Summary
Over the past two decades, the use of multiple biomarkers has changed cardiovascular disease management. Recently, several trials have assessed the diagnostic and prognostic performances of copeptin, especially in patients with heart failure or acute coronary syndromes. Primary results are interesting, with copeptin looking promising for: the management of patients who present at emergency departments early after chest pain onset and the risk stratification of patients with heart failure. The purpose of this article is to review the data on the place of copeptin in the management of patients with chest pain or heart failure.
Résumé
Le développement de plusieurs marqueurs a radicalement modifié la prise en charge des pathologies cardiovasculaires ces 20 dernières années. Récemment, plusieurs études ont évalué l’intérêt diagnostique et pronostique de la copeptine, notamment dans le contexte de l’insuffisance cardiaque et du syndrome coronaire aigu. Les premiers résultats sont prometteurs faisant de la copeptine un biomarqueur particulièrement intéressant dans l’amélioration de la prise en charge aux urgences des patients se présentant avec une douleur thoracique, d’une part, et dans la stratification du risque des patients atteints d’une insuffisance cardiaque, d’autre part. L’objectif de cet article est de revenir sur les données disponibles sur la copeptine dans le domaine de l’insuffisance cardiaque et dans le domaine de la douleur thoracique aux urgences.
Introduction
Over the past two decades, the introduction of multiple biomarkers has changed the landscape of cardiovascular diseases, especially in the management of patients with acute coronary syndromes (ACS) and heart failure (HF). Biomarkers can provide useful information for diagnostic, prognostic and therapeutic strategies.
In patients with chest pain, the predominant problem in clinical practice is to confirm or rule out a diagnosis of ACS as quickly as possible. This is important because:
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a high number of patients are referred to emergency departments (ED) due to suspected ACS;
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it is necessary to start early medical and/or invasive therapies in actual ACS patients in order to improve their prognosis.
Multiple biomarkers – including myoglobin, creatine phosphokinase (CPK) and CPK-MB – have been used in the past, but their delayed release after myocardial necrosis and/or their lack of specificity render them poorly exploitable in clinical practice and compromise their diagnostic performance. Currently, troponin assessment is the gold standard for the early detection of myocardial infarction (MI) and this has shown better aptitude (sensitivity, specificity, early detection) compared to older biomarkers. However, conventional troponin elevation usually still occurs relatively late (3–6 hours) after ACS onset, and multiple samplings are often required and recommended in those patients who present early (within 3 hours) after chest pain onset (CPO) . In addition, since the recent introduction of high-sensitivity troponin, there has been an increase in sensitivity and an improvement in early detection, but a decrease in specificity in ACS management. Indeed, many causes (e.g. ACS, acute HF, pulmonary embolism, myocarditis and severe sepsis) could lead to myocardial necrosis and, subsequently, to increased troponin levels in practice .
In contrast to ACS, in HF management, the major issue is the prognostic evaluation of patients with chronic HF rather than the diagnosis of acute HF. Indeed, B-type natriuretic peptide (BNP) and N-terminal pro-hormone BNP (NT-proBNP) have shown to be highly specific of HF and have drastically simplified the management of patients referred to ED for dyspnoea or suspected HF . By contrast, risk stratification remains a critical issue in HF management. Indeed, high-risk patients can therefore be considered for invasive strategies such as implantable assist devices and/or cardiac transplantation. Variables such as New York Heart Association (NYHA) class, right and left ventricular functions, BNP or variables obtained during cardiopulmonary exercise testing (e.g. VO 2 max) have been associated with the outcome of chronic HF patients . In spite of these advances, risk stratification of chronic HF patients needs further improvement. Indeed, there remains variability in prognosis, with some patients categorized as low risk who experience early major cardiac events and others categorized as high-risk who do not. In addition, since cardiopulmonary exercise testing is a time-consuming method that is rarely used for risk stratification in routine practice, some potent indicators may be lacking for an individual. As a consequence, there is a critical need for tools that may help physicians to guide therapeutic options in chronic HF, especially to better select patients who should be considered for invasive strategies.
Therefore, new biomarkers that can provide additional information may be of great interest in clinical practice to help physicians’ decisions . Copeptin, a surrogate for arginine vasopressin (AVP) secretion is a novel biomarker that has shown great potential in cardiovascular diseases, especially ACS and chronic HF. In this review, we summarize the results of the main studies that have investigated the diagnostic and prognostic performances of copeptin in the settings of ACS and HF.
