Abstract 11401: Late Initiation of Chronic CaMKII Inhibition Causes Regression in Rat Model of Progressive Heart Failure: Insights into the Underlying Cellular Mechanism
Background. Excessive activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) is linked to cardiomyopathy and arrhythmias. In heart failure (HF), cardiac CaMKII is upregulated. CaMKII has been proposed to be a therapeutic target for HF. However, the direct cardiac effect of chronic CaMKII inhibition in HF is unclear. We tested the hypothesis that chronic CaMKII inhibition would improve intrinsic cardiomyocyte basal and β-AR stimulated contraction and relaxation, thus playing a salutary role at later stages of HF.
Methods. Plasma levels of norepinephrine (NE), left ventricular (LV) and myocyte functional responses were compared in 3 groups of rats (6/group) for a period of 4 months (M): 1) isoproterenol (ISO)-treated, 4 M after receiving ISO (170 mg/kg sq for 2 days); 2) HF/CaMKII I, 3 M after receiving ISO, then KN-93, a CaMKII inhibitor (I) (70 µg/kg/day sq via mini pump) was initiated, and was given for 1 M; and 3) Controls.
Results. Compared with controls, ISO-treated rats had HF onset at 1 M after ISO and progressed to severe HF at 4 M with about 4-fold elevated plasma NE (1398 vs 554 pg/ml) and LV dilatation associated with increased myocyte length (ML, 152 vs121 μm) and heart-to-body weight ratio (H/BW, 7.9 vs 5.7 g/kg). Ejection fraction (38% vs 61%) and LV contractility (EES, 0.7 vs 1.2 mmHg/μl) were decreased. LV time constant of relaxation (τ) (17.6 vs 10.9 ms) was increased, parallel with about 50% reductions in cell contraction (dL/dtmax, 76 vs 152 μm/s), relaxation (dR/dtmax, 58 vs 119 μm/s) and decreased [Ca2+]i transient ([Ca2+]iT) (0.19 vs 0.28). HF myocyte response to β-AR stimulation (ISO, 10-8 M) was attenuated with significantly less increases in dL/dtmax (32% vs 79%) and [Ca2+]iT (18% vs 35%). Treatment with CaMKII I increased EES (1.1 mmHg/μl) and EF (59%), decreased τ (11.0 ms) and corrected the elevation of plasma NE (608 pg/ml) with retained normal ML (124 μm), H/BW (6.3 g/kg) dL/dtmax (149 μm/s), dR/dtmax (109 μm/s), and [Ca2+]iT (0.26). ISO-induced increase in dL/dtmax and [Ca2+]iT also returned close to normal control levels.
Conclusion. Chronic CaMKII inhibition prevents HF-induced sympathetic nervous system activation, leading to regression of LV and myocyte systolic and diastolic dysfunction and remodeling in rats with advanced HF.
- © 2012 by American Heart Association, Inc.