Cardiac remodeling pathways do not accelerate disease onset and severity in a mouse model of PLN-R14del cardiomyopathy

Background: PLN-R14del is a pathogenic Phospholamban (PLN) gene variant, characterized by ventricular arrhythmias and dilated cardiomyopathy in heterozygous carriers. Disease development is highly heterogeneous, indicating involvement of additional disease triggers, influencing both the onset and severity of the disease. Here, a heterozygous PLN-R14del mouse model (R14 ^Δ/+ ) with late-onset disease was used to investigate whether cardiac pressure overload induced stress, could accelerate disease onset. Methods and results: Transverse aortic constriction (TAC) was used to apply pressure overload to the heart of 10-week-old R14 ^Δ/+ mice and wild-type (WT) littermates. Sham operated animals were used as controls. Cardiac echocardiography was conducted prior to surgery and 6 weeks after TAC induction. Left ventricle (LV) wall thickness and ventricle and atria weight were strongly elevated 6-week after TAC surgery in both groups. Accompanied by changes in LV function, including a reduction in ejection fraction. There was, however, no difference between the WT and R14 ^Δ/+ groups. Both TAC groups developed comparable hypertrophic and fibrotic responses. Furthermore, differential gene expression showed comparable activation of cardiac remodeling and stress pathways, and changes in metabolic genes expression. Importantly, no induction of sarco-endoplasmic malformation was observed in R14 ^Δ/+ mice after TAC. Suggesting that activation of general cardiac stress and remodeling pathways do not act as disease triggers. Conclusion: Cardiac stress, induced by pressure overload, provoked robust cardiac remodeling with activation of common stress pathways. However, it did not induce PLN-R14del-specific sarco-endoplasmic malformation or accelerate disease progression, indicating that common cardiac stress pathways do not serve as triggers for PLN-R14del cardiomyopathy.