155 Phospholamban R14del Cardiomyopathy: a systematic summary of the pathophysiological mechanisms 7 First author and year of publication Species Type of study Main findings Doevendans (2019)60 n/a Cure PhospholambanInduced Cardiomyopathy (CURE-PlaN) CURE-PlaN network funded by the Foundation Leducq was started in 2019 with the ultimate goal of developing innovative disease-specific therapeutic modalities. Stroik (2020)61 hiPSC-CMs In vitro, functional readout Viral expression of a SERCA2a-activating PLN mutant improves calcium cycling and synchronicity in PLNR14del hiPSC-CMs. Eijgenraam (2020)62 Mouse Clinical examination, Pathological examination, Genetic analysis, In vivo, ex vivo, drug screening Homozygous transgenic PLN-R14del mice exhibit the same cardiac phenotype as human PLN-R14del cardiomyopathy patients, yet in an accelerated manner. Eplerenone or metoprolol did not improve cardiac function or survival in the mice. Bleijendaal (2020)63 Human in silico Diagnosis of PLN-R14del cardiomyopathy can be improved using machine learning and deep learning model methods by screening for abnormal T-waves. Jiang (2020)64 Human Clinical examination PLN-R14del family found in Southwestern China, exhibiting similar symptoms as previously described. CMR on the LPW is important for early disease discovery. Menzel (2020)65 Human, Mouse Molecular dynamics simulations, Protein analysis, functional readout Phosphorylation at either Ser16 or Thr17 converted PLN into a target for the phospho-adaptor protein 143-3 with different affinities. Phosphorylation of Thr17 therefore may become crucial for 14-3-3 recruitment to PLN-R14del. Pei & Maas (Preprint, 2020)66 Human Genetic analysis, Pathological examination, Genetic analysis, ex vivo Authors report differentially acetylated TF and expressed genes in FAO metabolisms and their downstream target in PLN-R14del hearts. Taha (2021)67 Human Clinical examination Echocardiographic characteristics of 281 PLN-R14del carriers. Pre-symptomatic mutation carriers with apical PSS in the apex are at higher risk of Vas. Van de Leur (2021)68 Human Clinical Examination DNN was developed on ECGs of 69 patients and evaluated on 17 patients. DNN visualizes diseasespecific ECG features and reveals yet unidentified features. Lopes (2021)69 Human Clinical examination ECG-based identification was strongly improved by using a transfer learning approach with sex classification. The QRS complex was found to be the most important region in the ECG for PLN-R14del identification. Nguyen (2021)70 Human Clinical examination, Genetic analysis Screening of a Vietnamese cohort of 230 familial and sporadic DCM patients for 58 genes. The diagnostic yield of PLNR41del was 2%. Feyen (2021)71 hiPSC-CMs in vitro, Pathological examination, Genetic analysis, functional readout, rescue with drug Single-cell RNA sequencing of PLN-R14del-CMs revealed the induction of the UPR pathway. PLNR14del hiPSC-CMs treated with a UPR activator (BiP) showed a dose-dependent amelioration of the contractility deficit. Cuello (2021)72 hiPSC-CMs in vitro, pathological examination, functional readout, rescue with drug RNA‐seq and proteomic analyses on PLNR14delCMs revealed dysfunction between the ER and mitochondria. Transduction of PLN-R14del EHTs with the Ca2+‐binding proteins GcaMP6f/parvalbumin improved the disease phenotype.
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