Copeptin in research applications

Copeptin is a peptide fragment from human precursor of vasopressin (126-164)
BACKGROUND: The role of the vasopressin system after acute myocardial infarction is unclear. Copeptin, the C-terminal part of the vasopressin prohormone, is secreted stoichiometrically with vasopressin. We compared the prognostic value of copeptin and an established marker, N-terminal pro-B-type natriuretic peptide (NTproBNP), after acute myocardial infarction.
METHODS AND RESULTS: In this prospective single-hospital study, we recruited 980 consecutive post-acute myocardial infarction patients (718 men, median [range] age 66 [24 to 95] years), with follow-up over 342 (range 0 to 764) days. Plasma copeptin was highest on admission (n=132, P<0.001, day 1 versus days 2 to 5) and reached a plateau at days 3 to 5. In the 980 patients, copeptin (measured at days 3 to 5) was elevated in patients who died (n=101) or were readmitted with heart failure (n=49) compared with survivors (median [range] 18.5 [0.6 to 441.0] versus 6.5 [0.3 to 267.0] pmol/L, P<0.0005). With logistic regression analysis, copeptin (odds ratio, 4.14, P<0.0005) and NTproBNP (odds ratio, 2.26, P<0.003) were significant independent predictors of death or heart failure at 60 days. The area under the receiver operating characteristic curves for copeptin (0.75) and NTproBNP (0.76) were similar. The logistic model with both markers yielded a larger area under the curve (0.84) than for NTproBNP (P<0.013) or copeptin (P<0.003) alone, respectively. Cox modeling predicted death or heart failure with both biomarkers (log copeptin [hazard ratio, 2.33], log NTproBNP [hazard ratio, 2.70]). In patients stratified by NTproBNP (above the median of approximately 900 pmol/L), copeptin above the median ( approximately 7 pmol/L) was associated with poorer outcome (P<0.0005). Findings were similar for death and heart failure as individual end points.
CONCLUSIONS: The vasopressin system is activated after acute myocardial infarction. Copeptin may predict adverse outcome, especially in those with an elevated NTproBNP (more than approximately 900 pmol/L).

Khan SQ, Dhillon OS, O'brien RJ, et al. C-terminal provasopressin (copeptin) as a novel and prognostic marker in acute myocardial infarction: Leicester Acute Myocardial Infarction Peptide (LAMP) study. Circulation. 2007;115(16):2103-10

BACKGROUND: The aim of the present study was to evaluate the capability B-type natriuretic peptide (BNP) as a prognostic marker in patients with acute destabilized heart failure in comparison with mid-regional pro-A-type natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), and the C-terminal part of the arginine vasopressin prohormone (Copeptin).
METHODS AND RESULTS: BNP, MR-proANP, MR-proADM, and Copeptin plasma concentrations were obtained in 137 patients with acute destabilized heart failure attending a tertiary care hospital. The end point was defined as all-cause mortality, and the study participants were followed for 365 days. Of the 137 patients enrolled, 41 died and 96 survived during follow-up. ROC curve analysis showed that the areas under curve for the prediction of 1-year mortality were similar for BNP (0.716; 95% CI 0.633-0.790), MR-proANP (0.725; 95% CI 0.642-0.798), MR-proADM (0.708; 95% CI 0.624-0.782), and Copeptin (0.688; 95% CI 0.603-0.764). Using tercile approaches, Kaplan-Meier curve analyses demonstrated that the predictive value of all four analytes for survival probability was comparable (log-rank test for trend, P < .001 for each). In multivariable Cox proportional-hazards regression analyses, increased BNP, MR-proANP, MR-proADM, and Copeptin plasma concentrations were the strongest predictors of mortality.
CONCLUSION: BNP is considered an established prognostic marker for heart failure patients. The present study provides evidence that MR-proANP, MR-proADM, and Copeptin measurements might have similar predictive properties compared with BNP determinations for one-year all-cause mortality in acute destabilized heart failure.

Gegenhuber A, Struck J, Dieplinger B, et al. Comparative evaluation of B-type natriuretic peptide, mid-regional pro-A-type natriuretic peptide, mid-regional pro-adrenomedullin, and Copeptin to predict 1-year mortality in patients with acute destabilized heart failure. J Card Fail. 2007;13(1):42-9

