Research Article, Int J Cardiol Res Vol: 12 Issue: 5

The Global and Specific Cardiovascular Burden of Spike-Based COVID-19 Vaccination

Karla Johanna Lehmann^*

¹Independent Researcher, Dresden, Germany

*Corresponding Author: Karla Johanna Lehmann,
Independent Researcher, Franz-Liszt-Str. 7a, D-01219 Dresden, Germany
E-mail: karla.lehmann@t-online.de

Received date: 09 October, 2023, Manuscript No. ICRJ-23-116101;

Editor assigned date: 11 October, 2023, PreQC No. ICRJ-23-116101 (PQ);

Reviewed date: 26 October, 2023, QC No. ICRJ-23-116101;

Revised date: 03 November, 2023, Manuscript No. ICRJ-23-116101 (R);

Published date: 10 November, 2023 DOI: 10.4172/2324-8602.1000519

Citation: Lehmann KJ (2023) The Global and Specific Cardiovascular Burden of Spike-Based COVID-19 Vaccination. Int J Cardiol Res 12:5.
 

Abstract

Keywords:

Spike-interaction with ACE2; Consequences of ACE2-downregulation; RAAS activation; Spike/Ang II associated health disorders; Spike-induced adverse reactions; cardiovascular adverse reactions; common mode of action; spike-based COVID-19 vaccination; diagnostic and treatment option

Abbreviations

Angiotensin-Converting-Enzyme (ACE); Angiotensin- Converting-Enzyme 2 (ACE2); Adverse Drug Reaction/Adverse Reaction (ADR/AR); Angiotensin I/II (Ang I/ II); Angiotensin 1-7 (Ang 1-7); Angiotensin Receptor Blockers (ARBs); Angiotensin1 Receptor (AT1R); Angiotensin2 Receptor (AT2R); European Medicines Agency (EMA); Infection Fatality Rate (IFR); Prolyl Oligo-Peptidase (POP); Propyl Carboxy- Peptidase (PCRP); Renin-Angiotensin-Aldosterone System (RAAS); Receptor Binding Domain (RBD); Transmembrane Protease Serine Subtype 2 (TMPRSS2)

Introduction

High safety requirements must be demanded of all vaccines used for preventive health protection, since they are administered to healthy people who want to protect their health from harmful influences. The German regulatory authority, for example, has defined a generally very ambitious goal in 2015: "The risks associated with the application of vaccines ought to be barely perceptible" [1]. The safety profile of COVID-19 vaccines should be particularly favorable, as the disease is only mild to moderate in the vast majority of cases and the Infection Fatality Rate (IFR) was calculated at a rather low level of 0.27%-0.36%[2,3].

From the start of the COVID-19 vaccination campaign, spontaneous reports of suspected Adverse Drug Reactions (ADRs) and associated deaths have been accumulating at an unusual high rate. In particular, fatalities and a wide range of cardiovascular ADRs were rather unknown for vaccines in the past. Although they did not rank first in frequency, ‘cardiac disorders’ (reaction group of EudraVigilance reporting System) were in the same frequency range in terms of hazard (up to 14.51% fatal outcome) with those of the nervous and respiratory system [4,5].

Acute, subacute and further expected chronic cardiovascular ADRs, as well as countless others, are most likely caused by activation of the Renin-Angiotensin-Aldosterone System (RAAS) due to downregulation of the cardio-protective enzyme ACE2 as a result of the demonstrated spike/ACE2 interaction [6-8]. Despite the fact that this mode of action provides a plausible rationale for most cardiovascular ADRs following spike-based vaccination, it has been largely ignored.

An updated analysis should clarify whether the total numbers of individual cases with adverse events and their fatal outcomes have continued to increase since 2021 [4]. Diagnostic and therapeutic options are proposed and discussed for spike-triggered symptoms.

Methodology

This analysis addresses the evaluation and interpretation of anonymously reported adverse reactions of vaccinated individuals to the EMA's publicly accessible EudraVigilance database since the start of the COVID-19 vaccination campaign. The interpretation is based on scientifically published original papers and reviews.

