proANP Concentrations Research Articles

Incomplete recovery of mechanical and endocrine left atrial functions one month after electrical cardioversion for persistent atrial fibrillation: a pilot study

BackgroundRestoration of the mechanical and endocrine functions of the left atrium remains controversial after electrical cardioversion treatment for persistent atrial fibrillation. The objective of the prospective study was to describe the recovery of the endocrine and mechanical functions of the left atrium.MethodsEvaluation of left atrium recovery after electrical cardioversion by the new speckle-tracking echocardiography technique and proANP measurement.ResultsTwenty patients suffering from persistent atrial fibrillation with no alteration of left ventricular ejection fraction were prospectively evaluated at baseline and then one month later by echocardiography, measuring left atrial volume and left atrial deformation (MPALS), as well as the proANP and BNP concentrations. One month after cardioversion 10 patients remained in sinus rhythm and 10 showed recurrent atrial fibrillation. No significant differences between the two groups in terms of clinical, echocardiographic and endocrine parameters were observed at baseline evaluation. We observed a significant reduction of left atrial volume only in the sinus group, whereas restoration of the left atrial deformation was only partial (18%) in that group. By contrast, we registered no significant changes in ANP concentration at one month in either the sinus or the atrial fibrillation groups.ConclusionThese results suggest that restoration of left atrium mechanical function is only partial one month after treatment of persistent atrial fibrillation by electrical cardioversion, whereas a significant reduction of left atrial volume was noted, explaining the remaining high level of ANP in the sinus group.

Breed Differences in Natriuretic Peptides in Healthy Dogs

BackgroundMeasurement of plasma concentration of natriuretic peptides (NPs) is suggested to be of value in diagnosis of cardiac disease in dogs, but many factors other than cardiac status may influence their concentrations. Dog breed potentially is 1 such factor.ObjectiveTo investigate breed variation in plasma concentrations of pro‐atrial natriuretic peptide 31‐67 (proANP 31‐67) and N‐terminal B‐type natriuretic peptide (NT‐proBNP) in healthy dogs.Animals535 healthy, privately owned dogs of 9 breeds were examined at 5 centers as part of the European Union (EU) LUPA project.MethodsAbsence of cardiovascular disease or other clinically relevant organ‐related or systemic disease was ensured by thorough clinical investigation. Plasma concentrations of proANP 31‐67 and NT‐proBNP were measured by commercially available ELISA assays.ResultsOverall significant breed differences were found in proANP 31‐67 (P < .0001) and NT‐proBNP (P < .0001) concentrations. Pair‐wise comparisons between breeds differed in approximately 50% of comparisons for proANP 31‐67 as well as NT‐proBNP concentrations, both when including all centers and within each center. Interquartile range was large for many breeds, especially for NT‐proBNP. Among included breeds, Labrador Retrievers and Newfoundlands had highest median NT‐proBNP concentrations with concentrations 3 times as high as those of Dachshunds. German Shepherds and Cavalier King Charles Spaniels had the highest median proANP 31‐67 concentrations, twice the median concentration in Doberman Pinschers.Conclusions and Clinical ImportanceConsiderable interbreed variation in plasma NP concentrations was found in healthy dogs. Intrabreed variation was large in several breeds, especially for NT‐proBNP. Additional studies are needed to establish breed‐specific reference ranges.

Glucagon-like peptide-1: effect on pro-atrial natriuretic peptide in healthy males

The antihypertensive actions of glucagon-like peptide-1 (GLP1) receptor agonists have been linked to the release of atrial natriuretic peptide (ANP) in mice. Whether a GLP1–ANP axis exists in humans is unknown. In this study, we examined 12 healthy young males in a randomized, controlled, double-blinded, single-day, cross-over study to evaluate the effects of a 2-h native GLP1 infusion. Plasma proANP concentrations were measured by an automated mid-region-directed proANP immunoassay and N-terminal pro B-type natriuretic peptide (BNP) on Roche Modular E170. Urine was collected for measurements of sodium excretion. Although GLP1 infusion increased the urinary sodium excretion markedly, there were no significant changes in either proANP or proBNP concentrations. When GLP1 infusion was stopped, sodium excretion declined rapidly. As proANP concentration reflects ANP secretion, our data could not confirm the existence of a GLP1–ANP axis in humans. Especially, the natriuretic effects of GLP1 seem unlikely to be mediated exclusively via ANP.

