Dilated Cardiomyopathy with Increased SR Ca(2+) Loading Preceded by a Hypercontractile State and Diastolic Failure in the α(1C)TG Mouse

Mice over-expressing the α(1−)subunit (pore) of the L-type Ca(2+) channel (α(1C)TG) by 4months (mo) of age exhibit an enlarged heart, hypertrophied myocytes, increased Ca(2+) current and Ca(2+) transient amplitude, but a normal SR Ca(2+) load. With advancing age (8–11 mo), some mice demonstrate advanced hypertrophy but are not in congestive heart failure (NFTG), while others evolve to frank dilated congestive heart failure (FTG). We demonstrate that older NFTG myocytes exhibit a hypercontractile state over a wide range of stimulation frequencies, but maintain a normal SR Ca(2+) load compared to age matched non-transgenic (NTG) myocytes. However, at high stimulation rates (2–4 Hz) signs of diastolic contractile failure appear in NFTG cells. The evolution of frank congestive failure in FTG is accompanied by a further increase in heart mass and myocyte size, and phospholamban and ryanodine receptor protein levels and phosphorylation become reduced. In FTG, the SR Ca(2+) load increases and Ca(2+) release following excitation, increases further. An enhanced NCX function in FTG, as reflected by an accelerated relaxation of the caffeine-induced Ca(2+) transient, is insufficient to maintain a normal diastolic Ca(2+) during high rates of stimulation. Although a high SR Ca(2+) release following excitation is maintained, the hypercontractile state is not maintained at high rates of stimulation, and signs of both systolic and diastolic contractile failure appear. Thus, the dilated cardiomyopathy that evolves in this mouse model exhibits signs of both systolic and diastolic failure, but not a deficient SR Ca(2+) loading or release, as occurs in some other cardiomyopathic models.