Midregional pro-A-type Natriuretic Peptide Research Articles

March 2021 at a glance: focus on epidemiology, prevention and COVID-19.

This issue hosts a landmark paper with the universal definition of heart failure (HF) developed by the HF Association (HFA), the HF Society of America and the Japanese HF Society and endorsed by four other HF societies.1 HF is defined as ‘a clinical syndrome with symptoms and/or signs caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion.’ Four stages are described: Stage A, for patients at risk for HF but without evidence of heart disease; Stage B, pre-HF, for patients without current or prior symptoms or signs of HF but with evidence of structural heart disease or abnormal cardiac function, or elevated natriuretic peptide levels; Stage C, HF, for patients with current or prior symptoms and/or signs of HF caused by a structural and/or functional cardiac abnormality; Stage D, advanced HF, for patients with severe symptoms and/or signs of HF at rest, recurrent hospitalizations despite guideline-directed medical therapy (GDMT), refractory or intolerant to GDMT, and requiring advanced therapies such as transplant, mechanical circulatory support, or palliative care.1 Stage D overlaps with advanced HF, as previously defined by a HFA position statement.2 A classification of HF according to left ventricular ejection fraction (EF) is also adopted with patients classified into those with reduced EF (HFrEF, EF ≤40%), mildly reduced EF (HFmrEF, EF 41-49%), preserved EF (HFpEF, EF ≥50%) and improved EF (HFimpEF, baseline EF ≤40%, a ≥10 point increase in EF and a second EF >40%).1 Attended by an outstanding editorial comments by Dr. Braunwald,3 and in line with recent consensus recommendations on definitions for the assessment of HF therapies,4 the universal definition of HF represents a fundamental framework to standardize the identification and classification of patients with HF both for daily practice and clinical studies. A substudy of SPRINT confirmed the role of kidney function and albuminuria for the prediction of HF events in hypertensive subjects. In addition, these variables did not influence the effects of intensive blood pressure control (target systolic blood pressure <120 mmHg), compared to standard treatment, for the reduction of HF risk.5 In PREVEND, enrolling 8202 individuals with a mean follow-up of 11.3 ± 3.1 years, N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-A-type natriuretic peptide (MR-proANP) and cardiac troponin T (cTnT) were associated with incident HF, and combined NT-proBNP and cTnT measurements improved HF risk prediction in overweight and obese subjects (both P < 0.001).6 These findings reinforce available evidence on the role of NT-proBNP, and/or the NT-proBNP and troponin combination, for the prediction of incident HF.7-9 Changes in the epidemiology and characteristics of cardiogenic shock and acute HF have occurred in the last years.10-13 Consistently, a systematic review and meta-regression of 285 studies, representing 15 million acute HF events, found a decline in 30-day mortality [odds ratio (OR) for a 10-year increment, 0.74, 95% confidence interval (CI) 0.61–0.91, P = 0.004] and 1-year mortality (OR 0.86, 95% CI 0.77–0.96, P = 0.007) after acute HF, in the last four decades. However, 30-day and 1-year readmission rates were unchanged.14 Left ventricular EF remains the most important measurement to classify patients with HF.1 In a cohort study on 499 153 patients in Australia, Stewart et al.14 identified sex-based differences in the risk of mortality associated with a left ventricular EF <65.0–69.9%, nadir of mortality in both sexes, with a greater risk at higher left ventricular EF values in women, compared with men. Advanced age is associated with a decline in GDMT use and higher mortality in patients with HF.15 In an analysis of BIOSTAT-CHF, Mordi et al.16 demonstrated that achieving higher doses of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) was associated with lower mortality or HF hospitalizations regardless of age, whereas achieving higher doses of β-blockers was associated with improved outcome only in younger patients (interaction P = 0.034). These findings could be helpful to refine ACEi/ARB and β-blocker up-titration in patients with HF.17 In line with available evidence showing worse clinical outcomes in COVID-19 patients with concomitant HF,18-22 an analysis of a Spanish cohort showed that NT-proBNP is frequently elevated in COVID-19 and independently associated with mortality (adjusted hazard ratio per logarithmic unit 1.28, 95% CI 1.13–1.44, P < 0.001).23 Cardiopulmonary and haemodynamic abnormalities characterize critically ill COVID-19 patients.18, 24 Of note, these patients showed a typical and rather specific inflammatory and cardiac myocyte-related microRNA up-regulation.25 Consistent with published data showing the lack of increased COVID-19 severity in patients treated with ACEi or ARBs despite increased ACE2 expression,19, 26, 27 an analysis on 1.4 million patients from the Swedish National Patient Registry did not find an association between the use of ACEi/ARBs or mineralocorticoid receptor antagonists and an increased risk of hospitalization for or death from COVID-19.28

Relationship between body mass index, cardiovascular biomarkers and incident heart failure.

