The multidimensional value of natriuretic peptides in heart failure, integrating laboratory and clinical aspects.

Natriuretic peptides (NP) play an essential role in heart failure (HF) regulation, and their measurement has improved diagnostic and prognostic accuracy. Clinical symptoms and objective measurements, such as NP levels, should be included in the HF definition to render it more reliable and consistent among observers, hospitals, and healthcare systems. BNP and NT-proBNP are reasonable surrogates for cardiac disease, and their measurement is critical to early diagnosis and risk stratification of HF patients. NPs should be measured in all patients presenting with dyspnea or other symptoms suggestive of HF to facilitate early diagnosis and risk stratification. Both BNP and NT-proBNP are currently used for guided HF management and display comparable diagnostic and prognostic accuracy. Standardized cutoffs for each NP assay are essential for data comparison. The value of NP testing is recognized at various levels, including patient empowerment and education, analytical and operational issues, clinical HF management, and cost-effectiveness.

Neuroendocrine response to diclofenac in healthy subjects: a pilot study.

PURPOSE: The precise effects of non-steroidal anti-inflammatory drugs on the neuroendocrine hydro-electrolytic regulation are not precisely understood. The aim of this pilot study was to evaluate, in healthy subjects, the neuroendocrine response of the antidiuretic system to intravenous diclofenac infusion. METHODS: For this single-blinded, cross-over study, we recruited 12 healthy subjects (50% women). Test sessions were divided into three observation times (pre-test; test; 48 h post-test), which were repeated equally on two different occasions, with the administration of diclofenac (75 mg in saline solution 0.9% 100 cc) on 1 day, or placebo (saline solution 0.9% 100 cc) on another day. The night before the test the subjects were asked to collect a salivary cortisol and cortisone sample, which was repeated on the night of the procedure session. Serial urine and blood samples were collected on the test day (for osmolality, electrolytes, ACTH, cortisol, copeptin, MR-proADM, MR-proANP; the last three represent more stable and analytically reliable molecules than their respective active peptides). Moreover, the subjects were evaluated with the bioimpedance vector analysis (BIVA) before and after the test. Forty-eight hours after the end of the procedure urine sodium, urine potassium, urine osmolality, serum sodium and copeptin were revaluated together with BIVA. RESULTS: No significant changes in circulating hormone levels were observed; anyway, 48 h after diclofenac, BIVA showed a significant water retention (p < 0.00001), especially in extracellular fluid (ECF) (16.47 ± 1.65 vs 15.67 ± 1.84, p < 0.001). Salivary cortisol and cortisone tended to increase only the night after placebo administration (p = 0.054 cortisol; p = 0.021 cortisone). CONCLUSION: Diclofenac resulted in an increased ECF at 48 h, but this phenomenon seems to be associated with a greater renal sensibility to the action of vasopressin rather than with an increase in its secretion. Moreover, a partial inhibitory effect on cortisol secretion can be hypothesized.

Association of physiological stress markers at the emergency department to readmission and death within 90 days: a prospective observational study.

Background: Predicting the risk of readmission or death in patients at the emergency department (ED) is essential in identifying patients who would benefit the most from interventions. We aimed to explore the prognostic value of mid-regional proadrenomedullin (MR-proADM), mid-regional pro-atrial natriuretic peptide (MR-proANP), copeptin, and high-sensitivity troponin T (hs-TnT) to identify patients with a higher risk of readmission and death among patients presenting with chest pain (CP) and/or shortness of breath (SOB) in the ED. Methods: This single-center prospective observational study included non-critically ill adult patients with a chief complaint of CP and/or SOB who visited the ED at Linköping University Hospital. Baseline data and blood samples were collected, and patients were followed up for 90 days after inclusion. The primary outcome was a composite of readmission and/or death from non-traumatic causes within 90 days of inclusion. Binary logistic regression was used and receiver operating characteristics (ROC) curves were constructed to determine the prognostic performance for predicting readmission and/or death within 90 days. Results: A total of 313 patients were included and 64 (20.4%) met the primary endpoint. MR-proADM > 0.75 pmol/L (odds ratio [OR]: 2.361 [95% confidence interval [CI]: 1.031 - 5.407], P = 0.042) and multimorbidity (OR: 2.647 [95% CI: 1.282 - 5.469], P = 0.009) were significantly associated with readmission and/or death within 90 days. MR-proADM increased predictive value in the ROC analysis to age, sex, and multimorbidity (P = 0.006). Conclusions: In non-critically ill patients with CP and/or SOB in the ED, MR-proADM and multimorbidity may be helpful for the prediction of the risk of readmission and/or death within 90 days.

