This is a summary, written by members of the CITF Secretariat, of:

Lu RXZ, Rafatian N, Zhao Y, Wagner KT, Beroncal EL, Li B, Lee C, Chen J, Churcher E, Vosoughi D, Wang Y, Baker A, Trahtemberg U, Li B, Pierro A, Andreazza AC, dos Santos CC, Radisic M. Heart-on-a-chip model of immune-induced cardiac dysfunction reveals the role of free mitochondrial DNA and therapeutic effects of endothelial exosomes. bioRxiv. doi: https://doi.org/10.1101/2023.08.09.552495.

The results and/or conclusions contained in the research do not necessarily reflect the views of all CITF members.

A CITF-funded study, published in preprint and not yet peer-reviewed, provided valuable insights into the mechanisms of myocardial inflammation and its effects on heart function using a heart-on-a-chip model. The findings highlight the potential of using extracellular vesicles as a treatment strategy for managing SARS-CoV-2-induced heart dysfunction. This study was led by Dr. Claudia dos Santos and Dr. Andrew Baker (both from Unity Health Toronto).

Key findings:

  • Human cell-based models of myocardial inflammation are lacking. The heart-on-a-chip model closely replicated the inflammatory responses seen in human SARS-CoV-2-induced myocarditis, including immune cell infiltration and increased proinflammatory cytokine levels.
  • Elevated levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) were found in both the model and COVID-19 patients with poor heart function, indicating a strong link between inflammation and heart damage.
  • Extracellular vesicles (HUVEC-EVs) derived from human umbilical endothelial cells, known to contribute to the preservation of vascular hemostasis, were found to reduce mitochondrial damage, mitigate myocardial inflammation, and improve heart function.
  • The extracellular vesicles were found to contain microRNAs that suppress proinflammatory responses through the toll-like receptor (TLR) pathway and a protein called nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), both of which regulate immune responses.

Researchers bioengineered a vascularized heart-on-a-chip system, known as Integrated Vasculature for Assessing Dynamic Events (InVADE), with circulating immune cells to model SARS-CoV-2-induced acute myocarditis to determine the pathophysiological hallmarks of heart inflammation. Blood levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) were measured in 40 patients, who were admitted to the medical-surgical intensive care units (MSICU) at St. Michael’s Hospital in Toronto with acute respiratory failure and suspicion of COVID-19 between March 2020 and March 2022.