Cardiac C-type natriuretic peptide gene expression and plasma concentrations in neonatal piglets

BackgroundC-type natriuretic peptide (CNP) is a member of the natriuretic peptide family. Cardiac ANP and BNP expressions are firmly established, whereas CNP expression in the mammalian heart remains controversial. In the present report, we used a porcine model of the neonatal period with high expressions of cardiac ANP and BNP in order to elucidate the cardiac CNP expression profile. MethodsPlasma and cardiac tissue were obtained from newborn piglets during the first 72h of life. The chamber-specific CNP mRNA contents were quantified by real-time PCR analysis. The proCNP concentrations in plasma and cardiac tissue extracts were quantified by a porcine-specific radioimmunoassay. ResultsCardiac CNP mRNA contents (n=24) were low compared to sites of known expression, where porcine seminal vesicle CNP mRNA contents were 200-fold higher. In addition, plasma proCNP concentrations in the newborn piglets (n=44) were exceedingly low compared to proANP concentrations (5.3pmol/L (3.2–8.6) vs. 3438pmol/L (2790–5418), p<0.0001). The proCNP concentrations in atrial tissue extracts were barely detectable (≤0.06pmol/g) (n=2) compared to ventricular proANP (130pmol/g (101–159)) and atrial proANP (12,303pmol/g (10,623–15,412)). ConclusionOur data show that the heart is not a major source of circulating proCNP in neonatal piglets.

ProANP plasma measurement predicts all-cause mortality in acutely hospitalised patients: a cohort study

ImportanceThe association of natriuretic peptide measurement with all-cause mortality in a broad selection of acutely admitted patients has not yet been examined.ObjectiveTo test the risk association between pro-atrial natriuretic peptide...

Plasma proANP and SDMA and microRNAs are associated with chronic mitral regurgitation in a pig model

ObjectiveNon-ischemic mitral regurgitation (MR) is primarily caused by myxomatous mitral valve (MV) disease leading to adaptive remodeling, enlargement, and dysfunction of the left ventricle. The aim of this study was to examine the regulation of plasma markers and several cardiac key genes in a novel porcine model of non-ischemic MR.Methods and resultsTwenty-eight production pigs (Sus scrofa) were randomized to experimental MR or sham surgery controls. MR was induced by external suture(s) through the posterior MV leaflet and quantified using echocardiography. The experimental group was subdivided into mild MR (mMR, MR=20–50%, n=10) and moderate/severe MR (sMR, MR >50%, n=6) and compared with controls (CON, MR ≤10%, n=12). Eight weeks postoperatively, follow-up examinations were performed followed by killing. Circulating concentrations of pro-atrial natriuretic peptide (proANP), l-arginine, asymmetric dimethylarginine, and symmetric dimethylarginine (SDMA) were measured. MV, anterior papillary muscle, and left ventricular free wall tissues were collected to quantify mRNA expression of eNOS (NOS3), iNOS (NOS2), MMP9, MMP14, ANP (NPPA), BNP (NPPB), and TGFB1, 2, and 3 and five microRNAs by quantitative real-time PCR. Pigs with sMR displayed markedly increased plasma proANP and SDMA concentrations compared with both controls and mMR (P<0.05). The expression of all genes examined differed significantly between the three localizations in the heart. miR-21 and miR-133a were differently expressed among the experimental groups (P<0.05).ConclusionsPlasma proANP and SDMA levels and tissue expression of miR-21 and miR-133a are associated with severity of chronic MR in an experimental porcine model.

The diagnostic relevance of NT‐proBNP and proANP 31–67 measurements in staging of myxomatous mitral valve disease in dogs

There is no agreement in current publications regarding the reliability of serum concentrations of natriuretic peptides (NPs) to detect dogs with subclinical myxomatous mitral valve disease (MMVD) and to differentiate between asymptomatic stages. We sought to compare N-terminal pro-B-type natriuretic peptide (NT-proBNP) and pro-atrial natriuretic peptide 31-67 (proANP) concentrations between various stages of canine MMVD and to investigate the influence of age, weight, and sex. In this prospective study, dogs were classified in different disease stages using the modified Canine Heart failure International Expert Forum (CHIEF) system. Serum NP concentrations were compared between groups. A total of 559 samples from 116 healthy dogs and 236 dogs with MMVD were analyzed. Using cut-off values (1207 pmol/L for NT-proBNP, 1578 fmol/mL for proANP), dogs with MMVD with and without congestive heart failure (CHF) could be differentiated with a sensitivity of 83% for both and specificities of 85% and 86%, respectively. Dogs staged in CHIEF B1 and B2 could not be distinguished based on NP concentrations due to wide variation within the groups. Intact females (means 598 pmol/L and 1036 fmol/mL, respectively) had significantly higher values of both NPs than intact males (315 pmol/L and 836 fmol/mL). NPs in canine MMVD are useful to discriminate between asymptomatic dogs and dogs with CHF. Due to a large overlap of NP-concentrations between the groups, NPs do not seem to be useful to differentiate between dogs in stages B1 and B2. Interpretation of NT-proBNP and proANP values should include consideration of sex-specific differences.

