In this study, we demonstrated that RBMS1 is critical for pathological cardiac hypertrophy, for the following reasons: (1) Overexpression of RBMS1 aggravated cardiac hypertrophy via disorganizing the sarcomere and cytoskeleton of cardiomyocyte in response to hypertrophy surgery; (2) The hazardous function of RBMS1 on pathological cardiac hypertrophy relied on alternative splicing of CTTN to active PI3K/AKT pathway; (3) Nortriptyline significantly improved cardiac function and alleviated pathological cardiac hypertrophy. This evidence concerns the gene CTTN and cardiac hypertrophy.