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Antagonism of the Thromboxane-Prostanoid Receptor as a Potential Therapy for Cardiomyopathy of Muscular Dystrophy.

ABSTRACT: Background Muscular dystrophy (MD) causes a progressive cardiomyopathy characterized by diffuse fibrosis, arrhythmia, heart failure, and early death. Activation of the thromboxane-prostanoid receptor (TPr) increases calcium transients in cardiomyocytes and is proarrhythmic and profibrotic. We hypothesized that TPr activation contributes to the cardiac phenotype of MD, and that TPr antagonism would improve cardiac fibrosis and function in preclinical models of MD. Methods and Results Three different mouse models of MD (mdx/utrn double knockout, second generation mdx/mTR double knockout, and delta-sarcoglycan knockout) were given normal drinking water or water containing 25 mg/kg per day of the TPr antagonist ifetroban, beginning at weaning. After 6 months (10 weeks for mdx/utrn double knockout), mice were evaluated for cardiac and skeletal muscle function before euthanization. There was a 100% survival rate of ifetroban-treated mice to the predetermined end point, compared with 60%, 43%, and 90% for mdx/utrn double knockout, mdx/mTR double knockout, and delta-sarcoglycan knockout mice, respectively. TPr antagonism improved cardiac output in mdx/utrn double knockout and mdx/mTR mice, and normalized fractional shortening, ejection fraction, and other parameters in delta-sarcoglycan knockout mice. Cardiac fibrosis in delta-sarcoglycan knockout was reduced with TPr antagonism, which also normalized cardiac expression of claudin-5 and neuronal nitric oxide synthase proteins and multiple signature genes of Duchenne MD. Conclusions TPr antagonism reduced cardiomyopathy and spontaneous death in mouse models of Duchenne and limb-girdle MD. Based on these studies, ifetroban and other TPr antagonists could be novel therapeutics for treatment of the cardiac phenotype in patients with MD.

SUBMITTER: West JD

PROVIDER: S-EPMC6898850 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Antagonism of the Thromboxane-Prostanoid Receptor as a Potential Therapy for Cardiomyopathy of Muscular Dystrophy.

West James D JD Galindo Cristi L CL Kim Kyungsoo K Shin John Jonghyun JJ Atkinson James B JB Macias-Perez Ines I Pavliv Leo L Knollmann Bjorn C BC Soslow Jonathan H JH Markham Larry W LW Carrier Erica J EJ

Journal of the American Heart Association 20191030 21

Background Muscular dystrophy (MD) causes a progressive cardiomyopathy characterized by diffuse fibrosis, arrhythmia, heart failure, and early death. Activation of the thromboxane-prostanoid receptor (TPr) increases calcium transients in cardiomyocytes and is proarrhythmic and profibrotic. We hypothesized that TPr activation contributes to the cardiac phenotype of MD, and that TPr antagonism would improve cardiac fibrosis and function in preclinical models of MD. Methods and Results Three differ ...[more]

PMID: 31662020

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Project description:AimsDuchenne muscular dystrophy (DMD) is an X-linked inherited disease due to dystrophin deficiency causing skeletal and cardiac muscle dysfunction. Affected patients lose ambulation by age 12 and usually die in the second to third decades of life from cardiac and respiratory failure. Symptomatic treatment includes the use of anti-inflammatory corticosteroids, which are associated with side effects including weight gain, osteoporosis, and increased risk of cardiovascular disease. Novel treatment options include blockade of the renin-angiotensin-aldosterone system, because angiotensin as well as aldosterone contribute to persistent inflammation and fibrosis, and aldosterone blockade represents an efficacious anti-fibrotic approach in cardiac failure. Recent preclinical findings enabled successful clinical testing of a combination of steroidal mineralocorticoid receptor antagonists (MRAs) and angiotensin converting enzyme inhibitors in DMD boys. The efficacy of MRAs alone on dystrophic skeletal muscle and heart has not been investigated. Here, we tested efficacy of the novel non-steroidal MRA finerenone as a monotherapy in a preclinical DMD model.Methods and resultsThe dystrophin-deficient, utrophin haploinsufficient mouse model of DMD was treated with finerenone and compared with untreated dystrophic and wild-type controls. Grip strength, electrocardiography, cardiac magnetic resonance imaging, muscle force measurements, histological quantification, and gene expression studies were performed. Finerenone treatment alone resulted in significant improvements in clinically relevant functional parameters in both skeletal muscle and heart. Normalized grip strength in rested dystrophic mice treated with finerenone (40.3 ± 1.0 mN/g) was significantly higher (P = 0.0182) compared with untreated dystrophic mice (35.2 ± 1.5 mN/g). Fatigued finerenone-treated dystrophic mice showed an even greater relative improvement (P = 0.0003) in normalized grip strength (37.5 ± 1.1 mN/g) compared with untreated mice (29.7 ± 1.1 mN/g). Finerenone treatment also led to significantly lower (P = 0.0075) susceptibility to limb muscle damage characteristic of DMD measured during a contraction-induced injury protocol. Normalized limb muscle force after five lengthening contractions resulted in retention of 71 ± 7% of baseline force in finerenone-treated compared with only 51 ± 4% in untreated dystrophic mice. Finerenone treatment also prevented significant reductions in myocardial strain rate (P = 0.0409), the earliest sign of DMD cardiomyopathy. Moreover, treatment with finerenone led to very specific cardiac gene expression changes in clock genes that might modify cardiac pathophysiology in this DMD model.ConclusionsFinerenone administered as a monotherapy is disease modifying for both skeletal muscle and heart in a preclinical DMD model. These findings support further evaluation of finerenone in DMD clinical trials.

Dataset Information

Antagonism of the Thromboxane-Prostanoid Receptor as a Potential Therapy for Cardiomyopathy of Muscular Dystrophy.

Publications

Antagonism of the Thromboxane-Prostanoid Receptor as a Potential Therapy for Cardiomyopathy of Muscular Dystrophy.

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