Secretion Of BNP Research Articles

A Comparative Study of Plasma N-Terminal Pro- Brain Natriuretic Peptide to Assess Asymptomatic Cardiovascular Disease in Type 2 Diabetic Patients

Background: This study aimed to assess NT-pro BNP level in patients of T2DM without overt cardiovascular disease to determine presence of Asymptomatic Left Ventricular Dysfunction (ALVD) compared with matched control group. Methods: This study conducted at SMS Hospital, Jaipur by selecting 60 patients of type 2 diabetes mellitus and 60 control of non-diabetic population. Information regarding demographic data, clinical symptoms, past medical history, laboratory parameters, NT pro-BNP and 2D Echocardiography collected from selected sample population for comparative analysis among both groups. Results: Patients of T2DM have significantly higher value of NT pro-BNP, blood sugar and HbA1c with proportionally increased diastolic dysfunction as compared to matched non-diabetic population (P<0.05). Absolute value of NT pro-BNP in patients of T2DM is directly correlated with age, duration of diabetes, Blood pressure, blood sugar level, HbA1c level, creatinine, total cholesterol and urine protein (positive correlation coefficient with P-value<0.05). Left ventricular ejection fractions were found statistically similar among both groups. Conclusion: Heart failure in patients with T2DM is a most crucial diabetic complication for diagnosis as well as management. Level of NT-pro BNP in blood stream is an important tool for early diagnosis of heart failure especially HFpEF. This study suggests that the secretion of NT-pro BNP is increased in patients with T2DM compared with control subject without overt heart disease. Therefore, measurement of NT-pro BNP paired might be a simple screening tool to identify patients with diabetes at risk for ventricular dysfunction requiring further examination with echocardiography.

Exercise-Induced NT-pro BNP Secretion in Hypertensive Patients Without Heart Failure Can Diagnose the Subclinical Left Ventricle Dysfunction

Abstract Hypertension is one of the main risk factors for developing left ventricle failure. The study was conducted at outpatient Clinic – Medlife, Memorial Hospital. It was an observational study. We analyzed the exercise-induced secretion of NT-pro BNP in hypertensive patients with normal ejection fraction and no symptoms or signs of heart failure. Comparing the levels of NT-pro BNP before and after exercise proved to be a good mean for diagnosing left ventricular dysfunction (LVD) in hypertensive patients with left ventricular remodeling.

0287: Diagnostic and prognostic value of NT-proBNP on percutaneous mitral commissurotomy (PMC)

Studies that investigate the secretion of BNP in diseases affecting the atrium are rare. The relationship between N-terminal proBNP (NT-proBNP) and the echocardiographic (TTE) and hemodynamic data were studied in cases of pure and isolated rheumatic mitral stenosis (RMS). 67 patients with MS (41±11 years), and 29 healthy individuals (age 36±11 years) were included in the study. Detailed TTE was performed before, one and six months after PMC. We measured NT pro BNP in systemic venous and left atrial (LA) before, immediately after, and one and 30 days after the procedure. Results The plasma levels of NT-proBNP were significantly higher in MS patients than in controls (103.2±116.8 VS 21.5±8.5pg/mL, p=0.004).We revealed a strong correlation between levels of NT pro-BNP in peripheral vein (PV) and in LA (r=0.819, p=0.001). NT-proBNP was higher in the LA than PV. We releaved a positive correlation with LA volume (0.470, p=0.001 and p=0.001, 0.681 respectively at the LA and at the PV), the absolute value of LV strain (r=0.524, p=0.001 and r=0.568, p=0.001) and the pulmonary artery pression (PAP) (r =0.312, p=0.01 and r=0.586 p=0.001). Negative correlations with LVEF (r=–0.421, p=0.001 and r=-0,462, p=0.000) and the longitudinal movement of the VD (r=-0,380, p=0.002 and r=–0,374, p=0.001) were observed. NT pro BNP falls immediately after PMC IN the sinus rhythm (SR) group patients but not in the atrial fibrillation (AF) group. Moreover, LA remodeling at six months is more pronounced in SR (SOG=0.04±0.07 VS 0.02±0.06 in the AF group; LA volume=5.94±6.5 VS 1.17±8.6 Conclusion In patients with RMS, NT-proBNP was positively correlated with LA enlargement and the PAP and could be a valuable marker to reflect the structural changes of the LA aftercmP, in patients with SR but not in those with AF.

The value of plasma NT-proBNP levels inpredicting the effect of drug conversion for paroxysmal atrial fibrillation

ObjectiveTo investigate the value of plasma NT-proBNP levels in predicting the effect of drug conversion for paroxysmal atrial fibrillation.MethodThe 132 patients with non-valvular paroxysmalatrial fibrillation were treated by oral loading...

