Copeptin

{{Short description|Protein fragment in Homo sapiens}} {{Use dmy dates|date=March 2017}} {{Infobox protein | name = Copeptin | image = Copeptine pour wikipedia.png | width = | caption = Diagram of the pre-pro-vasopressin precursor showing position and size in amino acids of AVP, neurophysin II and copeptin | Symbol = CT-proAVP | AltSymbols = copeptine | IUPHAR_id = | ATC_prefix = | ATC_suffix = | ATC_supplemental = | CAS_number = | CAS_supplemental = | DrugBank = | EntrezGene = | HGNCid = | OMIM = 192340 | PDB = | RefSeq = | UniProt = P01185 | ECnumber = | Chromosome = 20 | Arm = p | Band = 13 | LocusSupplementaryData = }}

'''Copeptin''' (also known as '''CT-proAVP''') is a 39-amino acid-long peptide derived from the C-terminus of pre-pro-hormone of arginine vasopressin, {{nobr|neurophysin II}} and copeptin. Arginine vasopressin (AVP), also known as the antidiuretic hormone (ADH), is encoded by the AVP gene and is involved in multiple cardiovascular and renal pathways and abnormal level of AVP are associated with various diseases. Hence measurement of AVP would be useful, but is not commonly carried out in clinical practice because of its very short half-life making it difficult to quantify. In contrast, copeptin can be immunologically tested with ease and therefore can be used as a vasopressin surrogate marker.

== Synthesis and secretion == Copeptin is a 39-amino acid-long, glycosylated peptide.<ref>{{cite journal | vauthors = Land H, Schütz G, Schmale H, Richter D | title = Nucleotide sequence of cloned cDNA encoding bovine arginine vasopressin-neurophysin II precursor | journal = Nature | volume = 295 | issue = 5847 | pages = 299–303 | date = January 1982 | pmid = 6276766 | doi = 10.1038/295299a0 | bibcode = 1982Natur.295..299L | s2cid = 4340962 }}</ref> It is synthesized mainly in the paraventricular neurons of the hypothalamus and in the supraoptic nucleus.<ref name="Acher 2002">{{cite journal | vauthors = Acher R, Chauvet J, Rouille Y | title = Dynamic processing of neuropeptides: sequential conformation shaping of neurohypophysial preprohormones during intraneuronal secretory transport | journal = Journal of Molecular Neuroscience | volume = 18 | issue = 3 | pages = 223–8 | date = June 2002 | pmid = 12059040 | doi = 10.1385/JMN:18:3:223 | s2cid = 45410716 }}</ref> During axonal transport, pre-pro-AVP is proteolytically cleaved into vasopressin, {{nobr|neurophysin II}} and copeptin.<ref>{{cite journal | vauthors = Repaske DR, Medlej R, Gültekin EK, Krishnamani MR, Halaby G, Findling JW, Phillips JA | title = Heterogeneity in clinical manifestation of autosomal dominant neurohypophyseal diabetes insipidus caused by a mutation encoding Ala-1→Val in the signal peptide of the arginine vasopressin/neurophysin II/copeptin precursor | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 82 | issue = 1 | pages = 51–6 | date = January 1997 | pmid = 8989232 | doi = 10.1210/jcem.82.1.3660 | doi-access = free }}</ref> These molecules are then stored in secretory granules in the posterior pituitary and released upon osmotic or non-osmotic (hemodynamical; stress-related) stimuli.<ref name="Acher 2002" />

== Function == Once secreted into the bloodstream, there is no known biological role for copeptin. However, when pre-pro-vasopressin is processed during the axonal transport, copeptin may contribute to the 3D folding of vasopressin.<ref name="Acher 2002" />