AimsThere are limited data examining whether body mass index (BMI) influences the association between cardiovascular biomarkers and incident heart failure (HF).Methods and resultsThirteen biomarkers representing key HF domains were measured: N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), mid‐regional pro‐A‐type natriuretic peptide (MR‐proANP), cardiac troponin T (cTnT), C‐reactive protein, procalcitonin, galectin‐3, C‐terminal pro‐endothelin‐1 (CT‐proET‐1), mid‐regional pro‐adrenomedullin, plasminogen activator inhibitor‐1, copeptin, renin, aldosterone, and cystatin‐C. Associations of biomarkers with BMI were examined using linear regression models, and with incident HF using Cox regression models. We selected biomarkers significantly associated with incident HF, and evaluated whether BMI modified these associations. Among 8202 individuals, 41% were overweight (BMI 25–30 kg/m2), and 16% were obese (BMI ≥30 kg/m2). Mean age of the cohort was 49 years (range 28–75), and 50% were women. All biomarkers except renin were associated with BMI: inverse associations were observed with NT‐proBNP, MR‐proANP, CT‐proET‐1 and aldosterone whereas positive associations were observed with the remaining biomarkers (all P ≤ 0.001). During 11.3 ± 3.1 years of follow‐up, 357 HF events were recorded. Only NT‐proBNP, MR‐proANP and cTnT remained associated with incident HF (P < 0.001), and a significant biomarker*BMI interaction was not observed (interaction P > 0.1). Combined NT‐proBNP and cTnT measurements modestly improved performance metrics of the clinical HF model in overweight (ΔC‐statistic = 0.024; likelihood ratio χ2 = 38; P < 0.001) and obese (ΔC‐statistic = 0.020; likelihood ratio χ2 = 32; P < 0.001) individuals.ConclusionsPlasma concentrations of several cardiovascular biomarkers are influenced by obesity. Only NT‐proBNP, MR‐proANP and cTnT were associated with incident HF, and BMI did not modify these associations. A combination of NT‐proBNP and cTnT improves HF risk prediction in overweight and obese individuals.

Prohormones in the Early Diagnosis of Cardiac Syncope.

BackgroundThe early detection of cardiac syncope is challenging. We aimed to evaluate the diagnostic value of 4 novel prohormones, quantifying different neurohumoral pathways, possibly involved in the pathophysiological features of cardiac syncope: midregional–pro‐A‐type natriuretic peptide (MRproANP), C‐terminal proendothelin 1, copeptin, and midregional‐proadrenomedullin.Methods and ResultsWe prospectively enrolled unselected patients presenting with syncope to the emergency department (ED) in a diagnostic multicenter study. ED probability of cardiac syncope was quantified by the treating ED physician using a visual analogue scale. Prohormones were measured in a blinded manner. Two independent cardiologists adjudicated the final diagnosis on the basis of all clinical information, including 1‐year follow‐up. Among 689 patients, cardiac syncope was the adjudicated final diagnosis in 125 (18%). Plasma concentrations of MRproANP, C‐terminal proendothelin 1, copeptin, and midregional‐proadrenomedullin were all significantly higher in patients with cardiac syncope compared with patients with other causes (P<0.001). The diagnostic accuracies for cardiac syncope, as quantified by the area under the curve, were 0.80 (95% confidence interval [CI], 0.76–0.84), 0.69 (95% CI, 0.64–0.74), 0.58 (95% CI, 0.52–0.63), and 0.68 (95% CI, 0.63–0.73), respectively. In conjunction with the ED probability (0.86; 95% CI, 0.82–0.90), MRproANP, but not the other prohormone, improved the area under the curve to 0.90 (95% CI, 0.87–0.93), which was significantly higher than for the ED probability alone (P=0.003). An algorithm to rule out cardiac syncope combining an MRproANP level of <77 pmol/L and an ED probability of <20% had a sensitivity and a negative predictive value of 99%.ConclusionsThe use of MRproANP significantly improves the early detection of cardiac syncope among unselected patients presenting to the ED with syncope.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01548352.

