Sildenafil does not improve cardiomyopathy in Duchenne/Becker muscular dystrophy

Abstract

Objective Duchenne and Becker muscular dystrophy (DBMD) are allelic disorders caused by mutations in dystrophin. Adults with DBMD develop life-threatening cardiomyopathy. Inhibition of phosphodiesterase 5 (PDE5) improves cardiac function in mouse models of DBMD. To determine if the PDE5-inhibitor sildenafil benefits human dystrophinopathy, we conducted a randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov, number NCT01168908). Methods Adults with DBMD and cardiomyopathy (ejection fraction ≤50%) were randomized to receive sildenafil (20mg three times daily) or placebo for 6 months. All subjects received an additional 6 months of open-label sildenafil. The primary endpoint was change in left ventricular end-systolic volume (LVESV) on cardiac MRI. Secondary cardiac endpoints, skeletal muscle function, and quality of life were also assessed. Results An interim analysis (performed after 15 subjects completed the blinded phase) revealed that 29% (4/14) of subjects had a ≥10% increase in LVESV after 6 months of sildenafil compared to 13% (1/8) of subjects receiving placebo. Subjects with LVESV >120ml at baseline were more likely to worsen at 12 months regardless of treatment assignment (p=0.035). Due to the higher number of subjects worsening on sildenafil, the Data and Safety Monitoring Board recommended early termination of the study. There were no statistically significant differences in outcome measures between treatment arms. Interpretation Due to the small sample size, comparisons between groups must be interpreted with caution. However, this trial suggests that sildenafil is unlikely to improve cardiac function in adults with DBMD.

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

“…Such studies have yielded mixed results in animal models, with modest improvements in cardiac function and pathology. Furthermore, human trials have offered little evidence of a beneficial cardiac effect of sildenafil treatment in adults with DMD or Becker muscular dystrophy (58,59). In light of our findings, it is possible that the shortcomings of these previous studies reflect the existence of other functional targets of muscle-derived NO, or additional targets of altered AMPK regulation, that contribute to dysfunction in dystrophic muscle (43,60,61).…”

Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy

“…The reported reduced recruitment of sufficient blood flow in patients with BMD during muscle activity responsible for relative ischemia [37] is improved by PDE5 inhibition in some studies [22,38,39], but not in all of them [23,24], which may relate to variations in methods applied. Corresponding reduced brain blood flow recruitment during activation was hypothesized to be present in patients with BMD and restored by PDE5 inhibition; the current data partly support this hypothesis.…”

“…Sildenafil is used to treat erectile dysfunction and pulmonary hypertension, and works by augmenting endogenous cGMP levels, thus promoting a normal NO response. Recently sildenafil/PDE5 administration was shown to reduce skeletal muscle and cardiac dysfunction and to ameliorate dystrophy in a mouse model of DMD [20][21][22], although no positive effect was found on skeletal or cardiac muscle function and brachial arterial forearm flow in 17 patients with BMD [23] or 15 patients with BMD/DMD [24]. In healthy subjects, including males and females, sildenafil does not change the cerebral blood flow (CBF) after a single oral dose of 100 mg measured by single photon emission computer tomography and transcranial Doppler [25], but it may do so in patients with dysfunctional NO signaling [26], such as patients with BMD.…”

Tadalafil Treatment Delays the Onset of Cardiomyopathy in Dystrophin‐Deficient Hearts

“…We also demonstrated that that both TRPC6 and m-calpain were increased in the myocardium of DMD patients, suggesting that the GRMD treatment effects can translate to DMD patients. The published clinical study with the short-acting PDE5 inhibitor sildenafil showed no efficacy in the DMD patients who were treated 10 ; however, those patients had decreased cardiac function on treatment initiation. The present data strongly support the prophylactic use of tadalafil to counter cardiomyopathy in DMD patients rather than treatment after pathology and functional decline are evident.…”

“…4 In models of heart failure, PDE5 inhibition has improved cardiomyopathy [5][6][7][8][9] ; however, a recent study of sildenafil in older (aged >15 years) DMD patients with clinical cardiomyopathy (ejection fraction ≤45%) failed to show any significant benefit with treatment for >6 months. 10 Sildenafil's lack of effectiveness in the above-mentioned DMD patient population does not eliminate the possibility that PDE5 inhibition could be prophylactic against cardiomyopathy development and progression if initiated early rather than being able to reverse preexisting pathology. In the current study, we tested this hypothesis using tadalafil, a PDE5 inhibitor that possesses a longer half-life than sildenafil (t 1/2 of 17.5 versus 4 hours for sildenafil).…”