Calmodulin kinase II inhibition protects against structural heart disease

β-Adrenergic receptor (βAR) stimulation increases cytosolic Ca²⁺ to physiologically augment cardiac contraction, whereas excessive βAR activation causes adverse cardiac remodeling, including myocardial hypertrophy, dilation and dysfunction, in individuals with myocardial infarction. The Ca²⁺-calmodulin-dependent protein kinase II (CaMKII) is a recently identified downstream element of the βAR-initiated signaling cascade that is linked to pathological myocardial remodeling and to regulation of key proteins involved in cardiac excitation-contraction coupling. We developed a genetic mouse model of cardiac CaMKII inhibition to test the role of CaMKII in βAR signaling in vivo. Here we show CaMKII inhibition substantially prevented maladaptive remodeling from excessive βAR stimulation and myocardial infarction, and induced balanced changes in excitation-contraction coupling that preserved baseline and βAR-stimulated physiological increases in cardiac function. These findings mark CaMKII as a determinant of clinically important heart disease phenotypes, and suggest CaMKII inhibition can be a highly selective approach for targeting adverse myocardial remodeling linked to βAR signaling.