Serial Assessment of Natriuretic Peptides in Patients Undergoing Interventional Closure of the Left Atrial Appendage

Closure of the left atrial appendage (LAA) to prevent cardioembolic events is an alternative therapy to oral anticoagulation in patients with non-valvular atrial fibrillation. The LAA is an important source of natriuretic peptides and its exclusion from the circulation may alter the blood level of these hormones, thereby influencing their diagnostic value and clinical effects. We aimed to prospectively assess potential changes in mid-regional pro A-type natriuretic peptide (MR-proANP) and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels 6 weeks and 6 months after interventional LAA closure using the WATCHMAN device. In 29 consecutive patients with successful LAA closure baseline MR-proANP level was 274±208pmol/l and decreased by -24.5±68 (p=0.07) and -15.0±44pmol/l (p=0.10) after 6 weeks and 6 months, respectively. The drop in the MR-proANP level after 6 weeks and 6 months was significant in patients with elevated (≥214pmol/l) baseline MR-proANP level (n=15: -54.3±78.0, p<0.01 and -31.8±45.4pmol/l, p=0.03, respectively) and those with reduced left ventricular ejection fraction (LVEF<45%, n=7: -87.4±97.3, p=0.02 and -60.3±42.6pmol/l, p=0.01, respectively). Baseline NT-proBNP level (median 1054pg/ml; IQR 621-1977pg/ml), sodium, potassium, mean systolic or diastolic blood pressure did not change significantly in the mentioned patient groups. After LAA closure, MR-proANP level decreased significantly in patients with elevated baseline MR-proANP level or reduced LVEF, whereas NT-proBNP level remained unchanged, thereby altering the correlation coefficient between the two biomarkers. Our findings should be considered when using these biomarkers for diagnostic or prognostic evaluation in patients with interventional LAA closure.

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.

Plasma concentrations of novel cardiac biomarkers before and after hemodialysis session

ObjectivesBiomarkers are useful for establishing disease severity or prognosis in patients with chronic kidney disease. The aim of our study was to determine the plasma concentrations of novel cardiovascular biomarkers in patients on chronic hemodialysis in the context of published upper reference limits (URL) of these biomarkers; and to compare the plasma concentrations of those same analytes before and after hemodialysis session. Design and methodsPlasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-A-type natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), C-terminal pro-arginine vasopressin (CT-proAVP, also known as Copeptin) and soluble ST2 (sST2) were measured in 28 patients before and after dialysis session. Of the 28 patients with conventional hemodialysis, 24 had low-flux hemofiltration and 4 had high-flux hemodiafiltration. ResultsMedian plasma concentrations of the biomarkers obtained before hemodialysis were as follows: NT-proBNP, 11,307ng/L (URL, 500ng/L); MR-proANP, 778pmol/L (URL, 250pmol/L); MR-proADM, 2.57nmol/L (URL, 0.52nmol/L); median CT-proET-1, 252pmol/L (URL, 75pmol/L); median CT-proAVP, 142pmol/L (URL, 19pmol/L); and median sST2, 27ng/mL (URL, 50ng/mL). Median relative analyte changes after low-flux vs. high-flux dialysis compared to predialysis values were +19% vs. −43% for NT-proBNP; +7% vs. −45% for MR-proANP; −2% vs. −63% for MR-proADM; −19% vs. −61% for CT-proET-1; +13% vs. −64% for CT-proAVP; and +2% vs. +3% for sST2. ConclusionsPlasma concentrations of the investigated biomarkers were markedly increased in chronic hemodialysis patients (with the exception of sST2). After hemodialysis session, analyte concentrations (with the exception of sST2) decreased significantly using a high-flux membrane but not if using a low-flux membrane.

Biomarkers of hemodynamic stress and aortic stiffness post-STEMI: a cross-sectional analysis

Methods Fifty-four patients four months after acute STEMI were enrolled in this cross-sectional, single-center study. Nterminal pro B-type natriuretic peptide (NT-proBNP), mid-regional pro-A-type natriuretic peptide (MR-proANP) and mid-regional pro-adrenomedullin (MR-proADM) levels were measured by established assays. Aortic stiffness was assessed by the measurement of pulse wave velocity using velocity-encoding, phase-contrast cardiovascular magnetic resonance imaging.

