In a “two-hit” mouse model for heart failure with preserved ejection fraction, the combination of a high-fat diet and inhibition of NOS (N-nitro-L-arginine methyl ester) reduced unfolded protein response effector X-box-binding protein 1 in the heart and increased iNOS activity that were critical for the resultant diastolic dysfunction (Schiattarella et al., 2019). Here, XBP1 is linked to heart failure.