Mid-regional Pro-atrial Natriuretic Peptide Levels Research Articles

Vasoactive peptides as biomarkers for the prediction of retinopathy of prematurity.

Retinopathy of prematurity (ROP) is a major complication in preterm infants. We assessed if plasma levels of midregional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET1) serve as early markers for subsequent ROP development in preterm infants <32 weeks gestation. Prospective, two-centre, observational cohort study. MR-proANP and CT-proET1 were measured on day seven of life. Associations with ROP ≥ stage II were investigated by univariable and multivariable logistic regression models. We included 224 infants born at median (IQR) 29.6 (27.1-30.8) weeks gestation and birth weight of 1160 (860-1435) g. Nineteen patients developed ROP ≥ stage II. MR-proANP and CT-proET1 levels were higher in these infants (median (IQR) 864 (659-1564) pmol/L and 348 (300-382) pmol/L, respectively) compared to infants without ROP (median (IQR) 299 (210-502) pmol/L and 196 (156-268) pmol/L, respectively; both P < 0.001). MR-proANP and CT-proET1 levels were significantly associated with ROP ≥ stage II in univariable logistic regression models and after adjusting for co-factors, including gestational age and birth weight z-score. MR-proANP and CT-proET1 measured on day seven of life are strongly associated with ROP ≥ stage II in very preterm infants and might improve early prediction of ROP in the future. Plasma levels of midregional pro-atrial natriuretic peptide and C-terminal pro-endothelin-1 measured on day seven of life in very preterm infants show a strong association with development of retinopathy of prematurity ≥ stage II. Both biomarkers have the potential to improve early prediction of retinopathy of prematurity. Vasoactive peptides might allow to reduce the proportion of screened infants substantially.

Exercise MR-proANP unmasks latent right heart failure in CTEPH

Abstract Background Chronic right heart failure is the major determinant of outcome in chronic thromboembolic pulmonary hypertension (CTEPH). Thus, its early detection is crucial for optimal patient management. Hemodynamic assessment with invasive right heart catheterization and the measurement of natriuretic peptides at rest are established diagnostic tools in this context. An elevated right atrial pressure (RAP) is a sensitive parameter of right right heart failure. Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a natriuretic peptide that reflects right atrial stress levels. There is a growing recognition of exercise diagnostics in the assessment of right heart failure, particularly in patients with normal or borderline findings at rest. There are no data on the dynamics of MR-proANP in correlation to RAP during physical exercise. Purpose The present study was designed to investigate the dynamics of RAP and MR-proANP during physical exercise in patients with CTEPH and to determine whether these parameters might serve as a tool to measure exercise-dependent atrial stress as an indicator of right heart failure. Methods This observational cohort study included 100 CTEPH patients who underwent right heart catheterization during physical exercise (eRHC). Blood samples for MR-proANP measurement were taken prior, during, and after eRHC. MR-proANP levels were correlated to RAP levels at rest, at peak exercise (eRAP), and during recovery. RAP at rest ≤7 mmHg was defined as normal and eRAP &amp;gt;15 mmHg as suggestive of right heart failure. Results During eRHC mean RAP increased from 6±4 mmHg to 16±7 mmHg (p&amp;lt;0.001). MR-proANP levels and dynamics correlated with RAP at rest (rs=0.61; p&amp;lt;0.001; figure 1a) and at peak exercise (rs=0.66; p&amp;lt;0.001; Figure 1b). Furthermore, the relative percent increase in MR-proANP correlated with the relative percent increase in eRAP (rs=0.52; p&amp;lt;0.001; Figure 1c) Logistic regression analysis revealed the peak MR-proANP level (B=0.058; p=0.004) and the right atrial area (B=0.389; p&amp;lt;0.001) to be associated with eRAP dynamics. A peak MR-proANP level ≥139 pmol/L (AUC=0.81) and recovery level ≥159 pmol/L (AUC=0.82) predicted an eRAP &amp;gt;15 mmHg. Physical exercise unmasked RH failure in 39% of patients with normal RAP at rest; they were also characterized by a more distinct increase in MR-proANP levels (p=0.005) and higher peak (p&amp;lt;0.001) and recovery levels (p&amp;lt;0.001). Conclusions RAP and MR-proANP dynamics unmask manifest and latent right heart failure in CTEPH patients, which may be useful in estimating prognosis. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): SFB 1213 area CP-01 projectWilliam G. Kerckhoff-FoundationKerckhoff Heart Research Institute (KHFI)German Center for Cardiovascular Research (DZHK)

The Prognostic Value of Cardiac Biomarkers in Patients with Acute Myocardial Infarction during and after Hospitalization