Cardiac Natriuretic Peptide Gene Expression and Plasma Concentrations During the First 72 Hours of Life in Piglets

Plasma measurement of cardiac natriuretic peptides constitutes promising markers of congenital heart disease. However, concentrations change rapidly and dramatically during the first days after delivery even in healthy neonates, which complicates clinical interpretation. It is unknown whether these changes in plasma concentrations are explained by corresponding changes in the cardiac gene expression. We quantified the chamber-specific mRNA levels of ANP (A-type natriuretic peptide) and BNP (B-type natriuretic peptide) and plasma pro-ANP and BNP-32 concentrations in healthy piglets during the first 72 hours of life (from 2 litters, n = 44). Chamber-specific ANP and BNP mRNA levels reflected hemodynamic neonate changes at birth but did not correlate with circulating natriuretic peptide concentrations. However, plasma pro-ANP and creatinine concentrations were closely correlated (P < .0001; r = 0.73). Plasma pro-ANP levels were highest on the day of delivery (5580 pmol/L [4320-6786] decreasing to 2484 pmol/L [1602-2898] after 72 hours, P < .0001). During the 72 hours, gel chromatography suggested that the translational products in circulation and in atrial tissue were immature, ie, unprocessed pro-ANP. In contrast to pro-ANP, BNP-32 plasma concentrations were low at delivery and peaked after 48 hours (12 [10.5-20.6] vs. 88.8 [71.7-101.4] pmol/L, P < .0001). To conclude, ANP and BNP gene expression differs considerably between cardiac chambers in the first 72 hours of life in healthy piglets, resembling the transition from fetal to neonate circulation. However, the cardiac gene expression does not explain plasma concentrations.

Natriuretic peptide proANP (1–98), a biomarker of ALI/ARDS in burns

Plasma atrial natriuretic peptide levels (proANP (1-98)), a parameter of myocardial dysfunction, have been reported to be increased in critically ill patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). The aim of the study was to examine if proANP is a biomarker of ALI/ARDS as assessed by the Sequential Organ Failure Assessment score (SOFA Lung ≥2) in burn patients, and how it compares to the corresponding values for age, total body surface area percent (TBSA%) and inhalation injury for mortality prediction. A group of 22 burn patients with a mean TBSA of 30% (10-75%) and a mean age of 52 years (25-84 years) was investigated during 2010. Organ dysfunction/failure was classified according to the SOFA score. The criteria for ALI/ARDS were based on SOFA Lung ≥2. ProANP (1-98) concentrations (nmoll(-1)) were measured by commercially available enzyme linked immunosorbent assay (ELISA) immunoassays (Biomedica Austria) on post-burn days 2 and 7. ProANP levels on day 7 post-burn positively correlated with a SOFA score day 7 post-burn, c=0.91. The receiver operating curve (ROC) analysis proved a sensitivity of 75% and a specificity of 75% for ALI/ARDS at cut-off values >3.35 nmoll(-1). The ROC value of proANP for ALI/ARDS (SOFA Lung ≥2) was significantly larger than that of age, TBSA% and inhalation injury: 0.90, 0.71, 0.74, and 0.69 (p<0.001). ProANP levels, as a biomarker of ALI/ARDS, in critically burn patients correlated with SOFA scoring. The inhalation injury did not lead to increase in proANP values.