BACKGROUND: Vasopressin has haemodynamic as well as osmoregulatory effects, and reflects the individual stress response. Copeptin is co-synthesized with vasopressin, directly mirroring vasopressin levels, but is more stable in plasma and serum. Both levels are increased in patients with septic shock. Lower respiratory tract infections (LRTI) are a precursor of sepsis. Thus, we investigated circulating levels and the prognostic use of copeptin for the severity and outcome in patients with LRTI.
MATERIALS AND METHODS: Five hundred and forty-five consecutive patients with LRTI and 50 healthy controls were evaluated. Serum copeptin levels were measured with a new chemiluminescent sandwich immunoassay. RESULTS: Of the 545 patients, 373 had community-acquired pneumonia (CAP), 60 acute exacerbations of chronic obstructive pulmonary disease (COPD), 59 acute bronchitis, 13 exacerbations of asthma and 40 other final diagnoses. Copeptin levels were significantly higher in patients with LRTI as compared to controls (P < 0.001) with highest levels in patients with CAP. Copeptin levels increased with increasing severity of CAP, as classified by the pneumonia severity index (PSI) (P < 0.001). In patients who died, copeptin levels on admission were significantly higher as compared to levels in survivors [70.0 (28.8-149.0) vs. 24.3 (10.8-43.8) pmol L(-1), P < 0.001]. The area under the receiver operating curve (AUC) for survival was 0.75 for copeptin, which was significantly higher as compared to C-reactive protein (AUC 0.61, P = 0.01), leukocyte count (AUC 0.59, P = 0.01) and similar to procalcitonin (AUC 0.68, P = 0.21).
CONCLUSIONS: Copeptin levels are increased with increasing severity of LRTI namely in patients with CAP and unfavourable outcome. Copeptin levels, as a novel biomarker, might be a useful tool in the risk stratification of patients with LRTI.

Müller B, Morgenthaler N, Stolz D, et al. Circulating levels of copeptin, a novel biomarker, in lower respiratory tract infections. Eur J Clin Invest. 2007;37(2):145-52

BACKGROUND: Natriuretic peptides, particularly brain natriuretic peptide (BNP), are elevated in heart failure and therefore considered to be excellent predictors of outcome. Vasopressin is also known to be related to the severity of heart disease. Copeptin--an inactive fragment of the vasopressin precursor--has not been previously investigated in the context of heart failure.
MATERIALS AND METHODS: We prospectively studied 268 patients with advanced heart failure after they had been discharged from the hospital. We investigated the ability of BNP and copeptin to predict death, re-hospitalization due to heart failure, and a combination of the two endpoints. RESULTS: Over a mean follow-up period of 15.8 months (up to 24 months), 83 patients died, 122 patients experienced worsening of heart failure, and 145 patients achieved the combined endpoint. Univariate predictors of death were copeptin, BNP, age and impaired kidney function. In multivariate analysis, copeptin (chi(2) = 16, P < 0.0001) and age (chi(2) = 4, P < 0.05) were independent predictors. Univariate predictors of re-hospitalization due to heart failure were copeptin, BNP, age and impaired kidney function. Furthermore, in multivariate analysis BNP (chi(2) = 18, P < 0.0001), age (chi(2) = 11.8, P < 0.001) and copeptin (chi(2) = 4.2, P < 0.05) were found to be independent predictors.
CONCLUSION: Our study is the first to show that copeptin is an excellent predictor of outcome in advanced heart failure patients. Its value is superior to that of BNP in predicting death and a combined endpoint, although BNP is still suitable for predicting chronic heart failure (CHF) re-hospitalization. Our data imply that vasopressin antagonism might be a new target to improve outcome in this population.

Stoiser B, Mörtl D, Hülsmann M, et al. Copeptin, a fragment of the vasopressin precursor, as a novel predictor of outcome in heart failure. Eur J Clin Invest. 2006;36(11):771-8

BACKGROUND: Arginine vasopressin (AVP) is a key regulator of water balance, but its instability makes reliable measurement difficult and precludes routine use. We present a method for quantifying AVP release by use of copeptin, a glycopeptide comprising the C-terminal part of the AVP prohormone.
METHODS: We measured copeptin in 50-microL serum and plasma samples from healthy individuals and from critically ill patients with sepsis. Our sandwich immunoluminometric assay used 2 polyclonal antibodies to amino acids 132-164 of pre-provasopressin.
RESULTS: The assay yielded results within 3 h. The analytical detection limit was 1.7 pmol/L, and the interlaboratory CV was <20% for values >2.25 pmol/L. The assay was linear on dilution of the analyte. Ex vivo copeptin stability (<20% loss of analyte) for at least 7 days at room temperature and 14 days at 4 degrees C was shown for serum and EDTA-, heparin-, and citrate plasma. Copeptin (median, 4.2 pmol/L; range, 1-13.8 pmol/L) was detectable in 97.5% of 359 healthy individuals and was not associated with age. Median concentrations were considerably higher in men than women, increased significantly after exercise, and were influenced by fasting and water load. Copeptin was significantly (P <0.001) increased in 60 critically ill patients with sepsis (median, 79.5 pmol/L; range, 10.6-228.0 pmol/L). The correlation between copeptin and AVP for 110 samples was r = 0.78 (P <0.0001).
CONCLUSIONS: Copeptin is stable for days after blood withdrawal and can be quickly and easily measured. The copeptin assay may be a useful alternative to direct measurement of AVP concentration.

Morgenthaler NG, Struck J, Alonso C, Bergmann A. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem. 2006;52(1):112-9

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