Objective: Myocardial infarction (MI) carries a strong risk of death and the development of major adverse cardiovascular events (MACE). A number of biomarkers have been proposed for risk stratification among patients with MI. The aim of this study was to determine whether elevated galectin-3 and midregional-pro atrial natriuretic peptide (MR-proANP) levels can be used as predictors of MACE in patients with acute myocardial infarction (AMI). Methods: Plasma levels of galectin-3 and MR-proANP were collected from 96 patients following their first AMI hospitalised in our clinic over the course of a year. Samples were taken on admission, and on the first and fifth day of hospitalization. During hospitalization, all patients were followed up for the occurrence of early major adverse cardiac events (MACE), defined as sudden cardiac arrest, new onset atrial fibrillation and need to use pressor amines. All patients were also followed up twelve months after AMI for the occurrence of late MACE defined as cardiac death, reinfarction and need for unscheduled PCI. Results: Patients who experienced early MACE had significantly higher galectin-3 and MR-proANP levels assessed on admission (p = 0.007, p = 0.003). ROC curve analysis found also galectin-3 concentration assessed on admission to be a strong predictor of late MACE (AUC = 0.75, p = 0.0061). MRproANP does not appear to have any value in predicting late MACE. Conclusions: A high concentration of galectin-3 and MR-proANP observed on admission in patients with acute myocardial infarction has significant prognostic value: it may identify patients at high risk of early adverse cardiac events after AMI. In contrast to MR-proANP, a high concentration of galectin-3 observed on admission may also identify patients at high risk of late MACE.

MR-proANP and NT-proBNP During Targeted Temperature Management Following Out-of-Hospital Cardiac Arrest: A Post hoc Analysis of the TTH48 Trial.

We aimed to evaluate the effect of prolonged targeted temperature management (TTM) in patients with out-of-hospital cardiac arrest (OHCA) on the levels of midregional pro-atrial natriuretic peptide (MR-proANP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) and assess their potential as prognostic biomarkers. A preplanned post hoc analysis of "Targeted temperature management for 48 h vs 24 h and neurologic outcome after out-of-hospital cardiac arrest: A randomized clinical trial (TTH48 trial)," where patients were randomized to TTM at 33°C ± 1°C of standard duration (24 hours) versus prolonged (48 hours). Blood samples were drawn from patients with OHCA at two Scandinavian university hospitals at admission to the ICU and at 24, 48, and 72 hours after reaching the target temperature. Primary outcome was levels of MR-proANP and NT-proBNP. Secondary outcome was cerebral performance category (CPC 1-5) at 6 months. Samples from 114 patients were analyzed. Prolonged TTM significantly decreased the levels of MR-proANP and NT-proBNP at 48 hours compared with standard 24 hours-TTM (p < 0.01). However, there were no significant differences at other time points. Patients with poor outcome (CPC 3-5) had a statistically significantly increased MR-proANP level at 24 hours (p < 0.01) and 72 hours (p < 0.01) compared with the good outcome group (CPC 1-2). Prognostic performance was best at 24 hours for both MR-proANP and NT-proBNP; with an AUC of 0.73 (confidence interval [95% CI]: 0.63-0.83) and 0.72 (95 % CI: 0.59-0.85), respectively. Prolonged TTM lowered the levels of both MR-proANP and NT-proBNP at 48 hours. MR-proANP may add prognostic information in postcardiac arrest patients. ClinicalTrials.gov ID: NCT01689077.

Respiratory morbidity in preterm infants predicted by natriuretic peptide (MR-proANP) and endothelin-1 (CT-proET-1)

BackgroundBronchopulmonary dysplasia (BPD) is a major complication in preterm infants <32 weeks. We aimed to assess whether plasma levels of mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET-1) predict respiratory morbidity.MethodsThis was a prospective, two-center, observational cohort study. MR-proANP and CT-proET-1 were measured at day 7 (±2) of life. Associations with duration of supplemental oxygen and the composite outcome of moderate or severe BPD or death (BPD/death) were investigated.ResultsTwo hundred and twenty-nine infants <32 weeks were included (median gestational age [GA] 29.6 weeks [interquartile range 29.0–30.7], median birth weight 1150 g [IQR 840–1410]). MR-proANP and CT-proET-1 were associated with the duration of supplemental oxygen in univariable analysis (both p < 0.001) but not after adjusting for co-factors. Infants with BPD/death showed higher plasma levels of MR-proANP (623.50 pmol/L [IQR 458.50–881.38] vs. 308.35 pmol/L [IQR 216.72–538.10]; p < 0.001) and CT-proET-1 (255.40 pmol/L [IQR 202.60–311.15] vs. 198.30 pmol/L [IQR 154.70–297.95]; p = 0.015) compared to infants without BPD/death. Levels of both biomarkers were significantly associated with BPD/death in univariable models but not after adjusting for co-factors.ConclusionsMR-proANP and CT-proET-1 are associated with the duration of supplemental oxygen and the composite outcome BPD/death, but their prognostic value does not complement that of clinical risk factors.ImpactPlasma levels of MR-proANP and CT-proET-1, measured on day 7 of life (±2 days) are associated in univariable analyses with duration of supplemental oxygen and the combined outcome of BPD or death in VLGA infants.Associations between both biomarkers and respiratory morbidity do not persist in multivariable models, in particular when gestational age is included.MR-proANP and CT-proET-1 have limited additional value to predict respiratory morbidity in VLGA infants compared to clinical parameters.

