Mid-regional pro-ANP Research Articles

Interplay between natriuretic peptides and left atrial mechanics and the relation to recurrence of atrial fibrillation following catheter ablation

The relationship between natriuretic peptides and atrial distension is not fully understood. We sought to examine their interrelationship and how they relate to atrial fibrillation (AF) recurrence following catheter ablation. We analyzed patients enrolled in the AMIO-CAT trial (amiodarone vs. placebo for reducing AF recurrence). Echocardiography and natriuretic peptides were assessed at baseline. Natriuretic peptides included mid-regional proANP (MR-proANP) and N-terminal proBNP (NT-proBNP). Atrial distension was assessed by left atrial strain measured by echocardiography. The endpoint was AF recurrence within 6 months after a 3-month blanking period. Logistic regression was used to assess the association between log-transformed natriuretic peptides and AF. Multivariable adjustments were made for age, gender, randomization, and left ventricular ejection fraction. Of 99 patients, 44 developed AF recurrence. No differences in natriuretic peptides nor echocardiography were observed between the outcome groups. In unadjusted analyses, neither MR-proANP nor NT-proBNP were significantly associated with AF recurrence [MR-proANP: OR = 1.06 (0.99–1.14), per 10% increase; NT-proBNP: OR = 1.01 (0.98–1.05), per 10% increase]. These findings were consistent after multivariable adjustments. However, atrial strain significantly modified the association between MR-proANP and AF (p for interaction = 0.009) such that MR-proANP was associated with AF in patients with high atrial strain [OR = 1.24 (1.06–1.46), p = 0.008, per 10% increase] but not in patients with low atrial strain. In patients with high atrial strain, an MR-proANP > 116 pmol/L posed a fivefold higher risk of AF recurrence [HR = 5.38 (2.19–13.22)]. Atrial natriuretic peptide predicts AF recurrence in patients with preserved atrial distension. Assessing atrial strain may assist the interpretation of natriuretic peptides.Graphical abstract

Effect of adrenaline on serum mid-regional pro-atrial natriuretic peptide and central blood volume.

New Findings What is the central question in this study? Atrial natriuretic peptide (ANP) is secreted in response to atrial wall distension and thus allows for evaluation, albeit indirect, of the central blood volume. Adrenaline has chronotropic and inotropic effects. We evaluated whether the chronotropic and inotropic effects of adrenaline were reflected in mid‐regional proANP. What is the main finding and its importance? Central blood volume remained stable with infusion of adrenaline and yet mid‐regional proANP increased. Thus, the chronotropic and inotropic state of the heart or adrenaline directly induces release of ANP variants from the myocytes. Atrial natriuretic peptide (ANP) has vasodilatory, natriuretic and diuretic properties. It is secreted in response to atrial wall distension and thereby provides an indirect evaluation of central blood volume (CBV). Adrenaline has chronotropic and inotropic effects that increase cardiac output. In the present study, we evaluated whether these effects were influenced by an increase in CBV and reflected in mid‐regional proANP (MR‐proANP) concentrations in the circulation, a stable proxy marker of bioactive ANP. Changes in CBV were evaluated by thoracic electrical admittance and haemodynamic variables monitored by pulse‐contour analysis during two intervals with graded infusion of adrenaline. Adrenaline infusion increased heart rate (by 33 ± 18%) and stroke volume (by 6 ± 13%), hence cardiac output (by 42 ± 23%; all P < 0.05). The increase in cardiac output did not result from an increase in CBV, because thoracic electrical admittance remained stable (−3 ± 17%; P = 0.230). Serum MR‐proANP concentrations were increased (by 26 ± 25%; P < 0.001) by adrenaline infusion and remained elevated 60 min postinfusion. We conclude that MR‐proANP in the circulation is affected not only by CBV, but also by increased chronotropy/inotropy of the heart, or that adrenaline directly induces release of ANP variants from the myocytes.

ProANP Metabolism Provides New Insights Into Sacubitril/Valsartan Mode of Action.

Sacubitril/valsartan (S/V) treatment is beneficial in patients with heart failure with reduced ejection fraction (HFrEF), but its mode of action remains elusive, although it involves the increase in ANP (atrial natriuretic peptide). Combining mass spectrometry and enzymatic assay in the plasma of 73 HFrEF patients treated with S/V and controls, we deciphered proANP processing that converts proANP into 4 vasoactive peptides. We found that proANP processing is sequential and involved meprin B, ECE (endothelin-converting enzyme) 1, and ANPEP (aminopeptidase N). This processing is limited in HFrEF patients via the downregulation of proANP production, corin, and meprin B activities by miR-425 and miR1-3p. S/V restored or compensated proANP processing by downregulating miR-425 and miR1-3p, hence increasing levels of proANP-derived bioactive peptides. In contrast, S/V directly and indirectly partially inhibited ECE1 and ANPEP. ECE1 partial inhibition resulted in a lower-than-expected increase in ET1 (endothelin 1), tilting the vasoactive balance toward vasodilation, and possibly hypotension. Furthermore, proANP glycosylation interferes with the midregional proANP assay -a clinical surrogate for proANP production, preventing any pathophysiological interpretation of the results. The analysis of S/V dose escalation with respect to baseline treatments suggests S/V-specific effects. These findings offer mechanistic evidence to the natriuretic peptide -defective state in HFrEF, which is improved by S/V. These data also strongly suggests that S/V increases plasma ANP by multiple mechanisms that involve 2 microRNAs, besides its protection from NEP (neprilysin) cleavage. Altogether, these data provide new insights on HFrEF pathophysiology and the mode of action of S/V.

