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{{Use dmy dates|date=March 2017}}
{{Use dmy dates|date=March 2017}}
'''Copeptin''' (also known as CT-proAVP) is a 39-[[amino acid]]-long [[peptide]] derived from a pre-pro-hormone consisting of [[vasopressin]], {{nobr|neurophysin II}} and copeptin.
'''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 involved in multiple cardiovascular and [[Kidney|renal]] pathways and abnormal level of AVP are associated with various diseases. Hence measurement of AVP would useful, but not commonly carried out in clinical practice because of its very short [[half-life]] making it difficult to quantify. In contrast, copeptin can be [[Immunology|immunologically]] tested with ease and therefore can be used as a vasopressin surrogate marker.
Arginine vasopressin (AVP), also known as the [[antidiuretic hormone]] (ADH), is involved in multiple cardiovascular and [[Kidney|renal]] pathways and functions.
However, vasopressin measurements are not commonly used in clinical practice because of the biochemical features of the [[molecule]]: its small size and very short [[half-life]] make vasopressin testing quite complicated and labor-intensive. On the other hand, copeptin can be [[Immunology|immunologically]] tested with ease and therefore be used as a vasopressin surrogate.


{{Infobox protein
{{Infobox protein
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== Synthesis and secretion ==
== Synthesis and secretion ==
Copeptin is a 39-[[amino acid]]-long, [[Glycosylation|glycosylated]] [[peptide]].<ref>{{cite journal|author1=Hartmut Land |author2=Günther Schütz |author3=Hartwig Schmale |author4=Dietmar Richter |title=Nucleotide sequence of cloned cDNA encoding bovine arginine vasopressin-neurophysin II precursor. |journal=Nature |year=1982 |issue=5847 |pages=299–303|doi=10.1038/295299a0|pmid=6276766 |volume=295}}</ref>  It is synthesized mainly in the paraventricular neurons of the [[hypothalamus]] and in the supraoptical nucleus.<ref name="Acher 2002">{{cite journal|author1=Roger Acher |author2=Jacqueline Chauvet |author3=Yves Rouille |title= Dynamic processing of neuropeptides: sequential conformation shaping of neurophypophysical preprohomones during intraneural secretory transport |journal=Journal of Molecular Neuroscience |year= 2002 |issue=3 |pages=223–228|doi=10.1385/JMN:18:3:223 |pmid=12059040 |volume=18}}</ref>  During [[axoplasmic transport|axonal transport]], pre-pro-AVP is [[Proteolysis|proteolytically]] cleaved into vasopressin, {{nobr|neurophysin II}} and copeptin.<ref>{{cite journal|author1 = David Repaske|author2 = Rita Medlej|author3 = Ebru Gültekin|author4 = M Krishnamani|author5 = George Halaby|author6 = James Findling|author7 = J Phillips III|title = Heterogeneity in clinical manifestation of autosomal dominant of neurohypophyseal diabetes insipidus caused by a mutation encoding Ala-1-> Val in the signal peptide of the arginine vasopressin/neurophysin II/copeptin precursor|journal = Journal of Clinical Endocrinology and Metabolism|year = 1997|volume = 82|issue = 1|pages = 51–56|pmid = 8989232|doi = 10.1210/jcem.82.1.3660}}</ref> These molecules are then stored in secretory granules in the [[posterior pituitary]] and released upon [[Osmotic pressure|osmotic]] or non-osmotic ([[Hemodynamics|hemodynamical]]; [[Physiological stress|stress]]-related) stimuli.<ref name="Acher 2002" />
Copeptin is a 39-[[amino acid]]-long, [[Glycosylation|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 }}</ref>  It is synthesized mainly in the paraventricular neurons of the [[hypothalamus]] and in the supraoptical 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 }}</ref>  During [[axoplasmic transport|axonal transport]], pre-pro-AVP is [[Proteolysis|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 }}</ref> These molecules are then stored in secretory granules in the [[posterior pituitary]] and released upon [[Osmotic pressure|osmotic]] or non-osmotic ([[Hemodynamics|hemodynamical]]; [[Physiological stress|stress]]-related) stimuli.<ref name="Acher 2002" />


