• Crit Care · Apr 2023

    Observational Study

    Major adverse cardiovascular events are associated with necroptosis during severe COVID-19.

    • Rosana Wiscovitch-Russo, Elsa D Ibáñez-Prada, Cristian C Serrano-Mayorga, Benjamin L Sievers, Maeve A Engelbride, Surya Padmanabhan, Gene S Tan, Sanjay Vashee, Ingrid G Bustos, Carlos Pachecho, Lina Mendez, Peter H Dube, Harinder Singh, Luis Felipe Reyes, and Norberto Gonzalez-Juarbe.
    • Infectious Diseases and Genomic Medicine Group, J Craig Venter Institute, 9605 Medical Center Drive Suite 150, Rockville, MD, 20850, USA.
    • Crit Care. 2023 Apr 20; 27 (1): 155155.

    BackgroundThe mechanisms used by SARS-CoV-2 to induce major adverse cardiac events (MACE) are unknown. Thus, we aimed to determine if SARS-CoV-2 can induce necrotic cell death to promote MACE in patients with severe COVID-19.MethodsThis observational prospective cohort study includes experiments with hamsters and human samples from patients with severe COVID-19. Cytokines and serum biomarkers were analysed in human serum. Cardiac transcriptome analyses were performed in hamsters' hearts.ResultsFrom a cohort of 70 patients, MACE was documented in 26% (18/70). Those who developed MACE had higher Log copies/mL of SARS-CoV-2, troponin-I, and pro-BNP in serum. Also, the elevation of IP-10 and a major decrease in levels of IL-17ɑ, IL-6, and IL-1rɑ were observed. No differences were found in the ability of serum antibodies to neutralise viral spike proteins in pseudoviruses from variants of concern. In hamster models, we found a stark increase in viral titters in the hearts 4 days post-infection. The cardiac transcriptome evaluation resulted in the differential expression of ~ 9% of the total transcripts. Analysis of transcriptional changes in the effectors of necroptosis (mixed lineage kinase domain-like, MLKL) and pyroptosis (gasdermin D) showed necroptosis, but not pyroptosis, to be elevated. An active form of MLKL (phosphorylated MLKL, pMLKL) was elevated in hamster hearts and, most importantly, in the serum of MACE patients.ConclusionSARS-CoV-2 identification in the systemic circulation is associated with MACE and necroptosis activity. The increased pMLKL and Troponin-I indicated the occurrence of necroptosis in the heart and suggested necroptosis effectors could serve as biomarkers and/or therapeutic targets. Trial registration Not applicable.© 2023. The Author(s).

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