Atrial natriuretic peptide (ANP) as an endogenous anxiolytic in patients with heart failure? – No replication of previous results showing an inverse association of anxiety and plasma ANP parameters

ObjectiveAn acute anxiolytic-like effect of atrial natriuretic peptide (ANP) has been demonstrated in several preclinical and clinical studies. In a so far singular study (Herrmann-Lingen et al., 2003), patients with congestive heart failure, who pathognomonicly display increased plasma ANP, showed a significant inverse association of anxiety symptoms and pro-ANP levels, giving rise to speculations about ANP as an endogenous anxiolytic. We tried to replicate and extend this preliminary finding. MethodsIn 56 patients suffering from heart failure with reduced left ventricular ejection fraction we measured ANP, mid-regional pro-ANP (MR-proANP) and cyclic guanosine monophosphate (cGMP) as plasma parameters of ANP functioning and characterized anxiety symptoms using the Hospital Anxiety and Depression Scale (HADS) and in addition the State Trait Anxiety Inventory (STAI) for state anxiety. Spearman rank correlation coefficients were calculated. ResultsNone of our plasma ANP parameters showed a significant association with anxiety symptoms as per HADS ratings. The same picture emerged with STAI state anxiety. ANP, MR-proANP and cGMP significantly correlated with each other. ConclusionIn another sample of patients with heart failure we were unable to replicate previous and preliminary cross-sectional findings of low anxiety in subjects with high plasma pro-ANP. Direct measurement of effector hormone ANP and its second messenger as well did not support our hypothesis. Chronically elevated ANP in heart failure might attenuate its potential anxiolytic effects. Longitudinal studies experimentally increasing ANP levels in anxious heart failure patients are needed to test if this approach has clinical psychotropic utility.

Intensive Lifestyle Intervention Increases Plasma Midregional Proatrial Natriuretic Peptide Concentrations in Overweight Children.

BackgroundOverweight adults have low circulating concentrations of ANP (atrial natriuretic peptide) and proANP fragments. We tested the hypothesis that an intensive lifestyle intervention with an intended weight loss would increase plasma concentrations of a proANP fragment in overweight children.Methods and ResultsWe measured MR‐proANP (midregional proANP) concentrations in plasma from overweight children who participated in the OOIS (Odense Overweight Intervention Study). OOIS randomized 115 overweight children (11–13 years, 55% girls) to an intensive day‐camp intervention arm with increased physical activity and healthy diet or to a less intensive standard intervention arm for 6 weeks. We used linear mixed‐effects modeling for repeated measures to estimate the difference in the mean change with 95% CIs in fasting plasma MR‐proANP concentrations between the 2 arms, and we used partial least squares regression analysis to identify candidate mediators. Differences in weight, fitness, and metabolic factors were also analyzed. At baseline, fasting plasma MR‐proANP concentrations were (median [interquartile range]) 35.0 pmol/L (26.8–42.0) in the day‐camp intervention arm and 37.2 pmol/L (31.7–44.7) in standard intervention arm participants, respectively. After 6 weeks intervention, children in the day‐camp intervention arm had increased their MR‐proANP (5.4 pmol/L [0.8–10.0], P=0.022) and their fitness (2.33 mL O2/min per kg [0.52–4.14], P=0.012) and they had deceased their body mass index (−2.12 kg/m2 [−2.59 to −1.65], P<0.001) as compared with children in standard intervention arm. In the partial least squares analysis, decreases in fasting insulin and in estimated insulin resistance were associated with the observed increase in MR‐proANP concentrations.ConclusionsAn intensive lifestyle intervention increases plasma MR‐proANP among overweight children.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT01574352.