Identification of individuals was not possible. According to the Ethics Committee of the Saxon State Medical Association (SLÄK), an ethics vote is not necessary for anonymised, non-personalised data.

The primary objective was to determine the total number of individual cases with ADRs and their fatal outcomes reported following spike-based vaccine applications. The second objective was to detect suspected cardiovascular adverse events associated with Tozinameran.

Data were retrieved from Web Reports of EudraVigilance of the European Medicines Agency (EMA) [9].

EudraVigilance is a system designed for collecting reports of suspected Adverse Drug Reactions (ADRs). The reaction is based on the MedDRA dictionary of terms for side effects (also known as ADRs). All evaluated adverse events correspond to the search terms of the EudraVigilance based on clinical characterisation. Laboratory values or diagnostic measures could not be attributed and were therefore not evaluated.

The EudraVigilance system allows the detection of signals of suspected side effects that were previously unknown and of new information on known side effects. Therefore, it seems to be suitable to help answer the questions raised.

The EudraVigilance database is updated weekly and the data is constantly growing. The cut-off date was July-31-2023 (all suspected ADRs and related fatalities as well as cardiac-and heartcirculatory system ADRs after vaccination with Tozinameran).

The total number of deaths was evaluated by summing the fatal outcomes in all 27 defined reaction groups [9].

The number of individual, clinically observed cases for a selected reaction resp. search term was retrieved from the reaction groups of Tab 6, which provides the most detailed level of information. Because several defined reaction groups of the EudraVigilance Web Reports contain information on relevant search terms/selected reactions (e.g. cardiac arrest, cardiac death, sudden cardiac death, sudden death, death), all reaction groups had to be systematically searched for these selected reactions.

The running total of individual cases available in Table 1 of EudraVigilance was the value that I have used to quantify the total number of individual cases that have been reported to EudraVigilance for the selected vaccine.

The frequency and percentage were used to quantitatively describe the adverse drug experiences.

Results

Since June 2021 to 31/7/2023, ADRs have been reported from 7 other spike-based vaccines. The total number of individual cases with ADRs after vaccination has approximately quadrupled from 525907 to 2256506 (Table 1). This corresponds to an average daily reporting rate of 2338 individual cases with adverse events since the start of the vaccination campaign (965 days since approval in UK on Dec. 8, 2020 to July 31, 2023).

Table 1: Total individual cases with any ADR (a) and fatal outcomes (b) after vaccination (2021 up to 5th June and 2023 up to 31st July)

However, as the total number of vaccinations was not reported, the incidence of adverse reactions to vaccination could not be calculated on a reliable basis.

However, it can be assumed that high-stress physicians or healthcare workers report only alarming reactions related to vaccination, such as new-onset, particularly severe, and deaths or reactions previously unusual for vaccination. Moreover, since the underlying mode of spike-action -downregulation of ACE2- is not disclosed, underreporting can rather be assumed. In this context, the deaths and cardiovascular side effects that were reported without knowledge of the mode of action but obviously with great concern to the national regulatory authorities and by them further to the EMA, as well as all other side effects of the COVID-19 vaccine, deserve special attention.

Most individual cases suffering from ADRs have been reported after application of Tozinameran; the total number increased almost sixfold to 1,231,990 (Table 1) followed by Vaxzevria with 548,409 und Moderna with 379,282 cases. The vaccinated were predominantly in the age range of 18-64 years (76%-78.6%). The proportion of over 85-year-olds was only 0.6%-2.1%. The percentages of children (17 years or younger) with adverse events after vaccination with AstraZeneca, Moderna, or Comirnaty, respectively, was 0.4%-3.1%. Overall, the proportion of women was slightly more than double that of men (approx. 69% vs approx. 28%).

