Limits...
Dilated cardiomyopathy with increased SR Ca2+ loading preceded by a hypercontractile state and diastolic failure in the alpha(1C)TG mouse.

Wang S, Ziman B, Bodi I, Rubio M, Zhou YY, D'Souza K, Bishopric NH, Schwartz A, Lakatta EG - PLoS ONE (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, USA.

ABSTRACT
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.

Show MeSH

Related in: MedlinePlus

Development of cardiac hypertrophy and heart failure in Cav1.2α1C transgenic mice.(A) Measurement of heart weight, (B) body weight, (C) heart/body weight ratio and (D) size of myocytes estimated from cell capacitance in Non-Transgenic (NTG), Non-Failing Cav1.2α1C-Transgenic (NFTG) and Failing Cav1.2α1C-Transgenic (FTG) mouse groups (8–12 mo). n =  9 NTG, 4 NFTG and 4 FTG in (A,B and C) and 26 NTG, 12 NFTG and 31 FTG in (D).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2607013&req=5

pone-0004133-g001: Development of cardiac hypertrophy and heart failure in Cav1.2α1C transgenic mice.(A) Measurement of heart weight, (B) body weight, (C) heart/body weight ratio and (D) size of myocytes estimated from cell capacitance in Non-Transgenic (NTG), Non-Failing Cav1.2α1C-Transgenic (NFTG) and Failing Cav1.2α1C-Transgenic (FTG) mouse groups (8–12 mo). n =  9 NTG, 4 NFTG and 4 FTG in (A,B and C) and 26 NTG, 12 NFTG and 31 FTG in (D).

Mentions: Heart weight in FTG was over two-fold greater than in NTG (Figure 1A). Body weight did not differ between NTG and NFTG but body weight increased by 15% in FTG, likely as a result of fluid accumulation (Figure 1B). The heart weight/body weight increased by 43% in NFTG vs NTG, by 27% in FTG vs. NFTG, and by 82% in FTG vs NTG (Figure 1C). The average myocyte size, estimated from cell capacitance, reflected the relative heart mass. It increased by 25% in NFTG vs NTG, and in FTG further increased by 29%. Thus, myocyte size in failing FTG averaged 61% more than that in NTG (Figure 1D).


Dilated cardiomyopathy with increased SR Ca2+ loading preceded by a hypercontractile state and diastolic failure in the alpha(1C)TG mouse.

Wang S, Ziman B, Bodi I, Rubio M, Zhou YY, D'Souza K, Bishopric NH, Schwartz A, Lakatta EG - PLoS ONE (2009)

Development of cardiac hypertrophy and heart failure in Cav1.2α1C transgenic mice.(A) Measurement of heart weight, (B) body weight, (C) heart/body weight ratio and (D) size of myocytes estimated from cell capacitance in Non-Transgenic (NTG), Non-Failing Cav1.2α1C-Transgenic (NFTG) and Failing Cav1.2α1C-Transgenic (FTG) mouse groups (8–12 mo). n =  9 NTG, 4 NFTG and 4 FTG in (A,B and C) and 26 NTG, 12 NFTG and 31 FTG in (D).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2607013&req=5

pone-0004133-g001: Development of cardiac hypertrophy and heart failure in Cav1.2α1C transgenic mice.(A) Measurement of heart weight, (B) body weight, (C) heart/body weight ratio and (D) size of myocytes estimated from cell capacitance in Non-Transgenic (NTG), Non-Failing Cav1.2α1C-Transgenic (NFTG) and Failing Cav1.2α1C-Transgenic (FTG) mouse groups (8–12 mo). n =  9 NTG, 4 NFTG and 4 FTG in (A,B and C) and 26 NTG, 12 NFTG and 31 FTG in (D).
Mentions: Heart weight in FTG was over two-fold greater than in NTG (Figure 1A). Body weight did not differ between NTG and NFTG but body weight increased by 15% in FTG, likely as a result of fluid accumulation (Figure 1B). The heart weight/body weight increased by 43% in NFTG vs NTG, by 27% in FTG vs. NFTG, and by 82% in FTG vs NTG (Figure 1C). The average myocyte size, estimated from cell capacitance, reflected the relative heart mass. It increased by 25% in NFTG vs NTG, and in FTG further increased by 29%. Thus, myocyte size in failing FTG averaged 61% more than that in NTG (Figure 1D).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus