Arginine vasopressin, also known as antidiuretic hormone, is a peptide involved in diverse physiological functions that is synthesized in the magnocellular neurons of the paraventricular and supraoptic nucleus of the hypothalamus . The release of vasopressin is chiefly regulated by a change in osmolality detected by osmoreceptors in the hypothalamus and also by input from left atrial volume receptors in response to a fall in extracellular fluid volume  (Fig. 1). Neuroendocrine hormones such as angiotensin-II  and norepinephrine  represent further regulators of vasopressin release. Overall, vasopressin is considered an important factor of the response and adaptation to stress, and exerts its effects via three different receptors types: the V1A, V1B, and V2 receptors. Vasopressin exerts its antidiuretic effects through the V2 receptor in the kidney . The V1A receptor is involved in vasoconstriction and platelet aggregation , and may play a role in cardiomyocyte hypertrophy . The V1B receptor is found in the anterior hypophysis and the Langerhans islets of the pancreas, wherein it mediates secretion of adrenocorticotrophic hormone, insulin, and glucagon .
Vasopressin is a small, short-lived peptide, and most assays measuring it have relatively limited sensitivity. Copeptin, that is, the C-terminal part of preprovasopressin, is separated from vasopressin during transport to the pituitary gland and is released from the neurohypophysis with vasopressin and a third peptide, neurophysin II (Fig. 1). Copeptin may aid in the intracellular processing of vasopressin during secretion, but its exact physiologic role, if any, remains unknown. Copeptin has been used as a surrogate marker of vasopressin because it generates in equimolar amounts with vasopressin and has a longer half-life and ex-vivo stability, which can provide valid measurements in human samples [9,10]. In recent years, copeptin has received considerable attention as a biomarker with several potential clinical applications in cardiovascular medicine. In the acute setting, copeptin can rule out myocardial infarction [11–13], and has been suggested as a prognostic tool in acute illness, as it is a more sensitive marker of endogenous stress levels than cortisol, and the magnitude of individual stress is generally well correlated with the severity of the disease in these conditions . A high circulating copeptin level is a predictor of adverse outcome and death in patients with stroke , myocardial infarction [16,17], heart failure [18,19], and renal failure . Copeptin also predicts incident diabetes [21,22] and abdominal obesity . However, despite the strong pathophysiological rationale linking the vasopressin system and blood pressure (BP), the association between copeptin and ambulatory BP measures has received little attention so far.
In the present issue of the Journal of Hypertension, Schön et al. report the findings of a large, population-based cross-sectional study, in which serum copeptin was assessed along with ambulatory BP and respiratory monitoring during sleep. All inhabitants of the Principality of Liechtenstein aged 25–41 years were invited to participate in the genetic and phenotypic determinants of blood pressure and other cardiovascular risk factors study. After excluding individuals with overt cardiovascular, renal, or other severe disease, known obstructive sleep apnea (OSA) syndrome, class II or III obesity (BMI ≥ 35 kg/m2), or current treatment for diabetes or hypertension, a total of 2012 young adults underwent plasma copeptin determination and office and 24-h ambulatory BP measurement. Sleep apnea was assessed in a subgroup of 1291 participants by using a device that combines night-time pulse oximetry with nasal flow measurement. The main study findings can be summarized as follows.
- Plasma copeptin levels were higher in men, and sex was a significant effect modifier of the relationship between copeptin and ambulatory BP. Copeptin was significantly and independently associated with night-time SBP and DBP and with night-time hypertension in men, but not in women. In men, the risk for night-time hypertension was 70, 70, and 80% higher in the third, fourth, and top quintile, respectively, than in the lowest quintile of copeptin distribution (P for trend = 0.016). No significant relationship was found with office or daytime BP in either sex.
- Copeptin was strongly associated with short-term BP variability, expressed as the standard deviation of both daytime and night-time BP. A significant relationship between copeptin and BP variability was present in men as well as in women, and for both SBP and DBP.
- In the subgroup of 1291 participants who also underwent overnight pulse oximetry with nasal flow measurement, a sizeable minority (16% of men and 4% of women) had an apnea–hypopnea index of at least 5 per hour, thus suggesting the presence of sleep apnea. Interestingly, copeptin levels were significantly higher in the participants with sleep apnea (3.6 pmol/l, interquartile range 2.7–5.9) than in those without (2.9 pmol/l, interquartile range 1.9–4.6, P < 0.0001). As expected, further independent correlates of sleep apnea included age, male sex, BMI, C-reactive protein levels, and serum uric acid. In a multivariate model, after accounting for the effect of night-time BP and the variables mentioned earlier, each log-transformed unit of copeptin was independently associated with a 51% increased risk of having sleep apnea (P = 0.039).
