The effect of the renin-angiotensin-aldosterone system inhibition on myocardial function in early and late phases of dilated cardiomyopathy in Tgaq*44 mice.

BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) determines progression of heart failure (HF) in humans, and RAAS inhibition is a major therapeutic strategy in HF. AIM: To assess the effect of angiotensin-converting enzyme inhibitor (ACE-I) and aldosterone receptor antagonist (ARA) therapy on the development of HF at its early and late stage in a murine model of dilated cardiomyopathy (Tgaq*44 mice). METHODS: Tgaq*44 mice at the early or advanced stage of HF received combined therapy including ACE-I (perindopril 2 mg/kg) and ARA (canrenone 20 mg/kg). Cardiac function was assessed by magnetic resonance imaging before and after 2 months of treatment. RESULTS: Combined therapy with perindopril and canrenone resulted in preserved systolic function at the early stage and reduced chamber dilatation at the advanced stage of HF in Tgaq*44 mice. CONCLUSIONS: Activation of the RAAS is involved in progression of HF in Tgaq*44 mice with dilated cardiomyopathy. Therapeutic efficacy of ACE-I and ARA to inhibit systolic dysfunction and cardiac chamber dilation depends on the stage of HF development.

Application of magnetic resonance imaging in vivo for the assessment of the progression of systolic and diastolic dysfunction in a mouse model of dilated cardiomyopathy.

BACKGROUND: The impairment of cardiac diastolic function is essential for the development and progression of heart failure, regardless of the systolic performance of the heart. Novel methods of diagnosis of diastolic dysfunction in experimental animals are needed in order to validate the effectiveness of novel heart failure treatment. AIM: The in vivo characterisation of diastolic and systolic function of the heart during heart failure progression in Tgalphaq*44 mice using magnetic resonance imaging (MRI) and original image analysis. METHODS: Cardiac function in vivo in both Tgalphaq*44 and FVB mice was analysed using MRI at 4.7 T. Magnetic resonance imaging was performed using an ECG triggered fast gradient echo (cine-like flow compensated FLASH) sequence. For the assessment of left ventricle (LV) dynamics at least 20 images per cardiac cycle were acquired in the midventricular short-axis projection at the level of papillary muscles. End-systolic (ESA) and end-diastolic (EDA) areas were estimated from the minimum and maximum values found in the area-time plot. Fractional area change (FAC) defined as (EDA-ESA)/EDA, ejection (ER) and filling (FR) rates defined as slope of the beginning part of the systolic and diastolic limbs were calculated. In addition, heart failure progression in Tgalphaq*44 mice was assessed by morphometric parameters (ventricular weight to body weight index and wet to dry lung weight index), level of BNP mRNA expression as well as survival. RESULTS: Systolic function assessed by FAC% and ER was stable but slightly impaired up to 10 months of age in Tgalphaq*44 mice as compared to the FVB mice. After 12 months of age of the Tgalphaq*44 mice there was a progressive deterioration of systolic function (ER at 10, 12, 14 months of age were 0.0188 +/- 0.00434, 0.0140 +/- 0.00474, 0.0115 +/- 0.00469 1/ms, respectively). Diastolic function of the Tgalphaq*44 hearts was preserved or even slightly augmented between 4 and 10 months of age, then at the age of 12 months and later profoundly impaired (FR at 10, 12, 14 months of age were 0.0280 +/- 0.01031, 0.0196 +/- 0.01050, 0.0158 +/- 0.00833 1/ms, respectively). CONCLUSIONS: The MRI allows reliable in vivo assessment of the systolic and diastolic function in Tgalphaq*44 mice. In Tgalphaq*44 mice after few months of stable and compensated phase of the heart failure decompensation develops that involves impairment of both systolic and diastolic and leads to the fully symptomatic dilated cardiomyopathy. The precise molecular mechanisms of the systolic and diastolic dysfunction and their relative contribution to the heart failure progression in Tgalphaq*44 mice remain to be established.

Detection of mitochondrial dysfunction by EPR technique in mouse model of dilated cardiomyopathy.

Tgalphaq44 mice with targeted overexpression of activated Galphaq protein in cardiomyocytes mimic many of the phenotypic characteristics of dilated cardiomyopathy in humans. However, it is not known whether the phenotype of Tgalphaq44 mice would also involve dysfunction of cardiac mitochondria. The aim of the present work was to examine changes in EPR signals of semiquinones and iron in Fe-S clusters, as compared to classical biochemical indices of mitochondrial function in hearts from Tgalphaq44 mice in relation to the progression of heart failure. Tgalphaq44 mice at the age of 14 months displayed pulmonary congestion, increased heart/body ratio and impairment of cardiac function as measured in vivo by MRI. However, in hearts from Tgalphaq44 mice already at the age of 10 months EPR signals of semiquinones, as well as cyt c oxidase activity were decreased, suggesting alterations in mitochondrial electron flow. Furthermore, in 14-months old Tgalphaq44 mice loss of iron in Fe-S clusters, impaired citrate synthase activity, and altered mitochondrial ultrastructure were observed, supporting mitochondrial dysfunction in Tgalphaq44 mice. In conclusion, the assessment of semiquinones content and Fe(III) analysis by EPR represents a rational approach to detect dysfunction of cardiac mitochondria. Decreased contents of semiquinones detected by EPR and a parallel decrease in cyt c oxidase activity occurs before hemodynamic decompensation of heart failure in Tgalphaq44 mice suggesting that alterations in function of cardiac mitochondria contribute to the development of the overt heart failure in this model.