== Surrogate vasopressin marker == The size and half-life of copeptin permit an easier immunological testing, compared to vasopressin, and hence copeptin is proposed as a reliable AVP surrogate.<ref>{{cite journal | vauthors = Robertson GL, Mahr EA, Athar S, Sinha T | title = Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma | journal = The Journal of Clinical Investigation | volume = 52 | issue = 9 | pages = 2340–52 | date = September 1973 | pmid = 4727463 | pmc = 333039 | doi = 10.1172/JCI107423 }}</ref><ref>{{cite journal | vauthors = Preibisz JJ, Sealey JE, Laragh JH, Cody RJ, Weksler BB | title = Plasma and platelet vasopressin in essential hypertension and congestive heart failure | journal = Hypertension | volume = 5 | issue = 2 Pt 2 | pages = I129-38 | year = 1983 | pmid = 6826223 | doi = 10.1161/01.hyp.5.2_pt_2.i129 | doi-access = free }}</ref> The clinical interest in copeptin testing is closely linked to the pathophysiological pathways in which vasopressin is involved: polydipsia-polyuria syndrome, hyponatremia, syndrome of inappropriate antidiuretic hormone secretion (SIADH) as well as heart failure and acute coronary syndrome.<ref name="Morgenthaler 2008">{{cite journal | vauthors = Morgenthaler NG, Struck J, Jochberger S, Dünser MW | title = Copeptin: clinical use of a new biomarker | journal = Trends in Endocrinology and Metabolism | volume = 19 | issue = 2 | pages = 43–9 | date = March 2008 | pmid = 18291667 | doi = 10.1016/j.tem.2007.11.001 | s2cid = 6008127 }}</ref>

=== In blood === The concentration of copeptin in the blood circulation ranges from 1 to 12 pmol/L in healthy individuals.<ref name="Morgenthaler 2008" /> The levels of copeptin are slightly higher in men than in women<ref name="Morgenthaler 2008" /> and are not influenced by age.<ref name="Morgenthaler 2008" /> In response to serum osmolality fluctuations, the kinetics of copeptin are comparable to those of vasopressin.<ref name="Morgenthaler 2008" /><ref>{{cite journal | vauthors = Szinnai G, Morgenthaler NG, Berneis K, Struck J, Müller B, Keller U, Christ-Crain M | title = Changes in plasma copeptin, the c-terminal portion of arginine vasopressin during water deprivation and excess in healthy subjects | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 92 | issue = 10 | pages = 3973–8 | date = October 2007 | pmid = 17635944 | doi = 10.1210/jc.2007-0232 | doi-access = free }}</ref> For example, patients with an electrolyte disorders such as diabetes insipidus with very low vasopressin concentrations also show very low copeptin concentrations in blood plasma.<ref>{{cite journal | vauthors = Katan M, Morgenthaler NG, Dixit KC, Rutishauser J, Brabant GE, Müller B, Christ-Crain M | title = Anterior and posterior pituitary function testing with simultaneous insulin tolerance test and a novel copeptin assay | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 92 | issue = 7 | pages = 2640–3 | date = July 2007 | pmid = 17426098 | doi = 10.1210/jc.2006-2046 | doi-access = free }}</ref> On the other hand, patients with syndrome of inappropriate antidiuretic hormone secretion show high concentrations of both vasopressin and copeptin.<ref>{{cite journal | vauthors = Fenske W, Störk S, Blechschmidt A, Maier SG, Morgenthaler NG, Allolio B | title = Copeptin in the differential diagnosis of hyponatremia | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 94 | issue = 1 | pages = 123–9 | date = January 2009 | pmid = 18984663 | doi = 10.1210/jc.2008-1426 | doi-access = free }}</ref>

