Heart Failure

Involvement of AVP in the pathogenesis of congestive heart failure has repeatedly been reported.Ref-41-43 In chronic congestive heart failure, AVP, through its V1- and V2-receptor-mediated effects, seems to contribute to the progression of left ventricular (LV) dysfunction by aggravating systolic and diastolic wall stress, and by directly stimulating ventricular hypertrophy and myocardial remodeling.Ref-44 Moreover, selective blockade of specific AVP receptors has been suggested to offer new clinical perspectives for treatmentRef-45 (see below).

The prognostic role of mature AVP in heart failure is well described. Studies looking at the neurohumoral activation in patients with acute MI found an elevation that lasted for more than 12 days, and those patients with elevated AVP and other neurohormones had a poorer prognosis.Ref-46,47

More recently, data on the role of copeptin as a biomarker in patients with CHF have been described in several studies. Patients with chronic heart failure and high levels of copeptin had a significantly poorer long-term prognosis than patients who had low plasma copeptin concentrations.Ref-48,49 Combined measurement of plasma copeptin together with B-natriuretic peptide concentrations could further improve outcome prediction in these patients.Ref-48,49

As mentioned previously, Khan et al. examined the role of copeptin in 980 consecutive patients after acute MI.Ref-31 In the follow-up of those patients, the prognostic value of copeptin was assessed alone or in combination with N-terminal B-type natriuretic peptide (NT-proBNP). Copeptin was raised in patients who died or were readmitted with heart failure compared with survivors (median 18.5 pmol/L vs. 6.5 pmol/L, p < 0.0005). In a logistic regression analysis, copeptin and NT-proBNP were significant independent predictors of death or heart failure at 60 days. Consideration of both markers gave added prognostic information beyond existing clinical characteristics, enabling patients to be stratified into low-, intermediate-, or high-risk groups.

The same research group subsequently reported on an association between copeptin and LV dysfunction in the very early stages after acute MI, which was maintained in the survivors during follow-up. Furthermore, copeptin was associated with the degree of LV remodeling after the acute event.Ref-50 Thus, the AVP system may have progressive effects on LV impairment beyond the acute phase of an MI. Several actions of AVP on the heart may account for the remodeling process, including myocyte protein synthesis via the V1-receptor,Ref-51 increased peripheral vasoconstriction, afterload and ventricular stress,Ref-52 and stimulation of cardiac fibroblasts.Ref-53 These observations were strengthened by the increased risk of elevated copeptin levels and clinical heart failure in those patients. This risk stratification at an early stage after acute MI remains important and may be useful to select treatment regimes in the future, such as the use of AVP receptor antagonists (vaptans). Although mixed reports on those drugs exist for CHF (EVEREST trial),Ref-54,55 no study has yet examined the use of vaptans in the human post-acute MI patient, although animal data on improved cardiac hemodynamics exist for conivaptan.Ref-56

thermo-fisher-brahms-copeptin-heart-failureQuartiles of Copeptin in heart failure patients
Kaplan-Meier plots of survival in heart failure patients grouped according to quartiles of plasma copeptin.
Figure taken from Neuhold et al.Ref-57
Neuhold and Pacher, following up on their first report,Ref-48 examined the role of copeptin in 786 patients across the whole spectrum of heart failure based on systolic dysfunction (LV ejection fraction ranging from 5% to 65%) and BNP values (ranging from 3 to 8536 pg/mL).Ref-57 They showed a strong and independent correlation between plasma copeptin levels and all-cause mortality. This was seen in the entire cohort of symptomatic (NYHA class II, III, and IV) patients, but was most compelling in the functional classes II and III. Patients with copeptin values < 5.75 pmol/L had the lowest mortality rate (< 12%) in the 24-month follow-up period, whilst patients in the highest quartile (> 21.7 pmol/L) had mortality rates > 50% (Figure).Ref-57

Voors and the OPTIMAAL investigators examined the prognostic role of copeptin in patients an after acute MI in a subset of patients of the OPTIMAAL (Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan) study.Ref-58 They confirmed the report by KhanRef-31 in a multicenter setting, demonstrating that copeptin is a strong marker for mortality and morbidity in patients with heart failure after acute MI, with an even stronger predictive value than BNP and NT-proBNP. Again, patients in the highest quartile (> 25.9 pmol/L) had significantly increased mortality compared with the other groups (about 40% during the follow-up of 33 ± 7 months). Furthermore, they could also demonstrate that serial measurements of copeptin during follow-up added predictive value over a single determination at baseline.Ref-58


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