Abstract 14810: Tadalafil Alleviates Functional Muscle Ischemia in Patients with Becker Muscular Dystrophy
Background: Becker muscular dystrophy (BMD) is a progressive, ultimately fatal X-linked muscle wasting disease for which there is no treatment. BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets neuronal nitric oxide synthase (nNOSμ ) to the sarcolemma. Our past work suggests that sarcolemmal nNOSμ normally is activated when muscles are exercised and the nitric oxide (NO) produced attenuates local alpha-adrenergic vasoconstriction, thereby optimizing muscle perfusion. We asked if this protective mechanism (“functional sympatholysis”) is defective, causing functional ischemia, in BMD patients with dystrophin mutations that disrupt sarcolemmal targeting of nNOSμ and if the ischemia can be alleviated by boosting NO-cGMP signaling with a phophodiesterase (PDE5A) inhibitor (tadalafil).
Methods: We measured reflex vasoconstriction as decreased forearm muscle oxygenation (ΔHbO2) with near infrared spectroscopy during lower body negative pressure (LBNP, -20 mmHg) at rest and during rhythmic handgrip (HG) at 20% maximum in 10 men with BMD (age: 37 ± 3 years, mean ± SE) and 7 healthy age-matched male controls. Then, men with BMD underwent a randomized placebo-controlled double-blind cross-over trial of single-dose (20 mg) oral tadalafil (clinicaltrials.gov NCT01070511).
Results: In healthy controls, reflex vasoconstriction was attenuated by 60 ± 8% during HG (ΔHb02: -18 ± 1% vs. -7 ± 2%, P<.01; rest vs. HG), documenting functional sympatholysis. In contrast, untreated BMD patients had no reflex attenuation during HG (ΔHb02: -19 ± 2% vs. -17 ± 2%, P>0.1; rest vs. HG), indicating functional ischemia. Most importantly, tadalafil fully restored sympatholysis in patients with BMD: after tadalafil, reflex vasoconstriction was attenuated by 52 ± 12% during HG (ΔHb02: -17 ± 2% vs. -9 ± 2%, P<0.01; rest vs. HG) whereas placebo had no effect (▵HbO2: -18 ± 2% vs. -17 ± 2%, P>0.1; rest vs. HG).
Conclusion: These data show that tadalafil alleviates functional muscle ischemia in patients with BMD and constitute the first-in-man proof-of-concept for PDE5A inhibition as a putative new treatment strategy for this and possibly other forms of muscular dystrophy accompanied by loss of sarcolemmal nNOSμ .
- © 2012 by American Heart Association, Inc.