=== Acute myocardial infarction === Several studies have shown that copeptin is released very early during the onset of an acute myocardial infarction (AMI),<ref name="Khan 2007">{{cite journal | vauthors = Khan SQ, Dhillon OS, O'Brien RJ, Struck J, Quinn PA, Morgenthaler NG, Squire IB, Davies JE, Bergmann A, Ng LL | display-authors = 6 | title = C-terminal provasopressin (copeptin) as a novel and prognostic marker in acute myocardial infarction: Leicester Acute Myocardial Infarction Peptide (LAMP) study | journal = Circulation | volume = 115 | issue = 16 | pages = 2103–10 | date = April 2007 | pmid = 17420344 | doi = 10.1161/CIRCULATIONAHA.106.685503 | doi-access = free }}</ref><ref name="Reichlin 2009">{{cite journal | vauthors = Reichlin T, Hochholzer W, Stelzig C, Laule K, Freidank H, Morgenthaler NG, Bergmann A, Potocki M, Noveanu M, Breidthardt T, Christ A, Boldanova T, Merki R, Schaub N, Bingisser R, Christ M, Mueller C | display-authors = 6 | title = Incremental value of copeptin for rapid rule out of acute myocardial infarction | journal = Journal of the American College of Cardiology | volume = 54 | issue = 1 | pages = 60–8 | date = June 2009 | pmid = 19555842 | doi = 10.1016/j.jacc.2009.01.076 | doi-access = free }}</ref> raising the question of its potential value in the diagnosis of AMI and particularly in ruling-out AMI.<ref name="Reichlin 2009"/><ref name="Keller 2010">{{cite journal | vauthors = Keller T, Tzikas S, Zeller T, Czyz E, Lillpopp L, Ojeda FM, Roth A, Bickel C, Baldus S, Sinning CR, Wild PS, Lubos E, Peetz D, Kunde J, Hartmann O, Bergmann A, Post F, Lackner KJ, Genth-Zotz S, Nicaud V, Tiret L, Münzel TF, Blankenberg S | display-authors = 6 | title = Copeptin improves early diagnosis of acute myocardial infarction | journal = Journal of the American College of Cardiology | volume = 55 | issue = 19 | pages = 2096–106 | date = May 2010 | pmid = 20447532 | doi = 10.1016/j.jacc.2010.01.029 | doi-access = free }}</ref><ref name="Maisel 2013">{{cite journal | vauthors = Maisel A, Mueller C, Neath SX, Christenson RH, Morgenthaler NG, McCord J, Nowak RM, Vilke G, Daniels LB, Hollander JE, Apple FS, Cannon C, Nagurney JT, Schreiber D, deFilippi C, Hogan C, Diercks DB, Stein JC, Headden G, Limkakeng AT, Anand I, Wu AH, Papassotiriou J, Hartmann O, Ebmeyer S, Clopton P, Jaffe AS, Peacock WF | display-authors = 6 | title = Copeptin helps in the early detection of patients with acute myocardial infarction: primary results of the CHOPIN trial (Copeptin Helps in the early detection Of Patients with acute myocardial INfarction) | journal = Journal of the American College of Cardiology | volume = 62 | issue = 2 | pages = 150–160 | date = July 2013 | pmid = 23643595 | doi = 10.1016/j.jacc.2013.04.011 | doi-access = free }}</ref> Indeed, copeptin is released much earlier than troponin, given that copeptin is actively released from the hypothalamus, while troponin occurs in the bloodstream as a breakdown product from dying cardiomyocytes,<ref>{{cite journal | vauthors = Boeckel JN, Oppermann J, Anadol R, Fichtlscherer S, Zeiher AM, Keller T | title = Analyzing the Release of Copeptin from the Heart in Acute Myocardial Infarction Using a Transcoronary Gradient Model | journal = Scientific Reports | volume = 6 | article-number = 20812 | date = February 2016 | pmid = 26864512 | pmc = 4749978 | doi = 10.1038/srep20812 | bibcode = 2016NatSR...620812B }}</ref> making the interpretation of their complementary kinetics a useful tool to rule-out AMI.<ref name="Reichlin 2009"/><ref name="Keller 2010"/> It has been shown that the combination of a negative result of troponin together with a negative result of copeptin can rule out AMI at emergency department presentation with a negative predictive value ranging from 95% to 100%.<ref name="Reichlin 2009" /><ref name="Keller 2010" /><ref name="Maisel 2013" /> These results have been confirmed in a randomised controlled trial.<ref>[http://www.escardio.org/congresses/esc-2013/congress-reports/Pages/709-BIC-8.aspx BIC-8] {{Webarchive|url=https://web.archive.org/web/20131206045531/http://www.escardio.org/congresses/esc-2013/congress-reports/Pages/709-BIC-8.aspx |date=6 December 2013 }}, on [http://www.escardio.org/congresses/esc-2013/Pages/welcome.aspx Site ESC2013] {{webarchive|url=https://web.archive.org/web/20131109224730/http://www.escardio.org/congresses/esc-2013/Pages/welcome.aspx |date=9 November 2013 }}. On 10 September 2013</ref><ref>[http://biomarqueursinfos.fr/actualites/actualite/copeptine-resultats-de-letude-interventionnelle-bic-8 Results of BIC-8] {{Webarchive|url=https://web.archive.org/web/20160303214059/http://biomarqueursinfos.fr/actualites/actualite/copeptine-resultats-de-letude-interventionnelle-bic-8 |date=3 March 2016 }}, on [http://biomarqueursinfos.fr/ Site biomarqueursinfos.fr] {{Webarchive|url=https://web.archive.org/web/20160110090941/http://biomarqueursinfos.fr/ |date=10 January 2016 }}. On 10 November 2013</ref><ref>[http://biomarqueursinfos.fr/%20actualites/actualite/copeptine-bic-8-interviews-des-pr-mockel-et-lindahl Interview of principal investigator and ESC reviewer on BIC-8 ] {{Webarchive|url=https://web.archive.org/web/20160304034938/http://biomarqueursinfos.fr/%20actualites/actualite/copeptine-bic-8-interviews-des-pr-mockel-et-lindahl |date=4 March 2016 }}, on [http://biomarqueursinfos.fr/ Site biomarqueursinfos.fr] {{Webarchive|url=https://web.archive.org/web/20160110090941/http://biomarqueursinfos.fr/ |date=10 January 2016 }}. On 10 November 2013</ref>