The roles of AVP and copeptin
AVP (also known as antidiuretic hormone [ADH]) is synthesized in the hypothalamus as a pre-pro-hormone, and is then transported to the neurohypophysis. It is released into the bloodstream from the posterior pituitary gland in response to changes in plasma osmolarity and reduced cardiac output. AVP levels increase with most acute illnesses and/or stress and play crucial roles in acute HF and osmoregulation. The hypoperfusion of peripheral organs leads to AVP secretion in order to maintain circulatory homeostasis by promoting renal water reabsorption via the vasopressin V 2 receptors located on the basolateral membrane of collecting duct cells of the kidney. Binding to these receptors, it activates adenylate cyclase and leads to the generation of cyclic adenosine monophosphate (cAMP), thus decreasing water clearance by moving the aquaporin 2 channels from the cytosol to the cellular surface. Enhanced expression of aquaporin channels in the kidney contributes to the development of oedema and hyponatraemia. Vasopressin coupling to V 1 receptors leads to an activation of the phosphatidylinositol pathway and mobilization of cytosolic calcium. Two subtypes exist: V 1a receptors on various cell types (e.g. heart and vessels) and V 1b in the anterior pituitary. V 1a stimulation in the arterial system leads to:
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vasoconstriction and cardiac remodelling (by increasing afterload);
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decreased systemic vascular resistance;
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increased cardiac output .
The mechanism of action of AVP is shown in Fig. 1 .
The direct role of AVP in chronic HF is not fully understood. AVP is a regulator of fluid dynamics and an indicator of adequate hypothalamo-pituitary-adrenal axis activation. Robust data have shown that AVP is related to HF severity and outcomes . During stress, AVP stimulation results in adrenocorticotropic hormone and cortisol secretion. AVP biomarkers have previously been shown to be rapid markers of individual stress levels, with good correlation with moderate stress . Because many clinical situations induce activation of the hypothalamic stress axis, especially in cardiovascular disease, AVP markers will have a low specificity but a high-sensitivity for individual disease such as ACS. However, AVP is unstable (short half-life and 90% bound to platelets) so it is not a reliable marker.
Copeptin, the C-peptide portion of pre-pro-vasopressin ( Fig. 2 ), is a 39-amino acid glycoprotein that is more stable than AVP, and is secreted in equimolar amounts. The exact function of copeptin is unknown. This peptide is easily measurable in peripheral blood, and represents a surrogate marker for AVP release in various clinical situations . It has emerged as a potential biomarker in various cardiac diseases such as HF and ACS.
Copeptin in ACS
The diagnosis and risk stratification in patients presenting with suspected non-ST elevation ACS (NSTE-ACS) usually rely on cardiac troponins (I and T) as biomarkers . Troponins are currently considered the gold standard for the detection of myocardial necrosis; they have also been shown to be strong indicators of prognosis in this setting . Nevertheless, the major weakness of these biomarkers is their delayed release after cell necrosis that consequently alters their diagnostic performance early after CPO. Owing to the high proportion of patients who present in ED with suspected ACS, new troponin assays have been developed to overcome this major limitation. High-sensitivity troponins allow earlier detection and have shown superiority in ACS diagnosis compared to conventional troponins . As a consequence, high-sensitivity troponins are now used as the reference for patients presenting with chest pain and/or suspected ACS . However, copeptin, by its independent pathophysiology and its rapid release after ACS, could further improve diagnostic accuracy in this setting.
Copeptin and prognosis in ACS
Copeptin has first been studied in order to investigate its prognostic potential in ACS ( Table 1 ). In patients presenting with MI, copeptin has been shown to be a strong predictor of worse outcome and a prognostic marker of death . Of note, its relevance was increased when used in combination with other biomarkers (NT-proBNP and troponins) . The pathophysiological background of troponins, natriuretic peptides and copeptin reflects different characteristics of cardiac homeostasis. Therefore a combination of biomarkers may give more information than a unique biomarker . Others studies have shown that copeptin can predict left ventricular dysfunction and clinical events related to HF in survivors of MI .
| Reference | Patients | Endpoint and results |
|---|---|---|
| O’Malley et al., 2014 | 4432 patients with NSTE-ACS | To assess the prognostic value of copeptin compared to natriuretic peptides and cardiac troponin Follow-up: 1 year Cardiac troponin I was the strongest predictor of all events Copeptin was associated with cardiovascular mortality (HR: 1.52, 95% CI: 1.10–2.11) and HF (HR: 1.70, 95% CI: 1.18–2.43), but not with MI (HR: 1.17, 95% CI: 0.89–1.54) after adjustment for cofounders Additional value on top of BNP and cardiac troponin I |
| Khan et al., 2007 | 980 MI patients | To assess the prognostic value of copeptin compared to natriuretic peptides Follow-up: 342 days Copeptin was predictive of the primary endpoint (death or HF; OR: 2.33, 95% CI: 1.55–3.49) Stronger prediction when added to NT-proBNP |
| Kelly et al., 2008 | 274 MI survivors | Association between copeptin levels and LV function or HF Follow-up: 155 days Copeptin predicted LV dysfunction and clinical events related to HF in post-MI patients (OR: 3.01, 95% CI: 1.10–8.21) |
| Voors et al., 2009 | 224 patients with HF after MI | Investigate the prognostic value of copeptin on mortality and morbidity Follow-up: 1 year Multivariate analysis showed that copeptin was independently correlated with mortality (OR: 1.83, 95% CI: 1.26–2.64) |
| Reinstadler et al., 2003 | 54 STEMI patients | Correlation between copeptin and infarct size or myocardial function (by CMR) Follow-up: 4 months High copeptin levels correlated with lower LVEF, greater infarct size and adverse remodelling |
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