The dangerousness of the reported side effects can be characterized on the basis of their fatal outcomes. Of a total of 2256506 individual cases for all 11 vaccines associated with suspected adverse reactions, 51740 cases were fatal (2.29%) (Table 1). Since the first approval of a COVID-19 vaccine in the European Community, this corresponds to 54 deaths every day. Moderna still appears to be the most dangerous (3.45% fatal outcomes), followed by Comirnaty (1.99%) and AstraZeneca (1.83%). The EudraVigilance adverse events reaction group "general disorders", which includes all cardiac deaths, sudden deaths, brain deaths, and unspecified deaths, topped the list with a total of 14022 fatal outcomes. The second most common fatal adverse events were those in the "cardiac dysfunction" reaction group, with 6472 deaths predominantly related to Tozinameran (n=3538) or Moderna (n=1466). For AstraZeneca and Janssen vaccines, this reaction group ranked 4th (n=1048) and 5th (n=259), respectively. The reaction groups "respiratory, thoracic and mediastinal disorders" (n=5813), "nervous system disorders" (n=5779 fatalities) and "infections and infestations" (n=4860) followed in descending order on the frequency ranks 3-5. Adverse events in the reaction group "vascular disorders" that had a fatal outcome ranked sixth (n=2513) with vaccination with Tozinameran (n=1107), Moderna (n=510), AstraZeneca (n=643), and Janssen (n=193).

In a second step, the frequency of different cardiovascular reactions to the spike-inducing mRNA vaccine Tozinameran was investigated according to the established EudraVigilance classification of search terms (Table 2).

Table 2: Tozinameran-suspected cardio-/heart-circulatory reactions (individual cases from the EudraVigilance-database of suspected adverse drug reaction reports up to 31.07.2023).

A first systematic review of the reported adverse events from 4 reaction groups resulted in an assignment to 19 superordinate groups, 15 to cardiac disorders (tachycardia, arrhythmia, bradyarrhythmia, atrial fibrillation/flutter, impaired stimulus formation/conduction; heart failure, cardiomyopathy, ventricular fibrillation or flutter; cardiac arrest/death; coronary artery disease, myocardial infarction; myo-/ pericarditis; chest pain, palpitations, extrasystoles) and 4 to heartcirculatory disturbances (blood pressure increase, blood pressure decrease, circulatory collapse and multi-organ dysfunction syndrome).

Tachycardiac rhythm disturbances were reported most frequently (n=36115), followed in descending order by chest pain (n=32358), palpitations (n=27123), increased blood pressure/hypertension including hypertensive crises or malignant hypertension (n=25907), myo-/pericarditis, carditis (n=23775), arrhythmia (n=13964), decreased blood pressure/hypotension (n=8799), heart failure (n=6496), coronary heart disease (n=5843), cardiac arrest/sudden cardiac death, death (n=5424), myocardial infarction (n=4069), atrial fibrillation/flutter (n=3997), extrasystoles (n=3094), bradyarrhythmia (n=2535), circulatory collapse (n=1986), cardiac/ventricular fibrillation/flutter (n=1753), cardiomyopathy (n=1119), impaired stimulus formation and conduction (n=827), and multi-organ dysfunction syndrome (n=325).

The most dangerous cardiovascular diseases in terms of fatal outcome (Table 2), were cardiac arrest/cardiac death/sudden death (86% fatal outcome) followed in descending order by multiorgan dysfunction syndrome (61.85% fatal outcome), myocardial infarction (in 21.36% fatal), heart/cardiac failure (in 14.61% fatal), circulatory collapse (in 10.44% fatal), cardiomyopathy (in 9.65% fatal), cardiac/ ventricular fibrillation/flatter (in 5.19% fatal), impaired stimulus formation and conduction (in 4.59% fatal), coronary artery disease (in 4.5% fatal), atrial fibrillation/flatter (in 2.68% fatal), hypotension (in 1.64% fatal), bradyarrhythmia (in 1.34% fatal), myo-/pericarditis/ carditis (in 1.14% fatal), arrhythmia (in 1.1% fatal), chest pain (in 0.62% fatal), blood pressure elevation/hypertension (in 0.44% fatal), tachycardia (in 0.35% fatal), extrasystoles (in 0.13% fatal), and palpitations (in 0.07% fatal).