== Biological role ==
== 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 [[Protein folding|folding]] of vasopressin.<ref name="Acher 2002" />
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 [[Protein folding|folding]] of vasopressin.<ref name="Acher 2002" />


== Clinical interest in copeptin testing ==
== 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|author1=Gary Robertson |author2=Ermelinda Mahr |author3=Shahid Athar |author4=Tushar Sinha |title=Development and Clinical Application of a New Method for the Radioimmunoassay of Arginine Vasopressin in Human Plasma |journal=Journal of Clinical Investigation |year=1973 |issue=9 |pages=2340–2352|doi=10.1172/JCI107423|pmid=4727463 |volume=52 |pmc=333039}}</ref><ref>{{cite journal|author1=J Preibisz |author2=J Sealey |author3=J Laragh |author4=R Cody |author5=B Weksler |title=Plasma and platelet vasopressin in essential hypertension and congestive heart failure |journal=Hypertension |year=1983 |issue=2 Pt 2 |pages=129–138|pmid=6826223 |volume=5 |doi=10.1161/01.hyp.5.2_pt_2.i129}}</ref>
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 }}</ref>
The clinical interest  in  copeptin testing is closely linked to the pathophysiological pathways in which vasopressin is involved : polydipsia-polyuria syndrome, hyponatremia, [[SIADH|syndrome of inappropriate antidiuretic hormone secretion]] (SIADH) as well as heart failure and acute coronary syndrome.<ref name="Morgenthaler 2008">{{cite journal|author1=Nils Morgenthaler |author2=Joachim Struck |author3=Stefan Jochberger |author4=Martin Dünser |title= Copeptin : clinical use of a new biomarker|journal=Trends in Endocrinology and Metabolism |year= 2008 |issue=2 |pages=43–49 |doi=10.1016/j.tem.2007.11.001 |pmid=18291667 |volume=19}}</ref>
The clinical interest  in  copeptin testing is closely linked to the pathophysiological pathways in which vasopressin is involved: polydipsia-polyuria syndrome, hyponatremia, [[SIADH|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 }}</ref>


=== Copeptin in blood circulation ===
=== In blood ===
The [[Molar concentration|concentration]] of copeptin in the [[blood circulation]] ranges from 1 to 12 p[[Mole (unit)|mol]]/L in healthy individuals.<ref name="Morgenthaler 2008" /> The levels of copeptine 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 [[Osmotic concentration|osmolality]] fluctuations, the kinetics of copeptine are comparable to those of vasopressin.<ref name="Morgenthaler 2008" /><ref>{{cite journal|author1=Gabor Szinnai |author2=Nils Morgenthaler |author3=Kaspar Berneis |author4=Joachim Struck |author5=Beat Muller |author6=Ulrich Keller |author7=Mirjam Christ-Crain |title=Changes in plasma copeptin, the C-terminal portion of arginine vasopressin during water deprivation and excesse in healthy subjects |journal=Journal of Clinical Endocrinology and Metabolism |year=2007 |issue=10 |pages=3973–3978|doi=10.1210/jc.2007-0232|pmid=17635944 |volume=92}}</ref> For example, patients with an electrolyte disorders such as [[diabetes insipidus]] with very low levels of vasopressin also show very low levels of copeptin in [[blood plasma]].<ref>{{cite journal|author1=Mira Katan |author2=Nils Morgenthaler |author3=Kashinat Dixit |author4=Jonas Rutishauser |author5=Georg Braant |author6=Beat Muller |author7=Mirjam Christ-Crain |title=Anterior and posterior pituitary function testing with simultaneous insulin tolerance test and a novel copeptine assay |journal=Journal of Clinical Endocrinology and Metabolism |year=2007 |issue=7 |pages=2640–2643|doi=10.1210/jc.2006-2046|pmid=17426098 |volume=92}}</ref> On the other hand, patients suffering from [[SIADH|syndrome of inappropriate antidiuretic hormone secretion]] show both high levels of vasopressin and copeptin.<ref>{{cite journal|author1=Wiebke Fenske |author2=Stefan Stork |author3=Anne Blechschmidt |author4=Sebastian Maier |author5=Nils Morgenthaler |author6=Bruno Allolio |title=Copeptin in the differential diagnosis of hyponatremia |journal=Journal of Clinical Endocrinology and Metabolism |year=2009 |issue=1 |pages=123–129|doi=10.1210/jc.2008-1426|pmid=18984663 |volume=94}}</ref>
The [[Molar concentration|concentration]] of copeptin in the [[blood circulation]] ranges from 1 to 12 p[[Mole (unit)|mol]]/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 [[Osmotic concentration|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 }}</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 }}</ref> On the other hand, patients suffering from [[SIADH|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 }}</ref>


