Abstract 2628: Cardiomyopathy in a Canine Model of Duchenne Muscular Dystrophy: Effects of Left Ventricle and Myocyte Systolic and Diastolic Functional Performance, L-Type Calcium Current Response and β-Adrenergic Modulation
Background. Duchenne muscular dystrophy (DMD) occurs due to dystrophin deficiency and afflicts 1/3300 males each year in the US. Heart failure (HF) directly leads to death in about 30% of cases. However, its cardiac pathophysiology is unclear. We assessed cardiac insufficiency in dogs with the DMD genetic homologue, golden retriever muscular dystrophy (GRMD). We tested the hypothesis that GRMD dogs would demonstrate impaired left ventricular (LV) myocyte function and [Ca2+]i regulation with desensitization of cardiac β-adrenergic signaling.
Methods. LV and myocyte basal contractile performance, Ca2+ current (ICa,L) and responses to β-adrenergic simulation were compared in 5 normal control (N) and 3 (late stage) GRMD dogs acutely instrumented to measure LV pressure and volume. Cardiac histopathological alterations were determined.
Results. Compared to controls, in GRMD dogs, stroke volume, ejection fraction (26% vs 48%) were significantly reduced. LV contractility measured by EES and MSW decreased 46% and 40%, respectively. LV time constant of relaxation (ô) (41.7±3.4 vs 28.8±2.1 ms) was increased by 44%. GRMD dogs exhibited altered response to dobutamine (DOB, 5 ìg/kg/min, iv). In controls, DOB caused 68% increase in EES and 24% decrease in τ (p<0.01). In GRMD, both EES (+5.9%) and τ (−3.5%) were relatively unchanged during DOB infusion. Importantly, these abnormalities of LV in GRMD were paralleled by concomitant depressions in myocyte contraction and relaxation indicated by decreased dL/dtmax (43%, GRMD: 69.5±7.6 vs N: 121.8±3.1 μm/s) and dR/dtmax (50%, 50.8±3.5 vs 101.6±1.6 μm/s) with reduced peak ICa,L (46%, 2.2±0.2 vs 4.1±0.1 pA/pF) accompanied by attenuated responses to β-adrenergic stimulation. Compared with normal myocytes, in GRMD myocytes, isoproterenol (10−8 M) produced significantly less increases in dL/dtmax (15.2% vs 64.4%), dR/dtmax (9.3% vs 60.2%), and ICa,L (11.2% vs 24.9 %). Histological evidence of LV dilatation was associated with significantly increased myocyte length (182.1±8.4 vs 118.4±6.2 μm), the length-width ratio, and degeneration.
Conclusions. Dystrophin deficiency results in LV and myocyte systolic and diastolic dysfunction, myocyte remodeling, and ICa,L reduction with impaired β-adrenergic regulation.