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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.

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.

SUBMITTER: Wang S

PROVIDER: S-EPMC2607013 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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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 Su S Ziman Bruce B Bodi Ilona I Rubio Marta M Zhou Ying-Ying YY D'Souza Karen K Bishopric Nanette H NH Schwartz Arnold A Lakatta Edward G EG

PloS one 20090106 1

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 ...[more]

PMID: 19125184

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Project description:BackgroundThe systolic and diastolic dyssynchrony is physiologically related, but measure different left ventricular mechanisms. Left ventricular systolic mechanical dyssynchrony (systolic LVMD) has shown significant clinical values in improving cardiac resynchronization therapy (CRT) response in the heart failure patients with dilated cardiomyopathy (DCM). Our recent study demonstrated that LV diastolic dyssynchrony (diastolic LVMD) parameters have important prognostic values for DCM patients. However, there are a limited number of studies about the clinical value of diastolic LVMD for CRT. This study aims to explore the predictive values of both systolic LVMD and diastolic LVMD for CRT in DCM patients.MethodsEighty-four consecutive CRT patients with both DCM and complete left bundle branch block (CLBBB) who received gated resting SPECT MPI at baseline were included in the present study. The phase analysis technique was applied on resting gated short-axis SPECT MPI images to measure systolic LVMD and diastolic LVMD, characterized by phase standard deviation (PSD) and phase histogram bandwidth (PBW). CRT response was defined as ≥ 5% improvement of LVEF at 6-month follow-up. Variables with P < 0.10 in the univariate analysis were included in the multivariate cox analysis.ResultsDuring the follow-up period, 59.5% (50 of 84) patients were CRT responders. The univariate cox regression analysis showed that at baseline QRS duration, non-sustained ventricular tachycardia (NS-VT), systolic PSD, systolic PBW, diastolic PSD, diastolic PBW, scar burden and LV lead in the scarred myocardium were statistically significantly associated with CRT response. The multivariate cox regression analysis showed that QRS duration, NS-VT, systolic PSD, systolic PBW, diastolic PSD, and diastolic PBW were independent predictive factors for CRT response. Furthermore, the rate of CRT response was 94.4% (17 of 18) in patients whose LV lead was in the segments with both the first three late contraction and the first three late relaxation; by contrast, the rate of CRT response was only 6.7% (1 of 15, P < 0.000) in patients whose LV lead was in the segments with neither the first three late contraction nor the first three late relaxation.ConclusionBoth systolic LVMD and diastolic LVMD from gated SPECT MPI have important predictive values for CRT response in DCM patients. Pacing at LV segments with both late contraction and late relaxation has potential to increase the CRT response.

Project description:AimsThe aims of this paper were to investigate the analytical performance of the nine prognostic scales commonly used in heart failure (HF), in patients with dilated cardiomyopathy (DCM), and to develop a unique prognostic model tailored to DCM patients.Methods and resultsThe hospital and outpatient records of 406 DCM patients were retrospectively analysed. The information on patient status was gathered after 48.2 ± 32.0 months. Tests were carried out to ascertain the prognostic accuracy in DCM using some of the most frequently applied HF prognostic scales (Barcelona Bio-Heart Failure, Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity, Studio della Streptochinasi nell'Infarto Miocardico-Heart Failure, Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure, Meta-Analysis Global Group in Chronic Heart Failure, MUerte Subita en Insuficiencia Cardiaca, Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure, Seattle Heart Failure Model) and one dedicated to DCM, that of Miura et al. At follow-up, 70 DCM patients (17.2%) died. Most analysed scores substantially overestimated the mortality risk, especially in survivors. The prognostic accuracy of the scales were suboptimal, varying between 60% and 80%, with the best performance from Barcelona Bio-Heart Failure and Seattle Heart Failure Model for 1-5 year mortality [areas under the receiver operating curve 0.792-0.890 (95% confidence interval 0.725-0.918) and 0.764-0.808 (95% confidence interval 0.682-0.934), respectively].Based on our accumulated data, a self-developed DCM prognostic model was constructed. The model consists of age, gender, body mass index, symptoms duration, New York Heart Association class, diabetes mellitus, prior stroke, abnormal liver function, dyslipidaemia, left bundle branch block, left ventricle end-diastolic diameter, ejection fraction, N terminal pro brain natriuretic peptide, haemoglobin, estimated glomerular filtration rate, and pharmacological and resynchronisation therapy. This newly created prognostic model outperformed the analysed HF scales.ConclusionsAn analysis of various HF prognostic models found them to be suboptimal for DCM patients. A self-developed DCM prognostic model showed improved performance over the nine other models studied. However, further validation of the prognostic model in different DCM populations is required.

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Dataset Information

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

Publications

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

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