In conclusion, cardiac hypertrophy/heart failure induced by pressure overload is caused by ROS-mediated destabilization of RyR2 (defective inter-domain interaction→CaM dissociation→Ca2+ leakage), and by increasing the binding affinity of CaM to RyR2 pharmacologically or genetically, the abnormal pathways leading to hypertrophy are inhibited, thereby suppressing the progression to heart failure. Here, RYR2 is linked to heart failure.