Relationship between natriuretic peptides and left atrial mechanics and their relation to recurrence of atrial fibrillation following catheter ablation

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Danish Heart Foundation (grant no.: 09-04-R72-A2408-22545, 10-04-R78-A2929-22588, 11-04-R84-A3230-22650, and 18-R125-A8534-22083), and the Heart Centre Research Committee at Rigshospitalet, Copenhagen. Background The relationship between natriuretic peptides and atrial distension is not completely understood. Furthermore, how they can be used together clinically has not been fully explored. Purpose We sought to examine their interrelationship and how they relate to atrial fibrillation (AF) recurrence following catheter ablation. Methods Patients scheduled for catheter ablation as part of a randomized controlled clinical trial were included. Patients who underwent pre-operative echocardiography and had natriuretic peptide measurements performed, specifically mid-regional proANP (MR-proANP) and N-terminal proBNP (NT-proBNP), were included in this analysis. Echocardiography included assessment of atrial distension by left atrial strain. The outcome was AF recurrence at 6 months after a 3-month blanking period. Logistic regression was performed to assess the association between log-transformed natriuretic peptides and AF. Multivariable adjustments were made for age, gender, randomization, and LVEF. Results Out of 99 patients 44 developed AF. No differences in natriuretic peptides nor echocardiographic measures were observed between the outcome groups. Neither MR-proANP nor NT-proBNP were univariable predictors of AF recurrence (MR-proANP: OR = 1.06 (0.99-1.14), p = 0.09, per 10% increase; NT-proBNP: OR = 1.01 (0.98-1.05), p = 0.38, per 10% increase). These findings were unchanged after multivariable adjustments. However, atrial strain significantly modified the association between MR-proANP and AF (p for interaction = 0.009) such that MR-proANP was a significant predictor of AF in patients with high atrial strain values (OR = 1.24 (1.06-1.46), p = 0.008, per 10% increase) but not in patients with low atrial strain values. Among patients with high atrial strain values, an MR-proANP &amp;gt; 116pmol/L was associated with a 10-fold increased risk of AF (OR = 9.78 (2.21-43.33), p = 0.003). figure. Conclusion Atrial natriuretic peptide predicts AF recurrence in patients with preserved atrial distension. Assessing atrial distension by echocardiography may assist the clinical interpretation of atrial natriuretic peptide concentration. Abstract Figure.

Plasma volume contraction reduces atrial natriuretic peptide after four days of hypobaric hypoxia exposure.

We investigated whether low arterial oxygen tension ([Formula: see text]) or hypoxia-induced plasma volume (PV) contraction, which reduces central blood volume (BV) and atrial distension, explain reduction in circulating atrial natriuretic peptide (ANP) after prolonged hypoxic exposure. Ten healthy males were exposed for 4 days to hypobaric hypoxia corresponding to an altitude of 3,500 m. PV changes were determined by carbon monoxide rebreathing. Venous plasma concentrations of midregional proANP (MR-proANP) were measured before and at the end of the exposure. At the latter time point, the measurement was repeated after 1) restoration of [Formula: see text] by breathing a hyperoxic gas mixture for 30 min and 2) restoration of BV by fluid infusion. Correspondingly, left ventricular end-diastolic volume (LVEDV), left atrial area (LAA), and right atrial area (RAA) were determined by ultrasound before exposure and both before and after fluid infusion at the end of the exposure. Hypoxic exposure reduced MR-proANP from 37.9 ± 18.5 to 24.5 ± 10.3 pmol/L (P = 0.034), LVEDV from 107.4 ± 33.5 to 91.6 ± 26.3 mL (P = 0.005), LAA from 15.8 ± 4.9 to 13.3 ± 4.2 cm2 (P = 0.007), and RAA from 16.2 ± 3.1 to 14.3 ± 3.5 cm2 (P = 0.001). Hyperoxic breathing did not affect MR-proANP (24.8 ± 12.3 pmol/L, P = 0.890). Conversely, fluid infusion restored LVEDV, LAA, and RAA to near-baseline values (108.0 ± 29.3 mL, 17.2 ± 5.7 cm2, and 17.2 ± 3.1 cm2, respectively, P > 0.05 vs. baseline) and increased MR-proANP to 29.5 ± 13.3 pmol/L (P = 0.010 vs. preinfusion and P = 0.182 vs. baseline). These findings support that ANP reduction in hypoxia is at least partially attributed to plasma volume contraction, whereas reduced [Formula: see text] does not seem to contribute.

Association between natriuretic peptides and left atrial structural and functional properties in atrial fibrillation following catheter ablation

