Title:

Assessment of the cardiac function in mice model of dilated cardiomyopathy (Tgαq*44) and atherosclerosis (apoE/LDLR-/-) by in vivo MRI

Author:

Tyrankiewicz, Urszula Teresa.

Subject:

heart failure ; dilated cardiomyopathy ; atherosclerosis ; mice ; MRI ; dobutamine

Abstract:

Heart Failure development may be a direct effect of pathological changes in the heart structure or cardiac function or may be an indirect effect of systemic pathological processes that influence the heart and lead to cardiac remodelling with the subsequent development of the heart failure. In both cases there is a progressive impairment of systolic and diastolic cardiac function and activation of mechanisms that allow the heart to adapt for pathological condition and maintain its function preserved as long as possible. Slowly progressive changes in the cardiac function at early stages of the heart failure are difficult to assess in patients due to lack of symptoms. Detailed studies on the heart failure and its mechanisms are possible however with the use of murine models of various pathologies. The aim of this work was to develop a dobutamine stress test protocol for cardiac magnetic resonance imaging (MRI) in mice in vivo and its application to the characterization of two different murine models of heart failure: Tgαq*44 mice that develop dilated cardiomyopathy and apoE/LDLR-/- mice at the advanced stage of atherosclerosis when fed standard (apoE/LDLR-/-S) or Low Carbohydrate High Protein diet (apoE/LDLR-/-LCHP). ; Cardiac function of the control and Tgαq*44 mice at the advanced stage of heart failure was measured in vivo using cine FLASH MRI (Bruker 4,7 T) at rest and under β-adrenergic test (dobutamine). Based on cardiac cycle curve fallowing parameters were obtained Ejection Fraction, Cardiac Output, Stroke Volume, End Systolic Volume and End Diastolic Volume. For determination of appropriate doses of dobutamine in the i.p. injection during MRI protocol, 5 different doses were injected i.p. in the range from 0,15 mg/kg to 20 mg/kg.Low and high dobutamine doses that uncovered cardiac inotropic changes and gave reproducible results, were: 0,5 and 5 mg/kg. These doses were applied to the characterization of cardiac changes in Tgαq*44 mice (at 4, 8 and 12 months of age) and in apoE/LDLR-/- mice at the advanced stage of atherosclerosis (when fed standard or after two months of LCHP diet).Results presented in this work confirmed previous data about resting cardiac function in Tgαq*44 mice and extended them. There was: increased filling rate in Tgαq*44 mice at the age of 6 months and decreased ejection rate, filing rate and ejection fraction at the age of 16 months and uncovered lack of cardiac chronotropic reserve at the age of 8 months, then cardiac systolic and diastolic kinetic deterioration at the age of 12 months of age. Further changes involved decreased ejection fraction and stroke volume (at the age of 15 months of age), and then, at the decompensation stage of disease(16-18 months of age): low and high dose of dobutamine uncovered cardiac ischemic response. Obtained results suggest profound influence of diastolic function at early stage in Tgαq*44 mice that proceed contractility impairment and cardiac decompensation in course of the development of dilated cardiomyopathy and successive exhaustion of cardiac chronotropic and inotropic reserve, with secondary impairment of coronary perfusion that leads to a typical ischemic dobutamine response. ; Changes in cardiac function as regards apoE/LDLR-/- mice were as follows: accelerated heart rate, decreased end diastolic volume and decreased stroke volume. ApoE/LDLR-/- mice on LCHP diet had additionally decreased end systolic volume. Dobutamine stress test confirmed preserved contractility (as decreased end systolic area and increased fractional area change) and uncovered lack of slice cardiac output in apoE/LDLR-/-S and apoE/LDLR-/-LCHP mice with lack of chronotropic reserve only in the latter group. In conclusion, MRI based methodology for the assessment of cardiac function using i.p. low and high dobutamine dose stress test allowed for better characterization of cardiac function in heart failure in Tgαq*44 mice developing dilated cardiomyopathy and apoE/LDLR-/- with advanced atherosclerosis then basal cardiac assessment neither assessment based on one dose. This experience may be well used in future experimental studies to explore cardioprotective therapies and mechanism of heart failure progression.

Place of publishing:

Kraków

Level of degree:

2 - studia doktoranckie

Degree discipline:

choroby układu krążenia

Degree grantor:

Uniwersytet Jagielloński. Collegium Medicum. Wydział Lekarski.

Promoter:

Stefan Chłopicki

Date:

2013

Date issued:

2013

Type:

Praca doktorska

Format:

application/pdf

Call number:

ZB-120423

ControlNumberVIRTUA:

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Language:

pol

Access rights:

nieograniczony

Location of original object:

Biblioteka Medyczna Uniwersytetu Jagiellońskiego- Collegium Medicum

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