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》

Prognostic value of different biomarkers for cardiovascular death in unselected older patients in the emergency department.

Risk stratification of elderly patients presenting with heart failure (HF) to an emergency department (ED) is an unmet challenge. We prospectively investigated the prognostic performance of different biomarkers in unselected older patients in the ED. We consecutively enrolled 302 non-surgical patients ⩾70 years presenting to the ED with a wide range of cardiovascular and non-cardiovascular comorbid conditions. N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-adrenomedullin (MR-proADM), mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET-1), ultrasensitive C-terminal pro-arginine-vasopressin (Copeptin-us) and high-sensitivity cardiac troponin T (hs-cTnT) were measured at admission. Two cardiologists independently adjudicated the final diagnosis of HF after reviewing all available baseline data using circulating NT-proBNP levels. A final diagnosis of HF was found in 120 (40%) of the 302 patients. All patients were followed up for cardiovascular death within the following 12 months. In order to test the prognostic performance of the investigated biomarkers we used boosting models with age and sex as mandatory covariates. Boosting is a statistical learning technique with built-in variable selection developed to obtain sparse and interpretable prediction models. Follow-up was 100% complete. During a median follow-up time of 225 days (interquartile range (IQR) 156-319 days), 30 (9.9%) of 302 patients (aged 81±6 years) had cardiovascular deaths. Of these 30 patients, 21 had HF and nine had no HF diagnosed prior to admission. The boosting model selected MR-proADM and hs-cTNT as predictors of cardiovascular deaths. The median values of MR-proADM and hs-cTnT at presentation were significantly higher in patients with cardiovascular deaths compared to surviving patients during follow-up (2.56 nmol/L (IQR 1.62-4.48) vs. 1.11 nmol/L (IQR 0.83-1.80), P<0.001 and 81 ng/L (IQR 38-340) vs. 17 ng/L (IQR 0.9-38), P=0.004). One unit increase in the log-transformed MR-proADM levels was associated with a 1.99-fold risk of death (95% confidence interval (CI) 1.61-2.45, P<0.001). The second marker, hs-cTnT, showed an increased predicted risk but was not significantly correlated to event-free survival (hazard ratio 3.22, 95% CI 0.97-10.68, P=0.056). Within different biomarkers, MR-proADM was the only predictor of cardiovascular deaths in unselected older patients presenting to the ED.

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

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 ... -  《-》

Cardiovascular Mortality in Chest Pain Patients: Comparison of Natriuretic Peptides With Novel Biomarkers of Cardiovascular Stress.

Natriuretic peptides are the standard biomarker for risk stratification in cardiovascular disease. Novel biomarkers of cardiovascular stress might allow refinement in risk stratification for patients with acute coronary syndrome (ACS). We tested the performance of these novel biomarkers for cardiovascular risk stratification in patients who presented with ACS. In the AtheroGene study, 873 patients presented with ACS in the emergency department. Biomarkers measured were: B-type natriuretic peptide (BNP), N-terminal pro BNP (NT-proBNP), midregional proatrial natriuretic peptide, midregional proadrenomedullin (MR-proADM), copeptin, and troponin I. The median follow-up time was 4 years and during this time 50 patients died from cardiac causes. Cox regression analysis for the continuous variables NT-proBNP and BNP showed a hazard ratio (HR) of 1.9 and 1.8, respectively, for 1 SD increase (P < 0.001 and P = 0.003) in the fully adjusted model. Novel biomarkers with MR-proADM had an HR of 3.2, followed by midregional proatrial natriuretic peptide with an HR of 1.9 (both P < 0.001), and copeptin with an HR of 1.6 (P < 0.001). C-index revealed MR-proADM as the best discriminator for identifying patients with the outcome with a C-index = 0.8, and C-index was 0.72 for NT-proBNP (P for comparison = 0.017). Integrated discrimination improvement for MR-proADM was 0.059 compared with NT-proBNP (P = 0.016), thus providing background that MR-proADM was better to identify persons with the outcome. Troponin I levels at the time of admission were not significant for risk stratification. In patients who present with ACS the novel biomarker, MR-proADM was the best predictor for outcome. MR-proADM adds modest information and is useful for risk prediction in ACS patients.

Sinning C ，Ojeda F ，Zeller T ，Zengin E ，Rupprecht HJ ，Lackner KJ ，Bickel C ，Blankenberg S ，Schnabel RB ，Westermann D ... -  《-》

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 ... -  《-》