Chapter Two - Copeptin in Heart Failure
Introduction
Heart failure (HF) is one of the most common reasons of death and hospitalization in the Western world with annual mortality rates over 50% for patients with end-stage HF disease (stage D) [1]. The introduction of modern HF treatments and advanced treatments options such as cardiac resynchronization therapy and implantable defibrillators have improved the prognosis and quality of life of HF patients, but HF remains a serious disease significantly shortening the life span even for patients with less advanced symptoms [2], [3]. In addition, HF will be an increasing burden on the hospital system in the future because the improved treatments of ischemic heart disease and the longevity of the population in general [4].
A key feature of HF is the abnormal activation of the complex neurohormonal system due to an overactive response of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone axis (RAAS), and the vasopressin system as well as to a wide spectrum of neuro-mediators. Hence, the pathophysiology of HF is complex and HF is often associated with combination of structural changes such as left ventricular remodeling and/or inflammatory and fibrotic changes in the myocardium. The modern medical HF treatment is mainly centered on the inhibition of overactive neurohormonal systems such as a blockade of the RAAS and SNS. However, research has made it clear that the vasopressin system is also a major player in the development and progression of HF. Arginine vasopressin (AVP), a small glycopeptide, is a modulator and regulator of osmoregulation and homeostasis in healthy individuals and in patients with HF. Increased levels of AVP have been shown to carry prognostic information in HF. Previous studies have investigated the effect of treatment with vasopressin antagonists in HF with beneficial effects on HF symptoms, but have until now failed to show an impact on survival.
A recently discovered biomarker, copeptin, has been introduced as a surrogate marker of vasopressin. Copeptin, the C-terminal part of pre-pro-vasopressin, has been investigated in HF and across a wide spectrum of cardiac and noncardiac diseases and has shown promise as a prognostic marker. As will be discussed below, several previous studies have shown that an elevated level of copeptin is associated with an increased mortality in both acute and chronic HF.
Biomarkers allow for insights into the molecular pathophysiology and biological pathways of HF and may mirror disease development and progression [5]. Recent research has focused on identifying biomarkers, which alone or in combination, could be useful in monitoring the treatment and as prognostic markers for future cardiovascular events such as hospitalizations and deaths due to HF.
This review will present the latest knowledge on copeptin in HF and discuss the possible uses of copeptin as a biomarker in the guidance of HF therapies, disease monitoring, and prognostic evaluation.
Section snippets
Neurohormonal Activation in HF
HF, a complex disease involving multiple organ systems, arises when the ability of the heart to pump sufficient amounts of blood is too low to supply the oxygen demands of the organs in the body either at rest or during exercise and cardiac output is achieved at the cost of increased cardiac filling pressures. HF is often a multimorbid condition with a high prevalence of comorbidity such as diabetes, renal failure, sleep apnea, and depression [6]. Symptoms of HF are diverse, but commonly
The Vasopressin System in HF
AVP, formerly known as antidiuretic hormone, is a key player in the regulation of many important physiologic pathways in the human body. AVP is synthesized in the hypothalamus in the magnucellular neurons of the supraoptic and paraventricular hypothalamic nuclei and stored in the hypophysis. AVP is an important regulator of fluid homeostasis and vascular tone in healthy individuals contributing to maintenance of equilibrium of the cardiovascular system. AVP is also an important regulator of
Limitations of Vasopressin Measurements in Clinical Settings
Reliable measurement of AVP in vivo is troublesome because of a range of hindering factors. AVP has very short half-time of 2–3 min in vivo as well and ex vivo and more than 99% of circulating AVP is bound to platelets. In addition, AVP is extremely unstable ex vivo even when stored at − 20 °C. In addition, most vasopressin assays have a limited sensitivity, require relatively large plasma volumes (≥ 1 mL) and cumbersome protein extraction during analysis, all of which contribute to the limited use
Structure and Function of Copeptin