Measurement of the total proANP product in mammals by processing independent analysis

The cellular processing of natriuretic propeptides is attenuated in heart disease, resulting in release of a mixture of unprocessed precursor, partially processed fragments, and the bioactive hormone. Here, we report a species-independent method for quantification of pro-atrial natriuretic peptide (proANP) and its products irrespective of variable post-translational processing. The processing-independent assay (PIA) was developed raising mono-specific antibodies against the C-terminus of sequence 1–16 in proANP. The assay procedure included plasma extraction followed by tryptic cleavage, which releases the assay epitope from the N-terminal region. The PIA was tested in elderly patients with symptoms of heart failure (n = 450), in pigs with acute myocardial infarction (n = 21), and in normal dogs and dogs with heart failure (n = 77). The epitope specificity permitted reliable measurement in man, dog, cat and pig. In human plasma, the PIA correlated well with an established proANP analysis (r = 0.86, P < 0.0001) but with a 5.5-fold difference in plasma level ( P < 0.0001). In pigs, the PIA measured 9.2-fold higher concentrations compared to a human assay (804 versus 87 pmol/L, P < 0.0001). The basal proANP concentration was 396 pmol/L in dogs: a dramatic increase was seen in canine heart failure. Our new processing- and species-independent proANP assay allows for the measurement of the total proANP product, irrespective of changes in post-translational maturation. We suggest that this tool should be used for comparative studies between human patients and porcine and canine models of human cardiac disease.

The quest for an atrium-specific biomarker

Dear Sir, With great interest we read the article by Maass et al. [1] who started a ‘quest for an atrium-specific biomarker’ using oligodeoxyribonucleotide (ODN) microarrays to identify differences in gene expression profile between atrial and ventricular myocardium. One of the ‘atrium-enriched genes’ is Nppa that has a ‘fold A/V microarray’ of 3.33 [1], whereas in hearts of healthy human adults, the concentration of Nppa transcripts, which encode preproANP (a precursor of atrial natriuretic peptide or ANP), is >100-fold higher in atrial than in ventricular myocardium [2, 3]. The explanation for this apparent discrepancy is that gene expression profiling was done with RNA extracted from neonatal rat atrial and ventricular cardiomyocytes. This particular choice of tissue is highly peculiar, assuming that the biomarker, once found, will be used in material originating from adult human patients. Foetal (and neonatal) rat (and human) atrial and ventricular myocardium possess roughly equal proANP concentrations [2, 3]. In adults, proANP is no longer found in healthy rat and human ventricular myocardium [2, 3] but reappears under pathological conditions such as heart failure and hypertension [3, 4]. Furthermore, the heart of newborns changes from a mainly glucose-metabolising tissue to a primarily fatty acid-oxidising tissue, thereby upregulating the expression of genes involved in fatty acid transport and β-oxidation [5]. Another cautionary note concerns the tendency to equate transcript/RNA levels as determined by ODN microarray analysis with protein levels. This may not be justified because: (1) Many genetic loci specify all kinds of non-protein-coding transcripts besides the classical polyadenylated protein-coding mRNAs that might contribute to the signals observed on ‘DNA chips’ [6]; (2) Depending on the stringency of the hybridisation and washing conditions, the same DNA probe may be bound by related nucleic acid sequences with different coding capacity; and (3) Cells possess multiple mechanisms to control gene expression at the post-transcriptional level [7], many of which affect the ratio between a specific mRNA and the protein(s) it encodes. In conclusion, to find heart chamber type-specific proteins that will potentially allow the identification of atrium- or ventricle-specific biomarkers in human adults, the use of adult human atrial and ventricular RNA for gene expression profiling is recommended, provided any novel candidate is tested at the protein level, e.g. by Western blot analysis.

Atrial Natriuretic Peptide Gene and Plasma Pro-ANP Concentration in Patients with Primary Open-Angle Glaucoma

Atrial Natriuretic Peptide Gene and Plasma Pro-ANP Concentration in Patients with Primary Open-Angle GlaucomaAtrial natriuretic peptide (ANP) appears to have a physiological role in volume and pressure homeostasis. Increased cardiac expression and synthesis of ANP suggest a possible local paracrine function in a number of tissues including the eye. Therefore, the identification of genetic markers may prove to be an important advance in the diagnosis of patients with glaucoma and hypertension. Plasma pro-ANP concentration was measured in 30 clinical patients. A significant elevated level of prehormone was observed in glaucoma patients with blood hypertension. Also, the distribution of the genotypes and alleles of the HpaII, SmaI and ScaI polymorphisms of the ANP gene was examined in 20 hypertensive patients with glaucoma and normotensive controls. The frequencies of the ANP genotypes and alleles did not differ significantly between controls and hypertensive patients. PCR-RFLP (polymerase chain reaction—restriction fragment length polymorphism) analysis shows a T2238→C transition in three hypertensive patients within the stop codon leading to the translation of ANP with an additional arginine. In the current study we also searched for any alterations in the 5' proximal promoter region of the ANP gene (-595 bp - -384 bp) in 20 glaucoma patients with hypertension using PCR-based SSCP (single-strand conformation polymorphism) analysis. No significant alterations in the 5' proximal promoter region of the ANP gene were observed among hypertensive patients. The structure of the ANP hormone encoded gene suggests potential importance in various diseases, but the regulatory function of ANP in the eye requires further investigations.

