Abstract 035: Mechanism of Chronic CaMKII Inhibition-Caused Regression of Heart Failure: Beneficial Effects on Neurohormonal Activation, Left Ventricular and Cardiomyocyte Contractile Function, [Ca2+]i Regulation and Beta-Adrenergic Modulation
Background: Recent evidence indicates that Ca2+/calmodulin-dependent protein kinase II (CaMKII) is upregulated in heart failure (HF), contributing to electric, structural and functional remodeling. CaMKII has been proposed to be a therapeutic target for HF. However, the role and mechanism of chronic CaMKII inhibition (I) in HF is unclear. We assessed the hypothesis that CaMKII I improves cardiomyocyte function, [Ca2+]i regulation, and β-adrenergic reserve, thus limiting HF progression.
Methods: We compared left ventricular (LV) and myocyte functional responses and plasma levels of norepinephrine (NE) over a period of 16 weeks (W) in 6 control (C) and 14 rats with HF induced by isoproterenol (ISO) (170 mg/kg sq for 2 days). After ISO for 12 weeks, HF animals were assigned to receive 4 W treatment with: placebo (saline) (n=6), KN-93 (70 µg/kg/day sq via mini pump) (n=6), or KN-92 (70 µg/kg/day sq via pump) (n=2), respectively.
Results: Compared with C, ISO-treated rats had HF onset at 4 W after ISO and progressed to severe HF at 16 W with increased plasma NE (1398 vs 342 pg/ml), decreased ejection fraction (EF, 37% vs 62%) and LV contractility (EES, 0.8 vs 1.3 mmHg/μl). LV time constant of relaxation (τ) (17.8 vs 10.6 ms) increased, accompanied with significant reductions in cell contraction (dL/dtmax, 78 vs 151 μm/s), relaxation (dR/dtmax, 59 vs 114 μm/s) and [Ca2+]i transient ([Ca2+]iT) (0.18 vs 0.28). HF myocyte response to β-AR stimulation (ISO, 10-8 M) was attenuated with significantly less increases in dL/dtmax (34% vs 79%) and [Ca2+]iT (19% vs 36%). The LV and myocyte dysfunction persisted in KN-92-treated HF group. In contrast, treatment with KN-93 significantly increased EES (1.2 mmHg/μl) and EF (60%), decreased τ (12.1 ms) and corrected the elevation of plasma NE (319 pg/ml). Importantly, basal myocyte contraction (dL/dtmax,147 μm/s), relaxation (dR/dtmax,107 μm/s), and [Ca2+]iT (0.25) improved. ISO-induced increase in dL/dtmax (71%) and [Ca2+]iT (32%) were augmented and close to normal control levels.
Conclusion: Chronic CaMKII I prevents HF-induced sympathetic nervous system activation and improves LV and cardiomyocyte basal and β-AR stimulated contraction and relaxation, thus playing a salutary role at later stages of HF.
- © 2013 by American Heart Association, Inc.