Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive heart condition which causes fibro-fatty myocardial scarring, ventricular arrhythmias, and sudden cardiac death. Most cases of ARVC can be linked to pathogenic mutations in the cardiac desmosome, but the pathophysiology is not well understood, particularly in early phases when arrhythmias can develop prior to structural changes. Here, we created a novel human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model of ARVC from a patient with a c.2358delA variant in desmoglein-2 (). These -mutant () hiPSC-CMs were compared against two wildtype hiPSC-CM lines via immunostaining, RT-qPCR, Western blot, RNA-Seq, cytokine expression and optical mapping. Mutant cells expressed reduced mRNA and had altered localization of desmoglein-2 protein alongside thinner, more disorganized myofibrils. No major changes in other desmosomal proteins were noted. There was increased pro-inflammatory cytokine expression that may be linked to canonical and non-canonical NFκB signaling. Action potentials in CMs were shorter with increased upstroke heterogeneity, while time-to-peak calcium and calcium decay rate were reduced. These were accompanied by changes in ion channel and calcium handling gene expression. Lastly, suppressing in control lines via siRNA allowed partial recapitulation of electrical anomalies noted in cells. In conclusion, the aberrant cytoskeletal organization, cytokine expression, and electrophysiology found hiPSC-CMs could underlie early mechanisms of disease manifestation in ARVC patients.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306340PMC
http://dx.doi.org/10.3390/jcm10143061DOI Listing

Publication Analysis

Top Keywords

cytokine expression
12
arvc
5
altered electrical
4
electrical biomolecular
4
biomolecular immunologic
4
immunologic phenotypes
4
phenotypes novel
4
novel patient-derived
4
patient-derived stem
4
stem cell
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!