Abstract Background Atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP) are acutely released from the atrial myocytes upon increased mechanical distension of the atria. The relationship between imaging measures of left atrial (LA) structure and function and natriuretic peptides following catheter ablation (CA) have not been clearly delineated. Purpose To characterize the relationship between LA structure and function and natriuretic peptides. Methods We performed an echocardiographic substudy of a randomized trial of AF patients scheduled for CA. Echocardiographic measurements included: LA volume at end-systole (LAVi), at end-diastole (LAEDVi), emptying fraction (LAEF), LA reservoir strain (LAs), and global longitudinal strain (GLS). Patients were stratified by tertiles of mid-regional proANP (MR-proANP) concentrations in circulation (&amp;lt;92 pmol/l, 92–146 pmol/l, &amp;gt;146 pmol/l), and NT-proBNP (&amp;lt;10pmol/l, 10–38 pmol/l, &amp;gt;38 pmol/l). Linear regressions were performed to compare baseline echocardiographic measures to natriuretic peptide concentrations at baseline, 1 month, 3 months and 6 months of follow-up. MR-proANP and NT-proBNP were logarithm transformed in these analyses. Multivariable adjustments were made for: age, gender, AF subtype, AF burden, rhythm during echocardiogram, rhythm at study visit for blood sampling, time known with AF, beta-blocker use, and CHA-2DS2-VASc score. Results We included 101 patients with AF. The mean age was 58 years, 82% were men, 46% had persistent AF. Increasing tertiles of MR-proANP at baseline were associated with abnormal LA size and function (3rd vs 1st tertile: LAVi: 42mL/m2 vs 32mL/m2; LAEDVi: 31mL/m2 vs 20mL/m2; LAEF: 38% vs 26%; LAs: 27% vs 19%; GLS: −18% vs −14%) whereas both LA and left ventricular measures were associated with increasing NT-proBNP concentrations at baseline. After multivariable adjustments, only LA volumes and LAEF remained significantly associated with MR-proANP, whereas only LA volumes and GLS remained significantly associated with NT-proBNP. At follow-up, impaired LA function associated with persistently elevated concentrations, which was not the case for LAVi (figure). Conclusion MR-proANP reflects LA dysfunction better than NT-proBNP. Measures of LA function rather than LAVi associates with persistently elevated natriuretic peptide concentrationsw, which may indicate that functional measures are more closely associated with evidence of LA myocardial stretch than LAVi. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): The Danish Heart Foundation

Cardiovascular biomarkers and echocardiographic findings at rest and during graded hypovolemic stress in women with recurrent vasovagal syncope.

Vasovagal reflex is the most common type of syncope but its etiology is not fully elucidated. Venous return and cardiac output are key in hemodynamic control. The aim of the study was to assess cardiovascular biomarkers and echocardiographic measures at rest and during hypovolemia in women with and without a history of vasovagal syncope. Fourteen women (aged 18-30) suffering from recurrent vasovagal syncope and 15 age-matched healthy women were included. Graded lower body negative pressure (LBNP) was used to create central hypovolemic stress until signs of presyncope occurred. Echocardiography was applied at rest and throughout LBNP. Cardiovascular biomarkers: copeptin, mid-regional proadrenomedullin, mid-regional pro-ANP, C-terminal proendothelin-1, and plasma norepinephrine were measured both at rest and throughout graded hypovolemia to presyncope. Women prone to vasovagal syncope presented with a narrower right ventricle (RV) (29 ± 1 vs 32 ± 1 mm, P < .05), smaller left atrium (36 ± 2 vs 47 ± 3 cm3 , P < .01) and lower cardiac output at rest (3.1 ± 0.2 vs 3.7 ± 0.2 L/min, P < .05) and during graded hypovolemia (P < .05). Copeptin was elevated at rest (4.3 ± 0.8 vs 2.5 ± 0.2 pmol/L, P < .05) and increased more in women with vasovagal syncope during progression of LBNP (P < .01). At rest, lower C-terminal proendothelin-1 (35 ± 5 vs 46 ± 2 pmol/L, P < .05) and higher norepinephrine levels (1.1 ± 0.1 vs 0.8 ± 0.1 nmol/L, P < .01) were seen in women with vasovagal syncope. Women prone to vasovagal syncope demonstrate reduced cardiac preload, lower cardiac output, as well as increased release of vasopressin in rest and during hypovolemic challenge. The results emphasize the importance of venous return and cardiac output in the pathogenesis of vasovagal syncope.

P5296A healthier lifestyle increases circulating pro-atrial natriuretic peptide concentrations in overweight children

