Abstract 9504: Phosphodiesterase Modulation of Cardiomyopathy in Murine and Canine Models of Muscular Dystrophy Treated With Sildenafil and Tadalafil
Patients with Duchenne muscular dystrophy (DMD) suffer from a myriad of musculoskeletal, respiratory, and cardiac symptoms.Cardiomyopathy is the second most common cause of death in DMD patients. The development of cardiomyopathy in these patients is often insidious, but untreated, many patients progress to overt heart failure. Current therapies used to treat the cardiomyopathy of DMD have been poorly studied since many of the same medications are used empirically from patients with congestive heart failure, despite the different underlying mechanical causes of heart failure in DMD patients. Using a well-established murine model of DMD, we treated mdx mice with phosphodiesterase-5 (PDE-5) inhibitors (sildenafil or tadalafil) for a duration of 1 month and 8 months. Treatment response was measured by dobutamine stress echocardiography parameters, proteomic expression, and histologic studies. We saw an increase in protein kinase G (PKG) levels in the sildenafil and tadalafil treated mice hearts, afterboth 1 month and 8 months of treatment, which suggests that the PDE-5 inhibitors’ mechanism of action is active in the heart. This was accompanied by a low level of atrial natriuretic peptide in the treated hearts compared to the untreated hearts at 8 months. Our results suggest that PDE-5 inhibition modulates and down-regulates the pro-fibrotic and pro-inflammatory cascade in the dystrophic mdx heart through TGF beta and SMAD2/3 pathways in an ERK-independent manner. Moreover, in a canine study in which dogs affected with golden retriever muscular dystrophy were treated with one of these 2 drugs for one month, both PDE-5 inhibitors resulted in improved left ventricular strain as measured with cardiac magnetic resonance imaging. There are some differences between the effects of the two PDE-5 inhibitors which is likely attributable to differences in the potency and specificity of these two agents at PDE5 inhibition. Further studies will continue to elucidate the role of PDE-5 inhibitors in the treatment of the dilated cardiomyopathy of DMD. Supported by Parent Project Muscular Dystrophy
- © 2012 by American Heart Association, Inc.