Causal relationship between COVID-19 and myocarditis or pericarditis risk: a bidirectional Mendelian randomization study

Should we re-evaluate the narratives?

A new study entitled “Causal relationship between COVID-19 and myocarditis or pericarditis risk: a bidirectional Mendelian randomization study”¹ has been published, which rejected the link between SARS-CoV-2 and an increased rate of myocarditis. In this article, a few skeptical thoughts that can be derived from the findings by Liu et al. are formulated with regard to the entire spike narrative.

First, the method is discussed and then (main section) doubts about the spike narrative are justified and plausibly argued why this study supports these doubts.

1. Liu et al. - a groundbreaking finding

The study used genetic variants (SNPs). SNPs serve as instrumental variables, as their random distribution at birth corresponds to natural randomization and thus reduces confounding and reverse causation. This bidirectional analysis tests both whether COVID-19 triggers myocarditis/pericarditis and whether a genetic predisposition to these heart diseases increases susceptibility to COVID-19.

The authors used data from genome-wide association studies (GWAS) of the COVID-19 Host Genetics Initiative (HGI, round 7) and from the Finnish database finngen_R9_I9 for their two-stage Mendelian randomization analysis (MR analysis). Three COVID-19 phenotypes were used as exposures: severe disease (13,769 cases, 1,072,442 controls), hospitalization (32,519 cases, 2,062,805 controls), and infection (122,616 cases, 2,475,240 controls). Myocarditis (1,521 cases, 191,924 controls) and pericarditis (979 cases, 286,109 controls) were analyzed as outcomes. In the reverse Mendelian randomization analysis, myocarditis and pericarditis were tested as exposures, and the COVID-19 phenotypes as outcomes.

For the selection of suitable SNPs, only those were considered that were either associated with COVID-19 (P < 5 × 10-⁸) or, in the reverse analysis, with myocarditis/pericarditis (P < 5 × 10-⁶) at GWAS level, independently (LD clumping, 10,000 kb) and with sufficient instrumental power (F-statistic > 10). Prior to MR analysis, data harmonization was also performed to ensure that the effects of the SNPs on exposure and outcome affected the same allele direction.

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Explanation:

(“LD clumping, 10,000 kb” means that SNPs that are strongly linked to each other (linkage disequilibrium, LD) are considered only once within a window of 10,000 kilobases (i.e., 10 megabases). This ensures that the selected SNPs are independent of each other and do not represent the same genetic information more than once).

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The authors performed an inverse-variance weighted (IVW) meta-analysis under a random-effects model as the main analysis and supplemented it with MR-Egger, simple mode, weighted mode and weighted median to validate the IVW results. Divergent SNPs were identified using MR-PRESSO and horizontal pleiotropy was assessed or corrected; the MR-Egger intercept served as an index of directional pleiotropy. Heterogeneity was tested via Cochrane's Q-test, and a leave-one-out sensitivity analysis examined the influence of individual SNPs on the causal relationship. In addition, funnel plots were used to assess potential biases, with all analyses performed using the “Two Sample MR” package in R.

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Explanation:

Inverse-Variance Weighted (IVW) meta-analysis: The main method for summarizing the effects of several genetic variants [Single Nucleotide Polymorphisms (SNPs)] and estimating the causal effect.

MR-Egger: Tests for directional pleiotropy, i.e., whether SNPs have an effect via paths other than the investigated exposure.

Simple Mode, Weighted Mode, Weighted Median: Complementary methods that estimate causality more robustly, even if some SNPs are erroneous or pleiotropic.

MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier): Detects aberrant SNPs and corrects for horizontal pleiotropy to avoid confounding effects.

Cochrane's Q-test: Checks heterogeneity, i.e., whether the effects of the SNPs vary greatly.

Leave-One-Out sensitivity analysis: Checks whether individual SNPs strongly influence the overall result.

Funnel plots: A visual check to see if the results could be biased.

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The whole Mendelian randomization analyses showed no causal association between genetically predicted COVID-19 and the risk of myocarditis or pericarditis, and vice versa, regardless of whether COVID-19 was severe, hospitalized, or general. Sensitivity analyses, tests for pleiotropic effects, and heterogeneity confirmed the robustness of the results, with no evidence of bias or single dominant genetic variants.