Mid-regional pro-atrial natriuretic peptide levels before and after hemodialysis predict long-term prognosis

BackgroundMid-regional pro-atrial natriuretic peptide (MR-proANP) is a strong prognostic biomarker in cardiovascular disease but there is limited data for its use among patients undergoing dialysis. MethodsThis was a cohort study of patients receiving maintenance hemodialysis from two Danish centers. Blood sampling and echocardiography were performed before and after a dialysis session. We calculated the area under the curve (AUC) for the receiver operating characteristics for diagnosing heart failure and Cox regressions for cardiovascular events and all-cause mortality. ResultsOf the 306 patients, 284 (93%) had MR-proANP measurements both before and after dialysis. Median concentration was 642 pmol/L (IQR 419–858) before and 351 pmol/L (IQR 197–537) after dialysis, a mean decrease of 330 pmol/L (43%, CI 296–364, P < 0.001). MR-proANP concentration both before and after dialysis was negatively correlated to left ventricular ejection fraction with no difference in predictive ability for heart failure, AUC before and after dialysis were 0.60 (CI 0.50–0.70) and 0.61 (CI 0.51–0.71) (P = 0.40). Median follow-up was 32 months (IQR 31–33), during which 99 patients (32%) had a cardiovascular event and 110 (36%) died. A doubling of MR-proANP concentration was associated with a hazard ratio (HR) of 1.6 (CI 1.3–1.9) before and 1.7 (CI 1.4–2.0) after dialysis for mortality and a HR of 1.5 (CI 1.2–1.9) before and 1.4 (CI 1.2–1.7) after dialysis for cardiovascular events (all P < 0.001). ConclusionThe MR-proANP concentration is elevated among patients undergoing hemodialysis and decreases during dialysis. MR-proANP concentration both before, after and intra-dialysis change strongly predicted cardiovascular events and all-cause mortality.

Postprandial variability of novel heart failure biomarkers in Fontan patients compared to healthy volunteers

BackgroundBlood-based biomarkers reflecting different components of cardiovascular pathophysiology are now used increasingly in patients with Fontan circulation due to univentricular congenital heart disease. Feeding alters haemodynamics significantly and, thus, may affect biomarker levels. As the haemodynamic responses to a meal differ between Fontan patients and normal subjects, we hypothesised that biomarker kinetics may also vary between these populations. MethodsIn 15 patients with Fontan physiology, and 15 matched healthy volunteers, 4 heart failure biomarkers were measured under fasting conditions, and 3 after additional timepoints over 2 h following ingestion of a standardised liquid meal. Changes in biomarker levels over time and the effect of Fontan physiology, sex and age were tested using repeated-measures mixed models. ResultsUnder fasting conditions, high-sensitivity C-reactive protein (hsCRP), mid-regional pro-adrenomedullin (MR-proADM) and C-terminal pro-endothelin-1 (CT-proET-1) were raised significantly in Fontan patients compared to controls. Postprandially, mid-regional pro-atrial natriuretic peptide (MR-proANP) decreased significantly in patients (max. mean decrease ∼7% after 120 min). Conversely, it increased in normal subjects (max. mean increase ∼8% after 60 min). The remaining biomarkers did not change significantly. ConclusionsThe ingestion of food triggers contrary deflections of MR-proANP levels in patients with Fontan circulation compared to normal subjects. Therefore, this parameter should be assessed under fasting conditions in order to correct for postprandial variability.

Mid-regional pro-atrial natriuretic peptide independently predicts short-term mortality in COVID-19.