=== Copeptin and acute myocardial infarction ===
=== 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|author1=Sohail Khan |author2=Onkar Dhillon |author3=Russel O’Brien |author4=Joachim Struck |author5=Paulen Quinn |author6=Nils Morgenthaler|author7=Iain Squire |author8=Joan davies |author9=Andreas Bergmann |author10=Leong NG |title= C-terminal provasopressin (copeptin) as a novel and prognostic marker in acute myocardial infarction : Leicester Acute Myocardial Infarction Peptide (LAMP) study |journal=Circulation |year=2007 |issue=16 |pages=2103–2110 |doi=10.1161/CIRCULATIONAHA.106.685503 |pmid=17420344 |volume=115}}</ref><ref name="Reichlin 2009">{{cite journal|author1=Tobias Reichlin |author2=Willibald Hochholzer |author3=Claudia Stelzig |author4=Kirsten Laule |author5=Heike Freidank |author6=Nils Morgenthaler |author7=Andreas Bergmann |author8=Mihael Potocki |author9=Markus Noveanu |author10=Tobias Breidhardt |author11=Andreas Christ |author12=Tujana Boldanova |author13=Ramona Merki |author14=Nora Schaub |author15=Roland Bingisser |author16=Michael Christ |author17=Christian Mueller |title= Incremental value of copeptine for rapid rule out of acute myocardial infarction |journal=Journal of the American College of Cardiology |year=2009 |issue=1 |pages=60–68 |doi=10.1016/j.jacc.2009.01.076 |pmid=19555842 |volume=54}}</ref> raising the question of its potential value in the [[Medical diagnosis|diagnosis]] of AMI and particularly in ruling-out AMI.<ref name="Reichlin 2009"/><ref name="Keller 2010">{{cite journal|author1=Till Keller |author2=Stergios Tzikas |author3=Tanja Zeller |author4=Ewa Czyz |author5=Lars Lillpopp |author6=Francisco M. Ojeda |author7=Alexander Roth |author8=Christoph Bickel |author9=Stephan Baldus |author10=Christoph R. Sinning |author11=Philipp S. Wild |author12=Edith Lubos |author13=Dirk Peetz |author14=Jan Kunde |author15=Oliver Hartmann |author16=Andreas Bergmann |author17=Felix Post |author18=Karl J. Lackner |author19=Sabine Genth-Zotz |author20=Viviane Nicaud |author21=Laurence Tiret |author22=Thomas F. Münzel |author23=Stefan Blankenberg |title=Copeptin improves early diagnosis of acute myocardial infarction |journal=Journal of the American College of Cardiology|date=11 May 2010 |volume=55 |issue=19 |pages=2096–2106 |doi=10.1016/j.jacc.2010.01.029|pmid=20447532 }}</ref><ref name="Maisel 2013">{{cite journal|author1=Alan Maisel |author2=Christian Mueller |author3=Sean-Xavier Neath |author4=Robert Christenson |author5=Nils Morgentahler |author6=James McCord |author7=Richard Nowak |author8=Gary Vilke |author9=Lori Daniels |author10=Judd Hollander |author11=Fred Apple |author12=Chad Cannon |author13=John Nagurney |author14=donald Schreiber |author15=Christopher deFilippi |author16=Christopher Hogan |author17=Deborah Diercks |author18=John Stein |author19=Gary headden |author20=Alexander Limkakeng |author21=Inder Anand |author22=Alan Wu |author23=Jana Papassotiriou |author24=Oliver Hartmann |author25=Stefan Ebmeyer |author26=Paul Clopton |author27=Alan Jaffe |author28=Frank Peacock |title=Copeptin helps in the early detection of patients with acute myocardial infarction: primary results of the CHOPINtrial (Copeptin Helps in the early detection Of Patients with acute myocardial INfarction) |journal=Journal of the American College of Cardiology |year=2013 |issue=2 |pages=150–160|doi=10.1016/j.jacc.2013.04.011|pmid=23643595 |volume=62}}</ref> Indeed, copeptin is released much earlier than [[Troponin]] 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" />  
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 }}</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 }}</ref> raising the question of its potential value in the [[Medical diagnosis|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 }}</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 }}</ref> Indeed, copeptin is released much earlier than [[Troponin|troponin]], given that copeptin is actively released from the [[Hypothalamus|hypothalamus]], while [[Troponin|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 | pages = 20812 | date = February 2016 | pmid = 26864512 | pmc = 4749978 | doi = 10.1038/srep20812 }}</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#.UpSmWcTuKmG BIC-8], 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], on [http://biomarqueursinfos.fr/ Site biomarqueursinfos.fr]. 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 ], on [http://biomarqueursinfos.fr/ Site biomarqueursinfos.fr]. On 10 November 2013</ref>
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#.UpSmWcTuKmG BIC-8], 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], on [http://biomarqueursinfos.fr/ Site biomarqueursinfos.fr]. 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 ], on [http://biomarqueursinfos.fr/ Site biomarqueursinfos.fr]. On 10 November 2013</ref>