Combination of cardiac color Doppler ultrasound, serum MR-ProANP and NT-ProBNP forecasted hypertensive LVH and LFH.

To analyze the value of the combined test of the cardiac color Doppler ultrasound, the serum middle receptor pro-atrial natriuretic peptide (MR-ProANP) and the N-terminal pro-brain natriuretic peptide (NT-ProBNP) in forecasting the hypertensive left ventricular hypertrophy (LVH) and left heart failure (LHF). All patients were subjected to cardiac color Doppler ultrasound examination to obtain left atrium volume index (LAVI), left ventricular end-diastolic diameter (LVEDD), early-diastolic peak flow velocity (E), early-diastolic mean flow velocity (e'), early-diastolic peak flow velocity/early-diastolic mean flow velocity (E/e') and left ventricular ejection fraction (LVEF). Biomarkers were performed to obtain serum MR-ProANP and NT-ProBNP concentrations, and statistical analysis was performed. The LVEF was obviously lower than that in the control group (P<0.01). The area under the receiver operating characteristic (ROC) curve (AUC) values of LVEF, E/e', serum MR-ProANP and NT-ProBNP alone were in the range of 0.7-0.8. The AUC, sensitivity and specificity of LVEF and E/e' combined with MR-ProANP and NT-ProBNP to diagnose hypertensive LVH and LHF were 0.892, 89.14% and 78.21%, which were higher than those of single diagnosis. In the heart failure group, LVEF was negatively correlated with serum MR-ProANP and NT-ProBNP concentrations (P<0.05), and E/e' was positively correlated with serum MR-ProANP and NT-ProBNP concentrations (P<0.05). Pump function and ventricular remodeling in patients with hypertensive LVH and LHF are closely related to serum MR-ProANP and NT-ProBNP levels. Combination of the two testing can improve the prediction and diagnostic efficacy of LHF.

Atrial Fibrillation, thromboembolic risk, and the potential role of the natriuretic peptides, a focus on BNP and NT-proBNP - A narrative review.

Atrial fibrillation (AF) is one of the most commonly encountered arrythmia in clinical practice. AF itself can be driven by genetic predisposition, ectopic electrical activity, and abnormal atrial tissue substrates. Often there is no single etiological mechanism, but rather a combination of factors that feed back to remodel and worsen tissue substrate, "AF begets AF". The clinical consequences of AF can often include emboli, heart failure, and early mortality. The classical AF cardioembolic (CE) concept requires thrombus formation in the left atrial appendage, with subsequent embolization. The temporal dissociation between AF occurrence and CE events has thrown doubt on AF as the driver of this mechanism. Instead, there has been a resurgence of the "atrial cardiomyopathy" (ACM) concept. An ACM is proposed as a potential mechanism of embolic disease through promotion of prothrombotic mechanisms, with AF instead reflecting atrial disease severity. Regardless, AF has been implicated in 25% to 30% of cryptogenic strokes. Natriuretic peptide(NP)s have been shown to be elevated in AF, with higher levels of both NT-proBNP and BNP being predictive of incidental AF. NPs potentially reflect the atrial environment and could be used to identify an underlying ACM. Therefore, this narrative review examines this evidence and mechanisms that may underpin the role of NPs in identifying atrial dysfunction, with focus on both, BNP and NTproBNP. We explore their potential role in the prediction and screening for both, ACM and AF. Moreover, we compare both NPs directly to ascertain a superior biomarker.

Exercise MR-proANP unmasks latent right heart failure in CTEPH.

