Copeptin

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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]

Blood levels

The concentration of copeptin in the blood circulation ranges from 1 to 12 pmol/L in healthy individuals.[4] The levels of copeptin are slightly higher in men than in women[4] and are not influenced by age.[4] In response to serum osmolality fluctuations, the kinetics of copeptin are comparable to those of vasopressin.[4][5] 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.[6] On the other hand, patients suffering from syndrome of inappropriate antidiuretic hormone secretion show high concentrations of both vasopressin and copeptin.[7]

Fenske[8] found the following normal values for levels in blood change changes during an osmostic load from hypertonic saline infusion:

  • Level during euvolemia: 2 and 38 pmol/L"[8]. Another view is "Median copeptin levels were significantly higher in the male volunteers compared with the females [median (range): 4.3 (0.4-44.3) compared with 3.2 (1.0-14.8) pmol/l"[9] and levels are modulated by gender (higher in males), eGFR higher when eGFR lower), left atrial size (higher when LA larger), and longer echocardiographic deceleration times (prolonged ventricular filling)[9].
  • Slope of change during hypertonic saline infusion: "slope of 0.74 pmol/L and mOsM/kg H2O ... (95% confidence interval [95% CI], 0.66 to 0.83)"[8]

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.[10][11] 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.[4]


Acute myocardial infarction

Several studies have shown that copeptin is released very early during the onset of an acute myocardial infarction (AMI),[12][13] raising the question of its potential value in the diagnosis of AMI and particularly in ruling-out AMI.[13][14][15] 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,[16] making the interpretation of their complementary kinetics a useful tool to rule-out AMI.[13][14] 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%.[13][14][15] These results have been confirmed in a randomised controlled trial.[17][18][19]

Cardiogenic shock

High concentrations of vasopressin during cardiogenic shock have been widely described.[20][21] It has been shown that the kinetics of copeptin are similar to vasopressin in that context.[22]

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.[23][24] Recently, a similar interest has been demonstrated for copeptin in heart failure.[12][25][26][27]

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. ↑ 4.0 4.1 4.2 4.3 4.4 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 8.0 8.1 8.2 Fenske WK, Christ-Crain M, Hörning A, Simet J, Szinnai G, Fassnacht M; et al. (2014). "A copeptin-based classification of the osmoregulatory defects in the syndrome of inappropriate antidiuresis". J Am Soc Nephrol. 25 (10): 2376–83. doi:10.1681/ASN.2013080895. PMC 4178436. PMID 24722436.
  9. ↑ 9.0 9.1 Bhandari SS, Loke I, Davies JE, Squire IB, Struck J, Ng LL (2009). "Gender and renal function influence plasma levels of copeptin in healthy individuals". Clin Sci (Lond). 116 (3): 257–63. doi:10.1042/CS20080140. PMID 18647134.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 12.0 12.1 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.
  13. ↑ 13.0 13.1 13.2 13.3 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.
  14. ↑ 14.0 14.1 14.2 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.
  15. ↑ 15.0 15.1 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.
  16. ↑ 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.
  17. ↑ BIC-8, on Site ESC2013 Archived 9 November 2013 at the Wayback Machine.. On 10 September 2013
  18. ↑ Results of BIC-8, on Site biomarqueursinfos.fr. On 10 November 2013
  19. ↑ Interview of principal investigator and ESC reviewer on BIC-8 , on Site biomarqueursinfos.fr. On 10 November 2013
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ 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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