Prognostic performance of serial in-hospital measurements of copeptin and multiple novel biomarkers among patients with worsening heart failure: results from the MOLITOR study.

In heart failure, various biomarkers are established for diagnosis and risk stratification; however, little is known about the relevance of serial measurements during an episode worsening heart failure (WHF). This study sought to investigate the trajectory of natriuretic peptides and multiple novel biomarkers during hospitalization for WHF and to determine the best time point to predict outcome. MOLITOR (Impact of Therapy Optimisation on the Level of Biomarkers in Patients with Acute and Decompensated Chronic Heart Failure) was an eight-centre prospective study of 164 patients hospitalized with a primary diagnosis of WHF. C-terminal fragment of pre-pro-vasopressin (copeptin), N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), and C-terminal pro-endothelin-1 (CT-proET1) were measured on admission, after 24, 48, and 72 h, and every 72 h thereafter, at discharge and follow-up visits. Their performance to predict all-cause mortality and rehospitalization at 90 days was compared. All biomarkers decreased during recompensation (P < 0.05) except MR-proADM. Copeptin at admission was the best predictor of 90 day mortality or rehospitalization (χ2  = 16.63, C-index = 0.724, P < 0.001), followed by NT-proBNP (χ2  = 10.53, C-index = 0.646, P = 0.001), MR-proADM (χ2  = 9.29, C-index = 0.686, P = 0.002), MR-proANP (χ2  = 8.75, C-index = 0.631, P = 0.003), and CT-proET1 (χ2  = 6.60, C-index = 0.64, P = 0.010). Re-measurement of copeptin at 72 h and of NT-proBNP at 48 h increased prognostic value (χ2  = 23.48, C-index = 0.718, P = 0.00001; χ2  = 14.23, C-index = 0.650, P = 0.00081, respectively). This largest sample of serial measurements of multiple biomarkers in WHF found copeptin at admission with re-measurement at 72 h to be the best predictor of 90 day mortality and rehospitalization.

Düngen HD ，Tscholl V ，Obradovic D ，Radenovic S ，Matic D ，Musial Bright L ，Tahirovic E ，Marx A ，Inkrot S ，Hashemi D ，Veskovic J ，Apostolovic S ，von Haehling S ，Doehner W ，Cvetinovic N ，Lainscak M ，Pieske B ，Edelmann F ，Trippel T ，Loncar G ... -  《ESC Heart Failure》

Multiple biomarker strategy for improved diagnosis of acute heart failure in older patients presenting to the emergency department.

Biomarkers can help to identity acute heart failure (AHF) as the cause of symptoms in patients presenting to the emergency department (ED). Older patients may prove a diagnostic challenge due to co-morbidities. Therefore we prospectively investigated the diagnostic performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) alone or in combination with other biomarkers for AHF upon admission at the ED. 302 non-surgical patients aged ≥ 70 years were consecutively enrolled upon admission to the ED. In addition to NT-proBNP, mid-regional pro-adrenomedullin (MR-proADM), mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET-1) and ultra-sensitive C-terminal pro-vasopressin (Copeptin-us) were measured at admission. Two cardiologists independently adjudicated the final diagnosis of AHF after reviewing all available baseline data excluding the biomarkers. We assessed changes in C-index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) for the multimarker approach. AHF was diagnosed in 120 (40%) patients (age 81±6 years, 64 men, 56 women). Adding MR-ADM to NT-proBNP levels improved C-index (0.84 versus 0.81; p=0.045), and yielded IDI (3.3%; p=0.002), NRI (17%, p<0.001) and continuous NRI (33.3%; p=0.002). Adding CT-proET-1 to NT-proBNP levels improved C index (0.86 versus 0.81, p=0.031), and yielded robust IDI (12.4%; p<0.001), NRI (31.3%, p<0.001) and continuous NRI (69.9%; p<0.001). No other dual or triple biomarker combination showed a significant improvement of both C-index and IDI. In older patients presenting to the ED, the addition of CT-proET-1 or MR-proADM to NT-proBNP improves diagnostic accuracy of AHF. Both dual biomarker approaches offer significant risk reclassification improvement over NT-proBNP.

Bahrmann P ，Bahrmann A ，Hofner B ，Christ M ，Achenbach S ，Sieber CC ，Bertsch T ... -  《-》

Comparative evaluation of B-type natriuretic peptide, mid-regional pro-A-type natriuretic peptide, mid-regional pro-adrenomedullin, and Copeptin to predict 1-year mortality in patients with acute destabilized heart failure.

Gegenhuber A ，Struck J ，Dieplinger B ，Poelz W ，Pacher R ，Morgenthaler NG ，Bergmann A ，Haltmayer M ，Mueller T ... -  《-》

Short-Term Influence of Radiofrequency Ablation on NT-proBNP, MR-proANP, Copeptin, and MR-proADM in Patients With Atrial Fibrillation: Data From the Observational SMURF Study.

There is limited knowledge on the short-term influence of radiofrequency ablation (RFA) of atrial fibrillation (AF) on 2 cardiac biomarkers; the N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the midregional fragment of the N-terminal of pro-ANP (MR-proANP) and 2 extracardiac biomarkers; the c-terminal provasopressin (copeptin) and the midregional portion of proadrenomedullin (MR-proADM). There are also limited data concerning cardiac production of the latter two. We studied 192 consecutive patients eligible for RFA of AF referred to the University Hospital, Linköping, Sweden. NT-proBNP, MR-proANP, copeptin, and MR-proADM levels were measured in peripheral blood, the coronary sinus (CS), and the left atrium before ablation, and in peripheral blood immediately and the day after RFA. The level of NT-proBNP decreased the day after RFA in participants in AF at the time of RFA, compared to the participants in sinus rhythm who showed a slight increase (P<0.001). Furthermore, regardless of the actual rhythm, the level of MR-proANP showed an increase immediately after RFA (P<0.001), followed by a decrease the day after ablation (P<0.001). Copeptin level showed a 6-fold increase immediately after RFA compared to baseline (P<0.001), whereas MR-proADM level increased the day after RFA (P<0.001). Levels of copeptin and MR-proADM were not higher in the CS compared to peripheral blood. RFA of AF is a strong stimulus with a significant and direct impact on different neurohormonal systems. We found no sign of a cardiac release of MR-proADM or copeptin. URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01553045.

Charitakis E ，Walfridsson H ，Alehagen U 《-》

Cardiovascular biomarkers predict post-discharge re-hospitalization risk and mortality among Swedish heart failure patients.

The aim of this study was to assess the predictive role of biomarkers, associated with cardiovascular stress and its neuroendocrine response as well as renal function, in relation to mortality and risk of re-hospitalization among consecutive patients admitted because of heart failure (HF). A total of 286 patients (mean age, 75 years; 29% women) hospitalized for newly diagnosed or exacerbated HF were analysed. Associations between circulating levels of mid-regional pro-adrenomedullin (MR-proADM), copeptin, C-terminal pro-endothelin-1, N-terminal pro-brain natriuretic peptide (NT-proBNP), cystatin C, and all-cause mortality as well as risk of re-hospitalization due to cardiac causes were assessed using multivariable Cox regression models. A two-sided Bonferroni-corrected P-value of 0.05/5 = 0.010 was considered statistically significant. All biomarkers were related to echocardiographic measurements of cardiac dimensions and function. A total of 57 patients died (median follow-up time, 17 months). In the multivariable-adjusted Cox regression analyses, all biomarkers, except C-terminal pro-endothelin-1, were significantly associated with increased mortality: NT-proBNP [hazard ratio (HR) 1.85, 95% confidence interval (CI) 1.17-2.17; P = 4.0 × 10-4 ], MR-proADM (HR 1.94, 95% CI 1.36-2.75; P = 2.2 × 10-4 ), copeptin (HR 1.70, 95% CI 1.22-2.36; P = 0.002), and cystatin C (HR 2.11, 95% CI 1.56-2.86; P = 1.0 × 10-6 ). A total of 90 patients were re-hospitalized (median time to re-hospitalization, 5 months). In multivariable Cox regression analyses, NT-proBNP was the only biomarker that showed significant association with risk of re-hospitalization due to cardiac causes (HR 1.43, 95% CI 1.10-1.87; P = 0.009). Among patients hospitalized for HF, elevated plasma levels of NT-proBNP, MR-proADM, copeptin, and cystatin C are associated with higher mortality after discharge, whereas NT-proBNP is the only biomarker that predicts the risk of re-hospitalization due to cardiac causes.

Molvin J ，Jujic A ，Bachus E ，Gallo W ，Tasevska-Dinevska G ，Holm H ，Melander O ，Fedorowski A ，Magnusson M ... -  《ESC Heart Failure》