Copeptin

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Copeptin (also known as CT-proAVP) is a 39-amino acid-long peptide deriving from a pre-pro-hormone consisting of vasopressin, neurophysin II and copeptin. Vasopressin (AVP), also known as the antidiuretic hormone (ADH), is involved in multiple cardiovascular and renal pathways and functions. However, vasopressin measurements are not commonly used in clinical routine, which is mainly due to 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 immunologically tested with ease and therefore be used as a vasopressin surrogate.

Copeptin

Diagram of the pre-pro-vasopressin precursor showing position and size in amino acids of AVP, neurophysin II and copeptin
Identifiers
Symbol CT-proAVP
Alt. symbols copeptine
OMIM 192340
UniProt P01185
Other data
Locus Chr. 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 the axonal transport, pre-pro-AVP will be proteolytically cleaved in vasopressin, neurophysin II and copeptin.[3] These molecules will then be stored in secretory granules in the posterior pituitary and released upon osmotic or non-osmotic (hemodynamical; stress-related) stimuli.[2]

Biological role

Once secreted into the blood stream, 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]

Clinical interests of the copeptin testing

The size and half-life of copeptin permit an easier immunological testing, compared to vasopressin, and hence copeptin is suggested to be used as a reliable AVP surrogate.[4][5] The clinical interests related to copeptin testing are 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]

Copeptin in blood circulation

The concentration of copeptin in the blood circulation ranges from 1 to 12 pmol/L in healthy individuals.[6] The levels of copeptine 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 copeptine are comparable to those of vasopressin.[6][7] 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.[8] On the other hand, patients suffering from syndrome of inappropriate antidiuretic hormone secretion show both high levels of vasopressin and copeptin.[9]

Copeptin and 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 more earlier than Troponin 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.[14][15][16]

Copeptin and cardiogenic shock

High concentrations of vasopressin during a cardiogenic shock have been widely described.[17][18] It has been shown that the kinetics of copeptin are similar to vasopressin in that context.[19]

Copeptin in heart faillure

The prognostic value of vasopressin for prediction of outcome in patients suffering from heart failure is known since the nineties. Patients presenting with high levels of vasopressin have a worsened outcome.[20][21] Recently, a similar interest has been demonstrated for copeptin in heart failure.[10][22][23][24]