=== Copeptin and cardiogenic shock ===
=== Cardiogenic shock ===
High concentrations of vasopressin during a [[cardiogenic shock]] have been widely described.<ref>{{cite journal|author1=Karl Lindner |author2=Hans Strohmenger |author3=Herman Ensinger |author4=Wulf Hetzel |author5=Friedrich Ahnefeld |author6=Michael Georgieff |title=Stress hormone response during and after cardiopulmonary resuscitation |journal=Anesthesiology |year=1992 |issue=4 |pages=662–668|pmid=1329579 |doi=10.1097/00000542-199210000-00008 |volume=77}}</ref><ref>{{cite journal|author1=Anette Krismer |author2=Volker Wenzel |author3=Karl Stadlbauer |author4=Viktoria Mayr |author5=Hannes Lienhart |author6=Richard Arntz |author7=Karl Lindner |title=Vasopressin during cardiopulmonary resuscitation : a progress report |journal=Critical Care Medicine |year=2004 |issue=9 Suppl |pages=S432–S435|doi=10.1097/01.CCM.0000134267.91520.C0|pmid=15508673 |volume=32}}</ref> It has been shown that the kinetics of copeptin are similar to vasopressin in that context.<ref>{{cite journal|author1=E Arnauld |author2=P Czernichow |author3=F Fumoux |author4=J Vincent |title=The effects of hypotension and hypovolaemia on the liberation of vasopressin during haemorrhage in the unanaesthetized monkey (Macaca mulatta) |journal=Pflugers Archives |year=1977 |issue=3 |pages=193–200|pmid=414200 |volume=371 |doi=10.1007/bf00586258}}</ref>
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 }}</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 }}</ref>