=== Cardiogenic shock === High concentrations of vasopressin during cardiogenic shock have been widely described.<ref>{{cite journal | vauthors = Lindner KH, Strohmenger HU, Ensinger H, Hetzel WD, Ahnefeld FW, Georgieff M | title = Stress hormone response during and after cardiopulmonary resuscitation | journal = Anesthesiology | volume = 77 | issue = 4 | pages = 662–8 | date = October 1992 | pmid = 1329579 | doi = 10.1097/00000542-199210000-00008 }}</ref><ref>{{cite journal | vauthors = Krismer AC, Wenzel V, Stadlbauer KH, Mayr VD, Lienhart HG, Arntz HR, Lindner KH | title = Vasopressin during cardiopulmonary resuscitation: a progress report | journal = Critical Care Medicine | volume = 32 | issue = 9 Suppl | pages = S432-5 | date = September 2004 | pmid = 15508673 | doi = 10.1097/01.CCM.0000134267.91520.C0 | s2cid = 36476296 }}</ref> It has been shown that the kinetics of copeptin are similar to vasopressin in that context.<ref>{{cite journal | vauthors = Arnauld E, Czernichow P, Fumoux F, Vincent JD | title = The effects of hypotension and hypovolaemia on the liberation of vasopressin during haemorrhage in the unanaesthetized monkey (Macaca mulatta) | journal = Pflügers Archiv | volume = 371 | issue = 3 | pages = 193–200 | date = November 1977 | pmid = 414200 | doi = 10.1007/bf00586258 | s2cid = 24651230 }}</ref>

=== Heart failure === The prognostic value of vasopressin for prediction of outcome in patients with heart failure has been known since the 1990s. Patients presenting with high levels of vasopressin have a worsened outcome.<ref>{{cite journal | vauthors = Rouleau JL, de Champlain J, Klein M, Bichet D, Moyé L, Packer M, Dagenais GR, Sussex B, Arnold JM, Sestier F | display-authors = 6 | title = Activation of neurohumoral systems in postinfarction left ventricular dysfunction | journal = Journal of the American College of Cardiology | volume = 22 | issue = 2 | pages = 390–8 | date = August 1993 | pmid = 8101532 | doi = 10.1016/0735-1097(93)90042-y | doi-access = free }}</ref><ref>{{cite journal | vauthors = Rouleau JL, Packer M, Moyé L, de Champlain J, Bichet D, Klein M, Rouleau JR, Sussex B, Arnold JM, Sestier F | title = Prognostic value of neurohumoral activation in patients with an acute myocardial infarction: effect of captopril | journal = Journal of the American College of Cardiology | volume = 24 | issue = 3 | pages = 583–91 | date = September 1994 | pmid = 7915733 | doi = 10.1016/0735-1097(94)90001-9 | doi-access = free }}</ref> Recently, a similar interest has been demonstrated for copeptin in heart failure.<ref name="Khan 2007" /><ref>{{cite journal | vauthors = Konstam MA, Gheorghiade M, Burnett JC, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C | title = Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial | journal = JAMA | volume = 297 | issue = 12 | pages = 1319–31 | date = March 2007 | pmid = 17384437 | doi = 10.1001/jama.297.12.1319 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Gheorghiade M, Konstam MA, Burnett JC, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C | title = Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials | journal = JAMA | volume = 297 | issue = 12 | pages = 1332–43 | date = March 2007 | pmid = 17384438 | doi = 10.1001/jama.297.12.1332 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Neuhold S, Huelsmann M, Strunk G, Stoiser B, Struck J, Morgenthaler NG, Bergmann A, Moertl D, Berger R, Pacher R | title = Comparison of copeptin, B-type natriuretic peptide, and amino-terminal pro-B-type natriuretic peptide in patients with chronic heart failure: prediction of death at different stages of the disease | journal = Journal of the American College of Cardiology | volume = 52 | issue = 4 | pages = 266–72 | date = July 2008 | pmid = 18634981 | doi = 10.1016/j.jacc.2008.03.050 | doi-access = free }}</ref>

== References == {{reflist|32em}}

Category:Neuropeptides Category:Ischemic heart diseases Category:Medical emergencies