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Susceptibility to innate immune activation in genetically mediated myocarditis
Daniel F. Selgrade, … , Kathleen J. Green, Elizabeth M. McNally
Daniel F. Selgrade, … , Kathleen J. Green, Elizabeth M. McNally
Published May 20, 2024
Citation Information: J Clin Invest. 2024;134(13):e180254. https://doi.org/10.1172/JCI180254.
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Research Article Cardiology Inflammation

Susceptibility to innate immune activation in genetically mediated myocarditis

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Abstract

Myocarditis is clinically characterized by chest pain, arrhythmias, and heart failure, and treatment is often supportive. Mutations in DSP, a gene encoding the desmosomal protein desmoplakin, have been increasingly implicated in myocarditis. To model DSP-associated myocarditis and assess the role of innate immunity, we generated engineered heart tissues (EHTs) using human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) from patients with heterozygous DSP truncating variants (DSPtvs) and a gene-edited homozygous deletion cell line (DSP–/–). At baseline, DSP–/– EHTs displayed a transcriptomic signature of innate immune activation, which was mirrored by cytokine release. Importantly, DSP–/– EHTs were hypersensitive to Toll-like receptor (TLR) stimulation, demonstrating more contractile dysfunction compared with isogenic controls. Relative to DSP–/– EHTs, heterozygous DSPtv EHTs had less functional impairment. DSPtv EHTs displayed heightened sensitivity to TLR stimulation, and when subjected to strain, DSPtv EHTs developed functional deficits, indicating reduced contractile reserve compared with healthy controls. Colchicine or NF-κB inhibitors improved strain-induced force deficits in DSPtv EHTs. Genomic correction of DSP p.R1951X using adenine base editing reduced inflammatory biomarker release from EHTs. Thus, EHTs replicate electrical and contractile phenotypes seen in human myocarditis, implicating cytokine release as a key part of the myogenic susceptibility to inflammation. The heightened innate immune activation and sensitivity are targets for clinical intervention.

Authors

Daniel F. Selgrade, Dominic E. Fullenkamp, Ivana A. Chychula, Binjie Li, Lisa Dellefave-Castillo, Adi D. Dubash, Joyce Ohiri, Tanner O. Monroe, Malorie Blancard, Garima Tomar, Cory Holgren, Paul W. Burridge, Alfred L. George Jr., Alexis R. Demonbreun, Megan J. Puckelwartz, Sharon A. George, Igor R. Efimov, Kathleen J. Green, Elizabeth M. McNally

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Figure 5

Strain-induced force loss in patient-derived DSP EHT models.

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Strain-induced force loss in patient-derived DSP EHT models.
(A) Optical...
(A) Optical mapping of heterozygous DSP p.E1597X and DSP p.R1951X EHTs compared with EHTs from healthy control demonstrates comparable conduction velocities, distinct from those seen in DSP–/– EHTs. (B) Fractional shortening was only minimally reduced at baseline in DSP p.E1597X and p.R1951X EHTs compared with healthy control (*< 0.05 by 2-way ANOVA, n = 9–12 EHTs per condition, data representative of 3 batches). (C and D) FTI values from DSP p.E1597X and p.R1951X EHTs showed no significant difference in FTI compared with healthy control EHTs at baseline conditions. However, when subjected to 5% or 10% strain, both p.E1597X and p.R1951X EHTs failed to augment contraction as seen with healthy control EHTs (D), consistent with the requirement for additional stressors to manifest reduced contractility and reflecting the reduced contractile reserved of DSP heterozygous EHTs (*< 0.05, **< 0.01, ***< 0.001 by 2-way ANOVA, n = 3 EHTs per condition from 3 independent batches, labeled as n1 = black dots, n2 = white dots, n3 = gray dots). (E) After LPS or HMGB1 exposure, DSPtv EHTs had more marked reduced fractional shortening compared with similarly exposed healthy control EHTs (**< 0.01, ***< 0.001, ****< 0.0001 by 2-way ANOVA, n = 12 EHTs per condition). (F) LPS stimulated greater IL-1β release into the media compared with healthy control (**< 0.01, ****< 0.0001 by Mann-Whitney U test, n = 8 EHTs per condition). Data presented as individual recordings normalized to average baseline measurement per EHT. Significance calculated based on mean value per EHT.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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