Considering the methodology, this study bypassed the usual bias and narrative weighting by selecting data sources and relied directly on a causal investigation that captures only unbiased, statistically significant signals. As a result, no causal signals were found.

The final conclusion of the authors is, in simple terms, that there is no “supportive genetic evidence” for an increased risk of myocarditis or pericarditis with COVID-19 infection.

This raises serious concerns about what data was used and the intentions behind establishing a clear weighting in favor of the vaccines regarding myocarditis and pericarditis risks.² ; ³ ; ⁴ It is recommended to critically re-evaluate these types of studies, which were based solely on model assumptions and/or prospective and/or retrospective cohorts. The datasets should be checked for significance, reliability, coverage limitations, age adjustments, temporal limitations, time-point limitations, exclusion and definition of long-term effects, definition of infection (whether sequenced and/or detected exclusively by qPCR), definition of “fully vaccinated” (>14 days after the 2nd dose), and other possible confounding factors.⁵

Since the authors used an up-to-date database, it can be assumed that they included both infected and transfected patients.

The results of Liu (Liu et al., 2025; ¹) are in agreement with, and causally underpin cohorts such as that of Tuvali et al.⁶

Nevertheless, the increased incidence of myocarditis, pericarditis⁷ ; ⁸ ; ⁹ ; ¹⁰, and sudden cardiac events¹¹ ; ¹² ; ¹³ ; ¹⁴ ; ¹⁵ reported in multiple cohorts remains a consistent observation that requires consideration, regardless of explanatory models.

A plausible mechanism in relation to Long Covid and “Post-Vac” should be considered if the infection and the spike are not the primary drivers, but only an initial trigger.

2. The Spike - A Deductive Investigation

The following limitations for the observations by Liu[Liu et al., 2025, ¹] should be noted first:

→ GWAS/MR only show inherited genetic predispositions.

→ Epigenetic reprogramming is acquired and therefore invisible to GWAS.

→ This explains why a “no signal” result does not mean “no reprogramming”.

However, an interesting question already arises here: As demonstrated by the team of Rudolf Jaenish and others¹⁶ ; ¹⁷ ; ¹⁸ ; ¹⁹ and plausibly discussed²⁰, the spike, the spike RNA and also the modRNA can reverse integrate via Line-1 (although the question of the frequency of these events has not been conclusively clarified in vivo). In addition, both spike and spike RNA have been detected transnuclearly.²¹ Other studies suggested Spike-Interactions with the P53 and DNA repair mechanisms.²² ; ²³ Given this assumption, the results of Liu [Liu et al., 2025, ¹] are contradictory if the spike is the causal pathogenic driver: If spike (by integration or by direct p53 interaction/cytotoxic mechanisms) were a causative pathogenic driver, DNA damage or genomic instability should result in cases of myocarditis or pericarditis. One could argue that there is a short-lived cytotoxicity of the spike. However, in order to reach the myocardial tissue, the spike protein would have to circulate systemically. This is not consistent with the cross-immunity already demonstrated for both T and B cells, which was even demonstrated in seronegative, naive subjects. ²⁴ ;²⁵ ; ²⁶ ; ²⁷ ; ²⁸

This observation aligns with a broader body of evidence demonstrating that chronic and acute viral infections can, in certain cases, result in persistent inflammatory states with neurological and systemic sequelae, independent of a specific viral protein. Chronic and acute viral infections have long been known, in certain cases, to lead to persistent inflammatory conditions that may result in neurological sequelae and fatigue syndromes. This phenomenon is not restricted to a specific viral component but is more likely attributed to immune dysregulation. Research in this area remains active and incompletely characterized.²⁹ ; ³⁰ ; ³¹ ; ³² ; ³³ ; ³⁴ ; ³⁵

This already raises the first doubt as to whether the spike is actually the driving component or merely a trigger under not fully understood conditions.

The EMA³⁶ published a summary of the study by Yonker et al.³⁷ On the EMA website, the study was marked as “Classified as internal/staff & contractors by the European Medicines Agency”.