Outcome prediction and temperature dependency of MR-proANP and Copeptin in comatose resuscitated patients

ObjectiveTo evaluate the prognostic potential of serum C-terminal provasopressin (CT-proAVP or Copeptin) and midregional pro-A-type natriuretic peptide (MR-proANP) to predict neurological outcome following resuscitation from cardiac arrest. MethodsIn this prospective observational study, we employed novel ultra sensitive immunoassay technology to examine serial serum samples from 134 cardiac arrest patients. Patients were either allocated to mild therapeutic hypothermia using an endovascular device or normothermia. Serial blood samples were obtained from resuscitated cardiac arrest survivors during their first 7 days in an intensive care unit, and serum Copeptin and MR-proANP were measured. Cerebral function assessments were made using cerebral performance categorization (CPC) at discharge from hospital. Copeptin and MR-proANP data were analyzed using dichotomized CPC scores (1–2 versus 3–5). ResultsSixty-nine patients (51%) had a poor outcome (CPC 3–5) at hospital discharge. MR-proANP and Copeptin peaked on day 1 (i.e. 0–24h) with the medians being 249.3pmol/L and 77.2pmol/L, respectively. In the first 48h maximum levels of MR-proANP and Copeptin showed an AUC in the ROC of 0.743 (95% CI: 0.658–0.828) and 0.677 (95% CI: 0.583–0.771). Binary logistic regression revealed MR-proANP and Copeptin within 48h after ROSC being significantly associated with functional outcome (p<0.05). Copeptin within 48h was also associated with outcome in the hypothermia group (p<0.05). ConclusionSystemic levels of MR-proANP and Copeptin peak early in cardiac arrest patients in the 48h post-resuscitation period. MR-proANP and Copeptin were highly predictive for poor outcome in comatose resuscitated patients.

Biomarkers of hemodynamic stress and aortic stiffness after STEMI: a cross-sectional analysis.

Aim. Increased aortic stiffness might adversely affect cardiac structure, function, and perfusion. Release of biomarkers of hemodynamic stress is thought to be enhanced by these alterations. We aimed to evaluate the association between biomarkers of hemodynamic stress and aortic stiffness assessed at a chronic stage after ST-segment elevation myocardial infarction (STEMI). Methods. Fifty-four patients four months after STEMI were enrolled in this cross-sectional, single-center study. N-terminal pro–B-type natriuretic peptide (NT-proBNP), mid-regional pro–A-type natriuretic peptide (MR-proANP), and mid-regional proadrenomedullin (MR-proADM) levels were measured by established assays. Aortic stiffness was assessed by the measurement of pulse wave velocity using phase-contrast cardiovascular magnetic resonance. Results. NT-proBNP, MR-proANP, and MR-proADM concentrations were all correlated with aortic stiffness in univariate analysis (r = 0.378, r = 0.425, and r = 0.532; all P < 0.005, resp.). In multiple linear regression analysis, NT-proBNP (β = 0.316, P = 0.005) and MR-proADM (β = 0.284, P < 0.020) levels were associated with increased aortic stiffness independently of age, blood pressure, and renal function. NT-proBNP was the strongest predictor for high aortic stiffness (area under the curve: 0.82, 95% CI 0.67–0.96). Conclusion. At a chronic stage after STEMI, concentrations of biomarkers for hemodynamic stress, especially NT-proBNP, are positively correlated with aortic stiffness. These biomarkers might also be useful as predictors of high aortic stiffness after STEMI.

Prognostic value of midregional pro-A-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide in patients with stable coronary heart disease followed over 8 years.

Pathophysiological studies suggest that A-type natriuretic peptides (ANPs) might provide valuable information beyond B-type natriuretic peptides (BNPs) about cardiac dysfunction in patients with coronary heart disease (CHD). We aimed to assess the predictive value of midregional pro-A-type natriuretic peptide (MR-proANP) for recurrent cardiovascular disease (CVD) events in stable CHD patients for whom information on N-terminal proBNP (NT-proBNP) was already available. Plasma concentrations of MR-proANP and NT-proBNP were measured at baseline in a cohort of 1048 patients aged 30-70 years with CHD who were participating in an in-hospital rehabilitation program. Main outcome measures were cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke. During a median follow-up of 8.1 years, 150 patients (incidence 21.1 per 1000 patient-years) experienced a secondary CVD event. MR-proANP was associated with a hazard ratio (HR) of 1.89 (95% CI, 1.01-3.57) when the top quartile was compared to the bottom quartile in the fully adjusted model (P for trend = 0.011). For NT-proBNP the respective HR was 2.22 (95% CI, 1.19-4.14) with a P for trend = 0.001. Finally, MR-proANP improved various model performance measures, including c-statistics and reclassification metrics, but without being superior to NT-proBNP. Although we found an independent association of MR-proANP as well as NT-proBNP when used as single markers with recurrent CVD events after adjustment for established risk factors, the results of a simultaneous assessment of both markers indicated that MR-proANP fails to provide additional prognostic information to NT-proBNP in the population studied.