Discussion

The most reliable findings on the tolerability of drugs and vaccines are provided by large-scale, prospective, Randomised and Controlled Trials (RCTs). However, these are not available for spike-based vaccines after approval.

The only way to obtain information on the post-authorisation safety profile of spike-based vaccines is to analyse adverse events reported to established pharmacovigilance systems such as the EMA's EudraVigilance system. However, limitations of this data collection must be taken into account. First of all, it must be noted that the database in itself does not allow for a simple causality assessment. Nevertheless, an unusual accumulation of reported side effects should not be ignored, but should be a reason for targeted systematic analyses and investigations. After all, spontaneous reports are officially considered an important instrument for the timely detection of risk signals.

Unfortunately, this database also does not allow for frequency calculations, as the corresponding vaccination rates from the reporting countries were not collected at the same time. It should also be taken into account that the frequency of reporting depends on the perception of the spectrum of adverse events, the willingness to report on them and the concentration of attention by the media. These factors can vary considerably from country to country. Any national biases can be compensated for, but not completely eliminated, by centralised EudraVigilance recording at EU level. In particular, because the information on all collected cases with adverse reactions was submitted to the EMA by the national authorities and marketing authorisation holders, the results are highly significant. They should not be ignored or trivialised. After all, it cannot be assumed that the unpaid extra effort of an anonymised adverse reaction report is made because of a triviality.

In this context, the growing total number of individual cases (to 2256506 cases) with adverse effects and their fatal outcomes (n=51740) (Table 1) associated with spike-based COVID-19 vaccines is already alarming. The increasing trend (cumulative number of vaccinated individuals with adverse events) is unbroken, especially in association with Moderna and Tozinameran. With an average of 2338 individuals affected/day in European countries, of which an average of 54/day died from their side effects (2.3% of those vaccinated with side effects), the decades of experience with conventional vaccines are far exceeded.

For example, the dangerousness of vaccinations, measured in terms of their fatal outcomes, was 0.32% in Germany in 2014 (12 out of 3720 vaccinated children/people with ADRs) [10], which is only about 1/7 from 2.3% mentioned above.

Similarly, the two influenza vaccines licensed in the EU (surface antigen, inactivated: licensed 29 November 2010 and split virion, inactivated: licensed 19 October 2009), which are widely used in European countries (e.g. 398.2 million doses in Germany in 2022/23, [11]), have been significantly more tolerable than the COVID-19 vaccines since approval, with only about 3.9 people affected/day (equivalent to 0.17% of those affected by adverse events after COVID-19 vaccination) and 0.2 fatal outcomes/day (equivalent to 0.37% fatal outcomes of adverse events after COVID-19 vaccination) or 5.5 people affected/day (corresponding to 0.24% of those affected by adverse events after COVID-19 vaccination) and 0.25 fatal outcomes/day (corresponding to 0.46% fatal outcomes of adverse events after COVID-19 vaccination), respectively [12,13].

Consequently, the magnitude (total number) and hazard (fatal outcomes) of adverse events associated with spike-based vaccines are significantly higher than those associated with other widely used vaccines.

The side effect spectrum of spike-based COVID-19 vaccines involves almost all organs. The current analysis has shown that the reaction group 'cardiac disorders' ranks second (n=6472) in terms of dangerousness (measured by the number of fatal outcomes) after the reaction group 'general disorders' (n=14022). It should be taken into account that some of the reported cardiovascular adverse events were not assigned to the 'cardiac disorders' reaction group due to the given classification, but to the 'general disorders' reaction group (e.g. death, cardiac death, brain death, sudden death, multi-organ failure, chest pain), the 'investigations' reaction group (blood pressure and heart rate abnormalities) and the 'vascular disorders' reaction group (hypertension, hypotension, cardiovascular collapse, shock).

Therefore, the reaction group 'cardiac disorders' is thus obviously smaller than it would be if it were correctly assigned.

