Abstract 13473: Impaired Atrial Natriuretic Peptide Potency in Human Acute Decompensated Heart Failure and Therapeutic Potential of a Novel Designer Peptide (MANP) Using an Innovative Ex-Vivo Precision Medicine Assay

Abstract

Introduction: Atrial natriuretic peptide (ANP) is the most potent endogenous activator of the guanylyl cyclase A receptor (GC-A) mediating cardiorenal protective actions by increasing cGMP production. To test the hypothesis that acute decompensated heart failure (ADHF) is associated with increased circulating ANP but with reduced GC-A potency, we developed an ex-vivo precision medicine assay to quantify the potency of circulating ANP in plasma from healthy and ADHF subjects. Further, we assessed the ex-vivo potency of MANP, a novel ANP analog with greater cGMP activation than ANP, also using plasma of healthy and ADHF subjects. Methods: For the potency assay, we engineered HEK293 cells to overexpress human GC-A. Plasma from individual healthy (n=4) and ADHF (n=4) subjects was incubated in the assay and cGMP was assessed. The endogenous ANP derived cGMP was evaluated against the cGMP response of equimolar synthetic ANP (S ANP ) to assess potency of ANP from each cohort. MANP mediated cGMP generation was also assessed in the assay using healthy and ADHF plasma. Results: Healthy plasma, in which plasma ANP was 26±5 pg/mL, generated 10.3±0.7 pmol/mL of cGMP. S ANP added to the assay to mimic endogenous ANP levels in healthy subjects produced 7.8±0.5 pmol/mL of cGMP. ADHF plasma with markedly elevated ANP (350±57pg/mL) generated 23.5±3.1 pmol/mL of cGMP. S ANP mimicking plasma ANP in ADHF produced 59.7±13.8 pmol/mL of cGMP, which was greater than cGMP generated from ADHF patient-derived plasma (p<0.05), consistent with reduced potency of endogenous ANP in ADHF. Low treatment dose of MANP (LD MANP ; 10 -8 M) in healthy plasma increased cGMP to 45±5.5 pmol/ml while high treatment dose (HD MANP ; 10 -6 M) increased cGMP to 167.1±14.1 pmol/mL. In markedly elevated ANP ADHF plasma, LD MANP increased cGMP to 60.4±9.7 pmol/mL while HD MANP increased cGMP to 200.8±5.4 pmol/mL (p<0.03 for both) demonstrating similar cGMP production by MANP in healthy and ADHF plasma. Conclusions: Employing a novel ex-vivo precision medicine ANP/GC-A/cGMP assay, we conclude that ADHF is characterized by elevated ANP yet with impaired potency in GC-A activation and cGMP generation. MANP overcomes this impairment and serves as a potential efficacious GC-A activating therapeutic in heart failure.