Copeptin (CT-proAVP) is a 39-aminoacid glycopeptide—the C-terminal part of pre-provasopressin and was first described in 1972 by Holwerda [31]. The molecular mass of copeptin is approximately 5 kDa [32]. Upon release from the hypophysis, copeptin is cleaved from vasopressin with an additional peptide called neurophysin in equimolar amounts (Fig. 2) [30]. Whether copeptin and neurophysin have any physiologic role, or if they are merely inactive protein residues after cleavage from AVP is still
Copeptin in Healthy Populations
Median copeptin concentrations in healthy controls have been found to be 4.7 (IQR 2.9–7.6) pmol/L—with higher levels in men than in women [38], [39]. The physiological mechanism of increased copeptin levels in males is unknown, but it has been proposed that an explanation could be a higher osmolar intake in men [28]. Similarly to copeptin, AVP levels have been found to be higher in men than in women [40]. Gender differences in AVP levels have not been found to be attributed to differences in
Copeptin in Other Heart Diseases than HF
As previously described, copeptin has been proposed as a marker of physiological stress levels and to be correlated with disease severity. It has been proposed that copeptin may have a role as a predictor of outcome and in the treatment strategy of patients admitted acutely to an emergency department (ED) or in acute illness in general [60], [61]. To further support this theory, copeptin has been found to be an outstanding biomarker in patients with community acquired pneumonia, septic, and
Copeptin in HF
The diagnosis of HF is based on the combination of symptoms and objective evidence of cardiac dysfunction often in combination with an elevated level of one of the natriuretic peptides (BNP, NT-proBNP, and/or MR-ANP), which are the gold standard biomarkers in HF. Symptoms of HF are often nonspecific and raise a wide spectrum of differential diagnoses. Patients with HF can experience symptoms due to congestion and/or low cardiac output and hence symptoms can arise from many different organ
Association of Copeptin and Hyponatremia in HF
Hyponatremia is a common electrolyte disturbance in HF and the presence of hyponatremia is often an indicator of disease progression and hence entry into more advanced stages of HF. Hyponatremia may be a marker reflecting increased neurohormonal activity and/or may be induced or worsened by medical HF therapy [104], [105], [106]. The presence of hyponatremia in HF has consistently been found to be a prognostic marker of increased mortality and hospitalization rates in both patients with acute
Copeptin and Comorbidity in HF
Impaired renal function is prevalent in HF and is associated with increased mortality [113]. The vasopressin system is activated in several conditions reflecting renal dysfunction. A large population-based cohort study found that higher copeptin levels were associated with lower 24-h urine volumes and increased systolic blood pressure [38]. In previous trials, copeptin levels have also been found to be associated with albuminuria and negatively associated renal function measured as the eGFR [38]
Copeptin Guiding Current HF Therapy
It has been suggested that copeptin may have a role in biomarker-guided therapy. Loncar et al. investigated the effect of beta-blocker up-titration on serum levels of NT-proBNP and copeptin. It was found that after 12 weeks of BB optimization, copeptin might reflect faster successful up-titration better than NT-proBNP in HFREF, while the opposite was found in patients with HFPEF [89]. The prognostic and therapeutic monitoring potential of copeptin and three other biomarkers (MR-proANP,
Conclusion and Future Perspectives on Copeptin in HF
Copeptin is a reasonable surrogate marker for AVP and measurement of copeptin is a simple method to evaluate AVP activation in patients with HF. Copeptin has been found to be an excellent marker of HF development in patients with ACS, in the risk stratification of patients with HF symptoms presenting acutely to an ED as well as an accurate marker of risk in both hospitalized and ambulatory patients with chronic HF. Hence, there is ample evidence on the potential in the use of copeptin in HF. It
Acknowledgments
The Research Fund of Copenhagen University Hospital, Rigshospitalet.
Conflict of Interest: None declared.
Search Criteria: A PubMed search was performed with the mesh terms “copeptin and heart failure” as well as a personal collection of articles of interest was used for the writing of this review.
References (122)
Vital epidemiologic clues in heart failure
J. Clin. Epidemiol.
(2000)- et al.
