CAMK2D causes heart failure in mice with RBM20 cardiomyopathy

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.