What is the clinical evidence from this study?

Study design: Other. Population: RBM20 cardiomyopathy. Intervention: Genetic deletion of Camk2d or hesperadin vs. Wild-type or vehicle-treated mice. Primary outcome: Mortality within 24 hours after arrhythmia induction (p=0.007).

What question did this study set out to answer?

This research aims to determine the role of CAMK2D in the pathogenesis of RBM20-related cardiomyopathy and its implications for treatment.

May 7, 2026Nature Cardiovascular Research0 citationsOpen Access

CAMK2D causes heart failure in mice with RBM20 cardiomyopathy

MHMaarten M. G. van den Hoogenhof JDJavier Duran TBThiago Britto-Borges

Key Result

In mouse models of RBM20 cardiomyopathy, genetic deletion of Camk2d or pharmacological inhibition with hesperadin improved cardiac function and reduced mortality after arrhythmia induction.

Key Points

This research aims to determine the role of CAMK2D in the pathogenesis of RBM20-related cardiomyopathy and its implications for treatment.
Used Rbm20/Camk2d double knockout mice to study heart failure and cardiac function.
Investigated the effects of CAMK2D splice variants and inhibition on cardiac dysfunction.
Administered ATP-competitive CAMK2 inhibitor hesperadin in Rbm20-p.Arg636Gln knockin mice.
Double knockout mice showed protection from heart failure and reduced risk of sudden cardiac death.
Increased phosphorylation of CAMK2D targets was observed in Rbm20-deficient hearts, indicating overactivation.
Hesperadin treatment resulted in improved cardiac function in Rbm20-p.Arg636Gln knockin mice.

Structured PICO

Does CAMK2D inhibition improve cardiac function and prevent sudden cardiac death in models of RBM20 cardiomyopathy?

Population

Mouse models of RBM20 cardiomyopathy (Rbm20 KO, Rbm20/Camk2d DKO, Rbm20-p.Arg636Gln KI, Rbm20-p.Pro635Leu KI) and human iPS cell-derived cardiomyocytes with RBM20 variants.

Intervention

Genetic deletion of Camk2d, AAV9-mediated reexpression of CAMK2D splice variants, or pharmacological inhibition with hesperadin (2.5 μg or 5 μg/kg for 4 weeks).

Comparator

Wild-type mice, Rbm20 KO mice, or vehicle (DMSO) treated mice.

Outcome

Cardiac function (ejection fraction, LVIDd, E/e') and survival after epinephrine/caffeine-induced arrhythmia.surrogate

CAMK2D overactivation, rather than mis-splicing alone, drives heart failure in RBM20 cardiomyopathy, making CAMK2D inhibition a promising therapeutic target.

Main Result

Absolute Event Rate: 37.5% vs 71%

p-value: p=0.007

Limitations

AAV-mediated overexpression cannot precisely be controlled and variations in the amount and mosaic patterns may limit the interpretation.
Hesperadin is not perfectly selective for CAMK2 and also inhibits other kinases such as Aurora kinase B, AMPK, Lck, MKK1, MAPKAP-K1, CHK1 and PHK.

Abstract

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.

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