Incremental value of biomarkers to clinical variables for mortality prediction in acutely decompensated heart failure: the Multinational Observational Cohort on Acute Heart Failure (MOCA) study
Int. J. Cardiol.
(2013) - et al.
Serial ST2 testing in hospitalized patients with acute heart failure
Am. J. Cardiol.
(2015) - et al.
Increased plasma arginine vasopressin levels in patients with congestive heart failure
J. Am. Coll. Cardiol.
(1983) - et al.
Urinary excretion of aquaporin-2 water channel exaggerated dependent upon vasopressin in congestive heart failure
Kidney Int.
(2004) - et al.
C-terminal provasopressin (copeptin) is associated with left ventricular dysfunction, remodeling, and clinical heart failure in survivors of myocardial infarction
J. Card. Fail.
(2008) - et al.
Copeptin: clinical use of a new biomarker
Trends Endocrinol. Metab.
(2008) - et al.
Copeptin, a stable peptide derived from the vasopressin precursor, is elevated in serum of sepsis patients
Peptides
(2005) - et al.
A new glycopeptide in pig, ox and sheep pituitary
Biochem. Biophys. Res. Commun.
(1979) - et al.
Lectin control of protein folding and sorting in the secretory pathway
Trends Biochem. Sci.
(2003)
Modifiable factors associated with copeptin concentration: a general population cohort
Am. J. Kidney Dis.
Vasopressin: sexual dimorphism in secretion, cardiovascular actions and hypertension
Am. J. Med. Sci.
Prognostic significance of cardiovascular biomarkers and renal dysfunction in outpatients with systolic heart failure: a long term follow-up study
Int. J. Cardiol.
Plasma copeptin levels predict mortality and hospitalization independently of plasma sodium and loop diuretics in outpatients with heart failure
J. Card. Fail.
Iron deficiency: prevalence and relation to cardiovascular biomarkers in heart failure outpatients
Int. J. Cardiol.
Assessment of conventional cardiovascular risk factors and multiple biomarkers for the prediction of incident heart failure and atrial fibrillation
J. Am. Coll. Cardiol.
Effects of left ventricular assist device support on biomarkers of cardiovascular stress, fibrosis, fluid homeostasis, inflammation, and renal injury
JACC Heart Fail.
Copeptin, a surrogate marker of vasopressin, is associated with microalbuminuria in a large population cohort
Kidney Int.
Incremental value of copeptin for rapid rule out of acute myocardial infarction
J. Am. Coll. Cardiol.
Copeptin improves early diagnosis of acute myocardial infarction
J. Am. Coll. Cardiol.
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)
J. Am. Coll. Cardiol.
Copeptin in acute coronary syndromes and heart failure management: state of the art and future directions
Arch. Cardiovasc. Dis.
Timing of immunoreactive B-type natriuretic peptide levels and treatment delay in acute decompensated heart failure: an ADHERE (Acute Decompensated Heart Failure National Registry) analysis
J. Am. Coll. Cardiol.
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.
Prognostic value of established and novel biomarkers in patients with shortness of breath attending an emergency department
Clin. Biochem.
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
J. Am. Coll. Cardiol.
Effect of beta blockade on natriuretic peptides and copeptin in elderly patients with heart failure and preserved or reduced ejection fraction: results from the CIBIS-ELD trial
Clin. Biochem.
Association of hyponatremia and elevated copeptin with death and need for transplantation in ambulatory patients with chronic heart failure
Am. J. Cardiol.
Copeptin (C-terminal pro arginine-vasopressin) is an independent long-term prognostic marker in heart failure with reduced ejection fraction
Heart Lung Circ.
ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines
J. Am. Coll. Cardiol.
When the heart runs out of hearts beats: treatment options for refractory end-stage heart failure
Circulation
Ten-year prognosis of heart failure in the community: follow-up data from the Echocardiographic Heart of England Screening (ECHOES) study
Eur. J. Heart Fail.