A few, small clinical studies had reported on the relationship between copeptin and 24-h BP or sleep apnea previously, and their findings were not straightforward [24–28]. In a study carried out in 84 hypertensive adolescents, serum copeptin levels among the participants with sustained hypertension were found to be higher than in those whose diagnosis of hypertension was not confirmed in 24-h ambulatory BP monitoring (white-coat hypertension), and a significant correlation was found between copeptin levels and nighttime BP load . In 76 hypertensive patients, serum copeptin levels correlated with night-time, but not daytime, BP . The few small studies that have investigated the relation between copeptin and sleep apnea have been conflicting, with copeptin levels in patients with OSA reported as being higher , similar , or lower  than in patients without sleep apnea. Thus, the findings by Schön et al. of a clear, independent relationship of copeptin with both ambulatory BP and sleep-related respiratory disorders in a large population appear to be both original and relevant.
A limitation of the study by Schön et al. is that it cannot demonstrate cause-and-effect relationships because of its cross-sectional design. As such, the study can at most provide hypotheses regarding the causal pathways linking the examined variables. On one hand, the vasopressin system is a major regulator of blood volume and arterial pressure. In the deoxycorticosterone acetate-salt model of hypertension, activation of the angiotensin type 1a receptors in the subfornical organ is required for hypertension, in part through stimulation of vasopressin release . Vasopressin plays a major role in the hypertension of transgenic mice with brain-specific hyperactivity of the renin–angiotensin system and BP is normalized after blockade of vasopressin V1A/V2 receptors , thus confirming a required role for vasopressin signaling in this model. Hence, the hypothesis can be made that activation of the vasopressin system may be one factor leading to a sustained increase of BP during nighttime.
On the other hand, the authors found a clear association between copeptin levels and sleep apnea, thus suggesting that the chain of events associated with sleep apnea might involve an activation of the vasopressin system. Intermittent obstruction of the upper airway, obstruction-induced hypoxia, and the frequent, repetitive arousals seen in OSA are believed to increase sympathetic activation and oxidative stress [31–33], which, in turn, may lead to release of vasopressin . These data are also in agreement with a rat model of sleep apnea-induced hypertension, in which inhibition of vasopressin release is able to counteract sleep apnea-associated BP increase . The findings by Schön et al. are in keeping with the hypothesis that OSA-induced activation of the vasopressin system might play a role in increasing nocturnal BP and short-term BP variability. Given that acute and repeated changes in BP occur during the night, nocturnal hypertension is frequent in OSA [34,35], and OSA has been associated to the future occurrence of nocturnal hypertension in longitudinal studies [36–38]. This may have clinical implications, given the strong adverse prognostic value of nocturnal hypertension [39,40], probably in part due to its greater stability and reproducibility [41,42]. In the general population, isolated nocturnal hypertension independently predicts cardiovascular outcome, even in those patients who are normotensive on office or ambulatory daytime BP measurement . OSA and high nocturnal BP might interact synergistically in determining the risk of brain damage assessed as white matter hyperintensities on brain MRI , a prognostically relevant marker of BP-related cerebral organ damage .
Increased short-term BP variability, an emerging risk factor for cardiovascular complications in the general population as well as in hypertensive patients [46,47], had also been reported previously in patients with sleep apnea . The findings of the study by Schön et al. suggest that circulating copeptin levels may be regarded as an integrated marker of the stressful events associated with sleep apnea as well as of the related BP changes, and might eventually act as a harbinger of future cardiovascular complications.
