# Rbm20 antisense oligonucleotides alleviate diastolic dysfunction in a mouse model of cardiometabolic heart failure (HFpEF)

## TL;DR

Scientists used antisense oligonucleotides to reduce heart stiffness in a mouse model of heart failure with preserved ejection fraction, improving diastolic function.

## Contribution

Partial inhibition of RBM20 with ASOs improved diastolic function in a cardiometabolic HFpEF model without primary titin defects.

## Key findings

- Partial RBM20 inhibition increased compliant titin isoforms and improved diastolic function.
- RBM20-ASOs reduced left ventricular stiffness and cardiac hypertrophy in mice with metabolic syndrome.
- The treatment preserved systolic performance despite ongoing systemic comorbidities.

## Abstract

Heart failure with preserved ejection fraction (HFpEF) is prevalent, deadly, and difficult to treat. Risk factors such as obesity and hypertension contribute to cardiac inflammation, metabolic defects, and pathological remodelling that impair ventricular filling in diastole. Titin based stiffness is a main determinant of diastolic function and can be adjusted by the splicing regulator RNA binding motif protein 20 (RBM20). Inhibition of RBM20 using antisense oligonucleotides (ASOs) induces expression of compliant titin isoforms, which reduce stiffness. However, dose finding and documenting utility in primarily cardiometabolic disease remains challenging.

Here, we optimized RBM20-ASO dosing in a HFpEF mouse model that closely mimics human disease, characterized by metabolic syndrome and comorbidities, but without primary defects in titin or RBM20. Partial inhibition of RBM20 (∼50%) selectively increased compliant titin isoforms, improving diastolic function while preserving systolic performance. This intervention reduced left ventricular stiffness, enhanced relaxation, and mitigated cardiac hypertrophy, despite ongoing systemic comorbidities.

Our findings demonstrate that targeting titin stiffness with Rbm20-ASOs can serve as an alternative or adjunctive therapeutic strategy for HFpEF to restore cardiac function and prevent further organ damage. The approach may offer benefits even in the presence of phenotypic heterogeneity and unresolved systemic comorbidities.

Graphical Abstract