Mid-regional Pro-atrial Natriuretic Peptide Research Articles

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.

Vasoactive Biomarkers Associated With Long-Term Incidence of Symptomatic Peripheral Arterial Disease and Mortality.

We evaluated if plasma biomarkers can predict incident peripheral arterial disease (PAD) and mortality in a longitudinal cohort study. Men (n = 3618) and women (n = 1542) were included in the Malmö Preventive Project and underwent analysis of: C-terminal endothelin-1 (CT-proET-1), N-Terminal prosomatostatin (NT-proSST), midregional proatrial natriuretic peptide (MR-proANP), procalcitonin (PCT), and copeptin. Participants were followed up for incident PAD and mortality until December 31, 2016. Median follow-up was 11.2 years (interquartile range 9.4-12.2). Cumulative incidence of PAD was 4.3% (221/5160), 4.5% in men (164/3618) and 3.7% in women (57/1542; P = .174). In an adjusted Cox proportional hazards regression model, higher CT-proET-1 (hazard ratio [HR] 1.8; 95% confidence interval [CI] 1.4-2.3), NT-proSST (HR 1.5; 95% CI 1.2-2.0), and MR-proANP (HR 1.7; 95% CI 1.3-2.3) were independently associated with incident PAD, and higher CT-proET-1 (HR 1.3; 95% CI 1.2-1.5), NT-proSST (HR 1.2; 95% CI 1.1-1.3), MR-proANP (HR 1.4; 95% CI 1.3-1.6), PCT (HR 1.1; 95% CI 1.0-1.2), and copeptin (HR 1.2; 95% CI 1.1-1.4) were independently associated with mortality. Increased levels of CT-proET-1, NT-proSST, and MR-proANP were independently associated with incident PAD, whereas all the vasoactive biomarkers were independently associated with mortality during follow-up.

Comparison of Natriuretic Peptides as Risk Markers for All-Cause Mortality and Cardiovascular and Renal Complications in Individuals With Type 1 Diabetes.

Few studies have compared midregional proatrial natriuretic peptide (MR-proANP) and N-terminal probrain natriuretic peptide (NT-proBNP). We compared their value as risk markers for all-cause mortality and cardiovascular (CV) and renal complications in individuals with type 1 diabetes. MR-proANP and NT-proBNP were measured in 664 individuals. Hazard ratios (HRs) were assessed per doubling of NT-proBNP or MR-proANP for risk of a composite of ischemic events, heart failure (HF), a combined renal end point of end-stage kidney disease (ESKD), decline in estimated glomerular filtration rate (eGFR) ≥30%, and all-cause mortality or individual end points. Adjustments included CV risk factors and addition of MR-proANP or NT-proBNP. Median follow-up was 5.1-6.2 years. MR-proANP was associated with higher risk of all-cause mortality (n = 57; HR 1.7, 95% CI 1.1-2.7), combined CV end point (n = 94; 1.6, 1.1-2.2), HF (n = 27; 2.8, 1.5-5.2), combined renal end point (n = 123; 1.6, 1.2-2.1), and ESKD (n = 21; 3.1, 1.2-7.8) independent of CV risk factors (P ≤ 0.02). After addition of NT-proBNP, significance for all end points was lost. A doubling of NT-proBNP was associated with higher risk of all-cause mortality (HR 1.5, 95% CI 1.2-1.8), the combined CV end point (1.3, 1.1-1.5), HF (1.7, 1.3-2.1), and the combined renal end point (1.3, 1.1-1.4) independent of CV risk factors (model 2 [P < 0.001]) and MR-proANP (model 3 [P ≤ 0.03]). There was no association with decline in eGFR ≥30% (n = 93). Higher NT-proBNP was independently associated with all-cause mortality, CV disease, HF, and the combined renal end point. MR-proANP was associated with all end points but decline in eGFR, although not independent of NT-proBNP. MR-proANP may contribute to the predictive value of NT-proBNP for risk stratification in type 1 diabetes.

Biomarkers improves prognostic and mortality prediction in pneumonia

Pneumonia exhibits mortality rates, between 20% and 50% in severe cases. Biomarkers are useful tools for antibiotic therapy modifications as well as diagnosis, prognosis and follow-up treatment of pneumonia. This review presents the biological and clinical features of various biomarkers in Pneumonia patients, including C-reactive protein, Procalcitonin, Coceptin, D-dimers, MRpro-ADM, (Mid-regional pro adrenomedullin), Corisol, Endothelin-1, Soluble Triggering Receptor Expressed on Myeloid Cells-1 (sTREM-1), Adrenomedullin, Endotoxin, Mid regional Pro-Atrial Natriuretic Peptide (MR-proANP), TNF-? Polymorphisms, Pentraxin 3. Keywords: Pneumonia, Community-acquired, Hospital-acquired, Ventilator-associated pneumonia (VAP), Biomarkers, Point of care testing.