Abstract Background Higher concentrations of atrial natriuretic peptides (ANP) are associated with a poor prognosis among patients with cardiovascular disease (CVD). Counter-intuitively, higher ANP concentrations in healthy populations are associated with an ideal American Heart Association Cardiovascular Health score, which includes high level of physical activity, normal body mass index (BMI), optimal levels of lipids, blood pressure (BP) and glucose. Along this line, overweight individuals have lower than expected ANP concentrations, and it has been proposed that this natriuretic handicap could play a role in overweight related disorders. The mechanism behind the natriuretic handicap is still not clear, but presence of insulin resistance with hyperinsulinemia has been implicated. Purpose We investigated whether an intensive lifestyle intervention with an intended weight loss, including an increased level of physical activity and a healthy diet, could increase plasma concentrations of mid-regional pro-ANP (MR-proANP), a stable marker of ANP secretion, in overweight children. In a mechanistic perspective, we investigated metabolic changes associated with increases in MR-proANP concentrations. Methods This study is an extension of the Odense Overweight Intervention Study (OOIS) which included 99 overweight children (11–13 years, 55% girls). The children were randomised to a Day Camp Intervention Arm (DCIA) and a Standard Intervention Arm (SIA) for 6 weeks. DCIA included 3 hours physical activity per day and a healthy diet according to Danish recommendations. SIA included 1 weekly fun-based physical activity session and 1 lifestyle education session. OOIS included measurements of anthropometry, body composition, lipids, BP, glucose and insulin. Linear regression analyses, expressed as unstandardized regression coefficients, were used to examine between-group differences in MR-proANP concentrations and to examine the associations between changes in MR-proANP and variables of interest. As we wanted to study physiological relationships, we pooled both arms to one group to increase power in the latter. Results At week 6, children in DCIA had lower BMI (−2.4kg/m2) and lower total body fat (−6.5%) but higher level of fitness (4.1 ml/O2/min/kg) compared to children in SIA. From baseline to week 6 DCIA increased MR-proANP concentrations (B (95% CI): 5.7 (1.2 to 10.2) pmol/l, P=0.014) more than SIA. Of the variables studied, we found an inverse association between fall in insulin and increase in MR-proANP concentrations (B (95% CI): −0.52 (−1.02 to −0.02) pmol/l/mIU/ml, P=0.041). None of the other associations between changes in variables reached statistical significance. Conclusion A healthier lifestyle, based on a healthy diet and a higher level of physical activity, increases MR-proANP among overweight children. In a mechanistic perspective, improved insulin sensitivity with lower insulin appears to be a factor that leads to higher MR-proANP. Acknowledgement/Funding Trygfonden (Grant number: 7-11-0700)

Plasma proatrial natriuretic peptide associates with lipid oxidation during exercise and cardiorespiratory fitness in healthy young adults

Atrial natriuretic peptide (ANP) is known for its natriuretic, diuretic, and vasodilatory properties. However, ANP also has metabolic effects stimulating lipolysis and lipid oxidation. Overweight individuals have decreased circulating ANP concentrations. It has been proposed that this potential ANP deficiency could have biological consequences in overweight-related disorders, including decreased lipolysis and lipid oxidation. The purpose of this study was to investigate the relationships between ANP, exercise-induced lipid oxidation, and cardiorespiratory fitness in 562 20-28-year-old healthy community-based women and men. We measured fasting plasma concentrations of mid-regional proANP (MR-proANP), a stable marker of ANP secretion, the respiratory exchange ratio (RER) during sub-maximal exercise, which provides an estimate of lipid oxidation, and maximal oxygen consumption (VO2-max) at the end of a maximal exercise test, which is a measure of cardiorespiratory fitness. An increase of 10 pmol/L in fasting plasma MR-proANP concentrations was related to an increase in relative VO2-max of 0.78 (95% CI 0.36–1.09) ml O2/min/kg and a decrease in RER of −0.0094 (−0.014 to −0.0045) in age- and sex-adjusted analysis (P < 0.001). Further adjusted for body mass index, a rise of 10 pmol/L in fasting plasma MR-proANP concentrations was associated with a rise in relative VO2-max of 0.60 (0.28–0.92) ml O2/min/kg and a fall in RER of −0.0096 (−0.015 to −0.0048) (P < 0.001). Fasting plasma MR-proANP concentrations associate with lipid oxidation during exercise and cardiorespiratory fitness in healthy young adults. The data support the existence of important connections between the endocrine heart, hemodynamics, and metabolism.

Abstract 147: Copeptin and Mid-Regional Pro-ANP in Women With Suspected or Confirmed Preeclampsia: Comparison With the sFlt-1/PlGF Ratio

Both arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) are believed to contribute to the pathogenesis of preeclampsia (PE), although current evidence is inconclusive. Here we studied AVP and ANP as biomarkers (measured as their surrogates copeptin and mid-regional pro-ANP, MR-proANP, respectively) for the prediction of PE and adverse pregnancy outcome, making use of a large prospective cohort study in 526 women with suspected or confirmed preeclampsia (age 18 - 48) originally aimed to evaluate the use of sFlt-1/PlGF ratio for the prediction of PE. Women with confirmed PE (n = 134) displayed higher copeptin (median 6 [range 1 - 61] vs. 4 [1 - 42] pM; P&lt;0.01) and MR-proANP (52 [2 - 342] vs. 31 [2 - 298] pM; P&lt;0.001) levels than 250 women with suspected PE. Yet, when subdividing the women according to sFlt-1/PlGF ratio (≥85 versus &lt;85), no differences in copeptin levels were observed (5 vs. 5 pM), while MR-proANP levels remained elevated in women with a sFlt-1/PlGF ratio ≥85 (64 vs. 32 pM; P&lt;0.0001). In accordance with this observation, copeptin correlated only marginally with sFlt-1 (r = 0.17), and not with PlGF, while MR-proANP correlated strongly with both, sFlt-1 (r= 0.30) and PlGF (r=-0.29). To discriminate maternal complications on top of traditional predictors (gestational age, parity, diastolic blood pressure and proteinuria), the sFlt-1/PlGF ratio displayed a higher C-index than copeptin and MR-proANP (0.74, 0.63 and 0.68, respectively, vs. 0.62 for the traditional predictors only), and the same was true for the discrimination of fetal/neonatal complications (C-index = 0.81, 0.76 and 0.78 vs. 0.76). Finally, multiple regression analysis revealed that both copeptin (P=0.015) and MR-proANP (P=0.024) were independent determinants of proteinuria but not blood pressure. In conclusion, both copeptin and MR-proANP levels are elevated in women with PE but have limited value to predict pregnancy complications when compared with the sFlt-1/PlGF ratio. Interestingly, copeptin (but not MR-proANP) effects appear to be largely independent from sFlt-1/PlGF, and predominantly reflect the renal phenotype in this condition.

