Acute myocardial injury in mdx hearts ameliorated by ARB but not ACE inhibitor treatment

Abstract

AbstractDuchenne muscular dystrophy (DMD) is a devastating muscle disease that afflicts males due to the loss of the protein dystrophin, resulting in muscle deterioration and cardiomyopathy. Dystrophin’s absence causes increased membrane fragility, myocyte death, and tissue remodeling. Inhibition of angiotensin signaling with ACE inhibitors or angiotensin receptor blockers (ARBs) is a mainstay of DMD therapy, with clinical guidelines recommending starting one of these therapies by the age of 10 to address cardiomyopathy.Using the mdx mouse model of DMD, we previously showed that isoproterenol causes extensive damage in dystrophic hearts, and treatment with the ARB losartan starting only 1 hour before isoproterenol dramatically reduced this myocardial injury. In the present study, we probed whether ACE inhibitors, which are more frequently prescribed, can deliver similar protection. Surprisingly, lisinopril treatment initiated 1 hour before isoproterenol failed to demonstrate any effect on injury in mdx hearts. Further, with a 2-week pretreatment, only losartan significantly lowered mdx cardiac injury, without any benefit associated with lisinopril treatment. These results confirm the ability of ARBs, but not ACE inhibitors, to prevent acute injury in mouse hearts, and prompt the question whether ARBs should be more frequently used for DMD cardiomyopathy because of these potential protective actions.