Myocarditis, a severe condition characterized by heart inflammation and impaired cardiac function, is a common cause of sudden cardiac death and heart transplants among young people. This condition can be triggered by both genetic and environmental factors, including viral infections and reactions to vaccinations. Recently, mutations in the DSP (desmoplakin) gene have been identified as a significant contributor to myocarditis. Desmoplakin is crucial for maintaining the structural integrity of heart muscle cells through desmosomes. Understanding the role of DSP mutations in myocarditis is essential for developing targeted therapies.

In a recent study, scientists from Northwestern University have made significant advances in modeling DSP-associated myocarditis using engineered heart tissues (EHTs) derived from human induced pluripotent stem cells (hiPSCs). These EHTs, created from cardiomyocytes (hiPSC-CMs) of patients with heterozygous DSP truncations (DSPtv) and a gene-edited homozygous deletion cell line (DSP-/-), allowed the researchers to investigate the innate immune activation and contractile dysfunction caused by DSP mutations.

The researchers discovered that DSP-/- EHTs exhibited baseline innate immune activation, hypersensitivity to Toll-like receptor stimulation, cytokine release, and significant contractile dysfunction. Using CRISPR/Cas9 technology, the team created DSP-/- cells and employed adenine base editing to correct specific DSP mutations. These gene-editing techniques were instrumental in developing accurate disease models. The EHTs, combining hiPSC-CMs with human cardiac fibroblasts, provided a 3D scaffold that closely mimics human heart tissue, enabling detailed functional and molecular analyses.

Treatment with NFκB inhibitors significantly improved contractile function in DSPtv EHTs. NFκB inhibition also attenuated the inflammatory impact on cardiac function in DSP-/- hiPSC-CMs monolayers, as revealed by CardioExcyte 96 field potential duration measurements. NFκB inhibitors reduced cytokine release and ameliorated contractile deficits, suggesting that targeting innate immune pathways could effectively manage myocarditis.

The researchers also demonstrated that genomic correction of DSP mutations using adenine base editing reduced inflammatory biomarker release and improved contractile function in EHTs.

Overall, this study advances our understanding of genetically mediated myocarditis. Using engineered heart tissues, the researchers showed that DSP mutations lead to increased immune activation and contractile dysfunction. These findings not only elucidate the molecular mechanisms underlying DSP-associated myocarditis but also identify potential therapeutic targets for clinical intervention.

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Find the original article here: https://www.jci.org/articles/view/180254

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