An Integrated Imaging and Circulating Biomarker Approach for Secondary Tricuspid Regurgitation.

Secondary tricuspid regurgitation (sTR) is frequent among patients with heart failure with reduced ejection fraction (HFrEF), however it confers considerable diagnostic challenges. The assessment of neurohumoral activation may constitute a valuable supplement to the current imaging-based diagnostic process. This study sought to investigate the expression of complementary biomarkers in sTR and to evaluate the effectiveness of integrating their assessment into the diagnostic process. We enrolled 576 HFrEF patients recording echocardiographic and biochemical measurements, i.e., N-terminal pro-B-type natriuretic peptide, mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin, C-terminal pro-endothelin-1 (CT-pro-ET1), and copeptin. Plasma levels of the aforementioned neurohormones were significantly elevated with increasing sTR severity (p < 0.001 for all). CT-pro-ET1 and MR-proANP were the closest related to severe sTR (adj. OR 1.46; 95%CI 1.11–1.91, p = 0.006 and adj. OR 1.45, 95%CI 1.13–1.87, p = 0.004, respectively). In patients with moderate-to-severe sTR, adding selected biomarkers (i.e., CT-pro-ET1 and MR-proANP) resulted in a substantial improvement in the discriminatory power regarding long-term mortality (C-statistic: 0.54 vs. 0.65, p < 0.001; continuous NRI 57%, p < 0.001). Circulating biomarkers closely relate to sTR severity and correlate with hemodynamic and morphologic mechanisms of sTR. Specifically, MR-proANP and CT-pro-ET1 are closely linked to the presence of severe sTR, and a combined assessment with the guideline recommended echocardiographic grading significantly improves individual risk stratification.

Pro B-type Natriuretic Peptide and Midregional Proadrenomedullin are Associated with Incident Carotid Stenosis During Long Term Follow-up

Background: Plasma biomarkers may be useful to detect healthy individuals at increased risk for atherosclerotic manifestations, such as carotid artery stenosis. The aim of this longitudinal cohort study was to evaluate new biomarkers in relation to C-reactive protein and conventional risk factors for carotid artery stenosis during long term follow-up MethodsThe following markers were measured in 5550 middle-aged subjects: C-reactive protein, lipoprotein-associated phospholipase A2, proneurotensin, midregional pro-adrenomedullin, midregional pro-atrial natriuretic peptide, N-terminal pro B-type natriuretic peptide, copeptin, and cystatin C. Subjects with prevalent carotid artery stenosis were excluded. Subjects were followed in national patient registers for 23.4 (interquartile range 19.5–24.3) years regarding incident carotid artery stenosis, both operated and non-operated. ResultsWhen including conventional risk markers in Cox regression, N-terminal pro B-type natriuretic peptide (Hazard ratio 1.36; 95% confidence interval 1.12–1.65; p = 0.002) was independently associated with incident carotid artery stenosis, whereas there were trends for C-reactive protein (HR 1.20; 95% confidence interval 0.98–1.48; p = 0.071), and midregional pro-adrenomedullin (Hazard ratio 1.21; 95% confidence interval 0.99–1.47; p = 0.061). Midregional pro-adrenomedullin (Hazard ratio 1.30; 95% confidence interval 1.03–1.65; p = 0.029) was independently associated with incident surgery for carotid artery stenosis, whereas there was a trend for N-terminal pro B-type natriuretic peptide (Hazard ratio 1.31; 95% confidence interval 1.00–1.72; p = 0.052). ConclusionsN-terminal pro B-type natriuretic peptide and midregional pro-adrenomedullin can be used as predictors for clinically detected carotid artery stenosis during long-term follow-up of healthy subjects.

