Ifetroban reduces coronary artery dysfunction in a mouse model of Duchenne muscular dystrophy.

Dilated cardiomyopathy contributes to morbidity and mortality in Duchenne muscular dystrophy (DMD), an inheritable muscle-wasting disease caused by a mutation in the dystrophin gene. Preclinical studies in mouse models of muscular dystrophy have demonstrated reduced cardiomyopathy and improved cardiac function following oral treatment with the potent and selective thromboxane A/prostanoid receptor (TPr) antagonist ifetroban. Furthermore, a phase 2 clinical trial (NCT03340675, Cumberland Pharmaceuticals) is currently recruiting subjects to determine whether ifetroban can improve cardiac function in patients with DMD. Although TPr is a promising therapeutic target for the treatment of dilated cardiomyopathy in DMD, little is known about TPr function in coronary arteries that perfuse blood through the cardiac tissue. In the current study, isolated coronary arteries from young (∼3-5 mo) and aged (∼9-12 mo) mice, a widely used mouse model of DMD, and age-matched controls were examined using wire myography. Vasoconstriction to increasing concentrations of TPr agonist U-46619 (U4) was enhanced in young mice versus controls. In addition, young mice displayed a significant attenuation in endothelial cell-mediated vasodilation to increasing concentrations of the muscarinic agonist acetylcholine (ACh). Since TPr activation was enhanced in young mice, U4-mediated vasoconstriction was measured in the absence and the presence of ifetroban. Ifetroban reduced U4-mediated vasoconstriction in young mice and both aged and control mice. Overall, our data demonstrate enhanced coronary arterial vasoconstriction to TPr activation in young mice, a phenotype that could be reversed with ifetroban. These data could have important therapeutic implications for improving cardiovascular function in DMD. This investigation revealed ) impaired acetylcholine-mediated vasodilation, ) increased U-46619-mediated vasoconstriction, and ) reversal of the increase in U-46619-mediated vasoconstriction by the thromboxane A/prostanoid receptor (TPr) antagonist ifetroban in left anterior descending coronary arteries isolated from young mice, a model of Duchenne muscular dystrophy (DMD). Ifetroban has been used in preclinical studies to demonstrate improved cardiac function in mouse models of muscular dystrophy and is currently being investigated in a phase 2 clinical trial in patients with DMD. The current study supports the role of ifetroban in improving coronary artery function in preclinical DMD models, which may contribute to improved cardiovascular health.