ProANP and proBNP in plasma as biomarkers of heart failure.

Aim: To compare the measurement of proANP and proBNP in plasma for the diagnosis of heart failure. Methods: In the PubMed search, a process of combining subject headings and terms regarding comparison of natriuretic peptides (proANP and proBNP) was performed. Results: 21 abstracts from research articles were screened with 14 articles assessed for eligibility. 11 papers were included for final analysis. We report comparable diagnostic accuracies of N-terminal proBNP and mid-regional proANP. Older methods for proANP measurement seem obsolete. Conclusion: Similar diagnostic performance of proANP and proBNP measurement for the diagnosis of heart failure was identified. Consequently, mid-regional proANP can be used when considering a diagnosis of heart failure.

Heart Failure Association of the European Society of Cardiology practical guidance on the use of natriuretic peptide concentrations.

Natriuretic peptide [NP; B-type NP (BNP), N-terminal proBNP (NT-proBNP), and midregional proANP (MR-proANP)] concentrations are quantitative plasma biomarkers for the presence and severity of haemodynamic cardiac stress and heart failure (HF). End-diastolic wall stress, intracardiac filling pressures, and intracardiac volumes seem to be the dominant triggers. This paper details the most important indications for NPs and highlights 11 key principles underlying their clinical use shown below. NPs should always be used in conjunction with all other clinical information. NPs are reasonable surrogates for intracardiac volumes and filling pressures. NPs should be measured in all patients presenting with symptoms suggestive of HF such as dyspnoea and/or fatigue, as their use facilitates the early diagnosis and risk stratification of HF. NPs have very high diagnostic accuracy in discriminating HF from other causes of dyspnoea: the higher the NP, the higher the likelihood that dyspnoea is caused by HF. Optimal NP cut-off concentrations for the diagnosis of acute HF (very high filling pressures) in patients presenting to the emergency department with acute dyspnoea are higher compared with those used in the diagnosis of chronic HF in patients with dyspnoea on exertion (mild increase in filling pressures at rest). Obese patients have lower NP concentrations, mandating the use of lower cut-off concentrations (about 50% lower). In stable HF patients, but also in patients with other cardiac disorders such as myocardial infarction, valvular heart disease, atrial fibrillation or pulmonary embolism, NP concentrations have high prognostic accuracy for death and HF hospitalization. Screening with NPs for the early detection of relevant cardiac disease including left ventricular systolic dysfunction in patients with cardiovascular risk factors may help to identify patients at increased risk, therefore allowing targeted preventive measures to prevent HF. BNP, NT-proBNP and MR-proANP have comparable diagnostic and prognostic accuracy. In patients with shock, NPs cannot be used to identify cause (e.g. cardiogenic vs. septic shock), but remain prognostic. NPs cannot identify the underlying cause of HF and, therefore, if elevated, must always be used in conjunction with cardiac imaging.

Effect of Neprilysin Inhibition on VariousNatriuretic Peptide Assays.

With sacubitril/valsartan treatment, B-type natriuretic peptide (BNP) concentrations increase; it remains unclear whether change in BNP concentrations is similar across all assays for its measurement. Effects of sacubitril/valsartan on atrial natriuretic peptide (ANP) concentrations in patients are unknown. Lastly, the impact of neprilysin inhibition on mid-regional pro-ANP (MR-proANP), N-terminal pro-BNP (NT-proBNP), proBNP1-108, or C-type natriuretic peptide (CNP) is not well understood. This study sought to examine the effects of sacubitril/valsartan on results from different natriuretic peptide assays. Twenty-three consecutive stable patients with heart failure and reduced ejection fraction were initiated and titrated on sacubitril/valsartan. Change in ANP, MR-proANP, BNP (using 5 assays), NT-proBNP (3 assays), proBNP1-108, and CNP were measured over 3 visits. Average time to 3 follow-up visits was 22, 46, and 84days. ANP rapidly and substantially increased with initiation and titration of sacubitril/valsartan, more than doubling by the first follow-up visit (+105.8%). Magnitude of ANP increase was greatest in those with concentrations above the median at baseline (+188%) compared with those with lower baseline concentrations (+44%); ANP increases were sustained. Treatment with sacubitril/valsartan led to inconsistent changes in BNP, which varied across methods assessed. Concentrations of MR-proANP, NT-proBNP, and proBNP1-108 variably declined after treatment; whereas CNP concentrations showed no consistent change. Initiation and titration of sacubitril/valsartan led to variable changes in concentrations of multiple natriuretic peptides. These results provide important insights into the effects of sacubitril/valsartan treatment on individual patient results, and further suggest the benefit of neprilysin inhibition may be partially mediated by increased ANP concentrations.