Mid-regional pro-atrial natriuretic peptide predicts cardiovascular mortality in patients undergoing hemodialysis

Abstract Background Cardiovascular diseases are major contributors to morbidity and mortality among patients with renal disease. Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a fragment of the precursor molecule of atrial natriuretic peptide, a hormone released from cardiomyocytes in response to volume overload. Small studies have shown that MR-proANP decreases during hemodialysis (HD). No studies have been large enough to investigate the predictive ability of MR-proANP for cardiovascular or all-cause mortality in HD patients. Purpose To investigate the effect of HD on the concentration of MR-proANP and the prognostic value for cardiovascular- and all-cause mortality among HD patients. Methods This was a cohort study of stable patients receiving maintenance HD from two centers. Blood samples were drawn before and after a dialysis session. We calculated the Kaplan-Meier survival estimate (KM) and performed Cox regressions for cardiovascular and all-cause mortality. We estimated hazard ratios (HR) both unadjusted and adjusted for age, sex, diabetes mellitus, years in HD and history of ischemic heart disease and stroke. Results All 306 patients in the cohort had data on at least one MR-proANP measurement and were included. Of these, 284 (93%) had a measurement both before and after HD. Baseline characteristics are shown in table 1. The mean MR-proANP was 762 pmol/L (IQR 419–858 pmol/L) before and 447 pmol/L (IQR 198–537 pmol/L) after HD, a mean decrease of 330 pmol/l (43%) (IQR 152–434 pmol/l, (P&amp;lt;0.01). The median follow-up was 32 months (IQR 31–33) during which 110 (36%) patients died. The most common cause of death was cardiac (n=29, 26%). Figure 1 shows the KM for cardiovascular- (panel A) and all-cause mortality (panel B) in quartiles 1–3 (before HD: green, after HD: black) compared to the 4. Quartile (before HD: red, after HD: yellow) for MR-ProANP concentration measurements before and after HD. The 4. quartile was &amp;gt;863.2 pmol/L before and &amp;gt;537.9 pmol/L after HD. A Cox regression including both the MR-ProANP concentration before and after HD showed that only the concentration after HD was an independent predictor of both cardiovascular and all-cause mortality (both P&amp;lt;0.01). In the unadjusted analysis a MR-ProANP in the 4. quartile after dialysis was associated with a HR of 5.5 (95% CI 2.6–11.7, P&amp;lt;0.01) for cardiovascular mortality. This was even stronger in the adjusted model with a HR of 6.5 (95% CI 2.9–14.4). For all-cause mortality there was a significant rise in mortality among patients in the 3. and 4. quartiles after dialysis, HR 2.5 (95% CI 1.3–4.8) and 5.7 (95% CI 3.1–10.5), respectively (P&amp;lt;0.01). This remained significant in the adjusted model, HR 2.0 (95% CI 1.0–4.0, P=0.04) and 4.7 (95% CI 2.5–8.7, P&amp;lt;0.01), for patients in the 3. and 4. quartile respectively. Conclusion The biomarker MR-ProANP level was almost halved after hemodialysis and the level measured after dialysis was a strong marker for mortality. Figure 1 Funding Acknowledgement Type of funding source: None

Assessment of causality of natriuretic peptides and atrial fibrillation and heart failure – a Mendelian randomization study in the FINRISK cohort

Abstract Background Natriuretic peptides are extensively studied biomarkers for atrial fibrillation (AF) and heart failure (HF). Their role in the pathogenesis of both diseases is not entirely understood and in previous studies several single nucleotide polymorphisms (SNPs) at the NPPA-NPPB locus associated with natriuretic peptides have been identified. Purpose We investigated whether a causal relationship exists between natriuretic peptides and AF as well as HF using a Mendelian randomization approach. Methods N-terminal pro B-type natriuretic peptide (NT-proBNP) (N=6669), B-type natriuretic peptide (BNP) (N=6674) and mid-regional pro atrial natriuretic peptide (MR-proANP) (N=6813) were measured in the FINRISK 1997 cohort. Thirty common SNPs related to NT-proBNP, BNP and MR-proANP were selected from prior studies. We performed six Mendelian randomizations for all three natriuretic peptide biomarkers and for both outcomes, AF and HF separately. Polygenic risk scores (PRS) based on multiple SNPs were used as the genetic instrumental variable in Mendelian randomizations. Results PRS were significantly associated with the three natriuretic peptides. PRS were not significantly associated with incident AF nor HF. Most cardiovascular risk factors showed significant confounding percentages, but no association with PRS. A causal relation, other than a weak one, is unlikely. Conclusion In our Mendelian randomization approach, based on common genetic variation at the NPPA-NPPB locus, associations of the common polymorphisms with natriuretic peptides and the protein biomarkers themselves with incident disease could be confirmed. A strong causal relationship between natriuretic peptides and incidence of AF as well as HF was ruled out. Therapeutic approaches targeting natriuretic peptides will therefore very likely work through indirect mechanisms. Comparison of hazard ratios Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme, German Ministry of Research and Education

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.