Heart disease and stroke statistics—2014 update: a report from the American heart association
Circulation
Novel biomarkers in chronic heart failure
Nat. Rev. Cardiol.
Heart failure
N. Engl. J. Med.
Neurohormonal activation in acute heart failure: results from VERITAS
Cardiology
Plasma urocortin 1 in human heart failure
Circ. Heart Fail.
Baseline and serial measurements of galectin-3 in patients with heart failure: relationship to prognosis and effect of treatment with valsartan in the Val-HeFT
Eur. J. Heart Fail.
Dietary sodium intake increases vasopressin secretion in man
J. Clin. Hypertens.
Effects of dietary protein intake on vasoactive hormones
Am. J. Physiol.
Antidiuretic action of vasopressin: quantitative aspects and interaction between V1a and V2 receptor-mediated effects
Cardiovasc. Res.
The use of vasopressin assays in physiology and pathophysiology
Semin. Nephrol.
Copeptin, a stable peptide derived from the vasopressin precursor, correlates with the individual stress level
Neuro Endocrinol. Lett.
Perspectives on Vasopressin
The human V3 pituitary vasopressin receptor: ligand binding profile and density-dependent signaling pathways
Endocrinology
Increased 90-day mortality in patients with acute heart failure with elevated copeptin: secondary results from the Biomarkers in Acute Heart Failure (BACH) study
Circ. Heart Fail.
Copeptin: a biomarker of cardiovascular and renal function
Congest. Heart Fail.
Arginine vasopressin antagonists for the treatment of heart failure and hyponatremia
Circulation
Osmotic and nonosmotic control of vasopressin release
Am. J. Physiol.
Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma
J. Clin. Invest.
Cited by (19)
Copeptin in fluid disorders and stress
2022, Clinica Chimica ActaCitation Excerpt :However, copeptin is lack of specificity and can be easily influenced by other stressors, so it is suggested to be used in the combination of other biomarkers to achieve an optimal prognostic value in stroke and other life threatening acute conditions. For patients with heart failure (HF), copeptin has been demonstrated a relatively good diagnostic accuracy [116,117]. In addition, it was found by Xu et al [118] that copeptin and NT-proBNP values increased as the NYHA grade increased in HF patients with reduced left ventricular ejection fraction, but not in patients with preserved left ventricular ejection fraction, suggesting a clinical value of risk stratification and disease severity of copeptin in HF.
Association between copeptin and contrast-induced nephropathy in patients with ST-elevation myocardial infarction
2019, Revista Portuguesa de CardiologiaCitation Excerpt :The relationship between copeptin and cardiac disorders such as heart failure, coronary artery disease and hypertension has been shown in many previous studies.29–31 Copeptin has been shown to be an independent marker for long-term prognosis in heart failure,32,33 it may be a marker for diagnosis of left ventricular dysfunction in hemodialysis patients,34 and is associated with coronary atherosclerosis in diabetic patients35,36 and with resistant hypertension.37 A rise in copeptin levels two days after STEMI has also been shown to be related to larger acute and chronic infarct size, and initially elevated copeptin level is related to myocardial function and remodeling four months after STEMI.
Limited Added Value of Circulating Inflammatory Biomarkers in Chronic Heart Failure
2017, JACC: Heart FailureCitation Excerpt :However, other biomarkers not measured in CORONA could increase the predictive powers of the models, as our studies have focused on inflammatory and ECM-related proteins. In particular, markers such as Growth Differentiation Factor 15 (GDF-15) and copeptin have shown promising results and could have improved our model further (37,38). Fourth, not all variables used for SHFS were available in our dataset.
Usefulness of copeptin in the diagnosis of acute coronary syndrome in the emergency department of a tertiary hospital
2016, Clinica e Investigacion en ArteriosclerosisArginine Vasopressin Plays a Role in Microvascular Dysfunction After ST-Elevation Myocardial Infarction
2023, Journal of the American Heart AssociationPredictive Value of Plasma Copeptin Level in Children with Acute Heart Failure
2022, Pediatric Cardiology