=== Copeptin in heart failure ===
=== Heart failure ===
The prognostic value of vasopressin for prediction of outcome in patients suffering from [[heart failure]] has been known since the nineties. 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 |title=Activation of neurohumoral systems in postinfarction left ventricular dyfunction |journal=Journal of the American College of Cardiology |year=1993 |issue=2 |pages=390–398|pmid=8101532 |volume=22 |doi=10.1016/0735-1097(93)90042-y|displayauthors=etal  }}</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 |year=1994 |issue=3 |pages=583–591|pmid=7915733 |volume=24 |doi=10.1016/0735-1097(94)90001-9|displayauthors=etal  }}</ref> Recently, a similar interest has been demonstrated for copeptin in heart failure.<ref name="Khan 2007" /><ref>{{cite journal|author1=Marvin Konstam |author2=Mihai Gheorghiade |author3=John Burnett |author4=Liliana Grinfeld |author5=Aldo Maggioni |author6=Karl Swedberg |author7=James Udelson |author8=Faiez Zannad |author9=Thomas Cook |author10=John Ouyang |author11=Christopher Zimmer |author12=Cesare Orlandi |author13=for the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators |title=Effects of oral tolvaptan in patients hospitalized for worsening heart failure : the EVEREST Outcome Trial |journal=Journal of the American Medical Association |year=2007 |issue=12 |pages=1319–1331|doi=10.1001/jama.297.12.1319|pmid=17384437 |volume=297}}</ref><ref>{{cite journal|author1=Mihai Gheorghiade |author2=Marvin A. Konstam |author3=John C. Burnett |author4=Liliana Grinfeld |author5=Aldo P. Maggioni |author6=Karl Swedberg |author7=James E. Udelson |author8=Faiez Zannad |author9=Thomas Cook |author10=John Ouyang |author11=Christopher Zimmer |author12=Cesare Orlandi |title=Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure : the EVEREST Clinical Status Trials |journal=Journal of the American Medical Association |year=2007 |volume= 297|issue=12 |pages=1332–1343 |doi=10.1001/jama.297.12.1332 |pmid=17384438}}</ref><ref>{{cite journal|author1=Stephanie Neuhold |author2=Martin Huelsmann |author3=Guido Strunk |author4=Brigitte Stoiser |author5=Joachim Struck |author6=Nils G. Morgenthaler |author7=Andreas Bergmann |author8=Deddo Moertl |author9=Rudolf Berger |author10=Richard Pacher |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 |date=July 2008 |volume=52 |issue=4 |pages=266–272 |doi=10.1016/j.jacc.2008.03.050|pmid=18634981}}</ref>
The prognostic value of vasopressin for prediction of outcome in patients suffering from [[heart failure]] has been known since the nineties. 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 }}</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 }}</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 }}</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 }}</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 }}</ref>
 
== Notes et references ==
{{reflist|2}}


== See also ==
== See also ==
=== Other articles of interest ===
* [[Vasopressin]]
* [[Vasopressin]]
* [[Troponin]]
* [[Troponin]]
Line 67: Line 60:
* [[Heart failure]]
* [[Heart failure]]
* [[Cerebral vascular accident]]
* [[Cerebral vascular accident]]
== References ==
{{reflist|32em}}


=== External links ===
=== External links ===

Revision as of 19:23, 30 November 2018

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, neurophysin II and copeptin. Arginine vasopressin (AVP), also known as the antidiuretic hormone (ADH), is involved in multiple cardiovascular and renal pathways and abnormal level of AVP are associated with various diseases. Hence measurement of AVP would useful, but 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.

Copeptin
File:Copeptine pour wikipedia.png
Diagram of the pre-pro-vasopressin precursor showing position and size in amino acids of AVP, neurophysin II and copeptin
Identifiers
SymbolCT-proAVP
Alt. symbolscopeptine
OMIM192340
UniProtP01185
Other data
LocusChr. 20 p13

Synthesis and secretion

Copeptin is a 39-amino acid-long, glycosylated peptide.[1] It is synthesized mainly in the paraventricular neurons of the hypothalamus and in the supraoptical nucleus.[2] During axonal transport, pre-pro-AVP is proteolytically cleaved into vasopressin, neurophysin II and copeptin.[3] These molecules are then stored in secretory granules in the posterior pituitary and released upon osmotic or non-osmotic (hemodynamical; stress-related) stimuli.[2]

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.[2]

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.[4][5] 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.[6]

In blood

The concentration of copeptin in the blood circulation ranges from 1 to 12 pmol/L in healthy individuals.[6] The levels of copeptin are slightly higher in men than in women[6] and are not influenced by age.[6] In response to serum osmolality fluctuations, the kinetics of copeptin are comparable to those of vasopressin.[6][7] 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.[8] On the other hand, patients suffering from syndrome of inappropriate antidiuretic hormone secretion show high concentrations of both vasopressin and copeptin.[9]

Acute myocardial infarction

Several studies have shown that copeptin is released very early during the onset of an acute myocardial infarction (AMI),[10][11] raising the question of its potential value in the diagnosis of AMI and particularly in ruling-out AMI.[11][12][13] 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,[14] making the interpretation of their complementary kinetics a useful tool to rule-out AMI.[11][12] 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%.[11][12][13] These results have been confirmed in a randomised controlled trial.[15][16][17]

