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J Am Heart Assoc. 2019 Nov 5;8(21):e011902. doi: 10.1161/JAHA.118.011902. Epub 2019 Oct 30.

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

Author information

1
Division of Allergy, Pulmonary, and Critical Care Vanderbilt University Medical Center Nashville TN.
2
Division of Cardiology Vanderbilt University Medical Center Nashville TN.
3
Division of Clinical Pharmacology Vanderbilt University Medical Center Nashville TN.
4
Division of Rheumatology and Immunology Department of Medicine Vanderbilt University Medical Center Nashville TN.
5
Department of Medicine Department of Pathology, Microbiology, and Immunology Vanderbilt University Medical Center Nashville TN.
6
Cumberland Pharmaceuticals Inc Nashville TN.
7
Division of Pediatric Cardiology Department of Pediatrics Vanderbilt University Medical Center Nashville TN.
8
Division of Pediatric Cardiology Department of Pediatrics Riley Hospital for Children and Indiana University School of Medicine Indianapolis IN.

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.

KEYWORDS:

Duchenne muscular dystrophy cardiomyopathy; TC receptor; receptor blocker

PMID:
31662020
DOI:
10.1161/JAHA.118.011902
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