Pro-brain natriuretic peptide as marker of cardiovascular or pulmonary causes of dyspnea in patients with terminal parenchymal lung disease

Background Increased plasma concentrations of pro-atrial natriuretic peptide (proANP) and pro-brain natriuretic peptide (proBNP) are features of left ventricular impairment. However, concentrations of proANP and proBNP in patients with isolated terminal parenchymal lung disease are not known. Therefore, we measured the plasma concentrations of natriuretic precursor peptides in patients with terminal parenchymal lung disease who had normal left ventricular function and who were referred for evaluation for lung transplantation. Methods We measured plasma N-terminal proANP and proBNP in patients undergoing right heart catheterization ( n = 50) and related results to hemodynamic variables obtained during catheterization. Results Plasma proBNP concentrations were unaffected in patients with terminal parenchymal lung disease and normal left ventricular function (median, 2.5 pmol/liter; range, 0–22; upper reference limit, 15 pmol/liter). In contrast, patients with primary pulmonary hypertension displayed more than a 40-fold increase in plasma proBNP concentrations (median, 107 pmol/liter vs 2.5 pmol/liter, p < 0.0001). Plasma N-terminal proANP increased moderately (median, 664 pmol/liter; range, 36–1,620; upper reference limit, 600 pmol/liter) but correlated to plasma proBNP concentrations ( r = 0.47, p < 0.0001). Finally, regional vascular proBNP concentrations revealed the heart as the secretory site. Conclusions Our findings strongly support the contention that natriuretic peptide measurements are efficient markers for cardiovascular causes of dyspnea. Moreover, our results eliminate natriuretic peptides as markers of moderate pulmonary hypertension in patients with terminal parenchymal lung disease.

N-terminal fragments of the proatrial natriuretic peptide in plasma and urine of kidney graft recipients.

Successful kidney transplantation normalizes elevated proatrial natriuretic peptide (proANP) plasma concentrations of renal failure patients in the early posttransplant period. We evaluated plasma and urinary proANP fragments in the late posttransplant period. Immunoreactive proANP(1-30) and proANP(31-67) were determined in 389 renal transplant (Rtx) recipients in the long-term, follow-up period and in 16 healthy controls. Rtx recipients had significantly higher concentrations of proANP(1-30) and proANP(31-67) in both plasma and urine than healthy controls. Although their graft function was normal, all of these long-term Rtx recipients were taking glucocorticoids, which increase proANP(1-30) and proANP(31-67) in the circulation to the extent found in this investigation. Two-thirds of these recipients were also taking cyclosporine, which also increases atrial peptides. Urinary proANP(31-67) was significantly higher than urinary proANP(1-30); 5.5-fold in Rtx patients and 2-fold in controls. Deterioration of renal graft function was associated with a rise of plasma proANP(1-30) from 0.98+/-0.66 to 6.28+/-3.55 nmol/l (P<0.0001) and plasma proANP(31-67) from 1.81+/-1.04 to 7.89+/-3.76 nmol/l (P<0.0001). Urinary excretion of proANP(1-30) increased from 0.27+/-0.34 to 5.96+/-5.07 nmol/24 hr (P<0.0001) and proANP(31-67) from 1.45+/-0.85 to 12.23+/-5.12 nmol/24 hr (P<0.0001). Also proteinuria enhanced plasma and urinary proANP fragments. ProANP(1-30) and proANP(31-67) of Rtx recipients are affected by immunosuppression, hypertension, renal failure, and proteinuria. One would have expected proANP(1-30) and proANP(31-67) not to normalize because of the glucocorticoids that they were receiving.

