158 Chapter 7 First author and year of publication Species Type of study Main findings Aboumsallem (2023)98 Mouse multi-omics characterization Cell-death and tissue-repair pathways were enriched and energy derivation processes were downregulated in hearts of 7 weeks old homozygous PLN-R14del mouse model. Kumar (2023)99 Humanized Mouse Pathological examination, functional readout, in vivo, ex vivo, rescue with drug Changes in Ca2+ handling and myofilament proteins resulted in decreased contractility. The depressive contractile effects were prevented by omecamtiv mecarbil, while MYK-461 had no effects. Van der Meer (2023)10 n/a newspaper article Authors estimate that approximately 25% of all transplanted patients carry the PLN-R14del mutation. Authors summarize the history, clinical onset, pathophysiology potential therapies, and patient participation. Vafiadaki (2023)100 n/a Review Reviewed studies till 2022 provide an overview on PLN-R14del disease pathophysiology and therapeutic approaches. Zanotti 20238 Human Clinical examination, Pathological examination, protein analysis, ex vivo Authors detected alteration in histology and the formation of perinuclear aggresomes in skeletal muscle tissue from an Italian patient carrying PLNR14del. Cleary (Preprint, 2023)101 HEK293 Protein interactions, in vitro, in silico PLN-R14del proteins showed significantly increased pentamer to monomer ratios and an increased affinity for homo-oligomerization and decreased binding affinity for SERCA compared to WT. Authors suggest that the R14del mutation stabilizes PLN in its pentameric form, decreasing its ability to regulate SERCA. De Brouwer (2023)102 Human Clinical trial: The PHOspholamban Related Cardiomyopathy Intervention Study (iPHORECAST) multicentre randomized trial ‘intervention in PHOspholamban RElated CArdiomyopathy STudy’ (i-PHORECAST) showed no significant improvement after eplerenone treatment in asymptomatic PLN p.Arg14del carriers. Maniezzi (Preprint, 2023)103 Mouse ex vivo, Functional readouts, Genetic/ Protein analysis PLN-R14del mouse cardiomyocytes shows a reduced ability to inhibit SERCA2a, arguing super-inhibition. Metabolism was found decreased and ER stress increased. The drug PST3093 showed no effect in PLN-R14del cardiomyocytes.’ Van Lint22 Human Clinical Examination The authors found no association between the amount of exercise and the susceptibility to develop ACM, DCM, VA, or HF in PLN p.(Arg14del) carriers. Doevendans PA (2023) 104 n/a Pro-Con Statement The author speculates whether all carriers should be offered preventive treatment. Con: These therapeutic steps are experimental and not ready to be offered to patients. de Boer (2023)105 n/a Pro-Con Statement The author speculates whether all carriers should be offered preventive treatment. Pro: PLN-R14del carriers have a 50% lifetime risk of developing severe disease, therefore we should not hesitate to offer preemptive medication. Taha (2023)106 Human Clinical Examination Deep neural network was able to discriminate PLN variant carriers (n = 278) from control subjects (n = 621) in echocardiographic deformation curves.
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