Potential and Limitations of Atrial Natriuretic Peptide as Biomarker in Pediatric Heart Failure-A Comparative Review.

Although B-type Natriuretic Peptide (BNP), N-terminal-proBNP (NT-proBNP), and mid-regional-proANP (MR-proANP) are included in current guidelines on heart failure in adults, no guideline considering these biomarkers in pediatric heart failure is available. A new drug class of neprilysin inhibitors as fixed-dose combination (Sacubitril/valsartan) has been introduced and is currently being investigated in children suffering from heart failure. Atrial Natriuretic Peptide (ANP) is discussed as a more useful alternative to BNP because it may grants better insights into the effects of this treatment. Thus, this review aimed to provide an overview of the current knowledge concerning ANP in pediatric heart failure and compares its suitability regarding diagnosis and prognosis of heart failure. A literature search using PubMed resulted in 147 publications of which 22 studies were classified as relevant. The review presents available ANP, NT-proANP, and MR-proANP level data in children (0–18 years). Summarizing, ANP shows only minor differences as marker for diagnosing and monitoring pediatric heart failure if compared to BNP. Due to its fast release, ANP offers the advantage of displaying rapid changes during therapy or operation. ANP is -like the other natriuretic peptides- influenced by age, presenting with the highest levels in very young infants. ANP also correlates with atrial pressure and volume overload in children. In addition, ANP determination in saliva appears to be a promising alternative to blood sampling. Similarly to NT-proBNP, NT-proANP, and MR-proANP offer better stability but only few data has been published in children and thus their potential is only presumable so far.

Prognostic and diagnostic significance of mid-regional pro-atrial natriuretic peptide in acute exacerbation of chronic obstructive pulmonary disease and acute heart failure: data from the ACE 2 Study

Purpose: To compare the diagnostic and prognostic value of mid-regional pro-ANP (MR-proANP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with acute dyspnea.Methods: MR-proANP and NT-proBNP were measured with commercial immunoassays at hospital admission (n = 313), on day 2 (n = 234), and before discharge (n = 91) and compared for diagnosing acute heart failure (HF; n = 143) and to predict mortality among patients with acute HF and acute exacerbation of chronic obstructive pulmonary disease (AECOPD; n = 84) separately.Results: The correlation coefficient between MR-proANP and NT-proBNP was 0.89 (p < 0.001) and the receiver-operating area under the curve (AUC) was 0.85 (95% CI 0.81–0.89) for MR-proANP and 0.86 (0.82–0.90) for NT-proBNP to diagnose acute HF. During a median follow-up of 816 days, mortality rates were 46% in acute HF patients and 42% in AECOPD patients. After adjustment for other risk variables by multivariate Cox regression analysis, MR-proANP and NT-proBNP concentrations were associated with mortality in patients with acute HF, but only MR-proANP were associated with mortality among patients with AECOPD: hazard ratio (lnMR-proANP) 1.98 (95% CI 1.17–3.34).Conclusion: MR-proANP and NT-proBNP concentrations provide similar diagnostic and prognostic information in patients with acute HF. In contrast to NT-proBNP, MR-proANP measurements also provided independent prognostic information in AECOPD patients.

Genome-Wide Association Study Implicates Atrial Natriuretic Peptide Rather Than B-Type Natriuretic Peptide in the Regulation of Blood Pressure in the General Population.

Cardiomyocytes secrete atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in response to mechanical stretching, making them useful clinical biomarkers of cardiac stress. Both human and animal studies indicate a role for ANP as a regulator of blood pressure with conflicting results for BNP. We used genome-wide association analysis (n=6296) to study the effects of genetic variants on circulating natriuretic peptide concentrations and compared the impact of natriuretic peptide-associated genetic variants on blood pressure (n=27 059). Eight independent genetic variants in 2 known (NPPA-NPPB and POC1B-GALNT4) and 1 novel locus (PPP3CC) associated with midregional proANP (MR-proANP), BNP, aminoterminal proBNP (NT-proBNP), or BNP:NT-proBNP ratio. The NPPA-NPPB locus containing the adjacent genes encoding ANP and BNP harbored 4 independent cis variants with effects specific to either midregional proANP or BNP and a rare missense single nucleotide polymorphism in NT-proBNP seriously altering its measurement. Variants near the calcineurin catalytic subunit gamma gene PPP3CC and the polypeptide N-acetylgalactosaminyltransferase 4 gene GALNT4 associated with BNP:NT-proBNP ratio but not with BNP or midregional proANP, suggesting effects on the post-translational regulation of proBNP. Out of the 8 individual variants, only those correlated with midregional proANP had a statistically significant albeit weak impact on blood pressure. The combined effect of these 3 single nucleotide polymorphisms also associated with hypertension risk (P=8.2×10-4). Common genetic differences affecting the circulating concentration of ANP associated with blood pressure, whereas those affecting BNP did not, highlighting the blood pressure-lowering effect of ANP in the general population.

