Chapter Two - Copeptin in Heart Failure

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Abstract

Heart failure (HF) is one of the most common causes of hospitalization and mortality in the modern Western world and an increasing proportion of the population will be affected by HF in the future. Although HF management has improved quality of life and prognosis, mortality remains very high despite therapeutic options. Medical management consists of a neurohormonal blockade of an overly activated neurohormonal axis. No single marker has been able to predict or monitor HF with respect to disease progression, hospitalization, or mortality. New methods for diagnosis, monitoring therapy, and prognosis are warranted. Copeptin, a precursor of pre-provasopressin, is a new biomarker in HF with promising potential. Copeptin has been found to be elevated in both acute and chronic HF and is associated with prognosis. Copeptin, in combination with other biomarkers, could be a useful marker in the monitoring of disease severity and as a predictor of prognosis and survival in HF.

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.

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