Relationships Between Biomarkers and Left Ventricular Filling Pressures at Rest and During Exercise in Patients After Myocardial Infarction

BackgroundIncreased pulmonary capillary wedge pressure (PCWP) is an independent prognostic predictor after myocardial infarction (MI), but PCWP is difficult to assess noninvasively in subjects with preserved ejection fraction (EF). We hypothesized that biomarkers would provide information regarding PCWP at rest and during exercise in subjects with preserved EF after MI. Methods and ResultsSeventy-four subjects with EF >45% and recent MI underwent right heart catheterization at rest and during a symptom-limited semisupine cycle exercise test with simultaneous echocardiography. Plasma samples were collected at rest for assessment of midregional pro–A-type natriuretic peptide (MR-proANP), N-terminal pro–B-type natriuretic peptide (NT-proBNP), galectin-3 (Gal-3), copeptin, and midregional pro-adrenomedullin (MR-proADM). Plasma levels of MR-proANP and PCWP were associated at rest (r = 0.33; P = .002) and peak exercise (r = 0.35; P = .002) as well as with changes in PCWP (r = 0.26; P = .03). Plasma levels of NT-proBNP and PCWP were weakly associated at rest (r = 0.23; P = .03) and peak exercise (r = 0.28; P = .02) but not with changes in PCWP (r = 0.20; P = .09). In a multivariable analysis, plasma levels of MR-proANP remained associated with rest and exercise PCWP (P < .01), whereas NT-proBNP did not. Plasma levels of Gal-3, copeptin, and MR-proADM were not associated with PCWP at rest or peak exercise. ConclusionsIn subjects recovering from an acute MI with preserved EF, plasma levels of natriuretic peptides, particularly MR-proANP, are associated with filling pressures at rest and during exercise.

Association of aortic stiffness with biomarkers of myocardial wall stress after myocardial infarction

BackgroundAortic pulse wave velocity (PWV) was linked to LV-geometry and -function in patients with kidney disease and non-ischemic cardiomyopathy. The role of aortic compliance after acute STEMI is so far unknown. In the present study, we prospectively investigated the relationship of increased aortic stiffness with biomarkers of myocardial wall stress 4months after STEMI. Methods48 STEMI patients who were reperfused by primary coronary angioplasty underwent cardiovascular magnetic resonance (CMR) at baseline and at 4-month follow-up. The CMR protocol comprised cine-CMR as well as gadolinium contrast-enhanced CMR. Aortic PWV was determined by velocity-encoded, phase-contrast CMR. Blood samples were routinely drawn at baseline and follow-up to determine N-terminal pro-B-type natriuretic peptide (NT-proBNP). In a subgroup of patients, mid-regional pro-adrenomedullin (MR-proADM) and mid-regional pro-A-type natriuretic peptide (MR-proANP) levels were determined. ResultsPatients with a PWV above median (>7.0m/s) had significantly higher NT-proBNP, MR-proADM and MR-proANP concentrations at 4-month follow-up than patients with a PWV below median (all p<0.02). PWV showed moderate to good correlation with NT-proBNP, MR-proAMD and MR-proANP levels 4months after STEMI (all p<0.05). Multivariate analysis revealed PWV, beside myocardial infarct size, as an independent predictor of 4-month NT-proBNP levels after correction for age, creatinine and LV ejection fraction (model r: 0.781, p<0.001). ConclusionAortic stiffness is directly associated with biomarkers of myocardial wall stress 4months after reperfused STEMI, suggesting a role for aortic stiffness in chronic LV-remodelling.

Body mass index in chronic heart failure: association with biomarkers of neurohormonal activation, inflammation and endothelial dysfunction

