In this study, we introduced the human Notch2 intracellular domain (hN2ICD) into mouse cardiomyocytes (CMs) to model the cardiac defects in patients with HCS and found that overexpression of hN2ICD in cardiomyocytes led to cardiac hypertrophy and left ventricular diastolic dysfunction with preserved ejection fraction (EF) in mice, resembling heart failure with preserved ejection fraction (HFpEF) in humans. The gene discussed is NOTCH2; the disease is heart failure.