ArticleCirculation research2016
Alternative Splicing of Titin Restores Diastolic Function in an HFpEF-Like Genetic Murine Model (TtnΔIAjxn).
Article in Circulation research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 40 citations in OpenAlex.
- Adjunctive nebulization of Idursulfase to intravenous treatment enhances cardiac proteome adaptations in IDS-KO mice.bioRxiv : the preprint server for biology · 2026Article
- The clinical pathophysiology of atrial fibrillation: outstanding questions from bedside to bench and back.Physiological reviews · 2026Review
- Mending the Achilles heels of titin in cardiac and musculoskeletal disease.Biophysical reviews · 2026Review
- Pathogenesis and Therapeutic Advances in Heart Failure with Preserved Ejection Fraction.Reviews in cardiovascular medicine · 2026Review
- In vitro approaches to mimic cardiac mechanical load dynamics for enhancing maturation and disease modelling.Cardiovascular research · 2025Review
- Atrial cardiomyopathy: From healthy atria to atrial failure. A clinical consensus statement of the Heart Failure Association of the ESC.European journal of heart failure · 2025Article
- What Is Cardiometabolic HFpEF and How Can We Study it Preclinically?JACC. Basic to translational science · 2025Review
- Unlocking the secrets of Cardiac development and function: the critical role of FHL2.Molecular and cellular biochemistry · 2025Review
- Management of Left Atrial Tachyrhythms in the Setting of HFpEF with Pulsed-Field Ablation: Treating Fire with Water?Therapeutics · 2024Article
- Chronic circadian rhythm disorder induces heart failure with preserved ejection fraction-like phenotype through the Clock-sGC-cGMP-PKG1 signaling pathway.Scientific reports · 2024Article
- Myofilament dysfunction in diastolic heart failure.Heart failure reviews · 2024Review
- Cardiac splicing as a diagnostic and therapeutic target.Nature reviews. Cardiology · 2023Review
- Titin (TTN): from molecule to modifications, mechanics, and medical significance.Cardiovascular research · 2022Review
- Article
- Current Understanding of Molecular Pathophysiology of Heart Failure With Preserved Ejection Fraction.Frontiers in physiology · 2022Review
- RBM20, a Therapeutic Target to Alleviate Myocardial StiffnessFrontiers in cardiovascular medicine · 2022Review
- The titin N2B and N2A regions: biomechanical and metabolic signaling hubs in cross-striated muscles.Biophysical reviews · 2021Review
- Review
- From Systemic Inflammation to Myocardial Fibrosis: The Heart Failure With Preserved Ejection Fraction Paradigm Revisited.Circulation research · 2021Review
- New Insights in RBM20 Cardiomyopathy.Current heart failure reports · 2020Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
rationalePatients with heart failure with preserved ejection fraction (HFpEF) experience elevated filling pressures and reduced ventricular compliance. The splicing factor RNA-binding motif 20 (RBM20) regulates the contour length of titin's spring region and thereby determines the passive stiffness of cardiomyocytes. Inhibition of RBM20 leads to super compliant titin isoforms (N2BAsc) that reduce passive stiffness.
objectiveTo determine the therapeutic potential of upregulating compliant titin isoforms in an HFpEF-like state in the mouse. METHODS AND
resultsConstitutive and inducible cardiomyocyte-specific RBM20-inhibited mice were produced on a Ttn(ΔIAjxn) background to assess the effect of upregulating compliant titin at the cellular and organ levels. Genetic deletion of the I-band-A-band junction (IAjxn) in titin increases strain on the spring region and causes a HFpEF-like syndrome in the mouse without pharmacological or surgical intervention. The increased strain represents a mechanical analog of deranged post-translational modification of titin that results in increased passive myocardial stiffness in patients with HFpEF. On inhibition of RBM20 in Ttn(ΔIAjxn) mice, compliant titin isoforms were expressed, diastolic function was normalized, exercise performance was improved, and pathological hypertrophy was attenuated.
conclusionsWe report for the first time a benefit from upregulating compliant titin isoforms in a murine model with HFpEF-like symptoms. Constitutive and inducible RBM20 inhibition improves diastolic function resulting in greater tolerance to exercise. No effective therapies exists for treating this pervasive syndrome; therefore, our data on RBM20 inhibition are clinically significant.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.