{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T10:54:46Z","timestamp":1792234486268,"version":"4.4.0"},"reference-count":117,"publisher":"Oxford University Press (OUP)","issue":"18","license":[{"start":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T00:00:00Z","timestamp":1661385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL158548"],"award-info":[{"award-number":["R01HL158548"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL134688"],"award-info":[{"award-number":["R01HL134688"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL136340"],"award-info":[{"award-number":["R01HL136340"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL132854"],"award-info":[{"award-number":["R01HL132854"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL084155"],"award-info":[{"award-number":["R01HL084155"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 HL136440"],"award-info":[{"award-number":["R01 HL136440"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01DK103850"],"award-info":[{"award-number":["R01DK103850"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["16SDG29930003"],"award-info":[{"award-number":["16SDG29930003"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,2,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The discovery of the heart as an endocrine organ resulted in a remarkable recognition of the natriuretic peptide system (NPS). Specifically, research has established the production of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) from the heart, which exert pleiotropic cardiovascular, endocrine, renal, and metabolic actions via the particulate guanylyl cyclase A receptor (GC-A) and the second messenger, cGMP. C-type natriuretic peptide (CNP) is produced in the endothelium and kidney and mediates important protective auto\/paracrine actions via GC-B and cGMP. These actions, in part, participate in the efficacy of sacubitril\/valsartan in heart failure (HF) due to the augmentation of the NPS. Here, we will review important insights into the biology of the NPS, the role of precision medicine, and focus on the phenotypes of human genetic variants of ANP and BNP in the general population and the relevance to HF. We will also provide an update of the existence of NP deficiency states, including in HF, which provide the rationale for further therapeutics for the NPS. Finally, we will review the field of peptide engineering and the development of novel designer NPs for the treatment of HF. Notably, the recent discovery of a first-in-class small molecule GC-A enhancer, which is orally deliverable, will be highlighted. These innovative designer NPs and small molecule possess enhanced and novel properties for the treatment of HF and cardiovascular diseases.<\/jats:p>","DOI":"10.1093\/cvr\/cvac125","type":"journal-article","created":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T11:10:47Z","timestamp":1661425847000},"page":"3416-3433","source":"Crossref","is-referenced-by-count":68,"title":["Natriuretic peptide pathways in heart failure: further therapeutic possibilities"],"prefix":"10.1093","volume":"118","author":[{"given":"S Jeson","family":"Sangaralingham","sequence":"first","affiliation":[{"name":"Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, Mayo Clinic , 200 1st Street SW, Rochester, MN 55905 , USA"},{"name":"Department of Physiology and Biomedical Engineering , Mayo Clinic 200 1st St SW, Rochester MN 55905 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Kuhn","sequence":"additional","affiliation":[{"name":"Institute of Physiology, University of Wuerzburg , Roentgenring 9, D-97070 Wuerzburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Cannone","sequence":"additional","affiliation":[{"name":"Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, Mayo Clinic , 200 1st Street SW, Rochester, MN 55905 , USA"},{"name":"Department of Medicine and Surgery, University of Parma , Via Gramsci 14, 43126 Parma , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2315-0330","authenticated-orcid":false,"given":"Horng H","family":"Chen","sequence":"additional","affiliation":[{"name":"Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, Mayo Clinic , 200 1st Street SW, Rochester, MN 55905 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"John C","family":"Burnett","sequence":"additional","affiliation":[{"name":"Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, Mayo Clinic , 200 1st Street SW, Rochester, MN 55905 , USA"},{"name":"Department of Physiology and Biomedical Engineering , Mayo Clinic 200 1st St SW, Rochester MN 55905 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,8,25]]},"reference":[{"key":"2023020319182038600_cvac125-B1","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/0024-3205(81)90370-2","article-title":"A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats","volume":"28","author":"de Bold","year":"1981","journal-title":"Life Sci"},{"key":"2023020319182038600_cvac125-B2","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/s41569-020-0381-0","article-title":"Cardiac natriuretic peptides","volume":"17","author":"Goetze","year":"2020","journal-title":"Nat Rev Cardiol"},{"key":"2023020319182038600_cvac125-B3","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/0006-291X(83)91675-3","article-title":"The amino acid sequence of an atrial peptide with potent diuretic and natriuretic properties","volume":"117","author":"Flynn","year":"1983","journal-title":"Biochem Biophys Res Commun"},{"key":"2023020319182038600_cvac125-B4","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/0006-291X(84)91077-5","article-title":"Purification and complete amino acid sequence of alpha-human atrial natriuretic polypeptide (alpha-hANP)","volume":"118","author":"Kangawa","year":"1984","journal-title":"Biochem Biophys Res