RBM20 Antisense Oligonucleotides Alleviate Diastolic Dysfunction in a Mouse Model of HFpEF

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) is a disease that is associated with a problem in relaxation during
the diastolic phase and a higher level of ventricular stiffness. The pathway through which R BM20 in the heart facilitates dysregulated
RNA splicing also plays a role in expression of the stiff isoforms of titin, which leads to diastolic dysfunction. Specific stimulation of
RBM20 has become a likely future molecular therapy to recover myocardial compliance.
Hypothesis: The hypothesis was that RBM20 antisense oligonucleotides (ASOs) have the potential to enhance diastolic function in a
mouse model of HFpEF.
Procedure: Metabolichypertensive mouse model of HFpEF was subjected to four weeks of RBM20 specific ASOs treatment. The titin
isoform expression and fibrosis, inflammation, and cardiac function were evaluated by means of echocardiography, pressurevolume loop
analysis, exercise testing, and myocardial molecular assays as compared to untreated controls with HFpEF.
Findings: The treatment with RBM20 ASO brought about the shift of more compliant titin isoforms and decreased myocardial fibrosis
and inflammatory signaling. The treated mice had better relaxation parameters, reduced end-diastolic pressure of the left ventricles and
high exercise capacity functionally. Notably, the systolic function was spared, which means that the diastolic performance was selectively
improved.
Conclusion: RBM20 ASOs can be used successfully to mitigate the main symptoms of diastolic dysfunction in HFpEF mice by
regulating titin splicing and decreasing fibrotic remodeling. The research results suggest that RBM20-guided therapy is an effective
approach in the HFpEF and should be further translated into practical work.