Circulating immunoreactive proANP (1–30) and proANP (31–67) responses to acute exercise

The circulating immunoreactive atrial natriuretic peptide (C-terminal; α-ANP) increases during exercise to become suppressed in the first hours of the recovery. The response of the N-terminal ANP fragments to acute exercise is not known while proANP (31–67) appears to be elevated with chronic exercise. We evaluated the plasma concentrations of the N-terminal ANP fragments (1–30) and (31–67) in oarsmen ( n=10) before and after two acute exercise bouts separated by 5 h. As control, measurements were made on a day with no exercise ( n=12). At rest, the concentrations of proANP (1–30) and proANP (31–67) were 344±42 and 810±172 pmol l −1, respectively. Half an hour after the first exercise bout, proANP (1–30) was elevated (to 404±48 pmol l −1; P<0.05) and decreased below the pre-exercise level (to 316±41 pmol l −1; P<0.05) 4 h into the recovery period. Also, 30 min after the second exercise session, the concentration of proANP (1–30) was elevated to 408±45 pmol l −1 ( P<0.05) and the pre-exercise level was re-established on the following morning. Thus, proANP (1–30), rather than proANP (31–67), responded to acute exercise. These results suggest that atrial distension and, therefore, the central blood volume changes markedly in athletes during a day with repeated exercise bouts.

Adsorption of natriuretic factors in uremia.

Patients with end-stage renal disease have a deranged sodium and water homeostasis leading to chronic volume overload. Atrial natriuretic peptides (ANPs) are circulating hormones that are involved in the regulation of volume homeostasis, blood pressure control, and electrolyte balance. In hemodialysis patients plasma ANPs are highly elevated and decrease during the dialysis session when fluid is removed. However, hemodialysis treatment never corrects the defect in the metabolism of these peptides and their circulating concentrations do not return to levels found in healthy controls. Besides uremia and chronic volume overload, other factors such as cardiac dysfunction or hypertension may contribute to the elevated plasma concentrations of ANPs. ProANP fragments which derive from the N-terminus of the ANP prohormone have been also found in the circulation and they have biological functions similar to alpha-ANP (ie, the C-terminus of the prohormone). The proANP peptides proANP(1-30), proANP(31-67), and proANP(1-98) are increased in patients undergoing regular hemodialysis treatment, but their decrease during the dialysis procedure is less pronounced than for alpha-ANP or cyclic GMP. Cellulose triacetate dialyzer membrane material lowered the plasma concentrations of proANP(1-30), proANP(31-67), and proANP(1-98) significantly more than polysulfone, whereas alpha-ANP and cyclic GMP were not differently affected. Aside from a variety of factors that influence circulating natriuretic factors in the uremic patient, there is evidence for differences in dialyzer membrane adsorption of these peptides which speculatively may be linked to dialysis-associated symptoms.

Fluid balance in patients with chronic renal failure assessed with N‐terminal proatrial natriuretic peptide, atrial natriuretic peptide and ultrasonography

The N-terminal proatrial natriuretic peptide (proANP) has become an important parameter for assessing the prognosis of patients with cardiac disease. Its use for evaluating the hydration status in patients with chronic renal failure, however, is still under investigation. The present study comprised 12 haemodialysis (HD) and 17 pre-dialysis patients. In the HD patients, the inferior vena cava diameter during quiet expiration (IVCe) was estimated by ultrasonography and plasma concentrations of N-terminal proANP, atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) were measured before and 4 h after termination of HD. In the pre-dialysis patients venous blood samples were taken during rest to measure plasma N-terminal proANP and ANP and serum creatinine. Normal values for N-terminal proANP and ANP were obtained from 18 healthy volunteers. The plasma concentrations of N-terminal proANP and ANP in healthy volunteers were 328 +/- 92 and 11.4.0 +/- 3.1 pM L-1, respectively. In pre-dialysis patients, serum creatinine ranged from 110 to 447 microM L-1 and was significantly correlated to plasma N-terminal proANP (r = 0.60, P < 0.05) but not to ANP. This may indicate that N-terminal proANP is more dependent on renal function for its clearance than ANP, which is probably cleared by extrarenal mechanisms as well. In HD patients, IVCe was significantly correlated to the three hormones before HD, most strongly to N-terminal proANP. After dialysis, IVCe was significantly correlated to ANP and cGMP but was not correlated to N-terminal proANP. This may suggest that proANP takes a longer time than other hormones to reflect changes in intravascular volume. In conclusion, N-terminal proANP is a hormone closely related to degree of renal function. Furthermore, it is a sensitive marker reflecting the interdialytic hydration status in HD patients, as indicated by its high correlation to IVCe, a standard method which is used frequently nowadays to assess the body hydration. However N-terminal proANP could not reflect the acute changes in fluid volume induced by HD, probably because it is slowly metabolized.