Cardiogenic shock

High concentrations of vasopressin during cardiogenic shock have been widely described.[18][19] It has been shown that the kinetics of copeptin are similar to vasopressin in that context.[20]

Heart failure

The prognostic value of vasopressin for prediction of outcome in patients suffering from heart failure has been known since the nineties. Patients presenting with high levels of vasopressin have a worsened outcome.[21][22] Recently, a similar interest has been demonstrated for copeptin in heart failure.[10][23][24][25]

See also

References

  1. ↑ Land H, Schütz G, Schmale H, Richter D (January 1982). "Nucleotide sequence of cloned cDNA encoding bovine arginine vasopressin-neurophysin II precursor". Nature. 295 (5847): 299–303. doi:10.1038/295299a0. PMID 6276766.
  2. ↑ 2.0 2.1 2.2 Acher R, Chauvet J, Rouille Y (June 2002). "Dynamic processing of neuropeptides: sequential conformation shaping of neurohypophysial preprohormones during intraneuronal secretory transport". Journal of Molecular Neuroscience. 18 (3): 223–8. doi:10.1385/JMN:18:3:223. PMID 12059040.
  3. ↑ Repaske DR, Medlej R, Gültekin EK, Krishnamani MR, Halaby G, Findling JW, Phillips JA (January 1997). "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". The Journal of Clinical Endocrinology and Metabolism. 82 (1): 51–6. doi:10.1210/jcem.82.1.3660. PMID 8989232.
  4. ↑ Robertson GL, Mahr EA, Athar S, Sinha T (September 1973). "Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma". The Journal of Clinical Investigation. 52 (9): 2340–52. doi:10.1172/JCI107423. PMC 333039. PMID 4727463.
  5. ↑ Preibisz JJ, Sealey JE, Laragh JH, Cody RJ, Weksler BB (1983). "Plasma and platelet vasopressin in essential hypertension and congestive heart failure". Hypertension. 5 (2 Pt 2): I129–38. doi:10.1161/01.hyp.5.2_pt_2.i129. PMID 6826223.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Morgenthaler NG, Struck J, Jochberger S, Dünser MW (March 2008). "Copeptin: clinical use of a new biomarker". Trends in Endocrinology and Metabolism. 19 (2): 43–9. doi:10.1016/j.tem.2007.11.001. PMID 18291667.
  7. ↑ Szinnai G, Morgenthaler NG, Berneis K, Struck J, Müller B, Keller U, Christ-Crain M (October 2007). "Changes in plasma copeptin, the c-terminal portion of arginine vasopressin during water deprivation and excess in healthy subjects". The Journal of Clinical Endocrinology and Metabolism. 92 (10): 3973–8. doi:10.1210/jc.2007-0232. PMID 17635944.
  8. ↑ Katan M, Morgenthaler NG, Dixit KC, Rutishauser J, Brabant GE, Müller B, Christ-Crain M (July 2007). "Anterior and posterior pituitary function testing with simultaneous insulin tolerance test and a novel copeptin assay". The Journal of Clinical Endocrinology and Metabolism. 92 (7): 2640–3. doi:10.1210/jc.2006-2046. PMID 17426098.
  9. ↑ Fenske W, Störk S, Blechschmidt A, Maier SG, Morgenthaler NG, Allolio B (January 2009). "Copeptin in the differential diagnosis of hyponatremia". The Journal of Clinical Endocrinology and Metabolism. 94 (1): 123–9. doi:10.1210/jc.2008-1426. PMID 18984663.
  10. ↑ 10.0 10.1 Khan SQ, Dhillon OS, O'Brien RJ, Struck J, Quinn PA, Morgenthaler NG, et al. (April 2007). "C-terminal provasopressin (copeptin) as a novel and prognostic marker in acute myocardial infarction: Leicester Acute Myocardial Infarction Peptide (LAMP) study". Circulation. 115 (16): 2103–10. doi:10.1161/CIRCULATIONAHA.106.685503. PMID 17420344.
  11. ↑ 11.0 11.1 11.2 11.3 Reichlin T, Hochholzer W, Stelzig C, Laule K, Freidank H, Morgenthaler NG, et al. (June 2009). "Incremental value of copeptin for rapid rule out of acute myocardial infarction". Journal of the American College of Cardiology. 54 (1): 60–8. doi:10.1016/j.jacc.2009.01.076. PMID 19555842.
