Abstract 17430: Abnormal Excitation-contraction Coupling Gain in Heart Failure With Preserved Ejection Fraction (HFPEF) Can be Rescued by Cardiosphere-derived Stem Cells
Heart failure with preserved ejection fraction (HFPEF) is a major public health problem refractory to conventional therapy. Previously-studied models of HFPEF were often unverified hemodynamically, leading to confusing results. Recently, Gallet et al (JACC BTS, 2016) showed that a phenotype-verified model of HFPEF, the Dahl Salt-sensitive (DS) rat fed high salt, can be rescued by cardiosphere-derived cells (CDCs). We used the same model to test the hypothesis that excitation-contraction (EC) coupling gain is decreased in HFPEF and restored by CDCs. We recorded membrane current and simultaneous intracellular calcium (Ca) dynamics in enzymatically-isolated patch clamped ventricular myocytes from control, HFPEF and CDC-treated HFPEF rats. Voltage protocols and solutions were designed to isolate L-type Ca current. We used the fluorescent Ca indicator fluo-4 AM (10 μM) and a Leica SP5 laser scanning confocal microscope to record Ca and cell shortening. All recordings were preceded by prepulses to achieve steady-state sarcoplasmic reticulum (SR) load. We found that the L-type Ca current amplitude (normalized for capacitance) was unchanged in HFPEF. However, the corresponding Ca transient amplitude was significantly decreased (by 22%, P<0.05), indicating reduced EC coupling gain. There was no change in SR Ca content, Ca transient uptake kinetics or diastolic Ca. Despite decreased Ca transient amplitude, cell shortening amplitude was unchanged. However, cell relaxation was slowed (t90 1.7x, P<0.05), suggesting increased myofilament Ca responsiveness. All of these changes were rescued by CDCs, consistent with the improvement in hemodynamics reported by Gallet et al. The changes in EC coupling gain may be explained in part by disruption of the EC coupling microdomain associated with loss of the t-tubule protein cBIN1 (cardiac isoform of bridging integrator 1) and reduced local expression of Cav1.2 and RyR, changes that are rescued by CDCs. We conclude that 1) reduced EC coupling gain and increased myofilament Ca responsiveness are prominent features of the cellular defects in myocytes isolated from phenotype-verified HFPEF, and 2) CDCs are an effective means for reversing these changes, consistent with their hemodynamic benefit in this model.
Author Disclosures: R. Zhang: None. X. Yue: None. Y. Fu: None. R. Gallet: None. E. Marban: None. R. Shaw: None. T. Hong: None. J.I. Goldhaber: None.
- © 2016 by American Heart Association, Inc.