Abstract 846: Chronic Cardiac Resynchronization Reverses Abnormal Calcium Handling in Failing Ventricular Myocytes
Cardiac resynchronization therapy (CRT) represents a promising treatment modality to alleviate LV dysfunction in humans with heart failure (HF). The underlying mechanisms contributing to improved cardiac function remain poorly understood. Using a canine chronic model of HF, we recently showed that the RyR2 channel becomes excessively active, resulting in leaky sarcoplasmic reticulum (SR) Ca stores in HF. The increase in RyR2 activity is caused by defective modulation of the channel by SR luminal Ca, a mechanism that normally operates to terminate SR Ca release and keep the RyR2 channels closed (i.e. refractory) during diastole. Using the same HF model, we now show that CRT resynchronization therapy reverses this defective RyR function and normalizes Ca handling in myocytes from failing hearts. Following CRT we observed significant improvements in parameters of in vivo cardiac performance in HF dogs, including reduction in LV dimension and increased LV synchrony and fractional shortening. In accordance with our previous findings, HF myocytes exhibited characteristic reductions in the amplitude of the cytosolic Ca transients and sarcoplasmic reticulum (SR) Ca load and an increase in the frequency of spontaneous Ca sparks. Also, the baseline intra-SR [Ca] was reduced in HF myocytes compared to control. Remarkably, following CRT, the amplitude of the Ca transients, frequency of spontaneous Ca sparks and intra SR Ca levels significantly changed toward normal values. At the single channel level, in RyRs from failing hearts the luminal Ca sensitivity was profoundly shifted toward lower concentrations compared with controls such that the channel was substantially activated at luminal Ca as low as 20 uM. CRT resulted in significant normalization of RyR function as evinced by normalization of luminal Ca dependency.. These results suggest that part of the recovery with CRT occurs through improvement of intracellular Ca handling, and in particular normalization of the RyR-mediated SR Ca leak.