Effects of different mean arterial pressure targets on plasma volume, ANP and glycocalyx-A randomized trial.

BackgroundArterial haematocrit (Hct) has been shown to decrease after anaesthesia induction, most probably because of an increased plasma volume (PV). The primary objective was to quantify change in PV if mean arterial pressure (MAP) was kept at baseline level or allowed to decrease to 60 mm Hg. Our secondary objective was to evaluate underlying mechanisms of this response.MethodsTwenty‐four coronary artery bypass patients were randomized to a higher (90 mm Hg, intervention group) or lower (60 mm Hg, control group) MAP by titration of norepinephrine. During the experimental procedure, no fluids were administered. Baseline PV was measured by 125I‐albumin and the change in PV was calculated from the change in Hct. Changes in MAP, plasma 125I‐albumin, colloid osmotic pressure, albumin, Mid Regional‐pro Atrial Natriuretic Peptide (MR‐proANP) and endothelial glycocalyx components were measured from baseline to 50 minutes after anaesthesia induction.ResultsThe MAP during the trial was 93 ± 9 mm Hg in the intervention group and 62 ± 5 mm Hg in the control group. PV increased with up to 420 ± 180 mL in the control group and 45 ± 130 mL in the intervention group (P < .001). Albumin and colloid osmotic pressure decreased significantly more in the control group. MR‐proANP increased in the control group but no shedding of the glycocalyx layer was detected in either of the groups.ConclusionAllowing mean arterial pressure to fall to 60 mm Hg during anaesthesia induction, increases the plasma volume due to reabsorption of interstitial water, with no ANP‐induced degradation of the endothelial glycocalyx.

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.

Current Use of Cardiac Biomarkers in Various Heart Conditions

Biomarkers are increasingly recognized to have significant clinical value in early identification and progression of various cardiovascular diseases. There are many heart conditions, such as congestive heart failure (CHF), ischemic heart diseases (IHD), and diabetic cardiomyopathy (DCM), and cardiac remodeling, in which the severity of the cardiac pathology can be mirrored through these cardiac biomarkers. From the emergency department (ED) evaluation of acute coronary syndromes (ACS) or suspected acute myocardial infarction (AMI) with cardiac marker Troponin to the diagnosis of chronic conditions like Heart Failure (HF) with natriuretic peptides, like B-type natriuretic peptide (BNP), N-terminal pro-B- type natriuretic peptide (Nt-proBNP) and mid regional pro-atrial natriuretic peptide (MR- proANP), their use is continuously increasing. Their clinical importance has led to the discovery of newer biomarkers, such as the soluble source of tumorigenicity 2 (sST2), galectin-3 (Gal-3), growth differentiation factor-15 (GDF-15), and various micro ribonucleic acids (miRNAs). Since cardiac pathophysiology involves a complex interplay between inflammatory, genetic, neurohormonal, and biochemical levels, these biomarkers could be enzymes, hormones, and biologic substances showing cardiac injury, stress, and malfunction. Therefore, multi-marker approaches with different combinations of novel cardiac biomarkers, and continual assessment of cardiac biomarkers are likely to improve cardiac risk prediction, stratification, and overall patient wellbeing. On the other hand, these biomarkers may reflect coexisting or isolated disease processes in different organ systems other than the cardiovascular system. Therefore, knowledge of cardiac biomarkers is imperative. In this article, we have reviewed the role of cardiac biomarkers and their use in the diagnosis and prognosis of various cardiovascular diseases from different investigations conducted in recent years.

Assessment of causality of natriuretic peptides and atrial fibrillation and heart failure: a Mendelian randomization study in the FINRISK cohort.

