Deleterious Effects of Hyperactivity of the Renin-Angiotensin System and Hypertension on the Course of Chemotherapy-Induced Heart Failure after Doxorubicin Administration: A Study in Ren-2 Transgenic Rat

Figures

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  Figure 1. Assessment of the cardiac functional parameters by echocardiography before administration of doxorubicin (basal values), at the end of doxorubicin administration (2 weeks values) and two weeks after termination of doxorubicin treatment (4 weeks values) in normotensive, transgene-negative Hannover Sprague-Dawley (HanSD) and hypertensive, Ren-2 transgenic (TGR) rats. Cardiac output (A), stroke volume (B), left ventricle ejection fraction (C), left ventricle fraction shortening (D), heart rate (E). * p < 0.05 compared with untreated animals of the same strain at the same time point. The values are means ± SEM.

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  Figure 2. Assessment of the cardiac morphological parameters by echocardiography before administration of doxorubicin (basal values), at the end of doxorubicin administration (2 weeks values) and two weeks after termination of doxorubicin treatment (4 weeks values) in normotensive, transgene-negative Hannover Sprague-Dawley (HanSD) and hypertensive, Ren-2 transgenic (TGR) rats. Left ventricle diastolic diameter (A), left ventricle anterior wall thickness in diastole (B), left ventricle anterior wall thickness in systole (C), left ventricle posterior wall thickness in diastole (D), left ventricle anterior wall thickness in (E), relative wall thickness (F). * p < 0.05 compared with untreated animals of the same strain at the same time point. The values are means ± SEM.

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  Figure 3. Weights and biochemical parameter. Body weight (A), kidney weight (B) and plasma albumin levels (C) two weeks after the last doxorubicin injection (at the end of the experimental protocol) in normotensive, transgene-negative Hannover Sprague-Dawley (HanSD) and hypertensive, Ren-2 transgenic (TGR) rats. * p < 0.05 compared with untreated animals of the same strain at the same time point. The values are means ± SEM and are pooled from the three series of experiments.

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  Figure 4. Whole heart weight (A), weights of individual components of the heart (B,C), their ratio (D) and wet and dry lung weights (E,F) two weeks after the last doxorubicin injection (i.e., at the end of the experimental protocol) in normotensive, transgene-negative Hannover Sprague-Dawley (HanSD) and hypertensive, Ren-2 transgenic (TGR) rats. * p < 0.05 compared with untreated animals of the same strain. # p <0.05 versus HanSD rats within the same protocol. The values are means ± SEM and are pooled from the three series of experiments.

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  Figure 5. The first data part of the left ventricular cardiac function assessment by invasive hemodynamic analysis performed two weeks after the last doxorubicin injection (i.e., at the end of the experimental protocol) in normotensive, transgene-negative Hannover Sprague-Dawley (HanSD) and hypertensive, Ren-2 transgenic (TGR) rats. Left ventricle peak pressure (A), left ventricle end-diastolic pressure (B), left ventricle end-diastolic volume (C), maximum rates of pressure rise (+dP/dt)max (D), maximum rates of pressure fall (−dP/dt)max (E), relaxation constant tau (F). * p < 0.05 compared with untreated animals of the same strain. The values are means ± SEM.

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  Figure 6. The second part of the data for the left ventricular cardiac function assessment by invasive hemodynamic analysis two weeks after the last doxorubicin injection (i.e., at the end of the experimental protocol) in normotensive, transgene-negative Hannover Sprague-Dawley (HanSD) and hypertensive, Ren-2 transgenic (TGR) rats. End-systolic pressure volume relationship (ESPVR) (A), end-diastolic pressure volume relationship (EDPVR) (B), left ventricle ejection fraction (C), preload recruitable stroke work (D), left ventricle wall stress (E), ventricular-arterial coupling (F). * p <0.05 compared with untreated animals of the same strain. The values are means ± SEM. # p < 0.05 compared with untreated HanSD rats.

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  Figure 7. Representative steady-state loops from the pressure-volume analysis performed in (A) untreated normotensive, transgene-negative Hannover Sprague-Dawley (HanSD) rats, (B) HanSD rats two weeks after the last doxorubicin injection (i.e., at the end of the experimental protocol), (C) untreated hypertensive, Ren-2 transgenic (TGR) rats and (D) TGR after doxorubicin administration. ESPVR, end-systolic pressure volume relationship (dotted red line). EDPVR, end-diastolic pressure volume relationship (blue line).

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  Figure 8. Right ventricle function. Assessment of the right ventricle diastolic diameter (A) and right ventricle ejection fraction (B) by echocardiography after the last doxorubicin injection (i.e., at the end of the experimental protocol) in normotensive, transgene-negative Hannover Sprague-Dawley (HanSD) and hypertensive, Ren-2 transgenic (TGR) rats. * p < 0.05 compared with untreated animals of the same strain. The values are means ± SEM.

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  Figure 9. Plasma and kidney biochemical parameters. Plasma and kidney norepinephrine (A,E), angiotensin II (ANG II) (B,F), angiotensin 1-7 (ANG 1-7) (C,G) levels and the ratio of ANG 1-7 to ANG II (D,H) after the last doxorubicin injection (i.e., at the end of experimental protocol) in normotensive, transgene-negative Hannover Sprague-Dawley (HanSD) and hypertensive, Ren-2 transgenic (TGR) rats. * p < 0.05 compared with untreated animals of the same strain. # p < 0.05 versus HanSD rats exposed to the same protocol. The values are means ± SEM.