OBJECTIVE: The present study was designed to investigate the dynamics of right atrial pressure (RAP) and mid-regional pro-atrial natriuretic peptide (MR-proANP) during physical exercise in patients with chronic thromboembolic pulmonary hypertension (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 prospective 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 >15 mmHg as suggestive of right heart failure. RESULTS: During eRHC mean RAP increased from 6 mmHg (standard deviation, SD 4) to 16 mmHg (SD 7; p < 0.001). MR-proANP levels and dynamics correlated with RAP at rest (rs = 0.61; p < 0.001) and at peak exercise (rs = 0.66; p < 0.001). Logistic regression analysis revealed the peak MR-proANP level (B = 0.058; p = 0.004) and the right atrial area (B = 0.389; p < 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 >15 mmHg. Physical exercise unmasked right heart failure in 39% of patients with normal RAP at rest; these patients were also characterized by a more distinct increase in MR-proANP levels (p = 0.005) and higher peak (p < 0.001) and recovery levels (p < 0.001). CONCLUSIONS: RAP and MR-proANP dynamics unmask manifest and latent right heart failure in CTEPH patients.

MR-proANP measured at admission is associated with incident atrial fibrillation in STEMI patients.

Atrial fibrillation (AF) is common following ST-segment elevation myocardial infarction (STEMI). Increased blood levels of mid regional pro atrial natriuretic peptide (MR-proANP) have been associated with a greater risk of incident AF. However, knowledge of the value of MR-proANP in predicting incident AF after STEMI is sparse. To assess whether MR-proANP measured at admission is associated with development of incident AF in patients with STEMI. 673 STEMI patients with no history of AF treated with primary percutaneous coronary intervention (pPCI) were prospectively enrolled from September 2006 to December 2008. Blood samples were drawn before the procedure. MR-proANP was measured by an automated processing assay. End point was incident AF. Median follow-up time was 5.5 years (interquartile-range 4.7-6.0), during which 63 patients developed AF. In a multivariable Cox regression model adjusted for relevant clinical and biochemical variables, MR-proANP was significantly associated with the development of AF (HR 1.18 per 100 pmol, 95% CI 1.11-1.28, p < 0.001). In a subgroup of patients who underwent echocardiography (N = 360), MR-proANP remained significantly associated with the development of AF (HR 1.39 per 100 pmol, 95% CI 1.13-1.71, p = 0.002) after adjusting for clinical and biochemical variables and left ventricular ejection fraction. When stratifying patients according to tertiles of MR-proANP, patients in the upper tertile displayed an 11 times greater risk of developing AF during follow-up as compared to patients in the lower tertile (HR 11.1, 95% CI 4.4-28.2, p < 0.001). Plasma MR-proANP measured at admission is an independent predictor of incident AF after STEMI.

Differential Impact of Biologic Therapy on Heart Function Biomarkers in Rheumatoid Arthritis Patients: Observational Study on Etanercept, Adalimumab, and Tocilizumab.

BACKGROUND: Rheumatoid arthritis (RA) represents the most frequent form of inflammatory arthritis, affecting approximately 1% of the population worldwide. The introduction of novel therapeutic strategies targeting proinflammatory cytokines (TNF-α and interleukin-6) revolutionized the treatment of RA. This kind of treatment, although effective in a substantial portion of patients, may potentially cause many side effects. Among them, cardiovascular safety is one of the main concerns. OBJECTIVES: In the present study, we investigated the impact of treatment with anti-TNF-α and anti-IL-6 agents on heart function and levels of heart function biomarkers. METHODS: To measure this, we used cardiac function biomarkers, such as NT-pro Brain Natriuretic Peptide, mid regional pro-Atrial Natriuretic Peptide, Galectin-3, and Heart-Type Fatty Acid-Binding Protein and compared them to patients treated with methotrexate as well as healthy controls. RESULTS: Patients treated with biologics were characterized by low disease activity or were in remission. The disease activity in these groups was significantly lower than in the methotrexate group. All patients recruited for the study were characterized by normal heart function measured using echocardiography (EF>50%). With the exception of MR-proANP between tocilizumab and adalimumab (median: 1.01 vs. 0.49 nmol/L, p<0.05), we failed to observe any significant differences in biomarkers levels between groups treated with biologics. Contrary to this, patients on MTX showed higher NT-proBNP levels compared to adalimumab and healthy controls (p<0.05 for both). Striking differences have been shown in regard to H-FABP. The levels of these biomarkers were elevated in all biologics and the methotrexate group compared to healthy controls. CONCLUSION: As this biomarker reflects potential heart injury, we suggest that heart damage proceeds in a continuous manner in RA patients despite effective treatment and attainment of remission/low disease activity. This finding, however, should be verified in a larger cohort of RA patients to ascertain if the routine assessment of H-FABP may be useful for the detection of patients with RA who are at risk of development of heart damage.

Diastolic stress echocardiography and biomarkers in patients with preserved left ventricle ejection fraction and heart failure symptoms.

BACKGROUND: Diastolic dysfunction (DD) is a diagnostic challenge in clinical practice. AIM: Our study aimed to evaluate the value of diastolic stress echocardiography (DSE) and heart failure (HF) biomarkers in patients with preserved left ventricular ejection fraction (LVEF) and HF symptoms. METHODS: All the consecutive patients with HF symptoms, preserved LVEF, and suspected DD were examined on transthoracic echocardiography (TTE) and DSE using the protocol according to the American Society of Echocardiography recommendations. Moreover, blood samples were taken 30 minutes before and after DSE for the following lab markers: N-terminal pro-B type natriuretic peptide (NT-proBNP), mid regional pro-atrial natriuretic peptide (MR-proANP), and serum soluble ST2 receptor (ST2). RESULTS: The study group included 80 patients (mean [standard deviation, SD] age, 69 (8.1) years; 25% males) with dyspnea (New York Heart Association classification IIa - 53; IIb - 17; III - 10) and risk factors: hypertension (96%), diabetes (41%), obesity (56%), and known coronary artery disease (10%). The rest transthoracic echocardiography (TTE) showed preserved systolic function (mean [SD], LVEF 61.1 [10.5]%) and normal or indeterminate diastolic function. DSE revealed a positive result for diastolic dysfunction in 17 patients (21%). The receiver operating characteristic (ROC) analysis showed that age (the area under the curve [AUC], 0.725; P < 0.01), left atrial volume indexed for body surface area [LAVI] rest (AUC, 0.722; P < 0.01), E/e' rest (AUC, 0.790; P < 0.01), and baseline NT-proBNP (AUC, 0.713; P < 0.01) predicted positive DSE. Other parameters, including body mass index, baseline E/A, DT, or e' were not predictive of DSE results. CONCLUSIONS: DSE revealed diastolic dysfunction in 21% of study patients and improved the diagnostic value of echocardiography. Rest NT-proBNP, but not MR-proANP and ST2, provided a diagnostic value for diastolic dysfunction.

Effect of a 3-Week Treatment with GLP-1 Receptor Agonists on Vasoactive Hormones in Euvolemic Participants.

CONTEXT: Glucagon-like-peptide-1 receptor agonists (GLP-1 RAs) exert cardiovascular benefits by reducing plasma glucose, body weight, and blood pressure. The blood pressure-lowering effect may be mediated by angiotensin II (ANG II) suppression and consecutive natriuresis. However, the role of ANG II and other vasoactive hormones on GLP-1 RA treatment has not been clearly defined. OBJECTIVE: This work aimed to investigate the effect of a 3-week treatment with the GLP-1 RA dulaglutide on vasoactive hormones, that is, renin, ANG II, aldosterone, mid-regional proatrial natriuretic peptide (MP-proANP), and natriuresis in euvolemic participants. METHODS: Randomized, double-blinded, placebo-controlled, crossover trials were conducted at University Hospital Basel, Switzerland. A total of 54 euvolemic participants, including 20 healthy individuals and 34 patients with primary polydipsia, received a subcutaneous injection of dulaglutide (Trulicity) 1.5 mg and placebo (0.9% sodium chloride) once weekly over a 3-week treatment phase. RESULTS: After a 3-week treatment phase, dulaglutide showed no effect on plasma renin, plasma ANG II, or plasma aldosterone levels in comparison to placebo. Natriuresis remained unchanged or decreased on dulaglutide depending on the measured parameter. Dulaglutide significantly decreased plasma MR-proANP levels (treatment effect: 10.60 pmol/L; 95% CI, -14.70 to -7.90; P < .001) and systolic blood pressure (median: 3 mm Hg; 95% CI, -5 to 0; P = .036), whereas heart rate increased (median: 5 bpm; 95% CI, 3-11; P < .001). CONCLUSION: In euvolemic participants, a 3-week treatment of dulaglutide reduced systolic blood pressure independently of plasma renin, ANG II, or aldosterone levels and urinary sodium excretion. The reduction in MR-proANP might be secondary to reduced arterial pulse pressure.

Admission of patients with chest pain and/or breathlessness from the emergency department in relation to risk assessment and copeptin levels - an observational study.

