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

Abstract

Heart failure (HF) patients frequently have elevated plasma renin activity. We examined the significance of elevated plasma renin activity in a translationally-relevant model of dilated cardiomyopathy (DCM), which replicates the progressive stages (A–D) of human HF. Female mice with DCM and elevated plasma renin activity concentrations were treated with a direct renin inhibitor (aliskiren) in a randomized, blinded fashion beginning at Stage B HF. By comparison to controls, aliskiren treatment normalized pathologically elevated plasma renin activity (p < 0.001) and neprilysin levels (p < 0.001), but did not significantly alter pathological changes in plasma aldosterone, angiotensin II, atrial natriuretic peptide, or corin levels. Aliskiren improved cardiac systolic function (ejection fraction, p < 0.05; cardiac output, p < 0.01) and significantly reduced the longitudinal development of edema (extracellular water, p < 0.0001), retarding the transition from Stage B to Stage C HF. The normalization of elevated plasma renin activity reduced the loss of body fat and lean mass (cachexia/sarcopenia), p < 0.001) and prolonged survival (p < 0.05). In summary, the normalization of plasma renin activity retards the progression of experimental HF by improving cardiac systolic function, reducing the development of systemic edema, cachexia/sarcopenia, and mortality. These data suggest that targeting pathologically elevated plasma renin activity may be beneficial in appropriately selected HF patients.

Cardiac-Specific Overexpression of Catalytically Inactive Corin Reduces Edema, Contractile Dysfunction, and Death in Mice with Dilated Cardiomyopathy

“…Transcript levels of GATA-4, a common transcription factor for corin, ANP, and BNP [32] remained unchanged among all three groups (Figure 5g). [22,35,36]. As expected, these markers were significantly increased above normal WT levels (corin-WT/WT) in both DCM groups ( Figure 5).…”

“…Pleural effusion, lung water retention, or lung edema are clinical manifestations of advanced HF (Stages C-D HF) in human [6,40] and in DCM mice, as we previously reported [22,35,36]. Necropsy analysis of sub-groups of mice at 90 days of age confirmed the presence of pleural effusion and lung edema in corin-WT/DCM mice (Figure 3a,b).…”

“…Plasma ANP, BNP, cGMP, and neprilysin are well known biomarkers of HF [41] that are elevated in mice with DCM by 90 days of age (Stages C-D HF) [22,35,36]. As expected, these markers were significantly increased above normal WT levels (corin-WT/WT) in both DCM groups ( Figure 5).…”

“…Similarly, lung edema (LW/BW) was significantly reduced in corin-Tg(i)/DCM vs. corin-WT/DCM mice ( Figure 3b, p < 0.05) but was not significantly different from WT group (Figure 3b). Female DCM mice at Stages C-D HF, like humans, accumulate edema in the lungs, and peripheral tissues (systemic edema), which can be measured by as increases in extracellular water (ECW; Figure 3c) using noninvasive quantitative magnetic resonance (QMR) for body composition monitoring as we previously reported [35]. By 90 days of age, corin-WT/DCM mice accumulated significantly elevated ECW levels as compared with corin-Tg(i)/DCM littermate mice (p < 0.0001, Figure 3c), though BW (Figure 2e) were relatively comparable.…”

“…Some of the protective effects of corin in DCM may be mediated through the non-catalytic domains of the molecule. To address this hypothesis, we investigated the effect of transgenic overexpression of catalytically inactive corin (corin-Tg(i)) in the heart of mice with DCM, which develop Stages A-D of human HFrEF in the setting of preserved kidney function [16,22,[34][35][36][37][38]. Our results indicate that catalytically inactive corin reduces lung and systemic edema, improves cardiac systolic dysfunction, and prolongs survival.…”