Myocardial Performance Index and Atrial Ejection Force in Patients with Duchenne's Muscular Dystrophy

Shabanian, Reza; Aboozari, Mina; Kiani, Ali Asghar; Seifirad, Soroush; Zamani, Gholamreza; Nahalimoghaddam, Ali; Kocharian, Armen

doi:10.1111/j.1540-8175.2011.01515.x

Cited by 20 publications

(24 citation statements)

References 33 publications

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“…The right ventricle, with its small mass and potentially smaller lesion sizes may be underrepresented in these studies. It is important to note that there remains little difference in hemodynamic function between the right and left ventricles of the mdx mouse; similar results are seen in DMD patients (6,58). The failure to observe interventricular hemodynamic differences may result from the tight coupling of the ventricles, in that dysfunction of the right ventricle will lead to dysfunction of the left ventricle.…”

Section: Discussionsupporting

confidence: 66%

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Early right ventricular fibrosis and reduction in biventricular cardiac reserve in the dystrophin-deficient mdx heart

Meyers

Townsend

2015

American Journal of Physiology-Heart and Circulatory Physiology

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Duchenne muscular dystrophy (DMD) is a progressive disease of striated muscle deterioration. Respiratory and cardiac muscle dysfunction are particularly clinically relevant because they result in the leading causes of death in DMD patients. Despite the clinical and physiological significance of these systems, little has been done to understand the cardiorespiratory interaction in DMD. We show here that prior to the onset of global cardiac dysfunction, dystrophin-deficient mdx mice have increased cardiac fibrosis with the right ventricle being particularly affected. Using a novel biventricular cardiac catheterization technique coupled with cardiac stress testing, we demonstrate that both the right and left ventricles have significant reductions in both systolic and diastolic function in response to dobutamine. Unstimulated cardiac function is relatively normal except for a significant reduction in the ventricular pressure transient duration compared with controls. These biventricular analyses also reveal the absence of a dobutamine-induced increase in isovolumic relaxation in the right ventricle of control hearts. Simultaneous assessment of biventricular pressure demonstrates a dobutamine-dependent enhancement of coupling between the ventricles in control mice, which is absent in mdx mice. Furthermore, studies probing the passive-extension properties of the left ventricle demonstrate that the mdx heart is significantly more compliant compared with age-matched C57BL/10 hearts, which have an age-dependent stiffening that is completely absent from dystrophic hearts. These new results indicate that right ventricular fibrosis is an early indicator of the development of dystrophic cardiomyopathy, suggesting a mechanism by which respiratory insufficiency may accelerate the development of heart failure in DMD.

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Section: Discussionsupporting

confidence: 66%

“…6). Interest- ingly, a similar shortening of the ejection period has been observed using tissue Doppler echocardiography in DMD patients (58). This shortened pressure transient is also present in younger mdx mice, suggesting that it is not related to the progression of dystrophic cardiac disease.…”

Section: Discussionmentioning

confidence: 63%

Early right ventricular fibrosis and reduction in biventricular cardiac reserve in the dystrophin-deficient mdx heart

Meyers

Townsend

2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…Shabanian et al also found increased mitral A wave velocities, decreased mitral E wave velocities, and decreased TDI lateral peak E wave velocities in patients with DMD. [22] Furthermore, we observed a good correlation between readers for PWD mitral E wave measures (ICC=0.82), PWD mitral A wave velocities (ICC=0.63) and TDI lateral LV peak E’ velocities (ICC=0.72). These results demonstrate that conventional measures of diastolic function are easy to obtain and can detect early changes in myocardial function during longitudinal studies in young children with DMD.…”

Section: Discussionmentioning

confidence: 61%

“…[33] Previous studies showed that MPI was increased in participants with MD who demonstrated normal cardiac function by systolic measures. [11, 22, 34, 35] We therefore looked at the utility of MPI as an early marker of cardiac dysfunction in our DMD cohort. PWD MPI detected subclinical disease in more subjects than TDI.…”

Section: Discussionmentioning

confidence: 99%

Feasibility and Reproducibility of Echocardiographic Measures in Children with Muscular Dystrophies

