156 Chapter 7 First author and year of publication Species Type of study Main findings Raad (2021)73 Humanized Mouse Clinical and pathological examination, functional readout, in vivo, ex vivo Humanized PLN-R14del mice exhibited adverse electrophysiological remodeling, absence of significant structural or hemodynamic changes, and increased arrhythmia susceptibility. Verstraelen (2021)74 Human Clinical examination This study developed a new mutation-specific prediction model that improved risk stratification for primary prevention of ICD implantation by developing a new mutation-specific prediction model for malignant VA in PLN-R14del carriers. Te Rijdt (2021)75 Human Clinical trial: The PHOspholamban Related Cardiomyopathy Intervention Study (iPHORECAST) This study investigates if pre-emptive treatment of 42 presymptomatic PLN-R14del carriers using 50 mg eplerenone, can reduce disease progression and postpone the onset of overt disease. Haghighi (2021)76 Humanized Mouse Clinical examination, Pathological examination, functional readout, in vivo, ex vivo, rescue with drug Humanized PLN-R14del mice exhibited impairment of atrioventricular conduction, in association with VA, which appeared to originate from the right ventricle in vivo. KN93 reversed this proarrhythmic parameter. Koch (2021)77 n/a in silico, in vitro Mathematical modeling and preliminary analyses suggest that the PLN-R14del could impair noise filtering, offering a new perspective on how this mutation causes cardiac arrhythmias. Grote Beverborg (2021)78 Mouse Clinical examination, Pathological examination, functional readout, in vivo, ex vivo, gene silencing rescue Mice harboring the PLN-R14del pathogenic variant recapitulate the DCM phenotype; subcutaneous administration of PLN-ASO prevents PLN protein aggregation, cardiac dysfunction, and leads to a 3-fold increase in survival rate. Taha (2021)79 Human Clinical examination LVMD has incremental prognostic value on top of LVEF in PLN-R14del carriers, particularly in those with preserved LVEF. Eijgenraam (2021)80 Mouse Clinical examination, Pathological examination, functional readout, in vivo, ex vivo Progression of PLN-R14Δ/Δ mice was investigated by echocardiography, ECG, tissue analysis, and transcriptomics and proteomics in week 3, 4, and 5 of age. Van der Klooster (2021)81 Human Clinical Examination In 7.2% of cardiomyocytes from PLNR14del patients, homogeneously distributed p62 accumulation was present. De Brouwer (2021)82 Human Clinical Examination Analysis of 933 PLN-R14del patients showed that low-voltage ECGs predict sustained VA and are more common in females, yet the prognostic value is greater in males. Kamel (2021)83 Zebrafish Clinical examination, Pathological examination, functional readout, in vivo, ex vivo, rescue with drug Zebrafish harboring the PLN-R14del pathogenic variant recapitulate alterations of cardiac intracellular Ca2+ dynamics already at the embryonic stages. In the adult heart, PLN-R14del-CMs show alterations in APD, clear variations in cardiac output, and cardiac remodeling. Istaroxime enhances cardiac output.
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