Abstract 492: Molecular Determinants of Ca2+-Handling Abnormalities Underlying Contractile Dysfunction in Dilated versus Fibrillating Goat Atria
Background: Atrial dilatation (AD) promotes atrial fibrillation (AF), and both cause dysfunctional atrial contractile remodeling. The molecular mechanisms underlying atrial contractile remodeling are poorly understood.
Methods: Isometric force of contraction (FC), transmembrane action potentials (APs) and rapid cooling contractures (RCC, a measure of sarcoplasmic reticulum [SR] Ca2+ load) were studied in right atrial muscle bundles of 10 goats with AD due to 4 weeks of AV block, 8 goats with repetitive atrial burst pacing induced AF (10 days) and 10 controls. Total and phosphorylated Ca2+ -handling and myofilament protein levels were quantified by Western blot.
Results: FC was lower in AF and AD; AP duration was shorter in AF only (Table⇓). RCC revealed decreased SR Ca2+ load in AF and AD. Protein levels of SR Ca2+-ATPase (Serca2a) and its inhibitor phospholamban (PLB) were unchanged, whereas protein kinase A (PKA) phosphorylated PLB (at Ser16) was reduced by 70% in AF and 62% in AD with no change in Ca2+/calmodulin-dependent kinase II (CaMKII) PLB phosphorylation (at Thr17). PKA phosphorylated (at Ser2809) Ca2+ release channels (RyR2) were unaltered, whereas CaMKII phosphorylated (at Ser2815) RyR2 increased by 146% and 166% in AF and AD. PKA phosphorylated myosin binding protein-C (MyBP-C, Ser282), a major regulator of contractility, was reduced by 49% exclusively in AD, whereas PKA phosphorylated troponin I (Tn-I) was decreased only in AF.
Conclusion: Both AD and AF decrease SR Ca2+ load, probably by dephosphorylated (activated) Serca2a-inhibitory PLB and CaMKII hyperphosphorylated (leaky) RYR2 channels. While the shorter AP and PKA dephosphorylated Tn-I further compromise contractility in AF, the reduced PKA phosphorylation of MyBP-C may impair contractility in AD. These studies provide novel insights into the molecular mechanisms of adverse contractile remodeling, a major contributor to AF and thromboembolic risk, in dilated and fibrillating atria.