Background: Titin is a giant protein spanning half of the sarcomere from Z-disk to M-band and acts as a molecular spring and mechanosensor in striated muscles. Cardiac titin contains a unique N2B region, which has been proposed to modulate elasticity of the titin filament and hypertrophy signaling. Knockout (KO) mice with a global N2B deletion had cardiac atrophy and diastolic dysfunction. However, the role of cardiomyocyte N2B in cardiac remodeling following stress is unknown.

Aim: To understand the contribution of cardiomyocyte N2B to cardiac remodeling in response to hemodynamic stress.

Methods:  We generated a tamoxifen‐inducible cardiomyocyte‐specific N2B-KO mouse line deleting only the N2B segment (exon 49) of titin. The mice were then challenged with transverse aortic constriction (TAC) to trigger pressure overload (PO) or aortocaval shunt to induce volume overload (VO).

Results: Tamoxifen-induced postnatal depletion of N2B in cardiomyocytes resulted in mild cardiac atrophy at baseline but with preserved systolic and diastolic function. However, we found that the N2B-KO mice displayed less cardiac dilatation after short-term shunt and to lesser extent after short-term TAC. This was associated with the re-expression of cardiac fetal genes (Nppa, Nppb and Myh7), marked apoptosis and ultimately resulted in increased mortality. However, contrary to their short-term detrimental phenotype, N2B-KO mice showed no significant effects on cardiac hypertrophic responses and hemodynamics during chronic hemodynamic overload after shunt and TAC, as assessed by echocardiographic, gravimentric, histological and molecular analyses.

Conclusions: These findings indicates a critical role for the N2B region of titin in maintaining the cardiac adaptation to short-term hemodynamic overload.