <40 years [12-14], the risk of consequential heart arrhythmia was significantly higher after vaccination than after COVID-19 [12], possibly supporting the apparent higher incidence of sudden deaths after COVID-19 vaccination than after COVID-19.

Indeed, myocarditis was only detected through active biochemical surveillance monitoring of post-COVID-19 athletes [13,14], which has not been used in athletes after SARS-CoV-2 mRNA vaccination. This is justifiable as more active follow-up after a symptomatic disease is expected rather than after a vaccine in otherwise healthy and asymptomatic people.

Indeed, the alleged similar increase in myocarditis risk following COVID-19 infection and SARS-CoV-2 mRNA vaccines was refuted. While findings of overwhelming increases in symptomatic myocarditis have been extensively demonstrated and reproduced, another strictly controlled Israeli dataset involving a large population study with 196,992 COVID-19 cases and 590,976 controls demonstrated similar myocarditis incidence between people who had been infected with COVID-19 and among non-COVID-19-infected patients [15].

Correspondingly, although an increase in sudden deaths among young people has been reported since the 1990s [16], the incidence of sudden deaths among athletes appears to have increased sharply in 2021 [17]. Chronologically, this coincides with the increased proportion of vaccinated athletes, with far more males affected than females, and the increase was particularly high in 2021 [5].

However, this is an anecdotal and empirical observation that has not been confirmed, while numbers are highly underestimated [18], obscuring a sudden death outbreak among athletes. Although preliminary and unofficial, specific data have been reported among professional male soccer players.

The number of sudden deaths during soccer training among the International Federation of Association Football (FIFA) professional soccer players ranged between five and 10 deaths yearly between 2009 and 2019, and only two were reported in 2020; there was a yearly average of 7.8 deaths between 2009 and 2020. In 2021, 31 sudden deaths were reported [17,19,20].

Correlation between myocarditis and sudden death

The correlations between myocarditis and sudden death vary widely according to the population studied [21]. However, it is accepted that a non-negligible percentage of sudden deaths occur due to myocarditis. Myocarditis is a major cause of sudden death among young people with an incidence that is twice as high in males than in females and is even more prevalent among athletes [21-23].

Hypothesis and objective

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.

. . . .

Dopamine, norepinephrine, and epinephrine are physiologically active molecules known as catecholamines. Catecholamines act both as neurotransmitters and hormones vital to the maintenance of homeostasis through the autonomic nervous system. Physiologic principles of catecholamines have numerous applications within pharmacology. Pheochromocytoma is a catecholamine-producing neoplasm relevant to clinical medicine.

Pathophysiology

Impaired neurotransmission or excess circulating levels of catecholamines leads to pathophysiologic effects. Congenital catecholamine deficiency may occur as an exceedingly rare inborn error of adrenal medullary development. Functional deficiency due to impaired mechanisms of catecholamine release, reuptake, or receptor sensitivity has neurophysiologic effects involving dysregulation of mood and attention. Excess catecholamines and their pathophysiologic equivalents may arise from several etiologies including exogenous administration of frank catecholamines, derivative adrenergic agonists (e.g., isoproterenol, phenylephrine), or reuptake inhibitors (e.g., amphetamines, cocaine). Excess levels also may occur from endogenous catecholamine overproduction from a pheochromocytoma. The pathophysiologic response is increased in an exaggerated sympathetic response due to the overactivation of adrenergic receptors.[10][11][12]

Clinical Significance

Catecholamines are implicated in the pharmacologic treatment of a multitude of diseases and disease processes. Epinephrine and norepinephrine are frequently used as vasopressor agents to treat acute hypotensive states, as well as in treatment algorithms for cardiac arrest. Their affinity to the alpha-1 receptor also is used to induce localized vasoconstriction to reduce bleeding during procedures such as wound closure. By the same mechanism, catecholamine-releasing agents in the form of sprays or ointments are used as nasal decongestants. The pharmacodynamic inhibition of catecholamine reuptake is commonly used in the psychiatric treatment of some depressive disorders, post-traumatic stress disorder, anxiety disorders, attention deficit disorder, and panic disorders. Catecholamine reuptake inhibitors also may be used to treat neuropathic and chronic musculoskeletal pain. Epinephrine is the universal treatment for anaphylaxis and is also used to treat other causes of laryngeal edema (e.g., croup) or bronchospasm.

The blockage of adrenergic receptors otherwise activated by catecholamines is an integral part of the treatment of hypertension, congestive heart failure, and other cardiovascular diseases.

Of the several types of neoplasms arising from the adrenal gland, pheochromocytomas are tumors of the adrenal medulla responsible for the unregulated secretion of catecholamines. Pheochromocytomas are particularly dangerous due to the overactivation of adrenergic receptors which cause episodes of hypertensive urgency. Patients with pheochromocytomas also may experience episodes of other uncomfortable sympathomimetic symptoms including palpitations, sweating, headaches, or anxiety. Pheochromocytomas are often amenable to surgery with or without pharmacotherapy targeting adrenergic blockade.

referenc link : https://www.ncbi.nlm.nih.gov/books/NBK507716/

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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.

Pillars and search methods for the proposed hypothesis.
Summary of the rationale and supporting data for the present hypothesis.

Discussion

Synthesizing Epidemiological, Anatomopathological, Molecular, and Physiological Findings to Propose a Hypothesis of Catecholamines as the Key Trigger of SARS-CoV-2 mRNA Vaccination-Induced Myocarditis and Sudden Death

Altogether, the evidence included the following: the epidemiological findings of COVID-19 mRNA vaccine-induced myocarditis and the potential increase in sudden deaths among young males, particularly athletes; anatomopathological findings during autopsies of myocardial tissue that demonstrated a clear state of catecholamine-triggered myocarditis in all cases; the notable presence of SARS-CoV-2 mRNA and enhanced SARS-CoV-2 spike protein production in adrenal medulla chromaffin cells; the overexpression of the DOPA decarboxylase enzyme in the presence of SARS-CoV-2 mRNA, leading to enhanced conversion of dopamine into noradrenaline; higher physiological catecholamine metabolism in younger people compared to older people, males more than females reinforced by the positive catecholamine response and sensitivity in the presence of androgens, and athletes more than non-athletes where the former is likely the most affected population; and more enhanced catecholamine response in vaccinated athletes than non-vaccinated or pre-vaccinated athletes. All this evidence was fully concordant, which supported the proposed hypothesis that catecholamines are a key player in the SARS-CoV-2 mRNA vaccine-induced myocarditis and the consequent apparent increase in sudden deaths.

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.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9372380/

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