Mice overexpressing the α1C-subunit of the L-type Ca2+ channel develop a hypercontractile state that progresses to dilated cardiomyopathy with increased SR Ca2+ loading and both systolic and diastolic failure.
This study demonstrates that dilated cardiomyopathy in the a1CTG mouse model exhibits both systolic and diastolic failure without deficient SR Ca2+ loading or release.
Mice over-expressing the alpha (1) ₛubunit (pore) of the L-type Ca2+ channel (alpha (1C) TG) by 4 months (mo) of age exhibit an enlarged heart, hypertrophied myocytes, increased Ca2+ current and Ca2+ transient amplitude, but a normal SR Ca2+ 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 Ca2+ 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 Ca2+ load increases and Ca2+ release following excitation, increases further. An enhanced NCX function in FTG, as reflected by an accelerated relaxation of the caffeine-induced Ca2+ transient, is insufficient to maintain a normal diastolic Ca2+ during high rates of stimulation. Although a high SR Ca2+ 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 Ca2+ loading or release, as occurs in some other cardiomyopathic models.
Wang et al. (Tue,) conducted a other in Dilated Cardiomyopathy. Overexpression of the α1C-subunit of the L-type Ca2+ channel (α1CTG) vs. Non-transgenic (NTG) littermates was evaluated on Cardiac hypertrophy, heart failure development, and Ca2+ handling characteristics. Mice overexpressing the α1C-subunit of the L-type Ca2+ channel develop a hypercontractile state that progresses to dilated cardiomyopathy with increased SR Ca2+ loading and both systolic and diastolic failure.