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

Abstract

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 A2/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) mdx 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 mdx mice versus controls. In addition, young mdx 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 mdx mice, U4-mediated vasoconstriction was measured in the absence and the presence of ifetroban. Ifetroban reduced U4-mediated vasoconstriction in young mdx mice and both aged mdx and control mice. Overall, our data demonstrate enhanced coronary arterial vasoconstriction to TPr activation in young mdx mice, a phenotype that could be reversed with ifetroban. These data could have important therapeutic implications for improving cardiovascular function in DMD.NEW & NOTEWORTHY This investigation revealed 1) impaired acetylcholine-mediated vasodilation, 2) increased U-46619-mediated vasoconstriction, and 3) reversal of the increase in U-46619-mediated vasoconstriction by the thromboxane A2/prostanoid receptor (TPr) antagonist ifetroban in left anterior descending coronary arteries isolated from young mdx 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.

Keywords: Duchenne muscular dystrophy; coronary artery; dilated cardiomyopathy; ifetroban.