If delving very deep into the structures that support flexibility and elasticity in tissues, one eventually arrives at specific proteins incorporated into cells and the extracellular matrix that act as springs or similar mechanical systems. Researchers here note that one such spring protein in heart muscle, known as titin, exhibits an increased proportion of less elastic isoforms in the context of heart failure. This makes heart muscle stiffer, and the heart less able to pump blood. Adjusting the regulation of isoform proportions to favor the more elastic isoforms can be achieved by inhibiting another specific protein, RBM20. The result is more elastic heart tissue and reduced pathology of heart failure.
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. Addressing the mechanical aspects of cardiac dysfunction at the level of myofilaments provides a direct approach to improve diastolic performance across diverse HFpEF phenotypes.
Titin is a giant myofilament protein and functions as a molecular spring, which generates passive force when sarcomeres are stretched, thereby aiding in returning the sarcomere to its resting length. Titin contributes up to ∼70% of left ventricular (LV) physiological passive stiffness. In HFpEF, increased titin stiffness has been identified as a key pathological factor contributing to LV diastolic dysfunction in human and animal models.
In the adult heart, there are two main isoforms of titin: N2B and N2BA, with the N2B isoform being the stiffest. RNA binding motif-20 (RBM20) is a major splicing regulator that determines isoform expression of titin. Complete inhibition of Rbm20 activity leads to the expression of N2BA-G titin, which is very long and highly compliant. Mice expressing N2BA-G titin exhibit reduced LV chamber stiffness and attenuated systolic contractility. Meanwhile, partial inhibition of RBM20 activity results in the expression of N2BA-N titins, which are larger than the N2BA but not as large as the N2BA-G isoform. Mice expressing N2BA-N titins show reduced LV chamber stiffness while maintaining normal baseline systolic function and enhanced exercise tolerance.
Inhibition of RBM20 using antisense oligonucleotides (ASOs) induces expression of compliant titin isoforms. 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.
Link: https://doi.org/10.1093/cvr/cvaf171
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