TY - JOUR
T1 - Normalizing plasma renin activity in experimental dilated cardiomyopathy
T2 - Effects on edema, cachexia, and survival
AU - Sullivan, Ryan D.
AU - Mehta, Radhika M.
AU - Tripathi, Ranjana
AU - Gladysheva, Inna P.
AU - Reed, Guy L.
N1 - Funding Information:
This study was supported by the National Institutes of Health grants NS089707 (to G.L.R.) and HL115036 (to I.P.G). We gratefully acknowledge the use of the QMR system and technical expertise from Ramesh Narayanan and Suriyan Ponnusamy. Many thanks to the husbandry, cagewash, supervisory, and veterinary staff of the UTHSC Cancer Research Building Laboratory Animal Care Unit for their animal care, attention to detail, and support throughout the study.
Funding Information:
Funding: This study was supported by the National Institutes of Health grants NS089707 (to G.L.R.) and HL115036 (to I.P.G).
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/8/2
Y1 - 2019/8/2
N2 - 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.
AB - 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.
KW - Aliskiren
KW - Cachexia/sarcopenia
KW - Dilated cardiomyopathy
KW - Edema
KW - Heart failure
KW - Neprilysin
KW - Plasma renin activity
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U2 - 10.3390/ijms20163886
DO - 10.3390/ijms20163886
M3 - Article
C2 - 31404946
AN - SCOPUS:85071282266
SN - 1422-0067
VL - 20
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 16
M1 - 3886
ER -