Role of Echo for Quantitative Diagnosis of CHF

Abstract

Abnormalities in intracellular calcium release and reuptake are responsible for decreased contractility in heart failure (HF). We have previously shown that cardiac ryanodine receptors (RyR2) are protein kinase A (PKA) hyperphosphorylated and depleted of the regulatory subunit calstabin2 in HF. Moreover, similar alterations in skeletal muscle RyR have been linked to increased fatigability in HF. To determine whether restoration of calstabin binding to RyR may ameliorate cardiac dysfunction in HF, we treated wildtype (WT) and calstabin2 / mice subjected to myocardial infarction with JTV519, a 1,4-benzothiazepine previously shown to increase calstabin binding to RyR. Echocardiography at 21 days post-MI demonstrated a significant increase in ejection fraction in WT mice treated with JTV519 (45.8 5.1%) compared with placebo (31.1 3.1%; P 0.05). Co-immunoprecipitation experiments revealed increased amounts of calstabin2 bound to the RyR2 channel in JTV519-treated WT mice. However, JTV519 did not show any of these beneficial effects in calstabin2 / mice with myocardial infarction. Additionally, JTV519 improved skeletal muscle fatigue in both WT and calstabin2 / mice with heart failure, by increasing the binding of calstabin1 to RyR1. The observation that treatment with JTV519 improved cardiac function in WT but not calstabin2 / mice indicates that calstabin2 binding to RyR2 is required for the beneficial effects in failing hearts. We conclude that JTV519 may provide a specific way to treat the cardiac and skeletal muscle myopathy in heart failure by increasing calstabin binding to RyR. SL3