With regard to the analysis of cardiovascular reactions associated with the spike-inducing mRNA vaccine Tozinameran, this does not matter, as the frequency of reporting of ‘search terms’ was evaluated (Table 2).

The qualitative and quantitative similarity of the side-effect profiles of the different COVID-19 vaccines, as well as their analogous mode of action, support the assumption that they are class-specific, as outlined earlier [4].

Spikes, whether SARS-CoV-2 spikes or spikes present elsewhere, such as mRNA-induced spikes, are able not only to trigger the desired immune response via Receptor-Binding Domain (RBD) of their subunit S1, but also to occupy their receptor ACE2 with nonneutralised components. The proven attachment of the spikes to ACE2 is not only the first step of viral fusion with host cells and a precondition of cytotoxic cell-fusion, but also leads to a downregulation of the cardiovascular protective enzyme ACE2 and a subsequent dysregulation or activation of the Renin-Angiotensin- Aldosterone System (RAAS) with increasing Ang II concentrations. This mode of action determines the side effect profile of spike-based COVID-19 vaccines.

The most significant effect of Ang II is undoubtedly the vasoconstriction, which can manifest itself acutely as blood pressure increase, hypertensive crisis, tachycardia/arrhythmia, acute left heart failure, ischaemia-related cardiac or CNS-symptoms, myocardial infarction, sudden (cardiac) death or stroke. Central and peripheral catecholaminergic activities amplify Ang II effects. Based on increased sodium reabsorption, in which aldosterone is involved in the kidney, and persistently increased sympathetic tone, slowly progressive blood pressure sequelae can develop.

It has been known for quite some time that Ang II controls cellular growth (hypertrophy and proliferation), adhesion, migration, intracellular matrix deposition and thereby influencing chronic adaptation processes in blood vessels and the heart muscle, such as socalled remodeling, as well as tissue repair and development of arteriosclerosis. Experimentally, the influence of AT1R activation on the electrical conductivity of myocytes proved to be relevant with regard to the triggering of a ventricular arrhythmia [14]. Besides, the adaptive immune system and inflammatory responses, together with the local renin-angiotensin-system, are involved in Ang II-induced organ injury [15].

The vasculature is to be seen as a link between biochemical processes and symptomatic tissue damage and is therefore frequently affected by their systemic and local changes.

It is therefore not surprising if precisely these clinically relevant consequences are observed after spike-based vaccination. Accordingly, tachycardia, arrhythmia, atrial fibrillation/flatter, bradyarrhythmia and impaired stimulus formation and conduction (n=57438 combined) dominated the cardiovascular side effect profile.

With 25907 reports of blood pressure increase/hypertension, these reached a substantial level, although there is no sensitization to the vasoconstrictor effects of Ang II.

The high number of cardiac arrest, sudden cardiac death and death associated with Tozinameran (n=5424) characterises the severity of the cardiovascular burden caused by heart failure, cardiomyopathy, cardiovascular collapse and ventricular fibrillation or flutter (n=16778 combined).

Coronary heart disease and myocardial infarction were reported a total of 9912 times. A plausible explanation in this context could be the downregulation of ACE2 resulting in increase in vasoconstrictive and platelet-activating and/or tachyarrhythmic Ang II effects, which can lead to coronary and microvascular circulatory disturbances with thrombus formation and ischaemic sequelae. Comorbidity as well as stress-related catecholaminergic enhancement may be added and worsen the condition.

Hypotension (n=8799) can occur in the context of neuropathic symptom complexes, but also in most severe disease processes, such as multi-organ failure/dysfunction, in which the response to Ang II declines.

Chest pain can have cardiac and non-cardiac causes. It may indicate a heart muscle disease, such as myocarditis. Clarification of the assignment requires further diagnostic measures. However, due to the large number of reports (n=32358), the symptom as such already achieves clinical relevance.

Palpitations (n=27123) are subjectively impressive. They can accompany tachycardic rhythm disturbances and arrhythmias, but do not have any disease value of their own. However, there would be no harm in explaining this side effect in the package leaflet.

