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C-type natriuretic peptide (CNP) is a cardiorenal-derived hormone that possesses potent anti-fibrotic, anti-hypertrophic, anti-apoptotic and cardiac unloading properties. While plasma and urinary CNP have been shown to be elevated in heart failure (HF) patients, limited studies have simultaneously characterized and evaluated the clinical utility of plasma and urinary CNP in acute decompensated HF (ADHF).
We hypothesize that plasma and urinary CNP are elevated and distinctly regulated in ADHF and elevation of both are a marker of disease severity and will have additional prognostic value for adverse outcomes.
ADHF patients (n=208) and healthy subjects (n=109) were prospectively recruited and urinary and plasma CNP, plasma NT-proBNP, eGFR and urinary protein/creatinine were determined. The 95th percentile (%) of CNP values from healthy subjects were used to establish normal cutoffs. ADHF patients were stratified based on whether their CNP levels were considered as elevated (> 95th % of normal) or normal (≤ 95th % of normal). The adverse outcomes were all-cause rehospitalization and/or death over 3.0 (1.0, 4.9) years of follow-up.
ADHF patients had elevated plasma and urinary CNP levels compared to healthy subjects [plasma CNP: 18.2 (10.7-30.3) vs 11.8 (9.5-15.0) pg/mL; urinary CNP: 43.1 (27.9-74.7) vs 15.8 (12.1-20.2) ng/g Cr; P<0.001 for all]. Notably, there was no significant correlation between plasma and urinary CNP. Plasma CNP positively correlated with length of hospital stay and plasma NT-proBNP, while urinary CNP positively correlated with female sex, LVEF, atrial fibrillation and plasma NT-proBNP. Using the 95th % cutoff levels for plasma and urinary CNP from healthy, we found that 23% of ADHF patients had both elevated plasma and urinary CNP, 44% had normal plasma and elevated urinary CNP, 9% had elevated plasma and normal urinary CNP and 24% had normal plasma and urinary CNP. Compared to the ADHF cohort with normal plasma and urinary CNP levels (reference), only elevation in both plasma and urinary CNP was significantly predictive of rehospitalization/death [HR: 1.82 (95%CI: 1.09-3.06), P=0.02] and rehospitalization [HR: 2.23 (95%CI: 1.20-4.12), P=0.01] but not death alone, after adjusting for age, sex, eGFR, urinary protein/creatinine ratio and plasma NT-proBNP.
This study is the largest to date to provide novel pathophysiological insights into plasma and urinary CNP. We report for the first time that elevations of both CNP indices are associated with disease severity and have prognostic utility beyond robust clinical risk models in ADHF.
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© 2020 Published by Elsevier Inc.