The authors should be commended for performing a nationwide study that involved the whole population of a country, that is, the Principality of Liechtenstein. Although compelling, the study findings should be viewed in the light of their limitations. First, it is not reported how many of the invited patients refused to participate and what were their characteristics. In a preliminary report from the same study, 51% of the eligible individuals could not be reached or declined to participate . In the present study , a total of 56% of male participants had daytime hypertension (defined as SBP ≥ 135 mmHg and/or DBP ≥ 85 mmHg), and 51% had nighttime hypertension (defined as SBP ≥ 120 mmHg and/or DBP ≥ 70 mmHg). Although it has been previously shown that ambulatory daytime BP tends to be higher than office BP in the young , the rates mentioned earlier look unexpectedly high for a population with an average age of 37 years, and should be taken into account in interpreting the study findings and applying them to different populations. Second, sleep apnea was evaluated through a device that combines continuous pulse oximetry and nasal flow. Unattended, portable monitoring records fewer physiologic variables than full in-laboratory polysomnography. As pulse oximetry has a low sensitivity for the diagnosis of OSA, especially in individuals with high values of oxygen saturation during wakefulness, in the study by Schön et al., pulse oximeter was combined with nasal flow monitoring obtained by using a nasal cannula connected to a pressure transducer. Despite an increased sensitivity for detecting OSA , this approach does not discriminate between central and obstructive apnea, and in-laboratory polysomnography remains the gold-standard technique for evaluating OSA. Third, the authors did not take into account the potential impact of average BP values on the association between copeptin levels and short-term BP variability. As the standard deviation of BP is directly related to its average values , the independent impact of any variable on BP variability should be properly evaluated after adjustment for average BP levels. Finally, the absence of a relation of copeptin with nighttime BP in women is intriguing, and sex-specific correlations of copeptin with diabetes and hypertension had also been reported in other cross-sectional studies . However, as nocturnal hypertension was present in 51% of men and in just 16% of women, the power for detecting an association between copeptin levels and nocturnal hypertension was lower in female participants.
Sources of funding: The position of Giacomo Pucci as an Adjunct Assistant Professor at the University of Perugia was funded by a grant from the Fondazione Cassa di Risparmio di Terni e Narni.
Authors’ disclosures: none.
Conflicts of interest
There are no conflicts of interest.
1. Morgenthaler NG, Struck J, Jochberger S, Dünser MW. Copeptin: clinical use of a new biomarker. Trends Endocrinol Metab
2. Bankir L. Antidiuretic action of vasopressin: quantitative aspects and interaction between V1a and V2 receptormediated effects. Cardiovasc Res
3. da Silva AQ, Fontes MA, Kanagy NL. Chronic infusion of angiotensin receptor antagonists in the hypothalamic paraventricular nucleus prevents hypertension in a rat model of sleep apnea. Brain Res
4. Benetos A, Gavras I, Gavras H. Norepinephrine applied in the paraventricular hypothalamic nucleus stimulates vasopressin release. Brain Res
5. Nielsen S, Chou CL, Marples D, Christensen EI, Kishore BK, Knepper MA. Vasopressin increases water permeability of kidney collecting duct by inducing translocation of aquaporin-CD water channels to plasma membrane. Proc Natl Acad Sci USA
6. Chatterjee K. Neurohormonal activation in congestive heart failure and the role of vasopressin. Am J Cardiol
7. Hiroyama M, Wang S, Aoyagi T, Oikawa R, Sanbe A, Takeo S, Tanoue A. Vasopressin promotes cardiomyocyte hypertrophy via the vasopressin V1A receptor in neonatal mice. Eur J Pharmacol