Extrasystoles (n=3094) are subjectively disturbing, but usually harmless. They can, however, also occur in the consequence of a heart attack or myocarditis and then require specific attention.

Multiorgan dysfunction/failure (n=325), associated with high lethality (61.85%), was reported infrequently compared to other spikeinduced adverse events. It is more likely to be associated with severe COVID-19 disease, which can occur despite vaccination.

So far, only myo-/pericarditis (23775 reports) from this spectrum has been attributed a vaccine-related signaling effect by the EMA. However, no plausible explanation was given although myo-/ pericarditis is only 5th in frequency and 13^th in cardiovascular hazard. Among all myo/pericarditis cases, only 15 cases (0.02%) were specified: Autoimmune myocarditis 5 times, immune-mediated 2 times, hypersensitivity 6 times, and post infectious 2 times. Neither the special distribution of ACE2 in the pericytes of the capillaries and small blood vessels of the myocardial tissue, in cardiomyocytes and endothelial cells, nor a possible pre-existing low ACE2 level linked to high Ang II concentrations, as in the multiple stressed older age (increased chymase and TMPRSS2 activity), was discussed as an explanation for the pathogenesis of the globally declared "myocarditis” [16]. Direct spike damage potential [17], genetically fixed low ACE2 activity or a situation additionally aggravated by stress were also not considered. Specific investigations failed to materialise. Even an alarming signal-the sudden cardiac death of two adolescentswas not used to clarify further "myocarditis" cases, despite resolute references by the authors to the suspected underlying stress cardiomyopathy caused by catecholamines (one could also say: toxic Ang II/Noradrenaline storm) [18].

The importance of acute cardiovascular reactions is underlined by the fact that deaths caused by them accounted for at least one third (35%) of all deaths associated with Tozinameran’s side effects. The cardiac adverse events with the most fatal outcomes were cardiac arrest (86%), multiorgan dysfunction (approximately 62%), myocardial infarction (21.4%), heart failure (14.6%) and circulatory collapse (10.44%).

Spike-induced ACE2 downregulation with subsequent activated RAAS and pathogenetically harmful, relevant Ang II increase and catecholaminergic amplification should be considered as causative of sudden and unexpected deaths until proven otherwise.

If spike-relevant symptoms are present, a comprehensive cardiovascular differential diagnosis should be performed, including testing of endothelial dysfunction and regional sequelae of possible vasoconstriction or cytotoxic tissue injury, an examination of the coagulation status and the immune system as well as the regional presence of vaccine spikes and generally of markers of the RAAS (Ang I/II, AT1R, AT2R, adrenaline/norepinephrine, Ang 1-7, MAS, ACE, ACE2, chymase, renin, aldosterone, antibodies-systemic and/or local, possibly on cells of the immune system and platelets). This diagnostic spectrum should also be taken into account appropriately when clarifying fatal outcomes associated with vaccination. Due to the high complexity of the RAAS, counter regulatory, competitive and reinforcing mechanisms need to be considered, as well as the multiple functions of its interacting components, genetic polymorphism and other individual characteristics, such as the status of ACE2 and MAS, POP/ PCRP activity, Ang II receptor activity, age, gender and comorbidity [8].

Recognition of this variety of factors may provide a clue as to why the proportion of vaccinated persons of older age, particularly over 85 years, who have reported adverse reactions is much lower (0.6%-2.1%) than the proportion of vaccinated persons between 18-64 years (76%-78.6%). It is known that with age there is increased conversion of Ang II to Ang 1-7 due to increased activity of the angiotensinases PRCP and POP, thereby reducing the harmful effects of Ang II. However, this is contradicted by the reduced ACE2 levels and increased chymase and TMPRSS2 activities in older age.

In contrast to countless clinically relevant publications on SARSCoV- 2 infection and its treatment or prevention, there is a large gap in the field of treatment of vaccination side effects. Considerable evidence suggests that both restoration of impaired ACE2 function and inhibition of activated, dysregulated RAAS should be able to attenuate or eliminate much of related adverse experiences. The efficacy of RAAS inhibitors has been repeatedly demonstrated. The following drug treatment options should be considered:

-Soluble recombinant ACE2 is in the clinical testing phase; it replaces functionally impaired ACE2 and stimulates protective RAAS components.

