Abstract 15611: Mild Renal Dysfunction Induces Cardiomyocyte Apoptosis and Cardiac Fibrosis: Prevented by Chronic Subcutaneous Cenderitide
Chronic kidney disease (CKD) increases cardiovascular morbidity by unclear mechanisms. We reported that mild renal impairment produced by unilateral nephrectomy (UNX) results in early cardiac fibrosis and mild diastolic impairment without hypertension (HTN) together with activation of pro-apoptotic genes. Natriuretic peptides (NP) are cardioprotective via guanylyl cyclase (GC) receptors. CD-NP is a novel dual GC receptor agonist which is antifibrotic via the GC-B receptor and aldosterone suppressing via GC-A which also enhances cell survival pathways. We hypothesized that mild renal dysfunction results in cardiomyocyte apoptosis and that CD-NP would suppress apoptosis and aldosterone activation thus preventing ventricular remodeling.
Methods: Wistar rats were studied, (Sham (S) n=10, UNX n=9, CD-NP + UNX n=9) 4 wk after UNX. LV mass, EF, Circ systolic strain (Cs) and, early (Csr-E) and late (Csr-A) diastolic strain rates and ratio were assessed by echo speckle tracking. LV fibrosis (Pic Red) was also determined. Apoptosis was evaluated via TUNEL staining. CD-NP was chronically administered subcutaneously (170ng/kg/min) for 2 weeks following UNX via osmotic minipumps.
Results: At 4wk after UNX, cardiac apoptosis was significantly increased in UNX compared to a normal control group, (S:0.2±0.1, UNX:36±15%). CD-NP prevented apoptosis (CD-NP UNX:0.9±0.3% vs UNX). Also, CD-NP suppressed LV fibrosis vs. UNX (S:2.4±0.1, UNX:4.2±0.5, UNX CD-NP:3±0.4%). Aldosterone was suppressed in CD-NP UNX vs. UNX. Echocardiography demonstrated EF, Csr-E and Csr-E/A ratio were higher in the CD-NP UNX group vs UNX consistent with improved systolic and diastolic function. Blood pressure and GFR were not different between groups. A reduction in urinary protein excretion was also observed. (all p<0.05)
Conclusion: Mild chronic impairment of renal function by UNX induces cardiomyocyte apoptosis, LV fibrosis and mild diastolic dysfunction in the absence of hypertension. Chronic delivery of the dual GC receptor agonist natriuretic peptide CD-NP decreased LV fibrosis in experimental mild renal insufficiency, suppressed aldosterone, prevented apoptosis, and improved overall diastolic function. These studies underscore an important kidney-heart connection.
- © 2011 by American Heart Association, Inc.