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Developing a rat model of dilated cardiomyopathy with improved survival.

ABSTRACT: To compare the continuous infusion and intermittent bolus injection administration protocols of doxorubicin (Dox) under the same cumulative dose (12 mg/kg), and establish a rat dilated cardiomyopathy model with improved survival, a total of 150 Sprague-Dawley (SD) rats were divided into three groups: a control group, administered with normal saline; a Dox 1 group, administration twice a week at 1 mg/kg; a Dox 2, administration once a week at 2 mg/kg. Mortality rates in the Dox 1 and Dox 2 groups were 22% and 48%, respectively (P<0.05). As shown by echocardiography, both Dox groups exhibited significant chamber dilatation and reduced cardiac function (all P<0.05 vs. control). Plasma brain natriuretic peptide and C-reactive protein concentrations were significantly increased (P<0.05) with both Dox regimens. The concentrations of Caspase-3 in myocardial tissues of rats significantly increased in both doxorubicin regimens. Myocardial metabolism imaging by histology and ¹⁸F-fluoro-deoxyglucose-positron emission tomography (¹⁸FDG-PET) both revealed decreased myocardial viability and necrosis, and even interstitial fibrosis, in left ventricles (LVs) in both Dox groups. Serum creatinine and aspartate aminotransferase concentrations were significantly higher in the Dox 2 model than in the Dox 1 model. Doxorubicin given at both regimens induced dilated cardiomyopathy, while its administration at lower doses with more frequent infusions reduced the mortality rate.

SUBMITTER: Shen LJ

PROVIDER: S-EPMC5172601 | biostudies-literature | 2016 Dec.

REPOSITORIES: biostudies-literature

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Developing a rat model of dilated cardiomyopathy with improved survival.

Shen Li-Juan LJ Lu Shu S Zhou Yong-Hua YH Li Lan L Xing Qing-Min QM Xu Yong-Liang YL

Journal of Zhejiang University. Science. B 20161201 12

To compare the continuous infusion and intermittent bolus injection administration protocols of doxorubicin (Dox) under the same cumulative dose (12 mg/kg), and establish a rat dilated cardiomyopathy model with improved survival, a total of 150 Sprague-Dawley (SD) rats were divided into three groups: a control group, administered with normal saline; a Dox 1 group, administration twice a week at 1 mg/kg; a Dox 2, administration once a week at 2 mg/kg. Mortality rates in the Dox 1 and Dox 2 groups ...[more]

PMID: 27921402

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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.

Project description:Analysis of the effects of aging on the development of dilated cardiomyopathy by characterizing both changes in ejection fraction (EF) and gene expression profile in 3 groups of male mice: Control (Cont or WT, n=11) and transgenic (Tg or KO) mice with either high EF (KO-H or Tg-H, n=7) or low EF (KO-L or Tg-L, n=6). We previously produced a line of transgenic mice (Tg) on a mixed genetic background where cardiac-specific overexpression of Cre recombinase reduced expression of the EP4 receptor gene. There were no obvious phenotypes in 10-12-week-old male Tg mice. To determine if a cardiac phenotype developed in aged mice, we assessed cardiac structure and function by echocardiography, histology and gene expression in 23-33-week-old male Tg and littermates (Cont). After echocardiography, hearts were removed to assess hypertrophy (MCSA), fibrosis (ICF) and macrophage infiltration by histological methods and for extraction of total RNA and protein. Cont mice had a normal EF of 80Â±0.6% (n=70), whereas Tg mice had a lower EF (60Â±2.7%, n=55, p<0.001) coupled with left ventricular dilatation. The distribution of EFs in the Tg mice was large, ranging from normal to below 30%. MCSA and infiltrating macrophages were not different between groups, but ICF increased by 35% in Tg mice. Cre protein levels in heart lysates did not correlate with either age or EF. In contrast to male Tg mice, female Tg mice had no cardiac dysfunction assessed by echocardiography from 12 to 28 weeks of age. To understand gene expression differences between Cont and Tg mice, whole genome gene expression profiling (Illumina BeadChips) on hearts of 30-32 week old male mice was done. Data indicated that 595 genes were overexpressed in the Tg hearts, 156 of which changed more than 2-fold, including genes involved in remodeling, inflammation, and oxidative stress. 512 genes were downregulated in the Cont hearts, 79 of which changed more than 2-fold, including genes involved with calcium handling, K+ channels, and fatty acid transport and metabolism. In conclusion, Cre overexpression and EP4 knock down in cardiac myocytes in aged male but not female Tg mice are in part associated with increased fibrosis, reduced EF and dilated cardiomyopathy; however, Cre protein itself does not seem to be responsible for the cardiomyopathy. The absence of cardiac dysfunction in female mice suggests a sexual dimorphism in the phenotype. Creation of the cardiac-myocyte specific EP4 KO mouse and littermate controls was described in JY Qian et al, Hypertension 2008: 51(pt 2):560-566. Total RNA extracted from left ventricle of control (Cont or WT, n =11) and cardiac-specific EP4 KO (Tg or KO, n=13) male mice (mean age 31 weeks).

Project description:Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular dilatation and impaired systolic function. Patients with DCM suffer from heart failure, arrhythmia, and are at risk of premature death. DCM has a prevalence of one case out of 2500 individuals with an incidence of 7/100,000/year (but may be under diagnosed). In many cases the disease is inherited and is termed familial DCM (FDC). FDC may account for 20-48% of DCM. FDC is principally caused by genetic mutations in FDC genes that encode for cytoskeletal and sarcomeric proteins in the cardiac myocyte. Family history analysis is an important tool for identifying families affected by FDC. Standard criteria for evaluating FDC families have been published and the use of such criteria is increasing. Clinical genetic testing has been developed for some FDC genes and will be increasingly utilized for evaluating FDC families. Through the use of family screening by pedigree analysis and/or genetic testing, it is possible to identify patients at earlier, or even presymptomatic stages of their disease. This presents an opportunity to invoke lifestyle changes and to provide pharmacological therapy earlier in the course of disease. Genetic counseling is used to identify additional asymptomatic family members who are at risk of developing symptoms, allowing for regular screening of these individuals. The management of FDC focuses on limiting the progression of heart failure and controlling arrhythmia, and is based on currently accepted treatment guidelines for DCM. It includes general measures (salt and fluid restriction, treatment of hypertension, limitation of alcohol intake, control of body weight, moderate exercise) and pharmacotherapy. Cardiac resynchronization, implantable cardioverter defibrillators and left ventricular assist devices have progressively expanding usage. Patients with severe heart failure, severe reduction of the functional capacity and depressed left ventricular ejection fraction have a low survival rate and may require heart transplant.

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Developing a rat model of dilated cardiomyopathy with improved survival.

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Developing a rat model of dilated cardiomyopathy with improved survival.

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