Assessing leg vascular responsiveness to tadalafil using MRI in boys with DMD: implications for adjuvant vasodilator therapy


Translational Research

Poster Number: S70


Sean Forbes, PhD, Department of Physical Therapy, University of Florida, Gainesville, Florida, USA, Luke Chase, University of Florida, Tanja Taivassalo, PhD, University of Florida

BACKGROUND: Boys with Duchenne muscular dystrophy (DMD) lack neuronal nitric oxide synthase (nNOSμ) at the sarcolemma of skeletal muscle, resulting in impaired local muscle perfusion, focal necrosis, and muscle damage during and following physical activity. Tadalafil (a phosphodiesterase 5, PDE5 inhibitor) is an FDA-approved vasodilator that has been shown to alleviate ischemia and normalizes blood flow after exercise. However, a phase 3 trial failed to improve the 6-minute walk distance largely resulting in its dismissal as a DMD therapeutic. We postulate that lack of accounting for variable disease severity and/or a lack of sufficient daily muscle activity may have accounted for the negative findings. OBJECTIVE: To determine the effects of tadalafil on the post-contractile MRI blood oxygenation level dependent (BOLD) response, a quantitative index of microvascular health, in DMD. METHODS: The post-contractile BOLD response was quantified in the tibialis anterior following dorsiflexion contractions before and after one tadalafil dose (0.6 mg/Kg) in DMD boys aged 8-13 years old (n=6). RESULTS: Tadalafil increased the BOLD-response from 1.9 (SD 1.6)% to 3.2 (SD 0.8)% in DMD (p=0.09), whereby the BOLD-response in unaffected controls was 4.4 (SD 1.7)%. Four out of 6 boys with DMD demonstrated tadalafil responsiveness, defined as >63% increase, which we consider a meaningful improvement in microvascular function based on previous BOLD reproducibility data. In responsive boys, the difference between pre and post-dosing was greater (Pre=1.0 (SD 0.4)%; Post=3.0 (SD 0.9)%, p<0.05). One patient who did not demonstrate an increase had the highest pre-dosing BOLD response, suggesting muscle oxygenation was not limiting. CONCLUSION: Our data strongly suggest that tadalafil can rescue activity-dependent microvascular impairment in DMD leg muscles in a majority of boys in the ambulatory age range. Furthermore, our data support that the post-contractile MRI-BOLD response can be used to screen for vascular responsiveness and stratify patients most likely to benefit from future clinical trials assessing vasodilators as adjuvant therapy for DMD.