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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.

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Electrophysiological effects of Cav1.2α1C overexpression in mouse ventricular myocytes.(A) Averaged peak current-voltage relationships demonstrate significant increase of ICa,L density at multiple depolarizing pulses in NFTG and FTG compared with NTG cardiomyocytes. The voltage protocol used to record ICa,L is shown in the inset. (B) Inactivation time constants (τfast and τslow) were determined from ICa,L traces depolarized to +10 mV fitted by double exponential equation: Y = Ymin+ A1×[1−exp(−t/τfast)] + A2×[1−exp(−t/τslow)], where Y is the fraction of recovery, A1 and A2 are the maximum values of the fast and slow component, and τfast and τslow are the time constants, respectively.
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pone-0004133-g002: Electrophysiological effects of Cav1.2α1C overexpression in mouse ventricular myocytes.(A) Averaged peak current-voltage relationships demonstrate significant increase of ICa,L density at multiple depolarizing pulses in NFTG and FTG compared with NTG cardiomyocytes. The voltage protocol used to record ICa,L is shown in the inset. (B) Inactivation time constants (τfast and τslow) were determined from ICa,L traces depolarized to +10 mV fitted by double exponential equation: Y = Ymin+ A1×[1−exp(−t/τfast)] + A2×[1−exp(−t/τslow)], where Y is the fraction of recovery, A1 and A2 are the maximum values of the fast and slow component, and τfast and τslow are the time constants, respectively.

Mentions: Peak ICa density in NFTG and FTG was increased compared to NTG, despite a significant increase in cell capacitance (293.5±15.02 pF, 330.93±13.53 pF vs 254.61±7.76 pF, respectively). No statistically significant difference was observed between NFTG and FTG (Figure 2A). Inactivation rate constants of ICaL are illustrated in Figure 2B. Tau fast did not differ among groups but Tau slow was prolonged in both TG groups compared to NTG. In rodent myocytes, the rested state Ca2+ transient in Figure 3 is usually the maximal that can be achieved, due to a maximum SR Ca2+ load and release achieved during rest. Upon continued stimulation from rest a typical negative staircase in Ca2+ transient typically occurs. This reflects, in part, a net reduction in cell and SR Ca2+ loading.


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)

Electrophysiological effects of Cav1.2α1C overexpression in mouse ventricular myocytes.(A) Averaged peak current-voltage relationships demonstrate significant increase of ICa,L density at multiple depolarizing pulses in NFTG and FTG compared with NTG cardiomyocytes. The voltage protocol used to record ICa,L is shown in the inset. (B) Inactivation time constants (τfast and τslow) were determined from ICa,L traces depolarized to +10 mV fitted by double exponential equation: Y = Ymin+ A1×[1−exp(−t/τfast)] + A2×[1−exp(−t/τslow)], where Y is the fraction of recovery, A1 and A2 are the maximum values of the fast and slow component, and τfast and τslow are the time constants, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0004133-g002: Electrophysiological effects of Cav1.2α1C overexpression in mouse ventricular myocytes.(A) Averaged peak current-voltage relationships demonstrate significant increase of ICa,L density at multiple depolarizing pulses in NFTG and FTG compared with NTG cardiomyocytes. The voltage protocol used to record ICa,L is shown in the inset. (B) Inactivation time constants (τfast and τslow) were determined from ICa,L traces depolarized to +10 mV fitted by double exponential equation: Y = Ymin+ A1×[1−exp(−t/τfast)] + A2×[1−exp(−t/τslow)], where Y is the fraction of recovery, A1 and A2 are the maximum values of the fast and slow component, and τfast and τslow are the time constants, respectively.
Mentions: Peak ICa density in NFTG and FTG was increased compared to NTG, despite a significant increase in cell capacitance (293.5±15.02 pF, 330.93±13.53 pF vs 254.61±7.76 pF, respectively). No statistically significant difference was observed between NFTG and FTG (Figure 2A). Inactivation rate constants of ICaL are illustrated in Figure 2B. Tau fast did not differ among groups but Tau slow was prolonged in both TG groups compared to NTG. In rodent myocytes, the rested state Ca2+ transient in Figure 3 is usually the maximal that can be achieved, due to a maximum SR Ca2+ load and release achieved during rest. Upon continued stimulation from rest a typical negative staircase in Ca2+ transient typically occurs. This reflects, in part, a net reduction in cell and SR Ca2+ loading.

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