Intolerance to ß-blockade in a mouse model of δ-sarcoglycan-deficient muscular dystrophy cardiomyopathy.
OBJECTIVE
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.


RESULTS
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 δ-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 β-adrenergic receptor mRNA were assessed. In β-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 β-blocked Sgcd(null) mice with the β-adrenergic agonist dobutamine led to markedly increased mortality. Patterns of sarcolemmal injury or β-adrenergic receptor mRNA could not account for this, though the acute rise in markers of active relaxation suggested abnormally high levels of intracellular calcium.


CONCLUSIONS
β-Blockers may not necessarily be beneficial in all cardiomyopathies, even when given at an early stage of development. Clinical trials of β-blockers in muscular dystrophy-associated cardiomyopathy may need to stratify patients by genotype.
Bauer
Ralf
R
Institute of Human Genetics, Newcastle University, International Center for Life, Newcastle upon Tyne, UK.
Blain
Alison
A
Greally
Elizabeth
E
Bushby
Kate
K
Lochmüller
Hanns
H
Laval
Steve
S
Straub
Volker
V
MacGowan
Guy A
GA
D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology; D058671:Adrenergic beta-1 Receptor Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004280:Dobutamine / Q000494:pharmacology; D006333:Heart Failure / Q000453:epidemiology; D006439:Hemodynamics / Q000187:drug effects; D008790:Metoprolol / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018101:Mice, Inbred mdx; D049288:Muscular Dystrophies, Limb-Girdle / Q000188:drug therapy* / Q000453:epidemiology / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000453:epidemiology / Q000503:physiopathology; D010210:Papillary Muscles / Q000473:pathology
D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D004280:Dobutamine; D008790:Metoprolol