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.

© 2014 American Academy of Neurology.

Figures

Figure 1. Functional sympatholysis is impaired in patients with DMD and rescued by acute PDE5 inhibition

(A) Left panel shows a representative tracing from a healthy control subject, showing that the lower-body negative pressure (LBNP)-induced decrease in forearm muscle oxygenation (HbO2 + MbO2) is greatly attenuated during mild handgrip exercise (gray dashed circle), demonstrating functional sympatholysis. At the end of each experiment, an arm cuff was inflated to suprasystolic pressure to occlude the forearm circulation, producing a maximal decrease in muscle oxygenation to calculate the total labile signal (TLS). Right panel shows summary forearm muscle oxygenation data from the 10 healthy control subjects studied at rest and during exercise expressed as a percentage of TLS. (B) Representative tracings from a patient with Duchenne muscular dystrophy (DMD) at baseline (pretreatment), showing that sympatholysis is impaired because handgrip fails to attenuate the LBNP response (gray dashed circle). Summary data are shown in the right panel for 10 boys with DMD. (C) Representative tracing from a subject with DMD treated with tadalafil, showing that the LBNP-induced decrease in forearm muscle oxygenation is greatly attenuated during mild handgrip exercise (black dashed circle). Summary data are shown in the right panel for 10 patients with DMD. (D) Representative tracing from a subject with DMD treated with sildenafil, showing that the LBNP-induced decrease in forearm muscle oxygenation is greatly attenuated during mild handgrip exercise (black dashed circle). Summary data are shown in the right panel for 6 patients with DMD. Data are reported as mean ± SEM. ns = not significant.

Figure 2. Sildenafil equally restores functional sympatholysis compared with tadalafil

Lower-body negative pressure (LBNP)-induced decreases on forearm muscle oxygenation by near-infrared spectroscopy at rest and during mild rhythmic handgrip exercise (n = 6). Data expressed as a percentage of the total labile signal (TLS). Data reported as mean ± SEM. PDE5 = phosphodiesterase type 5.

Figure 3. Postexercise hyperemia is impaired in DMD and rescued by tadalafil

Exercise-induced change in skeletal muscle blood flow, from rest to postexercise, in 10 patients with Duchenne muscular dystrophy (DMD) and 10 healthy controls. Data expressed as mean ± SEM. ns = not significant.