172 Chapter 7 Table 2: Systematic table including all treatment strategies performed and outcomes. Studies are sorted based on the mechanism of action. Therapy Strategy Target Executed study Positive outcome Disadvantages ref Current treatments ICD Arrhythmias Executed in 46% of DCM-PLN-R14del patients. Reduces the risk of deadly arrhythmias. up to 120 months.210 211,212 LVAD LV Executed in 30% of PLN patients. Bridge to transplantation or as an alternative for destination therapy. Therapy is still associated with substantial morbidity. 213 HTx Whole heart Executed in 18% of the DCM-PLNR14del patients. Most optimal treatment strategy up till now. Not many hearts are available. 214 Calcium regulation strategies Istraoxime SERCA2a activator Tested in PLNR14del zebrafish embryos and isolated adult CMs. Ameliorates the in vivo Ca2+ dysregulation and improves cardiac relaxation. Plasma half-life of less than 1 hour, intravenous injections required. Acceleration of Ca2+ uptake has been shown to promote arrhythmias.215 216 PST3093 “Selective” SERCA2a activator PLN-R14del mouse and hiPSC-CMs PST3093 affects Ca2+ dynamics parameters in PLN-R14del corrected CMs. WT only responded and tended to convert the corrected pattern into the R14del phenotype. 103,217 KN93 CaMKII inhibitor PLN-R14del Mouse quiescent LV and RV myocytes. KN93 reversed the proarrhythmic phenotype. Compensatory expression of key genes associated with Ca2+- cycling. Interacts but to inhibit CaMKII specifically, the more affinized compound is necessary.218 219 Parvalbumin- encoding virus Ca2+-binding protein PLN-R14del hiPSCCMs and EHTs. UPR expression was reduced and led to dynamic alterations within the ER-mitochondrial compartment. No force restoration. A large fraction of the expressed parvalbumin resided in the nucleus. 220 GCaMP6f -encoding virus Ca2+-buffering protein PLN-R14del hiPSCCMs and EHTs. Improved contractile force and mitochondria number. Reduction of UPR expression, dynamic alterations within the ERmitochondrial compartment. No difference in Ca2+ transient amplitude was detected. 221 Metoprolol β-blocker PLN-R14del Mouse Metoprolol significantly (p < 0.05) decreased heart rate. No increase in the survival rate. 222 DWORF SERCA activator PLN-R14del Mouse Overexpression delayed cardiac fibrosis, heart failure and increased life span >2-fold. DWORF did not improve calcium handling, possibly due to enhanced calcium reuptake in R14del mice. 108 Contractility modulation Omecamtiv mecarbil selective cardiac myosin activator Humanized PLNR14del mice Study found that the depressive contractile effects were prevented without affecting Ca2+ homeostasis. Induces continuous activation of resting myosin ATPase and increases myocardial oxygen consumption. 99
RkJQdWJsaXNoZXIy MTk4NDMw