BackgroundMid‐regional pro‐atrial natriuretic peptide (MR‐proANP) is a strong prognostic marker in several inflammatory, respiratory and cardiovascular conditions, but has not been studied in COVID‐19 yet.MethodsThis prospective, observational study of patients with COVID‐19 infection was conducted from 6 June to 26 November 2020 in different wards of a tertiary hospital. MR‐proANP, N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) and high‐sensitive cardiac troponin I levels on admission were collected and tested for their association with disease severity and 28‐day mortality.ResultsA total of 213 eligible patients with COVID‐19 were included in the final analyses of whom 13.2% (n = 28) died within 28 days. Median levels of MR‐proANP at admission were significantly higher in nonsurvivors (307 pmol/L IQR, [161 ‐ 532] vs 75 pmol/L [IQR, 43 ‐ 153], P < .001) compared to survivors and increased with disease severity and level of hypoxaemia. The area under the ROC curve for MR‐proANP predicting 28‐day mortality was 0.832 (95% CI 0.753 ‐ 0.912, P < .001). An optimal cut‐off point of 160 pmol/L yielded a sensitivity of 82.1% and a specificity of 76.2%. MR‐proANP was a significant predictor of 28‐day mortality independent of clinical confounders, comorbidities and established prognostic markers of COVID‐19 (HR 2.77, 95% CI 1.21 ‐ 6.37; P = .016), while NT‐proBNP failed to independently predict 28‐day mortality and had a numerically lower AUC compared to MR‐proANP.ConclusionHigher levels of MR‐proANP at admission are associated with disease severity of COVID‐19 and act as a powerful and independent prognostic marker of 28‐day mortality.

Cardiac biomarkers for risk stratification of arrhythmic death in patients with heart failure and reduced ejection fraction

ABSTRACT Objectives. Patients with heart failure and reduced left ventricular ejection fraction (HFrEF) are prone to ventricular tachyarrhythmias. We tested whether biomarkers C-terminal Endothelin 1 (CT-ET1), midregional pro atrial natriuretic peptide (MR-proANP) and midregional pro adrenomedullin (MR-proADM) might improve risk stratification for arrhythmic death. Methods: This prospective observational study included 160 heart failure patients with ischaemic cardiomyopathy (ICM) or non-ischaemic, dilated cardiomyopathy (DCM) and 30 control patients without heart disease. Primary endpoint was arrhythmic death (ArD) or resuscitated cardiac arrest (resCA). Results: A total of 61 patients died during the median follow-up of 7.0 [5.2–8.4] years. An ArD or resCA was observed in 48 patients. Plasma levels of CT-ET1 (p = 0.002), MR-proANP (p < 0.001) and MR-proADM (p = 0.013) were significantly higher in ICM or DCM patients compared to controls. MR-proANP levels in ICM patients were associated with a significantly increased risk for ArD or resCA (hazard ratio (HR) = 1.42, [95%CI: 1.08–1.85], p = 0.011) in a multivariable Cox regression model. Plasma levels of CT-ET1 (HR = 1.07 [0.98–1.17], p = 0.113) and MR-proADM (HR = 1.80 [0.92–3.55], p = 0.087) were not associated with ArD or resCA in ICM patients. No significant association with ArD or resCA was found in DCM patients. Multivariable Cox regression showed that CT-ET1 (HR = 1.14 [1.07–1.22], p < 0.001), MR-proANP (HR = 1.64 [1.29–2.08], p < 0.001) and MR-pro ADM (HR = 2.06 [1.12–3.77], p = 0.020) were associated with a higher risk for overall mortality. Conclusion: Patients with HFrEF had elevated levels of CT-ET1, MR-proANP and MR-proADM. Plasma levels of MR-proANP are useful as predictor for arrhythmic death in patients with ICM.

Prognostic value of right atrial dilation in patients with pulmonary embolism.

AimsRight atrial (RA) dilation and stretch provide prognostic information in patients with cardiovascular diseases. We investigated the prevalence, confounding factors and prognostic relevance of RA dilation in patients with pulmonary embolism (PE).MethodsOverall, 609 PE patients were consecutively included in a prospective single-centre registry between September 2008 and August 2017. Volumetric measurements of heart chambers were performed on routine non-electrocardiographic-gated computed tomography and plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) measured on admission. An in-hospital adverse outcome was defined as PE-related death, cardiopulmonary resuscitation, mechanical ventilation or catecholamine administration.ResultsPatients with an adverse outcome (11.2%) had larger RA volumes (median 120 (interquartile range 84–152) versus 102 (78–134) mL; p=0.013), RA/left atrial (LA) volume ratios (1.7 (1.2–2.4) versus 1.3 (1.1–1.7); p<0.001) and MR-proANP levels (282 (157–481) versus 129 (64–238) pmol·L−1; p<0.001) compared to patients with a favourable outcome. Overall, 499 patients (81.9%) had a RA/LA volume ratio ≥1.0 and a calculated cut-off value of 1.8 (area under the curve 0.64, 95% CI 0.56–0.71) predicted an adverse outcome, both in unselected (OR 3.1, 95% CI 1.9–5.2) and normotensive patients (OR 2.7, 95% CI 1.3–5.6). MR-proANP ≥120 pmol·L−1 was identified as an independent predictor of an adverse outcome, both in unselected (OR 4.6, 95% CI 2.3–9.3) and normotensive patients (OR 5.1, 95% CI 1.5–17.6).ConclusionsRA dilation is a frequent finding in patients with PE. However, the prognostic performance of RA dilation appears inferior compared to established risk stratification markers. MR-proANP predicted an in-hospital adverse outcome, both in unselected and normotensive PE patients, integrating different prognostic relevant information from comorbidities.

