Abstract 3539: Cellular and Functional Defects in a Canine Model of Heart Failure: A Longitudinal Study
In heart failure (HF), abnormalities of in vivo cardiac function are closely correlated with reduced sarcoplasmic reticulum (SR) Ca release and myocyte contractility, supporting the concept that HF is a result of deranged Ca cycling. However, most studies addressing the role and mechanisms of altered Ca handling in HF have been performed at advanced stages of HF providing little information as to whether these deficiencies are causes or consequences of HF. In the present study we compared the time course of development of alterations in myocyte Ca handling with deterioration of cardiac function, using a canine tachypacing model of chronic HF. LV fractional shortening decreased by 50 and 70 % of control values at 1 and >4 month of tachypacing, respectively. The frequency of Ca sparks and the rate of SR Ca leak increased progressively with the duration of tachypacing, while diastolic [Ca]SR decreased with the duration of tachypacing. These changes were paralleled by a progressive increase in the rate of reactive oxygen species generation, oxidation of ryanodine receptors (RyRs) and activation of caspase 3. Na/Ca exchange activity was significantly augmented at 1 mo, and remained upregulated thereafter. The SR Ca ATPase-mediated Ca uptake and the density of peak Ca current were not changed up to >4 mo of tachypacing. Arrhythmogenic events, including spontaneous SR Ca releases and delayed afterdepolarizations were significantly pronounced already at 1 mo and their frequency increased with HF progression. Notably, decreases in the amplitude of depolarization-induced Ca transients and single-cell contractions were observed only starting at the 4th month of tachypacing. These results suggest that arrhythmogenic disturbances in myocyte Ca handling occur at relatively early stages of HF preceding depression of SR Ca release and contractility. Furthermore, deterioration of intrinsic myocyte intracellular Ca release and contractile properties follows rather than precedes weakening of in vivo cardiac performance, and, thus, is not likely to play a causative role in the development of HF. Enhanced RyR-mediated SR Ca leak besides contributing arrhythmogenesis may contribute to the development of HF by initiation of cardiac remodeling and apoptotic pathways.
This research has received full or partial funding support from the American Heart Association, National Center.