Spurney

McCaffrey

Cnaan

et al. 2015

Journal of the American Society of Echocardiography

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Background Cardiac disease is a major cause of death in muscular dystrophies. The use of feasible and reproducible echocardiographic measures of cardiac function is critical to advance the field of therapeutics for dystrophic cardiomyopathy. Methods Participants aged 8 to 18 years with genetically confirmed Duchenne (DMD), Becker (BMD) or limb girdle (LGMD) muscular dystrophies were enrolled at five centers and a standardized echocardiogram (echo) was performed. Measures of systolic and diastolic function and speckle tracking echo (STE) derived cardiac strain were reviewed independently by two central readers. Furthermore, echo measures from DMD participants were compared to retrospective aged matched controls from a single site to assess measures of myocardial function. Results 48 participants (mean age of 13.3±2.7 years) were enrolled. Shortening fraction (SF%) had a greater inter-observer correlation (intra-class correlation coefficient; ICC=0.63) compared to ejection fraction (EF%; ICC=0.49). One reader could only measure EF% in 53% of participants. Myocardial performance index (MPI) measured by pulse wave Doppler and tissue Doppler imaging showed similar ICCs (0.55 and 0.54). STE showed a high ICC (0.96). Focusing on DMD participants (n=33), significantly increased mitral A wave velocities, lower E/A ratios and lower TDI mitral lateral E’ velocities were observed compared to age matched controls. STE demonstrated subclinical myocardial dysfunction with decreased average circumferential and longitudinal strain in 3 distinct subgroups: DMD participants with normal SF%; DMD participants with age <13 years; and DMD participants with MPI<0.40 compared to controls. Conclusions In a muscular dystrophy cohort, assessment of cardiac function is feasible and reproducible using SF%, diastolic measures and MPI. Cardiac strain measures identified early myocardial disease in DMD.

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“…Loss of dystrophin causes widespread effects on muscle signaling and metabolic pathways, leading to cell death and progressive replacement of functional muscle fibers with fibrotic connective tissue. This process results in profound muscle weakness, usually leaving DMD boys wheelchair-bound by their early teenage years and leading to death from the consequences of respiratory and/or cardiac muscle failure by age [20][21][22][23][24][25][26][27][28][29][30]. Current treatments, such as corticosteroids, slow disease progression only marginally (1), whereas gene-based approaches, such as exonskipping, although promising in preclinical studies, will need to overcome many technical and regulatory hurdles, as well becoming affordable, before they are a widely available therapy for DMD patients (2).…”

mentioning

confidence: 99%

A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy

Whitehead

Kim

Bible

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

142

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Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to nearnormal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases.statin | muscular dystrophy | fibrosis | inflammation | muscle force D uchenne muscular dystrophy (DMD) is a degenerative muscle disease caused by the absence of dystrophin, a large protein that links the cytoskeleton to the surface membrane in muscle cells. Loss of dystrophin causes widespread effects on muscle signaling and metabolic pathways, leading to cell death and progressive replacement of functional muscle fibers with fibrotic connective tissue. This process results in profound muscle weakness, usually leaving DMD boys wheelchair-bound by their early teenage years and leading to death from the consequences of respiratory and/or cardiac muscle failure by age 20-30. Current treatments, such as corticosteroids, slow disease progression only marginally (1), whereas gene-based approaches, such as exonskipping, although promising in preclinical studies, will need to overcome many technical and regulatory hurdles, as well becoming affordable, before they are a widely available therapy for DMD patients (2). Therefore, efficacious pharmaceutical agents that are cost-effective and already approved for human use are particularly attractive candidates for the current treatment of DM...

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Myocardial Performance Index and Atrial Ejection Force in Patients with Duchenne's Muscular Dystrophy

Cited by 20 publications

References 33 publications

Early right ventricular fibrosis and reduction in biventricular cardiac reserve in the dystrophin-deficient mdx heart

Early right ventricular fibrosis and reduction in biventricular cardiac reserve in the dystrophin-deficient mdx heart

Feasibility and Reproducibility of Echocardiographic Measures in Children with Muscular Dystrophies

A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy

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