CAMK2D causes heart failure in mice with RBM20 cardiomyopathy.
G, v.d.H.M.M., Javier, D., Thiago, B.B., Vasco, S., Elena, K., Laura, K., Friederike, S., C, L.D., Joshua, H., Laura, S., Julia, K., Theresa, B., Marcus, K., Christoph, M., Christoph, D., M, S.L., Matthias, D., & Johannes, B. (2026). CAMK2D causes heart failure in mice with RBM20 cardiomyopathy.. Nat Cardiovasc Res. https://doi.org/10.1038/s44161-026-00818-2
G vdHMM, Javier D, Thiago BB, Vasco S, Elena K, Laura K, et al. CAMK2D causes heart failure in mice with RBM20 cardiomyopathy.. Nat Cardiovasc Res. 2026; doi: 10.1038/s44161-026-00818-2
G vdHMM, Javier D, Thiago BB, et al. CAMK2D causes heart failure in mice with RBM20 cardiomyopathy.[J]. Nat Cardiovasc Res. 2026. DOI: 10.1038/s44161-026-00818-2.
@article{g2026,
author = {van den Hoogenhof Maarten M G and Duran Javier and Britto-Borges Thiago and Sequeira Vasco and Kemmling Elena and Konrad Laura and Schreiter Friederike and Lennermann David C and Hartmann Joshua and Schraft Laura and Kornienko Julia and Bock Theresa and Krüger Marcus and Maack Christoph and Dieterich Christoph and Steinmetz Lars M and Dewenter Matthias and Backs Johannes},
title = {CAMK2D causes heart failure in mice with RBM20 cardiomyopathy.},
journal = {Nat Cardiovasc Res},
year = {2026},
doi = {10.1038/s44161-026-00818-2},
note = {PMID: 42082791},
}
TY - JOUR AU - van den Hoogenhof Maarten M G AU - Duran Javier AU - Britto-Borges Thiago AU - Sequeira Vasco AU - Kemmling Elena AU - Konrad Laura AU - Schreiter Friederike AU - Lennermann David C AU - Hartmann Joshua AU - Schraft Laura AU - Kornienko Julia AU - Bock Theresa AU - Krüger Marcus AU - Maack Christoph AU - Dieterich Christoph AU - Steinmetz Lars M AU - Dewenter Matthias AU - Backs Johannes TI - CAMK2D causes heart failure in mice with RBM20 cardiomyopathy. T2 - Nat Cardiovasc Res PY - 2026 DO - 10.1038/s44161-026-00818-2 AN - PMID:42082791 ER -
Although heart disease arises from different etiologies, treatment remains largely one-size-fits-all, leaving many patients without optimal benefit, which highlights the need for cause-directed therapies. Pathogenic variants in RBM20, a cardiac splicing factor, lead to an aggressive form of dilated cardiomyopathy with high risk of ventricular arrhythmias. We hypothesized that the splicing target calcium/calmodulin-dependent kinase II delta (CAMK2D) is disease causing in RBM20 cardiomyopathy. Here we show that Rbm20/Camk2d double knockout mice are protected from heart failure and sudden cardiac death. In Rbm20-deficient hearts, phosphorylation of CAMK2D targets was increased, indicating that RBM20 loss results not only in mis-splicing of Camk2d transcripts but also in functional activation of CAMK2D signaling. Reexpression of individual CAMK2D splice variants in Rbm20/Camk2d double knockout mice reintroduced cardiac dysfunction, demonstrating that overactivation, rather than mis-splicing, drives disease. Treatment of Rbm20-p.Arg636Gln knockin mice with the ATP-competitive CAMK2 inhibitor hesperadin improved cardiac function. These findings identify CAMK2D overactivation as a central mechanism in RBM20 cardiomyopathy and support CAMK2D inhibition as a promising cause-directed therapy.