Rolf Schreckenberg, Nadine Woitasky, Nadja Itani, Laureen Czech, Péter Ferdinandy, Rainer Schulz Published: 12 October 2023 British Pharmaceutical Journal
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bph.16262.
Abstract
Background and Purpose
To protect against SARS-CoV-2 infection, the first mRNA-based vaccines, Spikevax (mRNA-1273, Moderna) and Comirnaty (BNT162b2, Pfizer/Biontech), were approved in 2020. The structure and assembly of the immunogen – in both cases, the SARS-CoV-2 spike (S) glycoprotein – are determined by a messenger RNA sequence that is translated by endogenous ribosomes. Cardiac side effects, which for the most part can be classified by their clinical symptoms as myo- and/or pericarditis, can be caused by both mRNA-1273 and BNT162b2.
Experimental Approach
As persuasive theories for the underlying pathomechanisms have yet to be developed, this study investigated the effect of mRNA-1273 and BNT162b2 on the function, structure, and viability of isolated adult rat cardiomyocytes over a 72 h period.
Key Results
In the first 24 h after application, both mRNA-1273 and BNT162b2 caused neither functional disturbances nor morphological abnormalities. After 48 h, expression of the encoded spike protein was detected in ventricular cardiomyocytes for both mRNAs. At this point in time, mRNA-1273 induced arrhythmic as well as completely irregular contractions associated with irregular as well as localized calcium transients, which provide indications of significant dysfunction of the cardiac ryanodine receptor (RyR2). In contrast, BNT162b2 increased cardiomyocyte contraction via significantly increased protein kinase A (PKA) activity at the cellular level.
Conclusions and Implications
Here we demonstrated for the first time, that in isolated cardiomyocytes, both mRNA-1273 and BNT162b2 induce specific dysfunctions that correlate pathophysiologically to cardiomyopathy. Both RyR2 impairment and sustained PKA activation may significantly increase the risk of acute cardiac events.