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Myocardial Recovery With Mechanical Circulatory Support Is Linked to Alternative Splicing and Subcellular
Thomas G Martin1,2, Dakota R Hunt2,3, Christopher C Ebmeier3
1Department of Molecular, Cellular, and Developmental Biology (T.G.M., C.A., L.A.L.), University of Colorado Boulder.
Circulation
|January 5, 2026
Summary
Cardiac reverse remodeling after left ventricular assist device (LVAD) therapy is linked to RNA splicing changes. Specifically, altered CAMK2D splicing and phosphorylation predict poor outcomes, impacting cardiomyocyte function.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Regenerative Medicine
Background:
- Cardiac reverse remodeling, characterized by reduced ventricular dilation and improved systolic function, is observed in a subset of heart failure patients.
- Left ventricular assist device (LVAD) therapy is associated with the highest incidence of this phenomenon.
- Identifying therapeutic targets for reverse remodeling is crucial for improving patient outcomes and quality of life.
Purpose of the Study:
- To identify molecular signatures associated with myocardial recovery in patients receiving LVAD therapy.
- To investigate the role of alternative RNA splicing and protein phosphorylation in LVAD-induced cardiac functional recovery.
- To elucidate the mechanisms underlying differential responses to LVAD therapy.
Main Methods:
- Integrated analysis of bulk RNA sequencing, quantitative proteomics, and quantitative phosphoproteomics on paired pre- and post-LVAD heart samples from responders and nonresponders.
- Functional investigations using primary rat cardiomyocytes and human engineered heart tissues.
- Analysis of controls without heart failure for comparative insights.
Main Results:
- Alternative RNA splicing emerged as the leading pathway associated with favorable LVAD response, with responders showing increased splicing factor expression.
- CAMK2D alternative splicing, particularly the inclusion of exon 14 encoding the nuclear variant CAMK2D-B, was a strong predictor of recovery.
- Nonresponders exhibited hyperphosphorylation of CAMK2D-B near its nuclear localization signal, preventing nuclear targeting and impairing cardiomyocyte calcium handling.
Conclusions:
- This study provides the first integrated omics analysis of LVAD-induced myocardial recovery.
- Increased expression and phosphorylation of nuclear CAMK2D predicted poor outcomes due to impaired cardiomyocyte calcium handling.
- Therapeutic strategies targeting CAMK2D subcellular localization or activity may benefit LVAD nonresponder patients.