Background: One of the most critical decisions that emergency department (ED) physicians make is the discharge versus admission of patients. We aimed to study the association of the decision in the ED to admit patients with chest pain and/or breathlessness to a ward with risk assessment using the Rapid Emergency Triage and Treatment System (RETTS), the National Early Warning Score (NEWS), and plasma levels of the biomarkers copeptin, midregional proadrenomedulin (MR-proADM), and midregional proatrial natriuretic peptide (MR-proANP). Methods: Patients presenting at the ED with chest pain and/or breathlessness with less than one week onset were enrolled. Patients were triaged according to RETTS. NEWS was calculated from the vital signs retrospectively. Results: Three hundred and thirty-four patients (167 males), mean age 63.8 ± 16.8 years, were included. Of which, 210 (62.8%) patients complained of chest pain, 65 (19.5%) of breathlessness, and 59 (17.7%) of both. Of these, 176 (52.7%) patients were admitted to a ward, and 158 (47.3%) patients were discharged from the ED. In binary logistic models, age, gender, vital signs (O2 saturation and heart rate), NEWS class, and copeptin were associated with admission to a ward from the ED. In receiver-operating-characteristics (ROC) analysis, copeptin had an incremental predictive value compared to NEWS alone (P = 0.002). Conclusions: Emergency physicians' decisions to admit patients with chest pain and/or breathlessness from the ED to a ward are related to age, O2 saturation, heart rate, NEWS category, and copeptin. As an independent predictive marker for admission, early analysis of copeptin might be beneficial when improving patient pathways at the ED.

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.

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

Background: 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.

Plasma mid-regional pro-atrial natriuretic peptide predicts cardiovascular events in patients with type 2 diabetes independently of subclinical organ damage.

AIM: The aim of this study was to investigate the association between plasma MR-proANP and cardiovascular disease (CVD) in a middle-aged population with type 2 diabetes. METHODS: MR-proANP was measured in 690 patients with type 2 diabetes participating in the epidemiological study CARDIPP (Cardiovascular Risk Factors in Patients with Diabetes-a Prospective Study in Primary Care). The outcome variables were incident major adverse cardiovascular events (MACE) and all-cause mortality. Patients were followed using the national Swedish Cause of Death Registry and the Inpatient Register. RESULTS: During the mean follow-up period of 10.8 years, MACE occurred in 111 patients and 102 patients died. The hazard ratio for an increment of MR-proANP of 1 pmol/l adjusted for sex, age, current smoking, previous CVD, HbA1c, serum cholesterol, eGFR, systolic blood pressure, C-reactive protein, aortic pulse wave velocity, left ventricular mass and intima media thickness in the carotid arteries was 1.007 (95% CI 1.000-1.013, P = 0.042) for MACE and 1.008 (95% CI 1.001-1.014, P = 0.017) for all-cause mortality. CONCLUSIONS: Elevated MR-proANP levels predict an increased risk for MACE and all-cause mortality in patients with type 2 diabetes independently of CVD risk factors and markers for subclinical organ damage.

Mid-Regional Proadrenomedullin and Mid-Regional Proatrial Natriuretic Peptide Clearance Predicts Poor Outcomes Better Than Single Baseline Measurements in Critically Ill Patients With Pneumonia: A Retrospective Cohort Study.

Background We assessed the ability of baseline and serial measurements of mid-regional proadrenomedullin (MR-proADM) and mid-regional proatrial natriuretic peptide (MR-proANP) to predict 28-day mortality in critically ill patients with pneumonia compared with Acute Physiological and Chronic Health Evaluation IV (APACHE IV) model and Sequential Organ Failure Assessment (SOFA) score. Methodology Biomarkers were collected for the first five days in this retrospective observational cohort study. Biomarker clearance (as a percentage) was presented as biomarker decline in five days. We investigated the relationship between biomarkers and mortality in a multivariable Cox regression model. APACHE IV and SOFA were calculated after 24 hours from intensive care unit admission. Results In 153 critically ill patients with pneumonia, 28-day mortality was 26.8%. Values of baseline MR-proADM, MR-proANP, and APACHE IV were significantly higher in 28-day nonsurvivors, but not significantly different for SOFA score. Baseline MR-proADM and MR-proANP, APACHE IV, and SOFA had a low area under the curve in receiver operating characteristics (ROC) curves. No optimal cut-off points could be calculated. Biomarkers and severity scores were divided into tertiles. The highest tertiles baseline MR-proADM and MR-proANP were not significant predictors for 28-day mortality in a multivariable model with age and APACHE IV. SOFA was not a significant predictor in univariable analysis. Clearances of MR-proADM and MR-proANP were significantly higher in 28-day survivors. MR-proADM and MR-proANP clearances had similar low accuracy to identify nonsurvivors in ROC curves and were divided into tertiles. Low clearances of MR-proADM and MR-proANP (first tertiles) were significant predictors for 28-day mortality (hazard ratio [HR]: 2.38; 95% confidence interval [CI]: 1.21-4.70; p = 0.013 and HR: 2.27; 95% CI: 1.16-4.46; p = 0.017) in a model with age and APACHE IV. Conclusions MR-proADM and MR-proANP clearance performed better in predicting 28-day mortality in a model with age and APACHE IV compared with single baseline measurements in a mixed population of critically ill with pneumonia.

