<p>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. A heterozygous PLN-R14del mouse model (R14^Δ/+) was used to investigate whether cardiac pressure induced by transverse aortic constriction (TAC), could accelerate disease onset.</p><p>Wild-type littermates and sham operated animals were used as controls. surgery. At 6-weeks, both TAC groups exhibited increased in left ventricular wall thickness, ventricular and atrial weights, and reduced ejection fraction, with 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, TAC did not induce sarco-endoplasmic reticulum malformation in R14^Δ/+ mice, suggesting that general cardiac stress and remodeling pathways are insufficient to trigger PLN-R14del cardiomyopathy .</p><p>In conclusion, TAC induced pressure overload provoked robust cardiac remodeling with activation of common stress pathways in young adult WT and R14^Δ/+ mice. It did not trigger PLN-R14del-specific sarco-endoplasmic malformation or accelerate disease progression. These findings imply that activation of common cardiac stress pathways alone may be insufficient to accelerate the onset of PLN-R14del cardiomyopathy in early adulthood.</p>