Acute Myocardial Infarction (AMI)

The combination of Copeptin and Troponin has already proved its safety and effectiveness in early and safely rule-out AMI in the recent BIC-8 interventional multicenter process study (Moeckel et al., EHJ. 2015).

For further information on this study please click here: Rule-out AMI.

The first results were reported by Khan and Ng.Ref-31 In 980 post-acute MI patients of the LAMP (Leicester Acute Myocardial Infarction Peptide) study, copeptin values were highest on day 1 after acute MI and declined to a stable, but still elevated, plateau, compared with healthy controls a t days 2–5.Ref-31 Copeptin levels were higher in patients who died or were readmitted with heart failure compared with event-free survivors. In particular, patients with copeptin levels in the highest quartile showed a > 40% event rate during the follow-up period.Ref-31

thermo-fisher-brahms-copeptin-acute-miROC curves at presentation for the diagnosis of acute MI Area under the receiver-operator characteristic (ROC) curves for troponin T and copeptin at presentation, and the combination of both markers in the diagnosis of acute myocardial infarction (MI).
Figure taken from Reichlin et al.Ref-32
This observation led to the examination of the potential role of copeptin in the diagnosis of acute MI. Reichlin and Müller studied the role of copeptin in the management of 487 consecutive patients with chest pain presenting to the emergency room (ER).Ref-32 In those patients with the final gold standard diagnosis of acute MI (17%), copeptin levels were already elevated 0–4 hours after the onset of symptoms, at a time when troponin T was still undetectable in many patients. Over the next hours copeptin levels declined, whilst troponin levels increased. These distinct kinetics resulted in an additive diagnostic value of both markers for the diagnosis of acute MI. The area und er the curve (AUC) of troponin alone in the first blood sample taken in the ER was 0.86, which was increased to 0.97 by adding copeptin (Figure). Using this approach, a negativ e troponin and copeptin at presentation of the patient in the ER < 14 pmol/L allowed acute MI to be ruled out, with a negative predictive value of > 99%.Ref-32

This report was independently confirmed by a multic enter trial in 1293 consecutive patients with suspected acute coronary syndrome (ACS). Combined measurement of copeptin and troponin T in the first blood sample taken at ER ad mission improved the c-statistic from 0.85 for troponin T alone to 0.94 for a combination of copeptin and troponin T. The effect was particularly prominent in patients presenting within 3 hours after chest pain onset to the ER. In this group, the combination increased the c-statistic from 0.77 to 0.91.Ref-33

At present, it is still unclear, how the combination of copeptin and troponin may perform in a world of highly sensitive troponin assays even if there are already studies which shows the added benefit of this combination.Ref-34 If the diagnostic accuracy to identify those ACS patients (for whom rapid intervention is mandatory) is lost, and patients are identified with trace amounts of troponin in their blood that may have prognostic (but less diagnostic) relevance, then the value of troponin as a diagnostic biomarker may change in the perception of the ER clinician. The CHOPIN trial (Copeptin helps in the early detection Of patients with acute myocardial infarction) may address this issue.Ref-35


Why is Copeptin elevated in acute MI?

The observed elevation of copeptin after acute MI has long been described for AVP, but based on the complexity of AVP measurement, this observation has never become of diagnostic relevance. However, despite insufficient assays being available, several studies tried to elucidate the AVP response in acute MI. Although limited to a few patients, Schaller and coworkers reported, back in 1986, on elevated AVP during the early phase of MI with a particularly poor prognosis.Ref-36

McAlpine and colleagues studied AVP and other neuro endocrine hormones after acute MI and found elevated plasma levels within 6 hours of onset of symptoms.Ref-37 Donald and coworkers examined the response of the entire hypot halamus–pituitary–adrenal axis to the stress of MI within 6 hours of onset of symptoms, and found plasma AVP, CRH, and cortisol highly elevated, whilst ACTH was suppressed compared with a reference population of healthy volunteers. During the follow-up period of 72 hours, the three elevated hormones declined irrespective of treatment with angiotensin-converting enzyme inhibitors, whilst ACTH values increased.Ref-38 The same group studied the neuroendocrine response after acute MI more closely in an animal model using sheep. They found that all three hormones, AVP, ACTH, and cortisol, were increased within 2 hours after inducing microembolization in the animals. In a subset of more frequently sampled animals, the peak response of AVP, ACTH, and cortisol occurred at 40 min after embolization. Whilst ACTH and cortisol returned to baseline within 6 hours, AVP was elevated for more than 12 hours.Ref-39

Despite the very early rise of AVP and other hormones related to stress response, none of these markers was followed up as a potential candidate for the diagnosis of acute MI due to severe limitations in the measurement of these hormones. Neither AVP, nor ACTH or cortisol are available in rapid and sensitive assay technology, which would allow a fast enough “vein-to-brain time” to influence the early diagnosis in an ER.

What triggers the rapid release of AVP/copeptin after an acute MI is still under debate. There are several possible explanations, but two hypotheses seem to be most likely. First, as described above, AVP is a substantial part of the endocrine stress response, resulting in ACTH and cortisol release. Therefore, it is not surprising that the body responds to acute and life-threatening diseases, such as MI or stroke, by a rapid AVP/copeptin release. This hypothesis is favored by some endocrinologists (including the author of this review), and copeptin is discussed to be a rapid and immediate biomarker of the individual stress response.Ref-40 However, following the release mechanism of AVP/copeptin for ACTH stimulation, this would strictly mean that the measurable copeptin in the circulation is the spillover of copeptin released in the portal system of the pituitary. Therefore a second trigger is likely that leads to AVP/copeptin secretion from the posterior pituitary. This could be cardiac underfilling resulting in baroreceptor stimulation as a result of the MI, or even direct damage to the cardiac baroreceptors. This speculation is supported by the fact that the highest copeptin elevation after MI is seen in patients with electrocardiographic signs of cardiac damage.Ref-32

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