The following comments were made on the Ema website:

”Conclusions:

• Comparing post-vaccine myocarditis with vaccinated controls:

• No differences in anti-SARS-CoV-2 antibody response

• No differences in neutralization

• No autoantibodies

• No underlying/co-infection

• No differences in SARS-CoV-2 specific T cell responses •

Differences detected:

• Increased cytokines, increased innate cell response

• Increased free Spike

Medicines Agency Implications/Considerations:

• Does not change risk/benefit ratio for COVID vaccines

• Spike directly inflames endothelium and cardiac pericytes?

• Why is Spike not bound by antibodies?

• Implications for treatment or post-vaccine myocarditis? Monoclonal antibodies, IVIG?

• Is Spike seen in other complications post- mRNA vaccination?

• Differences in S1 clearance in adolescents vs adults? Is this important?”

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A narrative of the spike protein as the primary driver of all idiopathic side effects – both after transfection and after infection – has been established. However, this narrative appears partially inconclusive and internally contradictory.

The questions that have not yet been sufficiently addressed, but are essential, are (as already explained in detail above):

An open question remains whether the spike protein acts as a primary pathogenic driver or rather as a secondary by-product and amplifier of systemic processes.

A key question is whether genetically distinguishable alterations in immune cells would be expected as a response to spike protein–myocyte interactions. Relatedly, it remains to be determined whether the uptake of spike protein by myocytes would result in detectable genomic abnormalities within these cells.

If the spike circulates systemically, it should have affected the monocytes via ACE2 and ACE2-independent entry mechanisms, as will be discussed below. Another unresolved issue is whether and how the spike protein could exert pathogenic effects in the absence of monocyte uptake or stable receptor binding, particularly if circulating in a free form.³⁸ ; ³⁹

To cause any damage at all, the spike protein would have to bind to ACE2 transmembrane enzyme, NRP1, or other co-receptors or receptor-like entry mechanisms, or directly damage the cell membrane.

However, ACE2 transmembrane-bound enzyme is not highly expressed in the myocardium, meaning that binding in the heart muscle is quantitatively very limited.⁴⁰ ; ⁴¹ ; ⁴² On the other hand, ACE2 would have to be strongly expressed in cardiomyocytes to enable increased entry of spikes. This has never been in vivo validated. Another possible mechanism could be the ACE2-driven syncytia formation proposed by Clemens et al.⁴³, for example.⁴⁴ However, this explanation is not consistent with the latest data from Liu[Liu et al., 2025, ¹], too, as syncytia formation is also associated with DNA damage ⁴⁵ ; ⁴⁶ ; ⁴⁷ ; ⁴⁸ ; ⁴⁹

The assumption that the spike protein is the main driver is also not consistent with the findings of Ota et al.⁵⁰ Ota et al. found spike protein expression in 43.8% of the transfected individuals. Many physicians “anecdotally” report side effects despite the absence of spike protein.This observation is in line with the findings of Yonker et al. [Yonker, 2023, ³⁷] who investigated whether S1 subunit detection was hindered by antigen clearance or antibody masking. To uncover potentially antibody-bound S1 in patients with myocarditis after modRNA injection, they treated plasma samples with dithiothreitol to denature immunoglobulins. After this treatment, S1 was detectable in the plasma of 34% of vaccinated controls and 29% of individuals in the myocarditis cohort.

Even under the assumption of long-term spike persistence in tissues, one would expect a stereotyped, predictable, and statistically significant immune response—a reproducible pattern of reaction under defined contextual conditions—as the spike protein, due to its intrinsic molecular structure and immunogenic properties, is known to trigger characterized signaling pathways. However, this notion of a "pattern" must not be misunderstood as a rigid or fixed immune template. Rather, it refers to a range of adaptive yet statistically traceable response profiles that emerge time- and mechanistically consistently under comparable biological conditions, shaped by host-specific factors such as the human leukocyte antigen (HLA) system type, prior immune history, and cellular context, or in other terms, canonical versus non-canonical.

Dmytrenko et al.⁵¹ developed a mouse model in which the human SARS-CoV-2 receptor protein ACE2 is specifically expressed in heart muscle cells (cardiomyocytes). Infection of these mice with an original SARS-CoV-2 variant not adapted to mice resulted in viral replication in the heart, accumulation of macrophages and moderate systolic dysfunction of the left ventricle.

