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

Abstract

Duchenne 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.

Progressive Proteome Changes in the Myocardium of a Pig Model for Duchenne Muscular Dystrophy

“…However, compared with the previously observed dramatically reduced abundance of numerous proteins of glycolysis and oxidative phosphorylation in skeletal muscle of the same animals , negative effects on bioenergetic pathways seem to be less pronounced in the myocardium. Nevertheless, this finding is in line with previous proteomic findings of decreased abundance of mitochondrial proteins in the heart of mdx and mdx-4cv mice (Lewis et al, 2010; and further supports the hypothesis that mitochondrial impairment is an important factor inducing DMD-related cardiomyopathy in humans (Meyers and Townsend, 2019).…”

“…Although the primary symptom of DMD is a progressive weakness of skeletal muscles ongoing with massive changes of tissue function and integrity, patients with DMD frequently develop cardiomyopathies in the second and third decade of life (for comprehensive reviews please refer to D'Amario et al, 2017;Hor et al, 2018;Kamdar and Garry, 2016;Meyers and Townsend, 2019;Townsend et al, 2007). Even though end-stage heart failure has become a major cause of death in DMD, the molecular pathology is poorly understood.…”

“…DMD-related cardiomyopathy has a prevalence of nearly one-third in patients aged 14 years and is observed in around one-half of 18-year-old patients (Shih et al, 2020). The typical pathology includes arrhythmias, systolic dysfunction, and dilated cardiomyopathy associated with fibrosis of the inferior and inferolateral walls of the left ventricle (for a detailed review please refer to Meyers and Townsend, 2019). Especially with improvements in respiratory management, heart failure is increasingly becoming the main cause of morbidity and mortality of patients with DMD (Hor et al, 2018).…”

Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy

“…ACEIs are an older drug class that is often used as the first line of therapy for general heart failure, and was the first to be used in trials to demonstrate improved cardiac function and survival among DMD patients [130,131]. For these reasons, they have often been named first in guidelines and recommendations regarding management of DMD cardiomyopathy and are more frequently prescribed [5,6,132,133]. ARBs are listed as a secondary option or an alternative in cases of poor ACEI tolerance, despite the fact that ARBs are equally effective when compared directly to ACEIs and better tolerated by patients, promoting improved compliance [134,135,136].…”

“…Losartan reduced cardiac damage 2.8-fold in mdx hearts without any significant effect on injury in wild type hearts. Surprisingly, neither acute nor chronic ACEI treatment had any effect on the extent of damage in the mouse heart, suggesting that direct blockade of AT 1 R may be necessary to achieve the full benefit of anti-angiotensin therapy in the dystrophic heart [133]. One potential explanation could be rooted in the fact that ACE is not strictly necessary for the production of AngII and activation of AT 1 R. AngII can be produced through the actions of other peptidases, most notably chymase, thus the inhibition of ACE does not eliminate AngII production [137,138,139].…”