P6348Phospholamban antisense oligonucleotides drive the reversal of cardiac dysfunction and multiple heart failure parameters during murine dilated cardiomyopathy

• Published in: European heart journal 2019-10, Vol.40 (Supplement_1)
• Main Authors: Spaeter, D, Hidalgo Gonzalez, A, Elbeck, Z, Yeh, S T, Siga, H, Damle, S S, Palmer, M, Kuo, C, Wang, Q D, Chien, K R, Fritsche-Danielson, R, Hansson, K, Mullick, A E, Knoell, R
• Format: Article
• Language: English
• ISSN: 0195-668X; 1522-9645
• DOI: 10.1093/eurheartj/ehz746.0944

Abstract Background Mice lacking muscle LIM protein (Mlp/Cspr3 −/−) develop dilated cardiomyopathy (DCM). Previous work established this model to be amenable to improvements in cardiac function by genetic ablation of phospholamban (PLN). Purpose To test the hypothesis that therapeutic reductions of PLN would similarly improve cardiac function, Mlp KO mice were administered an antisense oligonucleotide (ASO) targeting PLN. Methods Echocardiography measurements of ejection fraction (EF), end-diastolic volume (EDV) and end-systolic volume (ESV) were performed before and after treatment. In addition, global transcriptome profiling using 3'RNA-seq was performed to identify gene expression changes in diseased Mlp KO mice and following PLN ASO treatments. Mlp KO mice with ejection fraction (EF%) of less than 45% (median, 37.6%; interquartile range, 32.2–42.0%) were treated with vehicle (n=10) or PLN ASO (n=9) for 4 weeks. Results Three subcutaneous injections of PLN ASO were administered to Mlp KO mice resulting in 50–70% PLN reductions. Echocardiography performed at study end revealed improvements of EF (60±8 vs. 46±12%), ESV (31±11 vs. 56±21μl) and EDV (79±22 vs. 100±25μl) with PLN ASO treatment. Corrected for baseline values, PLN ASO treatment improved all echocardiographic measurements (p