  12. ↑ 12.0 12.1 12.2 Keller T, Tzikas S, Zeller T, Czyz E, Lillpopp L, Ojeda FM, et al. (May 2010). "Copeptin improves early diagnosis of acute myocardial infarction". Journal of the American College of Cardiology. 55 (19): 2096–106. doi:10.1016/j.jacc.2010.01.029. PMID 20447532.
  13. ↑ 13.0 13.1 Maisel A, Mueller C, Neath SX, Christenson RH, Morgenthaler NG, McCord J, et al. (July 2013). "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 of the American College of Cardiology. 62 (2): 150–160. doi:10.1016/j.jacc.2013.04.011. PMID 23643595.
  14. ↑ Boeckel JN, Oppermann J, Anadol R, Fichtlscherer S, Zeiher AM, Keller T (February 2016). "Analyzing the Release of Copeptin from the Heart in Acute Myocardial Infarction Using a Transcoronary Gradient Model". Scientific Reports. 6: 20812. doi:10.1038/srep20812. PMC 4749978. PMID 26864512.
  15. ↑ BIC-8, on Site ESC2013 Archived 9 November 2013 at the Wayback Machine.. On 10 September 2013
  16. ↑ Results of BIC-8, on Site biomarqueursinfos.fr. On 10 November 2013
  17. ↑ Interview of principal investigator and ESC reviewer on BIC-8 , on Site biomarqueursinfos.fr. On 10 November 2013
  18. ↑ Lindner KH, Strohmenger HU, Ensinger H, Hetzel WD, Ahnefeld FW, Georgieff M (October 1992). "Stress hormone response during and after cardiopulmonary resuscitation". Anesthesiology. 77 (4): 662–8. doi:10.1097/00000542-199210000-00008. PMID 1329579.
  19. ↑ Krismer AC, Wenzel V, Stadlbauer KH, Mayr VD, Lienhart HG, Arntz HR, Lindner KH (September 2004). "Vasopressin during cardiopulmonary resuscitation: a progress report". Critical Care Medicine. 32 (9 Suppl): S432–5. doi:10.1097/01.CCM.0000134267.91520.C0. PMID 15508673.
  20. ↑ Arnauld E, Czernichow P, Fumoux F, Vincent JD (November 1977). "The effects of hypotension and hypovolaemia on the liberation of vasopressin during haemorrhage in the unanaesthetized monkey (Macaca mulatta)". Pflügers Archiv. 371 (3): 193–200. doi:10.1007/bf00586258. PMID 414200.
  21. ↑ Rouleau JL, de Champlain J, Klein M, Bichet D, Moyé L, Packer M, et al. (August 1993). "Activation of neurohumoral systems in postinfarction left ventricular dysfunction". Journal of the American College of Cardiology. 22 (2): 390–8. doi:10.1016/0735-1097(93)90042-y. PMID 8101532.
  22. ↑ Rouleau JL, Packer M, Moyé L, de Champlain J, Bichet D, Klein M, Rouleau JR, Sussex B, Arnold JM, Sestier F (September 1994). "Prognostic value of neurohumoral activation in patients with an acute myocardial infarction: effect of captopril". Journal of the American College of Cardiology. 24 (3): 583–91. doi:10.1016/0735-1097(94)90001-9. PMID 7915733.
  23. ↑ Konstam MA, Gheorghiade M, Burnett JC, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C (March 2007). "Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial". JAMA. 297 (12): 1319–31. doi:10.1001/jama.297.12.1319. PMID 17384437.
  24. ↑ Gheorghiade M, Konstam MA, Burnett JC, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C (March 2007). "Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials". JAMA. 297 (12): 1332–43. doi:10.1001/jama.297.12.1332. PMID 17384438.
  25. ↑ Neuhold S, Huelsmann M, Strunk G, Stoiser B, Struck J, Morgenthaler NG, Bergmann A, Moertl D, Berger R, Pacher R (July 2008). "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 of the American College of Cardiology. 52 (4): 266–72. doi:10.1016/j.jacc.2008.03.050. PMID 18634981.

External links

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