Abstract 14421: Chronic CaMKII Inhibition Induces Diastolic Dysfunction
Background: Recent studies point to CaMKII as a novel therapeutic target in structural heart diseases. However, the role of CaMKII in maintaining normal diastolic function is under investigated.
Objective: We have tested the effect of chronic CaMKII inhibition on diastolic function in physiological condition and in compensatory cardiac hypertrophy.
Methods: Chronic CaMKII inhibition was achieved by CaMKIIδ knockout (KO) and in vivo daily injection of CaMKII inhibitor KN93 (10µmol/kg, IP) for 3 weeks. Compensatory hypertrophy was induced by moderate aortic thoracic banding (mTAB).
Results: mTAB induced similar hypertrophy in WT and KO mice. Left ventricle (LV) mass and ejection fraction (EF) were 109.2±7.4mg and 84±3.0% for KO hypertrophy and 112.8±12.2mg and 80 ±2.5% for WT hypertrophy, respectively (p>0.05). However, LV filling pressure and left atrium (LA) size were significantly increased in KO mice in baseline and in mTAB-induced hypertrophy characterized by increased transmitral inflow early diastolic velocity (E) to mitral annular early diastolic velocity (E’) ratio (baseline: 34.5±1.3 vs. 29.9±0.8; hypertrophy: 41.7±1.5 vs. 33.8±2.0, p<0.05, KO vs. WT) and LA area (baseline: 4.3±0.2 vs. 3.3±0.2mm2, p<0.05; hypertrophy: 6.1±0.2 vs. 5.1±0.2mm2, p<0.05, KO vs. WT). Dynamic LV P-V loop showed that compared to WT hypertrophy, KO hypertrophy mice had nearly doubled LV end-diastolic pressure (10.6±1.9 vs. 5.8±1.11mmHg, p<0.05), slowed LV pressure decline time constants (8.10±0.51 vs. 6.76±0.34ms, p<0.05), and steeper LV end-diastolic pressure-volume relationship (0.11±0.02 vs. 0.05±0.01mmHg×ul-1, p<0.05). Furthermore, 28% (5/18) KO hypertrophy mice with preserved EF had significant lung edema (doubled lung weight to body weight ratio) and doubled E/E’ ratio, indicating diastolic heart failure (HF), whereas no diastolic HF was found in WT hypertrophy mice. Similar to CaMKIIδ KO, diastolic dysfunction was observed in KN93 but not in KN92 injected hypertrophy mice.
Conclusion: Chronic CaMKII inhibition significantly impairs diastolic function. These results challenge recent idea that CaMKII inhibition is a beneficial treatment strategy in patients with structural heart disease by pointing to a caution of diastolic dysfunction.
- © 2011 by American Heart Association, Inc.