-ACE inhibitors have profound well-established clinical cardiovascular efficacy. They reduce the formation of Ang II, but not that caused by chymase (loss of efficacy!) and they inhibit the inactivation of the vasodilator tissue hormone bradykinin.

-Renin inhibitors have been approved since 2007. They prevent the formation of Ang II, but do not inhibit the breakdown of bradykinin. A comparative analysis between ACEI and renin inhibitors showed no essential differences in mortality and side effects [19].

-Angiotensin Receptor Blockers (ARBs) have been available since about 1995. Due to their mode action - selective inhibition of Ang II action at the AT1-receptor - they are particularly effective when Ang II and AT1R activity are high. Their effect is supported by the Ang II triggered activation of AT2R with favouring counterregulatory mechanisms (vasodilation/blood pressure reduction, tissue protection and inflammation inhibition, inhibition of aldosterone synthesis, especially reduction of myocardial fibrosis after acute myocardial infarction, suppression of pro-inflammatory cytokines, remodelling reduction, improved lipid metabolism, upregulation of endothelial NOS production, increased adiponectin levels, improvement of endothelial dysfunction, reduced production of adhesion molecules, anti-apoptosis) [20,21]. ACE2 expression of various tissues is increased [22,23]. They do not affect vasodilating kinins and the AT2- receptor. The advantages of ARBs, including their high tolerability, are convincing. The onset of action, which is not immediately apparent, must be taken into account.

In the case of dominant vasoconstrictive symptoms (e.g. blood pressure crises, ischaemia, sudden stabbing headaches, etc.), the use of vasodilators (e.g. calcium antagonists) or anti-catecholaminergic drugs should be considered additionally or alternatively.

A number of hypothetical treatment options are discussed. These include AT2R-agonists and Ang 1-7 analogues with possible ACE2- increasing effects [24,25]. Direct spike blockade/degradation or/and prevention of spike-induced cell fusion [26] or/and inhibition of spike/ ACE2-interaction [27] appear useful as long as spike production persists in the organism and is detectable [24,26,27].

Conclusions

The analysis of individual cases with ADRs and their fatal outcome after spike-based vaccination revealed an incredibly high global and specific cardiovascular burden with a sustained tendency to grow, which was previously unknown with conventional vaccines. As the incidence and severity of COVID-19 disease declines significantly, a fundamental re-evaluation of the benefit-risk assessment of these novel vaccines is mandatory.

In particular, not only the number of side effects and deaths should be considered, but also their unique side effect profile and the common mode of action. In this context, the following facts are important for a causal relationship between cardiovascular ADRs and numerous other as well as deaths and the spike-based vaccinations:

• Temporal association between spike-based vaccinations and adverse reaction/death reports submitted by regulatory authorities to the EMA's EudraVigilance database

• Proven mode of spike action: Binding with the RBD of S1-subunit to its receptor enzyme ACE2

• Spike binding induces downregulation of the cardiovascular protective ACE2 with subsequent activation of RAAS and increase of Ang II concentration.

• The side effect spectrum of spike-based vaccinations corresponds quite closely to Ang II effects.

There is no doubt that pathological hyperactivity of the reactive RAAS is undesirable and harm prevention can only be achieved by consistently refraining from any unfavorable influence. To avoid further harm, it is imperative that health professionals are educated about the consequences of spike-induced ACE2 downregulation and the resulting symptoms.

The therapy of undesirable consequences of spike-based vaccination is and remains a challenge. Knowledge and assessment of the influence of relevant factors of the complex RAAS and the Ang IIspecific effects are the basis for successful therapeutic intervention. An individualised approach depending on symptoms and differentiated diagnosis is essential.

Limitation

Limitations of the investigation result from the individual reporting and recording procedure, the lack of detailed individual information and of an appropriate vaccinated comparison population.

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