BackgroundLow body mass index (BMI) is associated with a poor outcome in chronic heart failure (CHF). An inverse association between BMI and adiponectin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been reported. The aim of the present study was to investigate whether novel markers of neurohormonal activation, inflammation, and endothelial dysfunction are associated with BMI in CHF.MethodsIn a cross-sectional study including 171 patients with CHF and a left ventricular ejection fraction (LVEF) ≤45% the impact of BMI on circulating plasma concentrations of adiponectin, α-defensins, high sensitivity C-reactive protein (hsCRP), copeptin, mid-regional pro-adrenomedullin (MR-proADM), NT-proBNP, and mid-regional pro-A-type natriuretic peptide (MR-proANP) were evaluated.ResultsIn multivariable linear regression analysis including age, sex, LVEF, New York Heart Association functional classification (NYHA), estimated glomerular filtration rate (eGFR), and diabetes, only NT-proBNP (β = −0.32) and adiponectin (β = −0.39) remained independently associated with BMI. MR-proANP was associated with BMI but adjusting for age attenuated the relation being no longer significant.ConclusionsAmong biomarkers typically increased in patients with CHF only adiponectin and NT-proBNP demonstrated independent inverse associations with BMI. This indicates a direct effect of these two biomarkers enhancing the wasting process seen in CHF.

Copeptin and MR-proADM in Umbilical Cord Plasma Reflect Perinatal Stress in Neonates Born to Mothers with Diabetes and MR-proANP Reflects Maternal Diabetes

To examine concentrations of three cardiovascular propeptides in umbilical cord plasma of neonates born to mothers with Type 1, Type 2 and gestational diabetes. Measurement of cardiovascular markers in umbilical cord plasma may potentially help identify neonates at risk of postnatal complications. Neonates born to mothers with diabetes have an increased risk of neonatal morbidity and mortality, and measurement of these new biomarkers may potentially help identify neonates at risk of these complications. Copeptin, midregional proadrenomedullin (MR-proADM) and mid-regional pro-A-type natriuretic peptide (MR-proANP) were measured in cord plasma of neonates (n = 63) born to mothers with the three types of diabetes. Associations with maternal glycemic control, mode of delivery and neonatal metabolic acidosis were examined. Umbilical cord plasma copeptin concentrations were lowest in neonates after elective cesarean sections (6.1 pmol/l; interquartile range [IQR]: 4.5-9.1) compared with emergency cesarean sections (156 pmol/l; IQR: 9.6-311; p = 0.019) and vaginal delivery (831 pmol/l; IQR: 107-2407; p < 0.0001). MR-proADM was also affected by mode of delivery; however, this seemed more likely to be caused by an inverse association with the acid-base balance. In this population, only MR-proANP plasma concentrations were related to type of diabetes. Neonates born to mothers with Type 1 diabetes had higher concentrations (median 260 pmol/l; IQR: 222-318) compared with Type 2 diabetes (175 pmol/l; IQR: 169-200; p = 0.003) and gestational diabetes (200 pmol/l; IQR: 149-276; p = 0.009). Umbilical cord plasma copeptin and MR-proADM concentrations primarily reflect perinatal stress associated with mode of delivery and the degree of fetal acidosis, whereas MR-proANP concentrations are higher in neonates born to mothers with Type 1 diabetes.

Pro–A-Type Natriuretic Peptide, Proadrenomedullin, and N-Terminal Pro–B-Type Natriuretic Peptide Used in a Multimarker Strategy in Primary Health Care in Risk Assessment of Patients With Symptoms of Heart Failure

ObjectiveUse of new biomarkers in the handling of heart failure patients has been advocated in the literature, but most often in hospital-based populations. Therefore, we wanted to evaluate whether plasma measurement of N-terminal pro–B-type natriuretic peptide (NT-proBNP), midregional pro–A-type natriuretic peptide (MR-proANP), and midregional proadrenomedullin (MR-proADM), individually or combined, gives prognostic information regarding cardiovascular and all-cause mortality that could motivate use in elderly patients presenting with symptoms suggestive of heart failure in primary health care. Methods and ResultsThe study included 470 elderly patients (mean age 73 years) with symptoms of heart failure in primary health care. All participants underwent clinical examination, 2-dimenstional echocardiography, and plasma measurement of the 3 propeptides and were followed for 13 years. All mortality was registered during the follow-up period. The 4th quartiles of the biomarkers were applied as cutoff values. NT-proBNP exhibited the strongest prognostic information with >4-fold increased risk for cardiovascular mortality within 5 years. For all-cause mortality MR-proADM exhibited almost 2-fold and NT-proBNP 3-fold increased risk within 5 years. In the 5–13-year perspective, NT-proBNP and MR-proANP showed significant and independent cardiovascular prognostic information. NT-proBNP and MR-proADM showed significant prognostic information regarding all-cause mortality during the same time. In those with ejection fraction (EF) <40%, MR-proADM exhibited almost 5-fold increased risk of cardiovascular mortality with 5 years, whereas in those with EF >50% NT-proBNP exhibited >3-fold increased risk if analyzed as the only biomarker in the model. If instead the biomarkers were all below the cutoff value, the patients had a highly reduced mortality risk, which also could influence the handling of patients. ConclusionsThe 3 biomarkers could be integrated in a multimarker strategy for use in primary health care.