AimsNatriuretic peptides are extensively studied biomarkers for atrial fibrillation (AF) and heart failure (HF). Their role in the pathogenesis of both diseases is not entirely understood and previous studies several single-nucleotide polymorphisms (SNPs) at the NPPA-NPPB locus associated with natriuretic peptides have been identified. We investigated the causal relationship between natriuretic peptides and AF as well as HF using a Mendelian randomization approach.Methods and resultsN-terminal pro B-type natriuretic peptide (NT-proBNP) (N = 6669), B-type natriuretic peptide (BNP) (N = 6674), and mid-regional pro atrial natriuretic peptide (MR-proANP) (N = 6813) were measured in the FINRISK 1997 cohort. N = 30 common SNPs related to NT-proBNP, BNP, and MR-proANP were selected from studies. We performed six Mendelian randomizations for all three natriuretic peptide biomarkers and for both outcomes, AF and HF, separately. Polygenic risk scores (PRSs) based on multiple SNPs were used as genetic instrumental variable in Mendelian randomizations. Polygenic risk scores were significantly associated with the three natriuretic peptides. Polygenic risk scores were not significantly associated with incident AF nor HF. Most cardiovascular risk factors showed significant confounding percentages, but no association with PRS. A causal relation except for small causal betas is unlikely.ConclusionIn our Mendelian randomization approach, we confirmed an association between common genetic variation at the NPPA-NPPB locus and natriuretic peptides. A strong causal relationship between natriuretic peptides and incidence of AF as well as HF at the community-level was ruled out. Therapeutic approaches targeting natriuretic peptides will therefore very likely work through indirect mechanisms.

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.

Cardiovascular biomarkers in the evaluation of patent ductus arteriosus in very preterm neonates: A cohort study

BackgroundThe evaluation of the patent ductus arteriosus (PDA) in the very premature neonate is a challenge. Echocardiography provides an interpretation of the hemodynamic condition. It is however, only a snapshot. Biomarkers may represent a physiological response to the hemodynamic alterations brought on by the PDA and may add to the identification of the clinical significant PDA. AimTo investigate the association between mid regional proadrenomodulin (MR-proADM), N-terminal pro b-type natriuretic peptide (NT-proBNP), mid regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro endothelin-1 (CT-proET1) and copeptin and echocardiographic measures of PDA. Study designCohort study with echocardiography performed on day 3 and 6. Blood samples from day 3. Subject139 consecutive neonates born at a gestational age <32 weeks. Outcome measuresThe main outcomes were presence of a PDA day 3 and 6, PDA diameter, left atrium to aorta ratio (LA:Ao-ratio), and descending aorta diastolic flow (DADF). ResultsAdjusted plasma levels of all investigated biomarkers, except CT-proET1, were found to be associated with both PDA diameter and LA:Ao-ratio, and also the presence of a large PDA. CT-proET1 and copeptin was found to be associated with abnormal DADF. Using pre-specified cut-off values NT-proBNP and MR-proANP day 3 seemed to be of value in identifying a large PDA day 3 and 6 in very preterm neonates. ConclusionAmong the investigated biomarkers NT-proBNP and MR-proANP performed best in relation to echocardiographic markers of PDA severity in very preterm neonates.

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.

Left atrial remodelling, mid-regional pro-atrial natriuretic peptide, and prognosis across a range of ejection fractions in heart failure.

Measures of structural and functional remodelling of the left atrium (LA) are emerging as useful biomarkers in heart failure (HF). We hypothesized that LA volume and its contribution to stroke volume (SV) would predict a composite endpoint of HF hospitalization or death in patients with HF. We recruited 57 controls and 86 patients with HF, including preserved and reduced left ventricular ejection fraction (LVEF). Cardiac magnetic resonance imaging was used to evaluate LA volumes and contribution to LV SV. Plasma mid-region pro-atrial natriuretic peptide (MR-proANP) was evaluated. LA volume was negatively correlated with LVEF (P = 0.001) and positively correlated with LV mass in HFrEF (P < 0.001) but not in HFpEF. LA volume at end-diastole was associated with the composite endpoint in HFrEF (hazard ratio 1.26, 95% confidence interval 1.01-1.54; P = 0.044), but not HFpEF (1.06, 0.85-1.30; P = 0.612), per 10 mL/m increase. Active contribution to SV was negatively associated with the composite endpoint in HFpEF (0.32, 0.14-0.66; P = 0.001), but not HFrEF (0.91, 0.38-2.1; P = 0.828) per 10% increase. MR-proANP was associated with the composite endpoint in HFpEF (1.46, 1.03-1.94; P = 0.034), but not in HFrEF (1.14, 0.88-1.37; P = 0.278), per 100 pM increase. We found different relationships between LA remodelling and biomarkers in HFrEF and HFpEF. Our results support the hypothesis that the pathophysiologic underpinnings of HFpEF and HFrEF are different, and atrial remodelling encompasses distinct components for each HF subtype.

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