Associations of cardiac stress biomarkers with incident type 2 diabetes and changes in glucose metabolism: KORA F4/FF4 study

BackgroundHigh N-terminal pro-brain-type natriuretic peptide levels have been associated with a lower risk of type 2 diabetes mellitus (T2D). However, less is known about other cardiac stress biomarkers in this context. Here we evaluated the association of mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-arginine vasopressin (copeptin), C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM) with incident T2D and changes in glucose metabolism.MethodsWe performed a prospective cohort study using data from the population-based KORA F4/FF4 study. 1773 participants (52.3% women) with MR-proANP measurements and 960 (52.7% women) with copeptin, CT-proET-1 and MR-proADM measurements were included. We examined associations of circulating plasma levels of MR-proANP, copeptin, CT-proET-1 and MR-proADM with incident T2D, the combined endpoint of incident prediabetes/T2D and with fasting and 2 h-glucose, fasting insulin, HOMA-IR, HOMA-B and HbA1c at follow-up. Logistic and linear regression models adjusted for age, sex, waist circumference, height, hypertension, total/HDL cholesterol ratio, triglycerides, smoking, physical activity and parental history of diabetes were used to compute effect estimates.ResultsDuring a median follow-up time of 6.4 years (25th and 75th percentiles: 6.0 and 6.6, respectively), 119 out of the 1773 participants and 72 out of the 960 participants developed T2D. MR-proANP was inversely associated with incident T2D (odds ratio [95% confidence interval]: 0.75 [0.58; 0.96] per 1-SD increase of log MR-proANP). Copeptin was positively associated with incident prediabetes/T2D (1.29 [1.02; 1.63] per 1-SD increase of log copeptin). Elevated levels of CT-proET-1 were associated with increased HOMA-B at follow-up, while elevated MR-proADM levels were associated with increased fasting insulin, HOMA-IR and HOMA-B at follow-up. These associations were independent of previously described diabetes risk factors.ConclusionsHigh plasma concentrations of MR-proANP contributed to a lower risk of incident T2D, whereas high plasma concentrations of copeptin were associated with an increased risk of incident prediabetes/T2D. Furthermore, high plasma concentrations of CT-proET-1 and MR-proADM were associated with increased insulin resistance. Our study provides evidence that biomarkers implicated in cardiac stress are associated with incident T2D and changes in glucose metabolism.

Mid-regional pro-atrial natriuretic peptide and copeptin as indicators of disease severity and therapy response in CTEPH.

BackgroundChronic thromboembolic pulmonary hypertension (CTEPH) leads to right heart failure. Pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA) restore pulmonary haemodynamics and allow cardiac recovery. This study examined the relationship of copeptin and mid-regional pro-atrial natriuretic peptide (MR-proANP) levels to disease severity and therapy response.MethodsThis observational cohort study included 125 patients (55 PEA/70 BPA) who underwent treatment and completed a 6-/12-month follow-up. Biomarkers, measured at baseline, prior to every BPA and at follow-up, were compared to 1) severe disease at baseline (right atrial pressure (RAP) ≥8 mmHg and cardiac index ≤2.4 L·min−1·m−2) and 2) optimal therapy response (no persistent pulmonary hypertension combined with a normalised RAP (mean PAP ≤25 mmHg, pulmonary vascular resistance (PVR) ≤3 WU and RAP ≤6 mmHg) or a reduction in mean PAP ≥25%, PVR ≥35% and RAP ≥25%).ResultsSeverely diseased patients had higher levels of MR-proANP (320 (246–527) pmol·L−1 versus 133 (82–215) pmol·L−1; p=0.001) and copeptin (12.7 (7.3–20.6) pmol·L−1 versus 6.8 (4.4–12.8) pmol·L−1; p=0.015) at baseline than the rest of the cohort. At baseline, MR-proANP (area under the curve (AUC) 0.91; cut-off value 227 pmol·L−1; OR 56, 95% CI 6.9–454.3) and copeptin (AUC 0.70; cut-off value 10.9 pmol·L−1; OR 1.5, 95% CI 1.2–1.9) identified severely diseased patients. After PEA/BPA, levels of MR-proANP (99 (58–145) pmol·L−1; p<0.001) and copeptin (6.3 (3.7–12.6) pmol·L−1; p=0.009) decreased and indicated optimal therapy response (MR-proANP <123 pmol·L−1 (AUC 0.70) and copeptin <10.1 pmol·L−1 (AUC 0.58)).ConclusionMR-proANP and copeptin levels are affected in CTEPH and decrease after therapy. MR-proANP identifies a severe disease status and optimal therapy response.

Biomarkers Enhance Discrimination and Prognosis of Type 2 Myocardial Infarction.