Gene expression of natriuretic peptides and their receptors type-A and-C after myocardial infarction in rats

The purpose of this study was to investigate myocardial mRNA expression of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) in different regions of the heart at three different time points after induction of myocardial infarction (MI) in rats. Furthermore, we examined putative changes in mRNA expression of natriuretic peptide receptors (NPRs), NPR-A and NPR-C, in myocardium and peripheral organs. Substantial increase in the mRNA levels of both BNP and ANP in the infarcted as well as non-infarcted regions were observed after induction of MI. These findings were paralleled by elevated circulating concentrations of ANP, BNP and N-terminal proANP (Nt-proANP). In addition, the mRNA levels of the clearance receptor, NPR-C, were augmented in the infarcted and non-infarcted regions of the left ventricular wall (LV), while it was decreased in the kidneys and lungs 28 days post-MI. Based on these data, we propose that, in addition to increased myocardial secretion of BNP and ANP, reduced peripheral clearance by NPR-C may contribute to the observed increase in circulating plasma concentrations of the natriuretic peptides after induction of MI in rats.

N-terminal proatrial natriuretic peptide and prognosis in patients with heart failure and preserved systolic function

Background: Congestive heart failure and preserved left ventricular systolic function is a common clinical condition. Although the prognosis in this type of heart failure is better in comparison to systolic dysfunction, prognostic markers to evaluate long-term outcome are lacking. The atrial peptide, N-terminal proatrial natriuretic peptide (proANP), has been shown to predict survival in patients with systolic dysfunction. We intended to evaluate the predictive capability of N-terminal proANP in patients with preserved systolic function (ejection fraction [EF] ≥ 0.40). Methods and Results: A clinical and echocardiographic examination was performed in 149 patients with idiopathic heart failure from a population-based cohort, and 84 patients were identified to have preserved systolic function, with an EF of 0.40 or greater. The patients were followed up during 7 years with regard to symptoms, treatment, hospitalization, and survival. The patients with normal EFs had greater plasma concentrations of N-terminal proANP compared with a control group, and N-terminal proANP level was an independent predictor of mortality (risk ratio, 2.44; 95% confidence interval, 1.28 to 4.67; P =.007). In addition, a high concentration of N-terminal proANP predicted an increased rate of hospitalization (50% for a level >1,200 pmol/L versus 19% for a level ≤1,200 pmol/L; P =.046) and a greater future dosage of diuretic (127 ± 102 vs 51 ± 39 mg; P =.007). Conclusion: N-terminal proANP level was an independent marker of increased mortality and morbidity in patients with preserved systolic function, whereas EF was not usable in this regard. It is suggested that this peptide could be used to identify clinically relevant left ventricular dysfunction in patients with EFs within the normal range.

Plasma levels and molecular forms of proatrial natriuretic peptides in healthy subjects and in patients with congestive heart failure.

A specific and sensitive radioimmunoassay (RIA) for the N-terminal fragment of proatrial natriuretic peptide (NproANP) was developed. Antiserum raised in rabbits against a mixture enriched with prohormone was 100% cross-reactive with human proANP(1-30). Plasma concentrations of proANP(1-30) and ANP immunoreactivities (ir-) were simultaneously measured in healthy subjects and patients with congestive heart failure (CHF; 26 dilated cardiomyopathy and 5 ischemic heart disease). High plasma levels of both ir-proANP(1-30) and ir-ANP were detected in CHF patients. Circulating ir-ANP levels were elevated in New York Heart Association functional Classes II and III patients but not in Class I patients. However, plasma levels of ir-proANP(1-30) were higher in asymptomatic patients than in healthy subjects, and markedly increased in patients of Classes II and III. Analysis of ir-proANP(1-30) by gel filtration chromatography or reverse-phase high pressure liquid chromatography revealed a 10 kDa peptide circulating as a distinct entity. These findings indicate that: (i) the most probable form of NproANP in human plasma is a 10 kDa peptide and (ii) in CHF patients the rise in plasma ir-proANP(1-30) levels is more pronounced than the variation in plasma ir-ANP. Thus, NproANP plasma levels may prove to be a more sensitive marker of left ventricular dysfunction than ANP.