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Atrial natriuretic peptide (ANP) is secreted under myocardial stress in heart failure (HF) as a compensatory mechanism sustaining cardiorenal homeostasis. Recent studies have underscored the importance of ANP in HF as with sacubitril/valsartan administration, ANP is markedly increased in the absence of an increase in BNP, supportive of ANP's cardiorenal enhancing properties. However, the presence of an ANP deficiency in HF may attenuate ANP's beneficial actions in HF. As ANP is highly susceptible to degradation by neprilysin, characterizing ANP levels within the circulation becomes difficult when assessing whether production or degradation may confer this deficiency state. By using ANP's biologically inactive equivalent, NTproANP, which is highly resistant to degradation, one may quantify production/secretion of the ANP system to assess the overall biological activity of ANP. Therefore, we sought to characterize NTproANP in human acute decompensated HF (ADHF) to elucidate this potential ANP deficiency state and to provide details into its regulation in ADHF. We prospectively recruited 47 healthy individuals without cardiovascular or metabolic disease to determine NTproANP in healthy subjects. A contemporary NTproANP cutoff was then created by using the 95th percentile NTproANP value within this healthy cohort, to distinguish amongst our 107 prospectively recruited ADHF patients whom had either NTproANP values below the NTproANP cutoff, deemed NTproANP Deficient, or above the cutoff, deemed having an Elevated NTproANP. Clinical biomarkers between subgroups were then compared to determine whether differences persisted based upon NTproANP levels. In ADHF, 20% of patients were NTproANP Deficient whereas 80% had an Elevated NTproANP . The NTproANP Deficient cohort demonstrated lower median NTproANP (116.1 vs. 708.6 pg/mL, p<0.0001), ANP (30.1 vs. 142.5 pg/mL, p=0.0003), and although lower, no significant difference in plasma cGMP (12.8 vs. 13.6 pmol/mL, p=0.37) when compared with ADHF patients with Elevated NTproANP levels. In contrast, NTproBNP markedly increased from 49 pg/ml in healthy subjects to 1690 pg/mL in ADHF NTproANP deficient patients to then 3845 pg/mL in ADHF patients with Elevated NTproANP(1690 vs. 3844.5 pg/mL, p=0.02). Further, NTproANP Deficient ADHF patients presented with no difference in ejection fraction (40% vs. 38%, p=0.8), yet had significantly higher body mass indices (37.6 vs. 32, p=0.02), and significantly lower neprilysin activity (4.7 vs. 17 nM/mL/min, p<0.0001). The presence of an NTproANP Deficient cohort within ADHF with lower neprilysin activity suggests ANP production is reduced in HF. In addition to validating the presence of an ANP deficiency in HF, this study further confirms that the ANP and BNP systems are differentially regulated in HF as depicted by marked differences in NTproANP and NTproBNP levels despite NTproANP subgroup classification. Augmenting the ANP system through either endogenous stimulation or exogenous supplementation may be crucial for therapeutic intervention.
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© 2020 Published by Elsevier Inc.