The observed incidence of type 2 myocardial infarction (T2MI) is expected to increase with the implementation of increasingly sensitive cTn assays. However, it remains to be determined how to diagnose, risk-stratify, and treat patients with T2MI. We aimed to discriminate and risk-stratify T2MI using biomarkers. Patients presenting to the emergency department with chest pain, enrolled in the CHOPIN study (Copeptin Helps in the early detection Of Patients with acute myocardial INfarction), were retrospectively analyzed. Two cardiologists adjudicated type 1 MI (T1MI) and T2MI. The prognostic ability of several biomarkers alone or in combination to discriminate T2MI from T1MI was investigated using receiver operating characteristic curve analysis. The biomarkers analyzed were cTnI, copeptin, MR-proANP (midregional proatrial natriuretic peptide), CT-proET1 (C-terminal proendothelin-1), MR-proADM (midregional proadrenomedullin), and procalcitonin. The prognostic utility of these biomarkers for all-cause mortality and major adverse cardiovascular event (a composite of acute myocardial infarction, unstable angina pectoris, reinfarction, heart failure, and stroke) at 180-day follow-up was also investigated. Among the 2071 patients, T1MI and T2MI were adjudicated in 94 and 176 patients, respectively. Patients with T1MI had higher levels of baseline cTnI, whereas those with T2MI had higher baseline levels of MR-proANP, CT-proET1, MR-proADM, and procalcitonin. The area under the receiver operating characteristic curve for the diagnosis of T2MI was higher for CT-proET1, MR-proADM, and MR-proANP (0.765, 0.750, and 0.733, respectively) than for cTnI (0.631). Combining all biomarkers resulted in a similar accuracy to a model using clinical variables and cTnI (0.854 versus 0.884, P=0.294). Addition of biomarkers to the clinical model yielded the highest area under the receiver operating characteristic curve (0.917). Other biomarkers, but not cTnI, were associated with mortality and major adverse cardiovascular event at 180 days among all patients, with no interaction between the diagnosis of T1MI or T2MI. Assessment of biomarkers reflecting pathophysiologic processes occurring with T2MI might help differentiate it from T1MI. All biomarkers measured, except cTnI, were significant predictors of prognosis, regardless of the type of myocardial infarction.

The impact of the glucagon-like peptide-1 receptor agonist liraglutide on natriuretic peptides in heart failure patients with reduced ejection fraction with and without type 2 diabetes.

To assess the effect of liraglutide, a glucagon-like peptide-1 receptor agonist, on urinary sodium excretion as well as on circulating adrenomedullin and copeptin levels in patients with type 2 diabetes (T2D). In the LIVE study, patients (n = 241) with left ventricular ejection fraction ≤45% were randomized to liraglutide 1.8 mg daily or placebo for 24 weeks, and 30% had a concomitant diagnosis of T2D. Plasma levels of N-terminal brain-natriuretic-peptide (NT-proBNP) (a predefined secondary endpoint), midregional pro-atrial-natriuretic-peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM) and copeptin were measured at baseline and after 24 weeks in this substudy. The potential effect modification of T2D was assessed. In the eligible subgroup of 231 patients with available biomarkers (115 randomized to liraglutide and 116 to placebo), MR-proANP decreased by 12% (P = .002) and NT-proBNP by 9% (P = .009) during liraglutide treatment compared with placebo at week 24. Interaction with T2D for the treatment effect of change in MR-proANP and NT-proBNP levels was P = .003 and P = .03, respectively. Consequently, in patients with T2D, liraglutide decreased MR-proANP by 27% (P < .001) and NT-proBNP by 25% (P = .02) compared with placebo, whereas no change was observed in patients without T2D. There was no effect of liraglutide on MR-proADM (P = .10) or copeptin (P = .52). Liraglutide decreased the A- and B-type natriuretic peptides significantly in patients with heart failure with reduced ejection fraction (HFrEF) and concomitant T2D, suggesting a beneficial mechanism of liraglutide in T2D patients with HFrEF.

Exercise dynamics of cardiac biomarkers and hemoconcentration in patients with chronic systolic heart failure

Mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), copeptin, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin measured by ultrasensitive assays (single-molecule troponin I, sm-TnI) provide prognostic information in patients with chronic systolic heart failure (HF). Exercise dynamics of these biomarkers and their post-exercise prognostic impact remain largely unknown. A total of 108 patients with HF and 25 controls underwent exercise stress testing. Biomarker levels and total protein concentration were measured before and immediately after exercise. During a follow-up of 1050±664 days, sixty patients experienced an adverse outcome defined as death, urgent heart transplantation or mechanical circulatory support implantation. Exercise induced significant hemoconcentration assessed as total protein (TP) increase that was comparable in control subjects and patients with HF after the correction for achieved workload (0.006 ± 0.002 g.dL-1.watt-1 for controls and 0.008 ± 0.005 g.dL-1.watt-1 for patients with HF, p=0.11). After correction for TP, exercise-induced increase in sm-cTnI was caused by hemoconcentration alone. In contrast, MR-proANP, NT-proBNP, copeptin and MR-proADM showed significant exercise-induced dynamics independent of hemoconcentration. Both baseline and post-exercise levels of NT-proBNP, MR-proANP, MR-proADM and copeptin were associated with adverse outcomes. Predictive value of baseline and post-exercise levels did not differ. MR-proANP, NT-proBNP, MR-proADM and copeptin showed significant hemoconcentration-independent dynamics upon exercise. Biomarkers measured immediately after exercise provided similar prognostic information as their baseline levels.

