Intolerance to β-blockade in a mouse model of δ-sarcoglycan-deficient muscular dystrophy cardiomyopathy

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.