157 Phospholamban R14del Cardiomyopathy: a systematic summary of the pathophysiological mechanisms 7 First author and year of publication Species Type of study Main findings Tabata (2021)84 Human Clinical examination Authors discovered 5 PLN-R14del patients in Japan. All patients were diagnosed with DCM, developed end-stage heart failure, and experienced VT. Badone (2021)85 hiPSC-CMs in vitro, functional readout, pathological examination PLN-R14del-CMs showed altered calcium handling. PST3093 was not effective in the mutant-CMs but affected Ca2+ dynamics parameters in the isogenic controls. De Boer (2021)86 n/a Review Described the PLN-R14del as an example of a monogenic driver of DCM with specific pathomechanisms. Driessen (2021)87 Human Clinical examination Buccal mucosa cells labeled with anti-plakoglobin antibodies revealed that the scores of PLN p.Arg14del patients were comparable to controls (p > 0.209), suggesting differences in underlying etiology. Van der Voorn (2022)88 Human Clinical examination, immuno-assay Collagen turnover ratio was significantly higher in patients with T wave inversion or premature ventricular contractions during an exercise tolerance test. Mittal (2022)89 hiPSC in vitro, model characterisation Study generated hiPSC lines from five PLN-R14del carriers and three non-carrier family members. All eight lines show the correct characterisation of pluripotency. Dave (2022)90 Humanized Mouse Pathological examination, in vivo gene editing using CRISPR/Cas9 Humanized PLN-R14del mice are more susceptible to developing VT; disruption of an hPLN-R14del allele by AAV9-CRISPR/Cas9 improves cardiac function and reduces VT susceptibility. Monda (2022)91 n/a Review Reviewed studies till 2021. Focuses mainly on PLNR14del’s ACM pathophysiology, clinical manifestation, risk stratification for sudden cardiac death, and management. Eijgenraam (2022)92 Mouse Clinical examination, Pathological examination, functional readout, in vivo, ex vivo Progression of PLN-R14Δ/Δ mice were investigated. Administration of a PLN-targeting antisense oligonucleotide halted further cardiac dysfunction, resulting in an increased life span and almost eliminated PLN aggregates. Deiman (2022)93 n/a Review In this review, an overview of how precision medicine can be approached as a treatment strategy for PLNR14del is discussed. Vera (2022)94 hiPSC in vitro, model characterisation Study generated hiPSC lines from two PLN-R14del carriers. All lines show the correct characterisation of pluripotency. Pei & Maas (Preprint, 2022)95 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 and hiPSCCMs of PLN-R14del patients. Vafiadaki (2022)96 Humanized Mouse, HEK293, H9c2 cells Protein interactions, ex vivo, in vitro, in silico Pulldown assays reveal that PLN-R14del exhibits increased binding to SERCA2a and HAX-1, SERCA2a activity is inhibited, causing a cascade of molecular events contributing to impaired Ca2+-homeostasis and arrhythmogenesis. Rogalska (2023)97 Mouse, hiPSC-CMs RNA-Sequencing splicing analysis >200 significant alternative splicing events and profiles were observed in the LV and RV. The most affected biological process was “cardiac cell action potential’’ and 2 genes (TRPM4/CAMK2D) which encode proteins regulating calcium homeostasis.
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