Normalizing Plasma Renin Activity in Experimental Dilated Cardiomyopathy: Effects on Edema, Cachexia, and Survival

Figures

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  Figure 1. Heart failure stages, study design, and effects of aliskiren, a direct renin inhibitor (DRI). (a) Schematic overview of the natural history of heart failure (HF) progression, biomarker changes, and experimental design (salmon-colored area), in an established model of dilated cardiomyopathy (DCM) in female mice as reported [27]. Mice with DCM were randomly treated with aliskiren (DCM+DRI) or nothing (DCM+vehicle) in drinking water (see Methods Section). Black hash-marks indicate time points for measurement of body composition, while echocardiography and blood-tissue collection were completed at 90 days. The impact of aliskiren treatment on plasma (b) renin activity, (c) angiotensin II (Ang II), and (d) aldosterone levels at 90 days. The number of DCM mice is indicated. For reference, values for wild-type (WT) littermates are shown as a blue line (n = 4). Data analyzed with one-way ANOVA and represented as mean ± SE. Not significant (NS), ++ p < 0.01, +++ p < 0.001 (red, WT vs. DCM+vehicle; black, WT vs. DCM+DRI), *** p < 0.001 (DCM+vehicle vs. DCM+DRI).

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  Figure 2. Direct renin inhibitor (DRI) treatment significantly improves survival and systolic function in mice with dilated cardiomyopathy (DCM). (a) Kaplan–Meier survival curves of control mice with DCM (DCM+vehicle, red, n = 13 deaths + 8 censored) vs. DCM mice treated with DRI (DCM+DRI, black, n = 21 deaths + 8 censored). WT (n = 4) values are provided for reference. (b) Short axis m-mode examples of DCM+vehicle and DCM+DRI treated mice at 90 days of age. (c,d) Left ventricular systolic function measured as ejection fraction (EF, WT = 62.8%) and fractional shortening (FS, WT = 34%). (e) Differences in cardiac output (CO, WT = 15.5 mL/min) between DCM+vehicle and DCM+DRI mice. (f) Pearson’s correlation analysis of 90-day EF and (g) CO vs. survival. DCM control mice (DCM+vehicle, red-circle, n = 20), DCM mice treated with DRI (DCM+DRI, black-square, n = 27). Differences between groups were analyzed by Mantel–Cox test and Mann–Whitney test. Pearson’s correlation coefficient (rp) and p-values are shown. Data are represented as mean ± SE, * p < 0.05, ** p < 0.01 (DCM+vehicle vs. DCM+DRI).

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  Figure 3. Morphometric changes at 90 days. Heart weight to body weight (HW/BW, %) and lung weight to body weight (LW/BW, %) ratios at a 90-day collection of censored subgroups. DCM control (DCM+vehicle) and aliskiren treated (DCM+DRI) group sizes are shown. For reference, the mean ratios for wild-type mice (WT, n = 4) for HW/BW are shown as a blue dashed line and the LW/BW as a solid blue solid line. Data were analyzed with two-tailed unpaired t-test and represented as mean ± SE. Not significant (NS), ++ p < 0.01, +++ p < 0.001, ++++ p < 0.0001 (red, WT vs. DCM+vehicle; black, WT vs. DCM+DRI), * p < 0.05 (DCM+vehicle vs. DCM+DRI).

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  Figure 4. Effects of direct renin inhibition on systemic changes in mouse whole-body composition associated with heart failure progression. Age-related changes in (a) body weight, (b) total water, (c) extracellular water (ECW), (d) fat, (e) lean mass, and (f) combined fat and lean mass in DCM mice with (DCM+DRI) or without renin inhibition (DCM+vehicle) by comparison to wild-type (WT, without DCM) mice. WT (n = 9–15), DCM+vehicle (n = 10–27), DCM+DRI (n = 17–29). (g–i) Pearson’s correlation between survival (days) and (g) body weight; (h) extracellular water; and (i) fat measurements at 90 days. DCM+vehicle mice (n = 20) and DCM+DRI mice (n = 27). Differences between groups were analyzed by two-way ANOVA. Data are represented as the mean ± SE. Pearson’s correlation coefficient (rp) and p-values shown. + p < 0.05, ++ p < 0.01, ++++ p < 0.0001 (red, WT vs. DCM+vehicle; black, WT vs. DCM+DRI), * p < 0.05, *** p < 0.001, **** p < 0.0001 (DCM+vehicle vs. DCM+DRI).

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  Figure 5. Impact of direct renin inhibitor, aliskiren (DRI-aliskiren) treatment on heart failure plasma biomarkers in female mice with dilated cardiomyopathy. (a) Atrial natriuretic peptide (ANP); (b) cyclic guanosine monophosphate (cGMP); (c) corin; and (d) neprilysin plasma levels. DCM+vehicle (red bar) and DRI-aliskiren treated (DCM+DRI, black bar) group numbers are indicated. For reference, values for wild-type (WT) mice are shown as a blue dashed line (n = 4). Data analyzed with one-way ANOVA and represented as mean ± SE. Not significant (NS), + p < 0.05, ++ p < 0.01 (red, WT vs. DCM+vehicle; black, WT vs. DCM+DRI) and *** p < 0.001 (DCM+vehicle vs. DCM+DRI).