223 Fatty Acid Oxidation in PLN R14del Cardiomyopathy 8 as well as the impact of lipid disturbances in PLN-R14del cardiomyopathy. In conclusion, we revealed valuable information on the histone acetylation activities and the transcriptome regulation in PLN-R14del hearts and PLN-R14del hiPSC-CMs when compared with controls. Integrating this data, we demonstrated a disturbed energy metabolism in PLN-R14del and identified upstream TFs regulating impaired FAO. CRISPR-Cas9-based therapy to correct PLNR14del and bezafibrate treatment to re-active mitochondrial FAO further illustrated the tight relationships between the mutation, impaired FAO, lipid accumulation, and Ca2+ handling and shed light to future therapeutic strategies for PLN-R14del patients. ACKNOWLEDGMENTS We are very thankful to the patients and their families for providing valuable cardiac tissue for research purposes. We further thank Marc P. Buijsrogge (in memoriam) for collecting cardiac tissues and Joyce van Kuik, Erica Sierra-de Koning and Petra van der Kraak for technical assistance with tissue processing. We thank Utrecht Sequencing Facility for providing sequencing service and data. Utrecht Sequencing Facility is subsidised by the University Medical Centre Utrecht, Hubrecht Institute, Utrecht University and The Netherlands X-omics Initiative (NWO project 184.034.019). We thank Prof. Joseph C. Wu from Stanford University for providing lines SCVI-111 and SCVI-273. Both first shared authors contributed equally and have the right to put their names forward for CV purposes. SOURCES OF FUNDING This work was supported by the Dutch PLN patient organisation Foundation PLN (JYP, RGCM, MH, JMIHG, FWA), Leducq grant (CURE-PLaN no. 18CVD01 to JYP, RGCM, JC, DF, IK, MM, PAD, JPvT,, MH, FWA), the NWO VENI grant (no. 016.176.136 to MH), ZonMW Open Competition grant (CONTRACT no. 09120012010018 to KGH, FWA, MH), National Institute of Health grants R01 LM010098 (MH, FWA) and R01HL152055, P01HL141084 (MM), Dutch Cardiovascular Alliance (DCVA) grant (DOUBLE-DOSE no. 2020B005 to MH, FvS, FWA, JPvT), ERA-CVD grant (SCALE no. 2019T109 to JYP, FvS, MH), Netherlands Foundation for Cardiovascular Excellence (CC), two NWO VIDI grants (no. 91714302 to CC and no. 016096359 to MCV), the ErasmusMC fellowship grant (CC), the RM fellowship grant of the UMC Utrecht (CC), and UCL Hospitals NIHR Biomedical Research Centre grant BRC86A (FWA), Horizon2020 ERC-2016-COG EVICARE (725229), Horizon 2020 BRAV3 (SC1-BHC-07-2019), NWO-TTP program (Harvey 2021/TTW/01038252), and ZonMWPSIDER (ZonMw file No: 40-46800-98-018) to JS. DISCLOSURES None
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