Dataset Information

PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy.

ABSTRACT:

Objective

To determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD).

Methods

In 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated orthostatic stress, measured as the decrease in forearm muscle oxygenation with near-infrared spectroscopy, and performed when the forearm muscles were rested or lightly exercised with rhythmic handgrip exercise. Then, the patients underwent an open-label, dose-escalation, crossover trial with single oral doses of tadalafil or sildenafil.

Results

The major new findings are 2-fold: first, sympatholysis is impaired in boys with DMD-producing functional muscle ischemia-despite contemporary background therapy with corticosteroids alone or in combination with cardioprotective medication. Second, PDE5 inhibition with standard clinical doses of either tadalafil or sildenafil alleviates this ischemia in a dose-dependent manner. Furthermore, PDE5 inhibition also normalizes the exercise-induced increase in skeletal muscle blood flow (measured by Doppler ultrasound), which is markedly blunted in boys with DMD.

Conclusions

These data provide in-human proof of concept for PDE5 inhibition as a putative new therapeutic strategy for DMD.

Classification of evidence

This study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis.

SUBMITTER: Nelson MD

PROVIDER: S-EPMC4118495 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Publications

PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy.

Nelson Michael D MD Rader Florian F Tang Xiu X Tavyev Jane J Nelson Stanley F SF Miceli M Carrie MC Elashoff Robert M RM Sweeney H Lee HL Victor Ronald G RG

Neurology 20140507 23

<h4>Objective</h4>To determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD).<h4>Methods</h4>In 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated or ...[more]

PMID: 24808022

Similar Datasets

Project description:BackgroundInsights into the progression of muscle impairments in growing boys with Duchenne muscular dystrophy (DMD) remain incomplete due to the frequent oversight of normal maturation as a confounding factor, thereby restricting the delineation of sole pathological processes.ObjectiveTo establish longitudinal trajectories for a comprehensive integrated set of muscle impairments, including muscle weakness, contractures and muscle size alterations, while correcting for normal maturation, in DMD.MethodsThirty-three boys with DMD (aged 4.3-17 years) were included. Fixed dynamometry, goniometry, and 3D freehand ultrasound were used to repeatedly assess lower limb muscle strength, passive range of motion (ROM) and muscle size, resulting in 161, 178 and 64 assessments for the strength, ROM and ultrasound dataset, respectively. To account for natural strength development, ROM reduction, and muscle growth in growing children, muscle outcomes were converted to unit-less z-scores calculated in reference to typically developing (TD) peers. This allows the interpretation of the muscle outcomes as deficits or alterations with respect to TD. Mixed-effect models estimated the longitudinal change in muscle impairments.ResultsAt 4.3-4.9 years of age, all muscle strength outcomes and several ROMs (i.e., dorsiflexion, hamstrings, and hip extension) showed deficits relative to TD, while m. medial gastrocnemius size was increased. Most muscle outcomes remained stable or slightly improved until the ages of 6.6-9.4 years (except knee flexion strength). After this period, muscle strength (-0.27 to -0.45 z-score/year; p < 0.0044), dorsiflexion ROM (-0.23 to -0.33 z-score/year; p < 0.0007), m. medial gastrocnemius size (-0.56 z-score/year; p = 0.0022), and m. rectus femoris size (-0.36 z-score/year; p = 0.0054) declined.ConclusionsThe current study established longitudinal trajectories of muscle impairments in boys with DMD. The results provided enriched history data and revealed promising outcome measures that could enhance the detection of the efficacy of novel therapeutic strategies. Future studies are necessary to validate these outcomes.

Dataset Information

PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy.

Objective

Methods

Results

Conclusions

Classification of evidence

Publications

PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy.

Similar Datasets

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