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Intolerance to beta-blockade in a mouse model of delta-sarcoglycan-deficient muscular dystrophy cardiomyopathy

Lookup NU author(s): Dr Ralf Bauer, Dr Alison Blain, Liz Greally, Emerita Professor Katherine Bushby, Professor Hanns Lochmuller, Dr Steven Laval, Professor Volker StraubORCiD, Dr Guy MacGowanORCiD


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Patients with mutations predisposing to cardiomyopathy often have routine assessments of left ventricular function. It is unclear whether asymptomatic mild cardiomyopathy should be treated with standard heart failure therapies. We tested the effect of metoprolol on cardiac haemodynamics and pathology in two animal models for muscular dystrophy and cardiomyopathy. Treatment started at an early stage in the development of the cardiomyopathy. Metoprolol was given orally (2.5 mg/kg/day) over 8 weeks to mdx mice (model for Duchenne muscular dystrophy) and delta-sarcoglycan-deficient (Sgcd(null)) mice (model for Limb girdle muscular dystrophy type 2F). In vivo pressure-volume loops, fibrosis, in vivo myocyte sarcolemmal injury, and beta-adrenergic receptor mRNA were assessed. In beta-blocked mdx mice, there was a beneficial reduction in afterload and restored contractility resulting in an increased stroke volume. In contrast, in Sgcd(null) mice, there was marked deterioration in haemodynamics (prolonged relaxation, Tau, and reduced stroke volume). Furthermore, challenging the beta-blocked Sgcd(null) mice with the beta-adrenergic agonist dobutamine led to markedly increased mortality. Patterns of sarcolemmal injury or beta-adrenergic receptor mRNA could not account for this, though the acute rise in markers of active relaxation suggested abnormally high levels of intracellular calcium. beta-Blockers may not necessarily be beneficial in all cardiomyopathies, even when given at an early stage of development. Clinical trials of beta-blockers in muscular dystrophy-associated cardiomyopathy may need to stratify patients by genotype.

Publication metadata

Author(s): Bauer R, Blain A, Greally E, Bushby K, Lochmuller H, Laval S, Straub V, MacGowan GA

Publication type: Article

Publication status: Published

Journal: European Journal of Heart Failure

Year: 2010

Volume: 12

Issue: 11

Pages: 1163-1170

Print publication date: 30/07/2010

ISSN (print): 1388-9842

ISSN (electronic): 1879-0844

Publisher: Oxford University Press


DOI: 10.1093/eurjhf/hfq129


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Funder referenceFunder name
Heart Research UK
Special Trustees of the Newcastle upon Tyne Hospitals
MD-NET 01GM0601German Ministry of Education and Research (BMBF, Bonn, Germany)