MR-proANP, a cardiovascular biomarker to predict late-onset preeclampsia and intrauterine growth restricted fetuses.

Midregional pro-atrial natriuretic peptide (MR-proANP) is a cardiac biomarker and the maternal serum levels could predict late-onset preeclampsia (PE) or intrauterine growth restriction (IUGR) at third trimester of pregnancy. We measured MR-proANP between 32 and 37 weeks of pregnancy prospectively: 32 patients suffered from PE and 22 developed IUGR. 676 patients exhibited no pregnancy complications. The median MR-proANP showed significantly higher results in PE (64.9 pmol/l (interquartile range (IQR) 36.3-105.2) and IUGR (59.7 pmol/l (IQR 39.7-163.0) groups compared to controls (38.7 pmol/l (IQR 29.7-49.2). Linear regression analysis showed association between PE and MR-proANP levels (Exp(ß) = 1.56; 95% CI: 1.34-1.81). AUC showed a predictive value for PE (AUC: 0.72) and IUGR (AUC: 0.71). Measuring MR-proANP in maternal serum between 32 and 37 weeks of pregnancy could help predicting IUGR and PE diagnosed after 34 week in pregnancy. Thus, we assume that MR-proANP may be an additional biomarker which mirrors the maternal cardiosvascular status next to sFlt-1/PLGF representing the angiogenic status.

Midregional pro atrial natriuretic peptide: a novel important biomarker for noise annoyance-induced cardiovascular morbidity and mortality?

BackgroundEnvironmental noise exposure has been associated with increased cardiovascular morbidity and mortality. Recently, noise annoyance was shown to induce atrial fibrillation, which was accompanied by significantly increased levels of midregional pro atrial natriuretic peptide (MR-proANP). Therefore, the aim of the present study was to analyze the association between noise annoyance, MR-proANP, incident cardiovascular events, and all-cause mortality.MethodsLevels of MR-proANP were measured in the first 5000 participants of the population-based Gutenberg Health Study. Annoyance was assessed separately for aircraft, road traffic, railway, neighborhood, and industrial/construction noise during the day and sleep.ResultsIn cross-sectional analyses, aircraft noise annoyance during day and sleep, industrial/construction noise annoyance during day, and railway noise annoyance during sleep were independently associated with increased levels of MR-proANP after multivariable adjustment. After a 5-year follow-up period, there were 43 cases of incident atrial fibrillation and 103 of incident cardiovascular disease (comprising atrial fibrillation, coronary artery disease, myocardial infarction, heart failure, or stroke). Moreover, there were 301 deaths after a mean follow-up of 7.42 ± 1.66 years. An odds ratio (OR) of 2.82 ([95% confidence interval (CI) 1.86; 4.35], p < 0.0001) for incident atrial fibrillation and an OR of 1.49 ([95% CI 1.13; 1.96], p = 0.0046) for incident cardiovascular disease per 1-standard deviation (SD) increase in MR-proANP levels were found. A 36% (hazard ratio: 1.36 [95% CI 1.19; 1.55], p < 0.0001) higher risk of death was found per 1-SD increase in MR-proANP levels.ConclusionsNoise annoyance may contribute to cardiovascular morbidity and mortality and is characterized by increased levels of MR-proANP.Graphic abstract

MR-proADM and MR-proANP levels in patients with acute pulmonary embolism.

The aim of this study was to determine levels of Mid-regional Pro-adrenomedullin (MR-proADM) and Mid-regional Pro-atrial Natriuretic Peptide (MR-proANP) in patients with acute pulmonary embolism (PE), the relationship between these parameters and the risk classification in addition to determining the relationship between 1and 3month mortality. 82 PE patients and 50 healthy control subjects were included in the study. Blood samples for Mr-proANP and Mr-proADM were obtained from the subjects prior to the treatment. Risk stratification was determined according to sPESI (Simplified Pulmonary Embolism Severity Index). Following these initial measurements, cases with PE were assessed in terms of all causative and PE related mortalities. The mean serum Mr-proANP and Mr-proADM levels in acute PE patients were found to be statistically higher compared to the control group (p < 0.001, p < 0.01; respectively) and statistically significantly higher in high-risk patients than low-risk patients (p < 0.01, p < 0.05; respectively). No statistical difference was determined in high-risk patients in case of sPESI compared to low-risk patients while hospital mortality rates were higher. It was determined that the hospital mortality rate in cases with Mr-proANP ≥ 123.30 pmol/L and the total 3-month mortality rate in cases with Mr-proADM ≥ 152.2 pg/mL showed a statistically significant increase. This study showed that Mr-proANP and MRproADM may be an important biochemical marker for determining high-risk cases and predicting the mortality in PE patients and we believe that these results should be supported by further and extensive studies.