Midregional Pro–A-Type Natriuretic Peptide for Diagnosis and Prognosis in Patients With Suspected Acute Myocardial Infarction

We hypothesized that midregional pro-A-type natriuretic peptide (MR-proANP), the stable midregional epitope of proANP, might be useful in the early diagnosis and risk stratification of patients with suspected acute myocardial infarction (AMI). In this multicenter study we measured MR-proANP, cardiac troponin T (cTnT), and high-sensitive cTnT (hs-cTnT) at presentation in 675 consecutive patients presenting to the emergency department with suspected AMI. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed 360 days for mortality and AMI. AMI was the final diagnosis in 119 patients (18%). Median MR-proANP levels at presentation were significantly higher in patients with AMI (189 pmol/L, interquartile range 97 to 341) versus patients with another final diagnosis (83 pmol/L, 49 to 144, p <0.001). However, neither the combination of MR-proANP with cTnT nor its combination with hs-cTnT significantly improved diagnostic accuracy as quantified by area under the receiver operating characteristic curve (0.91 vs 0.89 for cTnT alone, p = 0.086; 0.95 vs 0.96 for hs-cTnT, respectively, p = 0.02). Cumulative 360-day mortality/AMI rates were 2.4% in the first, 3.6% in the second, 9.5% in the third, and 18.8% in the fourth quartiles of MR-proANP (p <0.001). MR-proANP (area under the curve 0.76) predicted mortality/AMI independently of and more accurately than cTnT (area under the curve 0.62), hs-cTnT (area under the curve 0.71), and Thrombolysis In Myocardial Infarction risk score (area under the curve 0.72). Net reclassification improvements offered by the additional use of MR-proANP were 0.388 (p <0.001), 0.425 (p <0.001), and 0.217 (p = 0.007), respectively. In conclusion, MR-proANP improves risk prediction for 360-day mortality/AMI but does not seem to help in the early diagnosis of AMI.

Comparison of Midregional Pro–A-Type Natriuretic Peptide and the N-Terminal Pro–B-Type Natriuretic Peptide for Predicting Mortality and Cardiovascular Events

N-terminal pro-B-type natriuretic peptide (NT-proBNP) provides prognostic information on mortality and future cardiovascular events for individuals from the general population. A novel immunoassay was recently developed that measures a midregional fragment of pro-A-type natriuretic peptide (MR-proANP). We compared the capabilities of MR-proANP and NT-proBNP for predicting mortality and cardiovascular events in a population-based study. A total of 7819 patients participated in the population-based Prevention of Renal and Vascular End-stage Disease (PREVEND) study, a prospective observational study. Three clinical end points were studied: all-cause mortality, cardiovascular mortality, and cardiovascular events. After a median follow-up of 10.5 years, we used a Cox proportional hazards model to investigate the relationship between the 2 natriuretic peptides and the clinical end points. The Harrell C statistic and the integrated discrimination improvement (IDI) were used to compare MR-proANP and NT-proBNP. Increased plasma concentrations of both natriuretic peptides were associated with an increased risk of all-cause mortality and cardiovascular events, after adjustment for age, sex, and other cardiovascular risk factors. According to the Harrell C statistic analysis, the models with MR-proANP and NT-proBNP were comparable in predicting all-cause mortality, cardiovascular mortality, and cardiovascular events. In contrast to NT-proBNP, MR-proANP was not independently related to cardiovascular mortality. In all models, the IDI was higher for NT-proBNP than for MR-proANP. MR-proANP was as efficient as NT-proBNP in predicting all-cause mortality, cardiovascular mortality, and cardiovascular events; however, its association with cardiovascular mortality was not independent from other confounders.

Mid-regional pro atrial natriuretic peptide allows the accurate identification of patients with atrial fibrillation of short time of onset: A pilot study

Objectives Atrial fibrillation (AF) is a common arrhythmia; its most prevalent and devastating complication is stroke. A delay of AF onset > 48 h is believed to be clinically significant. Mid-regional pro A-type natriuretic peptide (MR-proANP) could be of interest in the identification of the time from onset of AF to presentation. Design and methods We measured MR-proANP plasma concentration at presentation in consecutive patients in whom onset of AF was determined, without evidence of concomitant acute heart failure. Results Forty-seven patients were included. Patients with an AF onset < 48 h (n = 19) had decreased MR-proANP concentrations versus patients with onset > 48 h (144.0 [129.2–213.7] versus 321.7 [236.4–425.6] pmol/L, p < 0.001); MR-proANP was the only independent variable associated with AF < 48 h according to multivariate analysis. Area under the ROC curve for identify AF onset < 48 h was 0.878 [95%CI 0.778–0.978]. Conclusions MR-proANP concentration may reliably identify the time from onset of AF to presentation.