Notes et references

  1. ↑ Hartmut Land; Günther Schütz; Hartwig Schmale; Dietmar Richter (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 Roger Acher; Jacqueline Chauvet; Yves Rouille (2002). "Dynamic processing of neuropeptides: sequential conformation shaping of neurophypophysical preprohomones during intraneural secretory transport". Journal of Molecular Neuroscience 18 (3): 223–228. doi:10.1385/JMN:18:3:223. PMID 12059040. 
  3. ↑ David Repaske; Rita Medlej; Ebru Gültekin; M Krishnamani; George Halaby; James Findling; J Phillips III (1997). "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 of Clinical Endocrinology and Metabolism' 82: 51–56. doi:10.1210/jc.82.1.51. PMID 8989232. 
  4. ↑ Gary Robertson; Ermelinda Mahr; Shahid Athar; Tushar Sinha (1973). "Development and Clinical Application of a New Method for the Radioimmunoassay of Arginine Vasopressin in Human Plasma". Journal of Clinical Investigation 52 (9): 2340–2352. doi:10.1172/JCI107423. PMID 4727463. 
  5. ↑ J Preibisz; J Sealey; J Laragh; R Cody; B Weksler (1983). "Plasma and platelet vasopressin in essential hypertension and congestive heart failure". Hypertension 5 (2 Pt 2): 129–138. PMID 6826223. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Nils Morgenthaler; Joachim Struck; Stefan Jochberger; Martin Dünser (2008). "Copeptin : clinical use of a new biomarker". Trends in Endocrinology and Metabolism 19 (2): 43–49. doi:10.1016/j.tem.2007.11.001. PMID 18291667. 
  7. ↑ Gabor Szinnai; Nils Morgenthaler; Kaspar Berneis; Joachim Struck; Beat Muller; Ulrich Keller; Mirjam Christ-Crain (2007). "Changes in plasma copeptin, the C-terminal portion of arginine vasopressin during water deprivation and excesse in healthy subjects". Journal of Clinical Endocrinology and Metabolism 92 (10): 3973–3978. doi:10.1210/jc.2007-0232. PMID 17635944. 
  8. ↑ Mira Katan; Nils Morgenthaler; Kashinat Dixit; Jonas Rutishauser; Beat Muller; Mirjam Christ-Crain (2007). "Anterior and posterior pituitary function testing with simultaneous insulin tolerance test and a novel copeptine assay". Journal of Clinical Endocrinology and Metabolism 92 (7): 2640–2643. doi:10.1210/jc.2006-2046. PMID 17426098. 
  9. ↑ Wiebke Fenske; Stefan Stork; Anne Blechschmidt; Sebastian Maier; Nils Morgenthaler; Bruno Allolio (2009). "Copeptin in the differential diagnosis of hyponatremia". Journal of Clinical Endocrinology and Metabolism 94 (1): 123–129. doi:10.1210/jc.2008-1426. PMID 18984663. 
  10. ↑ 10.0 10.1 Sohail Khan; Onkar Dhillon; Russel O’Brien; Joachim Struck; Paulen Quinn; Nils Morgenthaler; Iain Squire; Joan davies; Andreas Bergmann; Leong NG (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): 2103–2110. doi:10.1161/CIRCULATIONAHA.106.685503. PMID 17420344. 
  11. ↑ 11.0 11.1 11.2 11.3 Tobias Reichlin; Willibald Hochholzer; Claudia Stelzig; Kirsten Laule; Heike Freidank; Nils Morgenthaler; Andreas Bergmann; Mihael Potocki; Markus Noveanu; Tobias Breidhardt; Andreas Christ; Tujana Boldanova; Ramona Merki; Nora Schaub; Roland Bingisser; Michael Christ; Christian Mueller (2009). "Incremental value of copeptine for rapid rule out of acute myocardial infarction". Journal of the American College of Cardiology 54 (1): 60–68. doi:10.1016/j.jacc.2009.01.076. PMID 19555842. 
  12. ↑ 12.0 12.1 12.2 Till Keller; Stergios Tzikas; Tanja Zeller; Ewa Czyz; Lars Lillpopp; Francisco M. Ojeda; Alexander Roth; Christoph Bickel; Stephan Baldus; Christoph R. Sinning; Philipp S. Wild; Edith Lubos; Dirk Peetz; Jan Kunde; Oliver Hartmann; Andreas Bergmann; Felix Post; Karl J. Lackner; Sabine Genth-Zotz; Viviane Nicaud; Laurence Tiret; Thomas F. Münzel; Stefan Blankenberg (11 may 2010). "Copeptin improves early diagnosis of acute myocardial infarction.". Journal of the American College of Cardiology 55 (19): 2096–2106. doi:10.1016/j.jacc.2010.01.029. 
  13. ↑ 13.0 13.1 Alan Maisel; Christian Mueller; Sean-Xavier Neath; Robert Christenson; Nils Morgentahler; James McCord; Richard Nowak; Gary Vilke; Lori Daniels; Judd Hollander; Fred Apple; Chad Cannon; John Nagurney; donald Schreiber; Christopher deFilippi; Christopher Hogan; Deborah Diercks; John Stein; Gary headden; Alexander Limkakeng; Inder Anand; Alan Wu; Jana Papassotiriou; Oliver Hartmann; Stefan Ebmeyer; Paul Clopton; Alan Jaffe; Frank Peacock (2013). "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 of the American College of Cardiology 62 (2): 150–160. doi:10.1016/j.jacc.2013.04.011. PMID 23643595. 
  14. ↑ BIC-8, on Site ESC2013. On 10th september 2013
  15. ↑ Results of BIC-8, on Site biomarqueursinfos.fr. On 10th november 2013
  16. ↑ Interview of principal investigator and ESC reviewer on BIC-8 , on Site biomarqueursinfos.fr. On 10th november 2013
  17. ↑ Karl Lindner; Hans Strohmenger; Herman Ensinger; Wulf Hetzel; Friedrich Ahnefeld; Michael Georgieff (1992). "Stress hormone response during and after cardiopulmonary resuscitation". Anesthesiology 77 (4): 662–668. doi:10.1097/00000542-199210000-00008. PMID 1329579. 
  18. ↑ Anette Krismer; Volker Wenzel; Karl Stadlbauer; Viktoria Mayr; Richard Arntz; Karl Lindner (2004). "Vasopressin during cardiopulmonary resuscitation : a progress report". Critical Care Medicine 32 (9 Suppl): S432–S435. doi:10.1097/01.CCM.0000134267.91520.C0. PMID 15508673. 
  19. ↑ E Arnauld; P Czernichow; F Fumoux; J Vincent (1977). "The effects of hypotension and hypovolaemia on the liberation of vasopressin during haemorrhage in the unanaesthetized monkey (Macaca mulatta)". Pflugers Archives 371 (3): 193–200. PMID 414200. 
  20. ↑ J Rouleau; J de Champlain; M Klein; D Bichet; L Moye; M Packer; G Dagenais; B Sussex; J Arnold; F Sestier et al. (1993). "Activation of neurohumoral systems in postinfarction left ventricular dyfunction". Journal of the American College of Cardiology 22 (2): 390–398. PMID 8101532. 
  21. ↑ J Rouleau; M Packer; L Moye; J de Champlain; D Bichet; M Klein; Rouleau J; B Sussex; J Arnold; F Sestier et al. (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): 583–591. PMID 7915733. 
  22. ↑ Marvin Konstam; Mihai Gheorghiade; John Burnett; Liliana Grinfeld; Aldo Maggioni; Karl Swedberg; James Udelson; Faiez Zannad; Thomas Cook; John Ouyang; Christopher Zimmer; Cesare Orlandi; for the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators (2007). "Effects of oral tolvaptan in patients hospitalized for worsening heart failure : the EVEREST Outcome Trial". Journal of the American Medical Association 297 (12): 1319–1331. doi:10.1001/jama.297.12.1319. PMID 17384437. 
  23. ↑ Mihai Gheorghiade; Marvin A. Konstam; John C. Burnett; Liliana Grinfeld; Aldo P. Maggioni; Karl Swedberg; James E. Udelson; Faiez Zannad; Thomas Cook; John Ouyang; Christopher Zimmer; Cesare Orlandi (2007). "Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure : the EVEREST Clinical Status Trials". Journal of the American Medical Association 97 (12): 1332–1343. doi:10.1001/jama.297.12.1332. 
  24. ↑ Stephanie Neuhold; Martin Huelsmann; Guido Strunk; Brigitte Stoiser; Joachim Struck; Nils G. Morgenthaler; Andreas Bergmann; Deddo Moertl; Rudolf Berger; Richard Pacher (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): 266–272. doi:10.1016/j.jacc.2008.03.050. PMID 18634981. 

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