Combined Right Ventricular Preload and Afterload Challenge Induces Contractile Dysfunction and Ventricular Arrhythmia in an Age-dependent Manner in Isolated Hearts of Dystrophin-deficient Mice

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked recessive myopathy due to mutations in the dystrophin gene. Diaphragmatic weakness in DMD causes restrictive lung disease and excessive afterload on the right ventricle (RV). Thus, RV dysfunction in DMD develops early in disease progression. Herein, we deliver a 30-minute sustained RV preload and afterload challenge to isolated hearts of wildtype (Wt) and dystrophic (mdx4CV) mice at both young (2-6 month) and middle-age (8-12 month). Young dystrophic hearts exhibited greater pressure development than wildtype under unloaded conditions but following RV preload/afterload challenge exhibited similar contractile function as wildtype. Following RV preload/afterload challenge, young dystrophic hearts had an increased incidence of ventricular arrhythmias compared to wildtype. Hearts of middle-aged wildtype and dystrophic mice had similar contractile function during unloaded conditions, yet, after RV preload/afterload challenge, hearts of middle-aged dystrophic mice had severe RV contractile dysfunction and ventricular arrhythmogenesis, including ventricular tachycardia. Following load challenge, young and middle-aged dystrophic hearts had greater damage, measured via tissue LDH release, than wildtype mice of similar age. Our data indicate complex age-dependent changes in RV function and arrhythmogenesis with load in dystrophin deficiency, highlighting the need to avoid sustained RV load to forestall RV dysfunction and arrhythmia.