CRISPR/Cas9-engineered hPSC-CMs reveal that energy depletion, arrhythmias, and hypocontractility are key mechanisms and potential therapeutic targets in hypertrophic cardiomyopathy.
Our holistic and comprehensive approach showed that energy depletion affected core cardiomyocyte functionality. The engineered R453C-βMHC-mutation triggered compensatory responses in hPSC-CMs, causing increased ATP production and αMHC to energy-efficient βMHC switching. We showed that pharmacological rescue of arrhythmias was possible, while MHY7: MYH6 and mutant: wild-type MYH7 ratios may be diagnostic, and previously undescribed lncRNAs and gene modifiers are suggestive of new mechanisms.
Mosqueira et al. (Wed,) studied this question.