AbstractBackground and PurposeTo 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 ApproachAs 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 ResultsIn 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.Conclusion and ImplicationsHere, 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.