Cardiac side effects of RNA-based SARS-CoV-2 vaccines: Hidden cardiotoxic effects of mRNA-1273 and BNT162b2 on ventricular myocyte function and structure.

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. CONCLUSION 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.

New insights into paracrine mechanisms of human cardiac progenitor cells.

AIMS: Cardiac progenitor cells (CPCs) have been shown to promote cardiac regeneration in vivo. Understanding the function of CPCs is essential for further implementation of these cells in the treatment of cardiac diseases. The present study tested the hypothesis that adult CPC exert paracrine effects that lead to an improvement in the functional characteristics of cardiomyocytes. This study also investigated whether aging (we included patients aged between 4 months and 81 years) has any effect on the paracrine mechanisms of CPC. METHODS AND RESULTS: The supernatant of CPC generated both from human and rat hearts-so called 'conditioned cardiosphere medium' improved the contractile behaviour of isolated adult cardiomyocytes in a concentration-dependent manner after incubation for 24 h and increased the SERCA/NCX ratio. The observed positive effects on contractile behaviour were independent of the CPC donors' age. Conditioned cardiosphere media also normalized angiotensin II-induced contractile dysfunction. Cytokines released by CPC into the media were detected by cytokine arrays. CONCLUSION: The observed diversity of cytokines released by CPC needs to be further elucidated in detail. Nevertheless, CPC are a promising therapeutic approach in the field of cardiac disease. The methods described allow investigation of the underlying paracrine mechanisms in a standardized in vitro situation.