8. Tanoue A, Ito S, Honda K, Oshikawa S, Kitagawa Y, Koshimizu TA, et al. The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions. J Clin Invest
9. 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
10. Katan M, Morgenthaler NG, Dixit KC, Rutishauser J, Brabant GE, Muller B, Christ-Crain M. Anterior and posterior pituitary function testing with simultaneous insulin tolerance test and a novel copeptin assay. J Clin Endocrinol Metab
11. Keller T, Tzikas S, Zeller T, Czyz E, Lillpopp L, Ojeda FM, et al. Copeptin improves early diagnosis of acute myocardial infarction. J Am Coll Cardiol
12. Giannitsis E, Kehayova T, Vafaie M, Katus HA. Combined testing of high-sensitivity troponin T and copeptin on presentation at prespecified cutoffs improves rapid rule-out of non–ST-segment elevation myocardial infarction. Clin Chem
13. Lipinski MJ, Escárcega RO, D’Ascenzo F, Magalhães MA, Baker NC, Torguson R, et al. A systematic review and collaborative meta-analysis to determine the incremental value of copeptin for rapid rule-out of acute myocardial infarction. Am J Cardiol
14. Katan M, Christ-Crain M. The stress hormone copeptin: a new prognostic biomarker in acute illness. Swiss Med Wkly
15. Sun H, Sun T, Ma B, Yang BW, Zhang Y, Huang DH, Shi JP. Prediction of all-cause mortality with copeptin in cardio-cerebrovascular patients: a meta-analysis of prospective studies. Peptides
16. Khan SQ, Dhillon OS, O’Brien RJ, Struck J, Quinn PA, Morgenthaler NG, et al. C-terminal provasopressin (copeptin) as a novel and prognostic marker in acute myocardial infarction: Leicester Acute Myocardial Infarction Peptide (LAMP) study. Circulation
17. Mellbin LG, Ryden L, Brismar K, Morgenthaler NG, Ohrvik J, Catrina SB. Copeptin, IGFBP-1, and cardiovascular prognosis in patients with type 2 diabetes and acute myocardial infarction: a report from the DIGAMI 2 trial. Diabetes Care
18. Stoiser B, Mortl D, Hulsmann M, Berger R, Struck J, Morgenthaler NG, et al. Copeptin, a fragment of the vasopressin precursor, as a novel predictor of outcome in heart failure. Eur J Clin Invest
19. Goldsmith SR. Congestive heart failure: potential role of arginine vasopressin antagonists in the therapy of heart failure. Congest Heart Fail
20. Fenske W, Wanner C, Allolio B, Drechsler C, Blouin K, Lilienthal J, Krane V. German Diabetes, Dialysis Study Investigators. Copeptin levels associate with cardiovascular events in patients with ESRD and type 2 diabetes mellitus. J Am Soc Nephrol
21. Enhorning S, Wang TJ, Nilsson PM, Almgren P, Hedblad B, Berglund G, et al. Plasma copeptin and the risk of diabetes mellitus. Circulation
22. Enhorning S, Bankir L, Bouby N, Struck J, Hedblad B, Persson M, et al. Copeptin, a marker of vasopressin, in abdominal obesity, diabetes and microalbuminuria: the prospective Malmo Diet and Cancer Study cardiovascular cohort. Int J Obes
23. Schoen T, Hohmann E-M, Van Der Lely S, Aeschbacher S, Reusser A, Risch M, et al. Plasma copeptin levels and ambulatory blood pressure characteristics in healthy adults. J Hypertens
24. Tenderenda-Banasiuk E, Wasilewska A, Filonowicz R, Jakubowska U, Waszkiewicz-Stojda M. Serum copeptin levels in adolescents with primary hypertension. Pediatr Nephrol
25. Uzun F, Biyik I, Akturk IF, Yalcin AA, Erturk M, Oner E, et al. Serum copeptin levels in predicting nondippers in newly diagnosed hypertension. Blood Press Monit
2015; Apr 17 [Epub ahead of print]. PMID: 25919790.
26. Çınarka H, Kayhan S, Karataş M, Yavuz A, Gümüş A, Özyurt S, et al. Copeptin: a new predictor for severe obstructive sleep apnea. Ther Clin Risk Manag
27. Selcuk OT, Eyigor M, Renda L, Osma U, Eyigor H, Selcuk NT, et al. Can we use serum copeptin levels as a biomarker in obstructive sleep apnea syndrome? J Craniomaxillofac Surg
2015; Apr 3. [Epub ahead of print] doi: 10.1016/j.jcms.2015.03.031.
