Early Treatment With Lisinopril and Spironolactone Preserves Cardiac and Skeletal Muscle in Duchenne Muscular Dystrophy Mice

Abstract

Background Nearly-universal cardiomyopathy in Duchenne muscular dystrophy (DMD) contributes to heart failure and death. As DMD patients show myocardial fibrosis well before functional impairment, we postulated that earlier treatment using drugs with anti-fibrotic effect may be beneficial. Methods and Results Three groups of 10 utrn+/−;mdx or “het” mice with skeletal myopathy and cardiomyopathy that closely mimics clinical DMD were studied. One het group received spironolactone and lisinopril starting at 8 weeks-of-life (het-treated-8), a second received the same starting at 4 weeks-of-life (het-treated-4), and the third het group was untreated. At 20 weeks, all mice had normal EFs though circumferential strain rate was abnormal (−0.21±0.08) in untreated hets. This improved to −0.40±0.07 in het-treated-8 mice (p=0.003), and further improved to −0.56±0.10 in het-treated-4 mice (p=0.014 for het-treated-4 vs. het-treated-8). Treated mice showed less cardiomyocyte damage, with a 44% reduction in intra-cardiomyocyte serum IgG localization in het-treated-8 mice (p<0.0001), and further 53% reduction in het-treated-4 mice (p=0.0003 vs. het-treated-8); matrix metalloproteinases were similarly reduced. Cardiac, limb and diaphragm function by ex vivo muscle testing remained at 80% of normal with early treatment compared to a decline to 40% of normal skeletal muscle function without treatment. Conclusions These findings offer clinically-available medications with proven anti-fibrotic effect as a new therapeutic strategy in DMD. Early initiation greatly attenuated myocardial disease and, for the first time with these drugs, improved skeletal myopathy. Thus, early initiation of such agents warrants further clinical evaluation to maintain ambulatory, respiratory and cardiac function for DMD and related myopathies.

Myocardial Deformation Imaging

“…21,22 The sensitivity of these measures to alterations in deformation has resulted in their application, in both animal and human studies, to a variety of pathological conditions characterized by myocardial dysfunction despite preserved EF, including asymptomatic carriers of hypertrophic cardiomyopathy sarcomeric mutations, 23 Fabry's disease, 24 myocardial steatosis, 25,26 and rodent models of Duchenne muscular dystrophy. 27 Perhaps because of their less load-dependent nature, these measures have also proven informative in the setting of valvular heart disease in which alterations in loading conditions make EF a less reliable measure of contractile function, including severe aortic stenosis, 28 aortic regurgitation, 29 and mitral regurgitation. 30 In the case of coronary disease, global strain values obtained early after an acute myocardial infarction may effectively predict subsequent remodeling and functional recovery.…”

Arquitetura comparativa dos pulmões de camundongos normais e afetados pela Distrofia Muscular de Duchenne

“…Considerando que este modelo pré-clínico atualmente, vem sendo utilizado em diversos experimentos que abordam a melhora da função respiratória (Huang et al 2011, Rafael-Fortney et al 2011, Van Putten et al 2012) o estudo da morfologia comparativa histológica e ultraestrutural dos pulmões de mdx por meio da microscopia de luz e eletrônica de varredura e a comparação com animais BALB/ C57 (Mus musculus) tem o objetivo de aprimorar a interpretação e comparação de dados publicados além de identificar possíveis diferenças entre estes dois modelos. Para a microscopia eletrônica de varredura (MEV), adaptou--se a metodologia descrita por Lessa et al 2012 para o processamento dos pulmões.…”

Laparoscopic guided local injection in the X-linked muscular dystrophy mouse (mdx) diaphragm. An advance in experimental therapies for Duchenne Muscular Dystrophy

“…In recent years, the diaphragm muscle has been widely approached in the DMD studies [5][6][7] which demonstrate the concern of researchers in obtaining data about this muscle.…”

“…Considering these respiratory complications, several experimental therapies are being performed to improve the respiratory conditions DMD patients [5][6][7] , evidencing the importance of developing new techniques and advances to resources for experimental therapies, e.g pharmacological and stem cells. Since it extend the resources of DMD respiratory muscles intervention, the chances of these patients maintain their activities of daily living without the use of noninvasive ventilatory resources and patient survival increases.…”