Relation of natriuretic peptides and midregional proadrenomedullin to cardiac chamber volumes by computed tomography in patients without heart failure: from the ROMICAT Trial.

Stress myocyte biomarkers are used prognostically in patients with cardiovascular disease. We examined associations between amino-terminal pro-B-type natriuretic peptide (NT-proBNP), midregional pro-A-type natriuretic peptide (MR-proANP), and midregional proadrenomedullin (MR-proADM) concentrations and cardiac chamber volumes in chest pain patients without heart failure by use of computed tomography (CT). At the time of 64-slice CT scan, we acquired plasma and serum samples for these biomarkers from 346 patients [mean (SD) age 53 (12) years, 65% men]. Left atrial volume (LAV) and left ventricular volumes at end-diastole (LVEDV) and end-systole (LVESV) were measured and indexed to body surface area (LAVI, LVEDI, LVESI). Concentrations of both natriuretic peptides were correlated with LAV and LAVI (r = 0.19-0.32, all P <or= 0.0005) and MR-proADM with LV volumes and indices (r = -0.14 to -0.21, all P <or= 0.01). NT-proBNP and MR-proANP concentrations were higher in the top quartiles of patients than the lowest quartiles using LAV and LAVI, whereas MR-proADM concentrations were lower in the top quartiles of LV measures. In adjusted analyses, patients had 2- to 4-fold increased risk of LA enlargement for every incremental increase in log(10)NT-proBNP [LAV odds ratio (OR) 2.4, P = 0.03; LAVI OR 4.0, P = 0.003] and 10- to 13-fold increased risk of LA enlargement for every incremental increase in log(10)MR-proANP (LAV OR 10.7, P = 0.009; LAVI OR 13.1, P = 0.004). In patients without heart failure, both NT-proBNP and MR-proANP concentrations are independently associated with LA enlargement, whereas MR-proADM concentrations are correlated with LV volumes. This may partially explain the well-recognized value of natriuretic peptides for use in risk stratification.

Prognostic value of established and novel biomarkers in patients with shortness of breath attending an emergency department

ObjectivesAcute dyspnea is a common cause for emergency department visits. The aim of this study was to evaluate the prognostic value of established and novel biomarkers in patients with acute dyspnea. Design and methodsWe measured 10 biomarkers [B-type natriuretic peptide (BNP), midregional pro-A-type natriuretic peptide (MR-proANP), midregional-proadrenomedullin (MR-proADM), copeptin, C-terminal endothelin-1 precursor fragment (CT-proET-1), soluble ST2 (sST2), chromogranin A (CgA), adiponectin, proguanylin, and prouroguanylin] in 251 consecutive patients with acute dyspnea presenting to the emergency department of a tertiary care hospital. Outcome measure was all-cause mortality at 1 year. ResultsAt baseline decedents (n=62) had significantly higher median plasma concentrations of all 10 biomarkers than survivors (n=189). Applying univariate Cox proportional-hazard regression analyses, all biomarkers were significant outcome predictors displaying risk ratios (RR) from 1.4 to 2.4 (per 1 SD increase in log transformed values). In multivariate Cox proportional-hazard regression analysis, however, only MR-proANP (RR 1.6; 95% CI, 1.1–2.2; p=0.008), sST2 (RR 1.7; 95% CI, 1.3–2.3; p<0.001), and CgA (RR 1.5; 95% CI, 1.2–1.9, p<0.001) were independently associated with 1-year mortality. We provide a possible explanation for the complementary prognostic value of those three biomarkers in our cohort, where coincidence of heart failure and inflammatory pulmonary disease was common and also related to worse outcome. ConclusionsOur evaluation of biomarkers in patients with acute dyspnea suggests that MR-proANP, sST2, and CgA are strong, independent and complementary outcome predictors. MR-proANP is considered a specific marker of cardiac stretch, sST2 might reflect both inflammation and cardiac stretch, and CgA obviously indicates neuroendocrine activation in various diseases.