Midregional proatrial natriuretic peptide improves risk stratification after ischemic stroke.

To validate midregional proatrial natriuretic peptide (MR-proANP) for outcome prediction and diagnosis of cardioembolic stroke etiology compared to established clinical variables. In this prospective multicenter cohort study, we quantified MR-proANP levels in ischemic stroke patients within 24 hours of onset. Primary outcome measures were 90-day mortality, unfavorable functional outcome (modified Rankin Scale score >2), and cardioembolic stroke etiology diagnosed during hospitalization. Of 788 included patients, 783 completed their 90-day follow-up, and 118 patients (15%) died. After full adjustment, MR-proANP levels were associated with 90-day mortality (adjusted hazard ratio 6.12, 95% confidence interval [CI] 2.36-15.84, p = 0.01) and functional outcome (adjusted odds ratio [aOR] 2.46, 95% CI 1.05-5.74, p = 0.038). For mortality prediction, adding MR-proANP to the regression model increased its discriminatory accuracy, and the continuous net reclassification index (cNRI) was 49% (95% CI 26%-78%, p < 0.001). For functional outcome, there was no significant improvement in discrimination or reclassification. Cardioembolic stroke etiology and the diagnosis of atrial fibrillation at hospital discharge were associated with MR-proANP with an aOR of 2.10 (95% CI 1.11-3.97, p = 0.02) and 18.35 (95% CI 7.94-42.45, p < 0.001), respectively. The cNRI of MR-proANP for cardioembolic stroke etiology was not significant, as opposed to atrial fibrillation (78%, 95% CI 60%-89%, p < 0.001). MR-proANP levels ≥289 pmol/L had a specificity of 86% and sensitivity of 48% for the diagnosis of atrial fibrillation. MR-proANP is a newly validated blood biomarker providing additional prognostic information for mortality after stroke. Higher MR-proANP levels were associated with cardioembolic stroke etiology and, even more strongly, atrial fibrillation.

Effect of liraglutide on atrial natriuretic peptide, adrenomedullin, and copeptin in PCOS.

ContextWomen with polycystic ovary syndrome (PCOS) have an increased risk of cardiovascular disease (CVD), and biomarkers can be used to detect early subclinical CVD. Midregional-pro-adrenomedullin (MR-proADM), midregional-pro-atrial natriuretic peptide (MR-proANP) and copeptin are all associated with CVD and part of the delicate system controlling fluid and hemodynamic homeostasis through vascular tonus and diuresis. The GLP-1 receptor agonist liraglutide, developed for treatment of type 2 diabetes (T2D), improves cardiovascular outcomes in patients with T2D including a decrease in particular MR-proANP.ObjectiveTo investigate if treatment with liraglutide in women with PCOS reduces levels of the cardiovascular biomarkers MR-proADM, MR-proANP and copeptin.MethodsSeventy-two overweight women with PCOS were treated with 1.8 mg/day liraglutide or placebo for 26 weeks in a placebo-controlled RCT. Biomarkers, anthropometrics, insulin resistance, body composition (DXA) and visceral fat (MRI) were examined.ResultsBaseline median (IQR) levels were as follows: MR-proADM 0.52 (0.45–0.56) nmol/L, MR-proANP 44.8 (34.6–56.7) pmol/L and copeptin 4.95 (3.50–6.50) pmol/L. Mean percentage differences (95% CI) between liraglutide and placebo group after treatment were as follows: MR-proADM −6% (−11 to 2, P = 0.058), MR-proANP −25% (−37 to −11, P = 0.001) and copeptin +4% (−13 to 25, P = 0.64). Reduction in MR-proANP concentration correlated with both increased heart rate and diastolic blood pressure in the liraglutide group. Multiple regression analyses with adjustment for BMI, free testosterone, insulin resistance, visceral fat, heart rate and eGFR showed reductions in MR-proANP to be independently correlated with an increase in the heart rate.ConclusionIn an RCT, liraglutide treatment in women with PCOS reduced levels of the cardiovascular risk biomarkers MR-proANP with 25% and MR-proADM with 6% (borderline significance) compared with placebo. The decrease in MR-proANP was independently associated with an increase in the heart rate.