LAUSR

Objective: Heart failure (HF) with preserved ejection fraction (HFpEF) is characterized by a preserved cardiac EF, the presence of HF symptoms and diastolic dysfunction. There is a lack of animal models for exploring the mechanisms and treatments of HFpEF. This study aimed to test if cardiomyocyte (CMs) specific, inducible Cavβ2a transgenic (Cavβ2a TG) mice, having hypercontractile CMs, could be a model for HFpEF. Methods: High (HE) and low (LE) expression Cavβ2a TG mice were studied since transgene expression at the age of 2m till the age of 8m monthly to evaluate the systolic and diastolic function. At 8m, animals were euthanized for intra-left ventricular hemodynamic measurement, myocyte function and histological analyses, and Western blotting measurements. Results: LE and HE TG ventricular myocytes (VMs) had greater Ca2+ currents at the age of 2m (LE increased by 95.5%; HE increased by 171.9% ) and maintained at a similar level at the age of 8m. VM contraction and calcium transients had greater amplitudes in TG than in control VMs while the time from the peak contraction to 90% relaxation and the tau of Ca2+ transient decay of VMs were not different between groups probably due to enhanced NCX expression and increased SERCA activity because of increased phospholamban phosphorylation at the Thr17 site. Till 8m, LE and HE mice had a higher level of mortalities than control mice (LE: 32%, HE: 15%, control:5%), but more HE (87.5%) mice showed pleural effusion. The EF was highest in LE mice at the age of 2m but decreased to the same (>60%) as in HE and control mice at 8m. The ratio of mitral E to mitral inflow A wave velocities (E/A) was increased significantly at 3 and 4m then decreased to the lowest in HE at 5m followed by a rise at 6-8m, while LE mice had the lowest E/A at 5m and 6m and increased at 8m. E wave to mitral annulus e’ velocity (e’ wave) was higher in LE and HE groups than control mice. More fibrosis of the LV tissue, cardiomyocyte necrosis was observed in HE than in LE hearts. LE and HE mice had greater left ventricular wall relaxation rates, as indicated by larger reversed radial and longitudinal strain rates. Conclusion: LE and HE mice showed progression of diastolic dysfunction, from impaired relaxation to restrictive filling pattern. Cavβ2a TG mouse is a model for HFpEF for exploring HF pathobiology and mechanisms.