This experiment indicates that the monocytes played a major role in the inflammatory infiltration. Beyond that, however, it is not clear whether the spike was the primary driver. In the experiment the mice models were directly injected with the entire replication-capable virus. Following the heat map, however, a more sustained and longer expression of nucleocapsid and ORF1 is shown to drive inflammation.

The authors emphasize that observed heart damage is not necessarily caused by direct infection of the heart muscle cells, but also by systemic inflammatory reactions. (“...do not provide a means to specifically elucidate the contribution of cardiac infection to cardiac pathogenesis, as extracardiac infection and resultant systemic inflammation could contribute to cardiac injury.”) This is a classic cautious indication that many effects that could be seen as direct spike protein consequences in the narrative could actually be indirect.

The idea of systemic inflammation is consistent with the observation by Yang et al.⁵² They also show that a systemic Sars-Cov-2 infection leads to overactive recruitment of monocytes in cardiac tissue infected with Sars-Cov-2, in which cardio myocytes increasingly express and secrete CCl2 chemokine ligands. This suggests that heart damage is a consequence of immune activation, not a direct cytotoxic effect of the virus or spike protein.

Junqueira et al.⁵³ also suggest that an inflammatory but not directly cytotoxic reaction could be the driver of myocarditis rather than a direct spike mechanistically driven reaction. This is also in line with the considerations of Meidaninikjeh et al.⁵⁴ who discussed the role of the cytokine storm in Sars-Cov-2 infections.

From the fact - which will only be briefly adressed here - that Sars-Cov-2 can infiltrate monocytes both ACE2-dependently and independently [Meidaninikjeh et al., 2021;⁹] the following consideration should be taken into account:

It seems rational that even in a non-severe infection, immunological reprogramming of monocytes (and other [not only immune) cells] is already a direct consequence of systemically circulating viral load.⁵⁵ ; ⁵⁶ ; ⁵⁷ ; ⁵⁸ In the following, this is assumed as a plausible premise for further argumentation.

It has been experimentally proven that empty LNPs trigger epigenetic remodelling of the immune system. This has been shown for monocytes, macrophages and dendritic cells.⁵⁹ ; ⁶⁰ ; ⁶¹ ; ⁶² ; ⁶³ ; ⁶⁴ In addition, Quin et al.⁶⁵ showed transgenerational consequences of this reprogramming in vivo in a mouse study using 2 models, which makes the data valid and reproducible. Furthermore, Dey et al.⁶⁶ demonstrated that LNPs can also shift MHC1/2 expression profiles.

From this it can be deduced that infiltrated monocytes, for example, initiate a cascade of signal transduction that leads to intracellular and in consequence to paracrine⁶⁷ ; ⁶⁸ ; ⁶⁹ ; ⁷⁰ ⁷¹ ; ⁷² systemic effects. Moreover it is evident that monocytes maturate into macrophages as well as dendritic cells.⁷³ ; ⁷⁴ ; ⁷⁵ ; ⁷⁶

Discussion

The presented data suggests, that it is not the spike but shifted cytokine profiles and systemic immune alterations that are the actual driving force. If the entire immune response - in contrast to a natural infection - and the associated cytokine profiles have been refunctionalized and epigenetically altered immune cells are involved, as was also suggested in the comments by Yonker et al. (“Increased cytokines, increased innate cell response”), dysfunctionality that goes far beyond known immune responses should be expected.

This is consistent with the observations of Bruce Patterson's group⁷⁷ ; ⁷⁸ who found non-classical monocytes in the brain carrying the spike. The spike persistence seems plausible, since the ideopathic effects of modRNA together with the LNP effects will probably also have a systemic effect on the proteasome system.⁷⁹

As discussed under CFS, this is not a new phenomenon in post-viral complications. However, the new and poorly understood process is the LNPs and modRNA, which are likely to potentiate these effects and direct them into idiopathic pathways, as they are not limited to immune cells that are transfected-as discussed in a previous articles.⁸⁰ A further point that concludes the discussion and is all too often overlooked in LNP-modRNA technology and spike narratives is that between just 1 - 15 percent of genetic material makes it to the endosomal escape for translation.⁸¹ ; ⁸² ; ⁸³ Before that, many changes deeply interfere with intracellular communication and the modRNA supresses immonogenicity (see⁸⁴). Furthermore, it can be assumed that only around 50 % of LNPs actually carry genetic material.⁸⁵

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