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

BACKGROUND: Mid-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. METHODS: This 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. RESULTS: Of 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). CONCLUSION: The 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.

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

BACKGROUND: High 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. METHODS: We 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. RESULTS: During 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. CONCLUSIONS: High 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.

MR-proANP and incident cardiovascular disease in patients with type 2 diabetes with and without heart failure with preserved ejection fraction.

BACKGROUND: Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a useful biomarker in outpatients with type 2 diabetes (T2D) to diagnose heart failure (HF). Elevated B-type natriuretic peptides are included in the definition of HF with preserved ejection fraction (HFpEF) but little is known about the prognostic value of including A-type natriuretic peptides (MR-proANP) in the evaluation of patients with T2D. METHODS: We prospectively evaluated the risk of incident cardiovascular (CV) events in outpatients with T2D (n = 806, mean ± standard deviation age 64 ± 10 years, 65% male, median [interquartile range] duration of diabetes 12 [6-17] years, 17.5% with symptomatic HFpEF) according to MR-proANP levels and stratified according to HF-status including further stratification according to a prespecified cut-off level of MR-proANP. RESULTS: A total of 126 CV events occurred (median follow-up 4.8 [4.1-5.3] years). An elevated MR-proANP, with a cut-off of 60 pmol/l or as a continuous variable, was associated with incident CV events (p < 0.001). Compared to patients without HF, patients with HFpEF and high MR-proANP (≥ 60 pmol/l; median 124 [89-202] pmol/l) and patients with HF and reduced ejection fraction (HFrEF) had a higher risk of CV events (multivariable model; hazard ratio (HR) 2.56 [95% CI 1.64-4.00] and 3.32 [1.64-6.74], respectively). Conversely, patients with HFpEF and low MR-proANP (< 60 pmol/l; median 46 [32-56] pmol/l) did not have an increased risk (HR 2.18 [0.78-6.14]). CONCLUSIONS: Patients with T2D and HFpEF with high MR-proANP levels had an increased risk for CV events compared to patients with HFpEF without elevated MR-proANP and compared to patients without HF, supporting the use of MR-proANP in the definition of HFpEF from a prognostic point-of-view.

MR-proANP level predicts new onset atrial fibrillation in patients with acute myocardial infarction.

OBJECTIVE: MR-pro ANP is a novel peptide with multiple biological functions, especially within the cardiovascular system. It plays an important role in physiological and pathological processes in the human body and its level may be clinically relevant in new onset atrial fibrillation. The aim of this study was to determine whether elevated MR-proANP level is a predictor of new-onset atrial fibrillation in patients with acute myocardial infarction. METHODS AND RESULTS: The study included 96 patients with their first diagnosis of acute myocardial infarction hospitalized in the Department of Interventional Cardiology within one year. The plasma levels of MR-proANP were determined on admission, and on the first and fifth day of hospitalisation by BRAHMS MRproANP KRYPTOR. New onset AF was diagnosed in 9.4% of patients during hospitalisation; the level of MR proANP was also found to be significantly higher in this group of patients compared to those without arrhythmia (p = 0.017). ROC curve analysis indicates that the concentration of MR-proANP is a good predictor of AF diagnosed during the hospitalisation in patients with acute myocardial infarction (AUC = 0.738, p = 0.0011). CONCLUSIONS: MR-proANP might be a good predictor of new-onset atrial fibrillation in patients with acute myocardial infarction.