ANP system activity predicts variability of fat mass reduction and insulin sensitivity during weight loss

IntroductionIn weight loss trials, a considerable inter-individual variability in reduction of fat mass and changes of insulin resistance is observed, even under standardized study conditions. The underlying mechanisms are not well understood. Given the metabolic properties of the atrial natriuretic peptide (ANP) system, we hypothesized that ANP signaling might be involved in this phenomenon by changes of ANP secretion or receptor balance. Therefore, we investigated the impact of systemic, adipose and myocellular ANP system on metabolic and anthropometric improvements during weight loss. MethodsWe comprehensively investigated 143 subjects (31 male, 112 female) before and after a 3 month-standardized weight loss program. The time course of BMI, fat mass, insulin sensitivity, circulating mid-regional proANP (MR-proANP) levels as well as adipose and myocellular natriuretic receptor A (NPR-A) and C (NPR-C) mRNA expression were investigated. ResultsBMI decreased by −12.6±3.7%. This was accompanied by a remarkable decrease of adipose NPR-C expression (1005.0±488.4 vs. 556.7±465.6; p<0.001) as well as a tendency towards increased adipose NPR-A expression (4644.7±946.8 vs. 4877.6±869.8; p=0.051). Weight loss induced changes in NPR-C (ΔNPR-C) was linked to relative reduction of total fat mass (ΔFM) (r=0.281; p<0.05), reduction of BMI (r=0.277; p<0.01), and increase of free fatty acids (ΔFFA) (r=−0.258; p<0.05). Basal NPR-C expression and weight loss induced ΔNPR-C independently explained 22.7% of ΔFM. In addition, ΔMR-proANP was independently associated with improvement of insulin sensitivity (standardized ß=0.246, p<0.01). DiscussionANP receptor expression predicted the degree of weight loss induced fat mass reduction. Our comprehensive human data support that peripheral ANP signalling is involved in control of adipose tissue plasticity and function during weight loss. (Funded by the Deutsche Forschungsgemeinschaft (KFO281/2), the Berlin Institute of Health (BIH) and the German Centre for Cardiovascular Research (DZHK/BMBF); ClinicalTrials.gov number: NCT00850629).

Cardiac natriuretic peptides in plasma increase after dietary induced weight loss in obesity.

BackgroundCardiac natriuretic peptides are established biomarkers in heart disease, but are also affected by body mass index (BMI). The purpose of the present study was to examine the impact of weight loss and changes in body composition following dietary intervention on plasma concentrations of the prohormones to A- and B-type natriuretic peptides (proANP and proBNP) and adrenomedullin (proADM).ResultsA total of 52 healthy obese subjects, 47 women and 5 men (BMI 36.5 ± 5.6 kg/m2) were randomised to either an intensive weight reduction programme using a combination of very low calorie diet (810 kcal/day) and conventional hypo-energetic diet (1200 kcal/day) for 52 weeks, or to a control group that was offered diet-related counselling. N-terminal proBNP (NT-proBNP), mid-regional proANP (MR-proANP) and proADM (MR-proADM) and body composition using dual-energy x-ray absorptiometry (DEXA) scanning were determined at baseline and after 52 weeks. Comparisons between groups were analysed using t-tests. Changes from the baseline within the groups were analysed with paired tests. Changes in the variables, delta (∆), were calculated as 52 weeks minus the baseline.In the intervention group, BMI decreased by almost 20% (31.6 ± 6.2 vs. 37.1 ± 6.1 kg/m2; P <0.001) with a loss of body fat of 23.5 ± 15.5% (P < 0.001). Plasma concentrations of NT-proBNP and MR-proANP increased (from 55 ± 31 to 97 ± 55 pg/ml; P < 0.001, and from 59 ± 21 to 74 ± 26 pmol/L; P < 0.001), whereas MR-proADM decreased (from 573 ± 153 to 534 ± 173 pmol/L; P <0.001). Changes (Δ) in MR-proANP correlated with Δfat mass (r = −0.359; P = 0.011) and Δglucose (r = −0.495; P <0.001), while increases in NT-proBNP were primarily associated with reduced plasma glucose (r = −0.462; P <0.001). A modest but significant weight loss of 6% (P < 0.001) was found in the control group with no changes in plasma concentrations of NT-proBNP or MR-proANP, and a minor change in MR-proADM.ConclusionsPlasma NT-proBNP and MR-proANP concentrations increase and MR-proADM concentration decreases during weight loss, underlining the dynamic impact of BMI, body composition and glucose metabolism on these cardiovascular biomarkers.