Copeptin (C-terminal provasopressin): A promising marker of arrhythmogenesis in arrhythmia prone subjects?

Neurohormones have drawn particular attention in the recent years possiblyduetotheirpotentialdiagnosticandprognosticvalues inavarietyof clinical conditions includingcongestiveheart failure(CHF), acutemyocardial infarction (AMI), etc. Among neurohormones, arginine vasopressin (AVP) has been known to be secreted by hypothalamus in response to hypovolemia and increased plasma osmolality [1], and was also demonstrated to be a marker of the presence and severity of CHF [2]. However as described below, the potential association between AVP system and arrhythmogenesis may also confer some important therapeutic and prognostic implications in arrhthmia-prone patients. In the recent years, due to the instability and rapid clerance [1], the clinical utility of AVP has beengraduallyabandonedtosomedegree, andcopeptin(CP), anothernovel neurohormone of the AVP system, has come into use in the clinical practice. CP, the C-terminal portion of provasopressin [1], is co-released with AVP from hypothalamus. CP is structurally more stable, and hence may mirror the stable levels of AVP associated with the severity of the related disease [1]. CP was recently demonstrated to be a strong predictor of mortality and morbidity in patients suffering heart failure after an AMI [1]. In another study [3], CP was found to be associated with left ventricular dysfunction (inverse correlation between copeptin levels and left ventricular ejection fraction (LVEF)) in the early (at discharge) and late stages (on follow-up) of AMI indicating that hyperactivation of the AVPsystemseems tobea contributor (via inducing remodelling) and/or a consequence in the process of heart failure development. However, as an absolute clinical implication inCHF, substantial levels of CPmay indirectly denotepoor systemicperfusionassociatedwithdepressed left ventricular systolic function (a notion consistent with a previous study that demonstrated a negative correlation between AVP and cardiac index [2]). CHF is a well known trigger for malign ventricular arrhythmias through various mechanisms including structural alterations of myocardium, increased myocardial wall tension, adrenergic activation, enhanced effects of the AVP system on the heart, etc. AVP (co-secreted with CP) was suggested to induce protein synthesis, cardiac hypertrophy [4] and collagen synthesis in cardiac fibroblasts [5] in rats that may not only induce myocardial remodelling but may also create an arrhythmogenic substrate for malign ventricular arrhythmias indicating direct arrhythmogenic effects of AVP on myocardium in patients with CHF. It may be suggested that the association between CP levels and arrhythmogenesis may be dependent on left ventricular function, to some extent. However, this association may still persist even after adjustment for parameters of left ventricular function (LVEF, etc.) suggesting CP as an arrhythmogenic marker in arrhythmia-prone patients without heart failure as well. In the absence of heart failure, CP may still remain associated with arrhythmogenesis through various potentialmechanisms: CPwas found to be associatedwith the individual stress level [6]. In a very recently published study, CP was reported to have an additional diagnostic value in AMI (for rapid rule out) as an endogenous stress marker [7]. Hyperactivation of the adrenergic system is generally suggested to trigger malign ventricular arrhythmias and sudden cardiac death (SCD) in arrhythmia-prone subjects [8], and iswell known to be associated with the endogenous stress level. Therefore, CP may be regarded as a promising biochemical marker of arrhythmogenesis in arrhytmia-prone patients with and without heart failure. It may be suggested that besides conventional indices of arrhythmogenesis (QT dispersion, T wave alternance (TWA), heart rate variability (HRV), etc.), clinicians are in need of novel biochemicalmarkers thatmay rapidly and reliably predict the risk for arrhythmogenesis and arrhythmic mortality in arrhythmia-prone patients. CP, the novel and promising marker with strong predictive values, may help predict arrhythmia risk, and may help determine the therapeutic strategy in these patients. However, future large scale studies particularly focusing on the link between arrhythmogenesis and CP in arrhythmia-prone subjects are still warranted to confirm the clinical utility of CP in these patients. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [9].