28. Ozben S, Guvenc TS, Huseyinoglu N, Sanivar HS, Hanikoglu F, Cort A, Ozben T. Low serum copeptin levels in patients with obstructive sleep apnea. Sleep Breath
29. Hilzendeger AM, Cassell MD, Davis DR, Stauss HM, Mark AL, Grobe JL, Sigmund CD. Angiotensin type 1a receptors in the subfornical organ are required for deoxycorticosterone acetate-salt hypertension. Hypertension
30. Littlejohn NK, Siel RB Jr, Ketsawatsomkron P, Pelham CJ, Pearson NA, Hilzendeger AM, et al. Hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent. Am J Physiol Regul Integr Comp Physiol
31. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest
32. Tamisier R, Pepin JL, Remy J, Baguet JP, Taylor JA, Weiss JW, Lévy P. 14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans. Eur Respir J
33. Lavie L. Obstructive sleep apnea syndrome—an oxidative stress disorder. Sleep Med Rev
34. Suzuki M, Guilleminault C, Otsuka K, Shiomi T. Blood pressure ‘dipping’ and ‘nondipping’ in obstructive sleep apnea syndrome patients. Sleep
35. Pucci G, Fiorenzano G, Schillaci G. Obstructive sleep apnea and reverse dipping: the bad companions. J Hypertens
36. Li AM, Au CT, Ng C, Lam HS, Ho CK, Wing YK. A four-year prospective follow-up study of childhood obstructive sleep apnea and its association with blood pressure. Chest
37. Hla KM, Young T, Finn L, Peppard PE, Szklo-Coxe M, Stubbs M. Longitudinal association of sleep-disordered breathing and nondipping of nocturnal blood pressure in the Wisconsin Sleep Cohort Study. Sleep
38. Guillot M, Sforza E, Achour-Crawford E, Maudoux D, Saint-Martin M, Barthélémy JC, Roche F. Association between severe obstructive sleep apnea and incident arterial hypertension in the older people population. Sleep Med
39. Sega R, Facchetti R, Bombelli M, Cesana G, Corrao G, Grassi G, Mancia G. Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population: follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. Circulation
40. Hansen TW, Li Y, Boggia J, Thijs L, Richart T, Staessen JA. Predictive role of the nighttime blood pressure. Hypertension
41. Omboni S, Parati G, Palatini P, Vanasia A, Muiesan ML, Cuspidi C, Mancia G. Reproducibility and clinical value of nocturnal hypotension: prospective evidence from the SAMPLE study (Study on Ambulatory Monitoring of Pressure and Lisinopril Evaluation). J Hypertens
42. O’Brien E. 24-h ambulatory blood pressure measurement in clinical practice and research: a critical review of a technique in need of implementation. J Intern Med
43. Fan HQ, Li Y, Thijs L, Hansen TW, Boggia J, Kikuya M, et al. International Database on Ambulatory Blood Pressure in relation to Cardiovascular Outcomes investigators. Prognostic value of isolated nocturnal hypertension on ambulatory measurement in 8711 individuals from 10 populations. J Hypertens
44. Lee S, Thomas RJ, Kim H, Seo HS, Baik I, Yoon DW, et al. Association between high nocturnal blood pressure and white matter change and its interaction by obstructive sleep apnea among normotensive adults. J Hypertens
45. Debette S, Beiser A, DeCarli C, Au R, Himali JJ, Kelly-Hayes M, et al. Association of MRI markers of vascular brain injury with incident stroke, mild cognitive impairment, dementia, and mortality: the Framingham Offspring Study. Stroke
46. Kikuya M, Hozawa A, Ohkubo T, Tsuji I, Michimata M, Matsubara M, et al. Prognostic significance of blood pressure and heart rate variabilities: the Ohasama Study. Hypertension
47. Pringle E, Phillips C, Thijs L, Davidson C, Staessen JA, de Leeuw PW, et al. Syst-Eur investigators. Systolic blood pressure variability as a risk factor for stroke and cardiovascular mortality in the elderly hypertensive population. J Hypertens
48. Steinhorst AP, Gonçalves SC, Oliveira AT, Massierer D, Gus M, Fuchs SC, et al. Influence of sleep apnea severity on blood pressure variability of patients with hypertension. Sleep Breath
49. Conen D, Schön T, Aeschbacher S, Paré G, Frehner W, Risch M, Risch L. Genetic and phenotypic determinants of blood pressure and other cardiovascular risk factors (GAPP). Swiss Med Wkly
50. Conen D, Aeschbacher S, Thijs L, Li Y, Boggia J, Asayama K, et al. Age-specific differences between conventional and ambulatory daytime blood pressure values. Hypertension
51. Erman MK, Stewart D, Einhorn D, Gordon N, Casal E. Validation of the ApneaLink for the screening of sleep apnea: a novel and simple single-channel recording device. J Clin Sleep Med
52. Schillaci G, Verdecchia P, Borgioni C, Ciucci A, Porcellati C. Lack of association between blood pressure variability and left ventricular mass in essential hypertension. Am J Hypertens
53. Then C, Kowall B, Lechner A, Meisinger C, Heier M, Koenig W, et al. Plasma copeptin is associated with type 2 diabetes in men but not in women in the population-based KORA F4 study. Acta Diabetol