Commun"},{"key":"2023020319182038600_cvac125-B5","doi-asserted-by":"crossref","first-page":"14332","DOI":"10.1016\/S0021-9258(17)42597-X","article-title":"Atrial natriuretic factor selectively activates particulate guanylate cyclase and elevates cyclic GMP in rat tissues","volume":"259","author":"Waldman","year":"1984","journal-title":"J Biol Chem"},{"key":"2023020319182038600_cvac125-B6","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/332078a0","article-title":"A new natriuretic peptide in porcine brain","volume":"332","author":"Sudoh","year":"1988","journal-title":"Nature"},{"key":"2023020319182038600_cvac125-B7","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1152\/physrev.00022.2015","article-title":"Molecular physiology of membrane guanylyl cyclase receptors","volume":"96","author":"Kuhn","year":"2016","journal-title":"Physiol Rev"},{"key":"2023020319182038600_cvac125-B8","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/BF03349021","article-title":"Expression of natriuretic peptide receptors in human adipose and other tissues","volume":"19","author":"Sarzani","year":"1996","journal-title":"J Endocrinol Invest"},{"key":"2023020319182038600_cvac125-B9","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1172\/JCI59701","article-title":"Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes","volume":"122","author":"Bordicchia","year":"2012","journal-title":"J Clin Invest"},{"key":"2023020319182038600_cvac125-B10","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.molmet.2017.12.017","article-title":"Cardiac natriuretic peptides promote adipose \u2018browning\u2019 through mTOR complex-1","volume":"9","author":"Liu","year":"2018","journal-title":"Mol Metab"},{"key":"2023020319182038600_cvac125-B11","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.jacc.2011.05.011","article-title":"A genetic variant of the atrial natriuretic peptide gene is associated with cardiometabolic protection in the general community","volume":"58","author":"Cannone","year":"2011","journal-title":"J Am Coll Cardiol"},{"key":"2023020319182038600_cvac125-B12","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1161\/CIRCRESAHA.110.226712","article-title":"Feedback control through cGMP-dependent protein kinase contributes to differential regulation and compartmentation of cGMP in rat cardiac myocytes","volume":"107","author":"Castro","year":"2010","journal-title":"Circ Res"},{"key":"2023020319182038600_cvac125-B13","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1126\/science.2935937","article-title":"Atrial natriuretic peptide elevation in congestive heart failure in the human","volume":"231","author":"Burnett","year":"1986","journal-title":"Science"},{"key":"2023020319182038600_cvac125-B14","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1016\/j.jacc.2018.01.021","article-title":"N-terminal pro-B-type natriuretic peptide in the emergency department: the ICON-RELOADED study","volume":"71","author":"Januzzi","year":"2018","journal-title":"J Am Coll 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of live cells: hormone-stimulated cAMP hydrolysis is faster than hormone-stimulated cAMP synthesis","volume":"280","author":"Nikolaev","year":"2005","journal-title":"J Biol Chem"},{"key":"2023020319182038600_cvac125-B30","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1042\/cs0720031","article-title":"Atrial natriuretic peptide inhibits the effect of endogenous angiotensin II on plasma aldosterone in conscious sodium-depleted rats","volume":"72","author":"Chartier","year":"1987","journal-title":"Clin Sci"},{"key":"2023020319182038600_cvac125-B31","doi-asserted-by":"crossref","first-page":"F121","DOI":"10.1152\/ajprenal.00478.2006","article-title":"Guanylyl cyclase\/natriuretic peptide receptor-A gene disruption causes increased adrenal angiotensin II and aldosterone levels","volume":"293","author":"Zhao","year":"2007","journal-title":"Am J Physiol Renal Physiol"},{"key":"2023020319182038600_cvac125-B32","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1093\/cvr\/cvaa023","article-title":"Coronary microvascular dysfunction in hypertrophy and heart failure","volume":"116","author":"Camici","year":"2020","journal-title":"Cardiovasc Res"},{"key":"2023020319182038600_cvac125-B33","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1002\/ejhf.1671","article-title":"Endothelium-dependent and independent coronary microvascular dysfunction in patients with heart failure with preserved ejection fraction","volume":"22","author":"Yang","year":"2020","journal-title":"Eur J Heart Fail"},{"key":"2023020319182038600_cvac125-B34","doi-asserted-by":"crossref","first-page":"4039","DOI":"10.1172\/JCI74281","article-title":"Endothelial C-type natriuretic peptide maintains vascular homeostasis","volume":"124","author":"Moyes","year":"2014","journal-title":"J Clin 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cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I","volume":"34","author":"Frantz","year":"2013","journal-title":"Eur Heart J"},{"key":"2023020319182038600_cvac125-B47","doi-asserted-by":"crossref","first-page":"e139910","DOI":"10.1172\/jci.insight.139910","article-title":"C-type natriuretic peptide moderates titin-based cardiomyocyte stiffness","volume":"5","author":"Michel","year":"2020","journal-title":"JCI Insight"},{"key":"2023020319182038600_cvac125-B48","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1161\/HYPERTENSIONAHA.110.160796","article-title":"The aging heart, myocardial fibrosis, and its relationship to circulating C-type natriuretic peptide","volume":"57","author":"Sangaralingham","year":"2011","journal-title":"Hypertension"},{"key":"2023020319182038600_cvac125-B49","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1056\/NEJMoa1409077","article-title":"Angiotensin-neprilysin inhibition versus enalapril in heart 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