Abstract 14718: Intrinsic Cardiomyocyte Defects and Dystrophic Cardiomyocyte in a Canine Model of Duchenne Muscular Dystrophy
Background: Duchenne muscular dystrophy (DMD) is a common and lethal genetic disease. Cardiomyopathy frequently causes mortality in DMD patients. However, the precise mechanism is poorly understood. Although cardiac fibrosis, hemodynamic and ECG abnormalities have been described, it is unclear whether the contractile dysfunction observed with DMD is an intrinsic property of the cardiomyocytes. We tested the hypothesis that defects in LV myocyte force-generating capacity and relaxation with impaired [Ca2+]i regulation may be the primary cause of dystrophic cardiomyopathy.
Methods: In a Golden Retriever muscular dystrophy (GRMD) dog model, we simultaneously compared myocyte β1-adrenoceptor (AR) expression, LV and myocyte basal contractile function, [Ca2+]i transient ([Ca2+]iT), Ca2+ current (ICa,L) and response to β-AR stimulation in 7 control and 4 late stage GRMD dogs acutely instrumented to measure LV pressure and volume.
Results: Compared to controls, GRMD dogs had decline in LV function and β-adrenergic reserve. Ejection fraction (27% vs 50%) and LV contractility (EES, 3.9 vs 6.8 mmHg/ml) were significantly decreased. LV time constant of relaxation (τ) (43.7 vs 29.1 ms) was increased. In GRMD dogs, infusion of dobutamine (5 μg/kg/min, iv) caused a significantly less increase in EES (7% vs 66%) and decrease in τ (3% vs 24%). Importantly, these LV abnormalities were accompanied by concomitant depressions in LV myocyte contraction and relaxation indicated by significant decreases in dL/dtmax (64.9 vs 122.1μm/s), dR/dtmax (52.7 vs 109.8 μm/s), [Ca2+]iT (0.17 vs 0.26) and peak ICa,L (2.6 vs 4.8 pA/pF). Compared to controls, in GRMD, myocytes β1-AR protein levels decreased approximately 49% (0.37 vs 0.72). Isoproterenol (10-8 M) produced significantly less increases in dL/dtmax (13.7% vs 62.9%), dR/dtmax (7.8% vs 60.4%), [Ca2+]iT (10.1% vs 28.9%) and ICa,L (9.1% vs 25.6%). Histological evidence of LV dilatation was associated with significantly increased myocyte length (180.4 vs 117.8 μm), length-width ratio, and degeneration.
Conclusions: Dystrophin deficiency results in intrinsic defects of cardiomyocytes, leading to LV and myocyte systolic and diastolic dysfunction and LV myocyte remodeling with impaired β-adrenergic regulation.
- © 2013 by American Heart Association, Inc.