BNP in Hemodialysis Patients

The natriuretic peptides comprise at least three molecules (A, B, and C), which play an important role in BP and volume homeostasis, with biologic actions on kidney, heart, and blood vessels (1). ANP is secreted mainly by the right atrium, BNP is produced by the cardiac ventricles, and CNP is produced mainly by endothelial cells. Their biologic effects include increased GFR, natriuresis, and diuresis; vasorelaxation with decreased cardiac preload and afterload; suppression of renin-angiotensin-aldosterone axis, sympathetic outflow, ADH, and endothelin; and inhibition of mitogenesis in vascular smooth muscle cells, growth factor–mediated hypertrophy in cardiac fibroblasts, and cardiac remodeling (1). Increased left ventricular (LV) volume or pressure overload, such as occurs in congestive heart failure and hypertension, enhance the secretion of BNP from the ventricles. Plasma levels of BNP are elevated in patients with congestive heart failure in proportion to the severity of myocardial systolic and diastolic …

Les peptides natriurétiques de type B

Summary B-type natriuretic peptides (brain natriuretic peptide [BNP] and its aminoterminal precursor fragment NT-pro-BNP) have become important diagnostic tools for assessing patients with heart failure. Age, body mass index and renal function of the patients, as well as biological variability of these markers must be taken into account when analysing both BNP and NT-pro-BNP levels. BNP, the biologically active form, is easily degraded in vitro and pre-analytical cautions are necessary. It is now recognized that rather than a 1:1 secretion of BNP and NT-pro-BNP, a mixture of cleaved and uncleaved pro-BNP, is present in the circulation in more or less degraded forms. The lack of natriuretic peptide assay standardization is linked to the variable cross reactivity of this heterogeneous form in the commercial immunoassays.

Ventricular function and natriuretic peptides in sequentially combined models of hypertension

Hemodynamic parameters and natriuretic peptide levels were evaluated in cardiac hypertrophy produced by sequentially applied renovascular (RV) and deoxycorticosterone acetate-salt (DS) models of hypertension. We studied hypertensive rats by RV or DS treatment at 2 and 4 wk, as well as by the combination of 2 wk of each treatment in an inverse sequence: RV 2 wk/DS 2 wk (RV2/DS2) and DS 2 wk/RV 2 wk (DS2/RV2). The in vivo cardiac function, interstitial fibrosis, and synthesis and secretion of types A (ANP) and B (BNP) natriuretic peptides were monitored in hypertensive models compared with their corresponding sham (Sh2, Sh4). There were no differences in relaxation parameters among RV or DS groups and combined treatments. Left ventricular +dP/dt(max) increased only in RV4 (P < 0.01 vs. Sh4), and this increase was abolished in RV2/DS2. Interstitial collagen concentration increased after 4 wk in both RV4 and RV2/DS2 groups. Although there were no changes in collagen concentration in either DS2 or DS4 groups, clipping after 2 wk of DS (DS2/RV2) remarkably stimulated interstitial fibrosis (P < 0.01 vs. DS2). Plasma BNP increased in RV treatment at 4 wk (P < 0.001 vs. Sh4), but not in DS. Interestingly, RV applied after the 2 wk of DS treatment induced a marked increase in BNP levels (P < 0.001 vs. Sh4). In this regard, plasma BNP appears to be a reliable indicator of pressure overload. Our results suggest that the second stimulus of mechanical overload in combined models of hypertension determines the evolution of hypertrophy and synthesis and secretion of ANP and BNP.

Can plasma levels of N-terminal pro-brain natriuretic peptide be useful in predicting the risk of developing chronic pulmonary hypertension in patients with pulmonary embolism?

We read with great interest the manuscript by Dentali and colleagues [1] on the role of N-terminal pro-brain natriuretic peptide (Nt-proBNP) as a biomarker of pulmonary hypertension in patients with pulmonary embolism (PE). Risk stratification of patients with PE has recently received considerable attention because the availability of specific cardiac biomarkers might facilitate the identification of patients at high risk of shortor long-term complications and improve therapeutic decision making. Pro-hormone BNP is a 108 amino acid peptide that is synthesized in the myocytes, and is cleaved by an endoprotease into two polypeptides: the inactive Nt-proBNP and the biologically active BNP. The secretion and release of the pro-hormone BNP is enhanced during the hemodynamic stress that is associated with ventricle dysfunction due to volume expansion and pressure overload. Chronic thromboembolic pulmonary hypertension (CTPH) is a relatively common, serious complication of PE, whose early identification is problematic [2]. Dentali et al. [1], in their study of 49 patients with PE, find that there is a correlation between the plasma levels of Nt-proBNP and pulmonary artery systolic pressures (PAPs), and that low plasma Nt-proBNP levels have high negative predictive value (97.2%) for CTPH, suggesting that measurement of plasma Nt-proBNP may be useful to rule out preclinical or symptomatic CTPH. This manuscript is original and interesting; however, some methodological flaws may limit its clinical relevance. As acknowledged by the authors [1], one of the limitations is that the study population was small and heterogenous in terms of baseline characteristics, time from the index event and type and duration of antithrombotic treatment. As a matter of fact, the plasma levels of Nt-proBNP are influenced by several physiological conditions and disease states [3], including age, gender, ethnicity, obesity, renal impairment and the severity of PE. Unfortunately, the sample size of this study [1] was not large enough to weigh each of these confounding factors in a multivariate analysis. In addition, since patients develop CTPH approximately 2 years after a first episode of symptomatic PE [2], in order to ascertain a possible role of BNP on early diagnosis of CTPH, the follow-up of the studied patients should have been longer and less variable. Finally, the test is limited by a high intra-individual variability in the plasma levels of Nt-proBNP, associated with the circadian rhythm of hemodynamic indices, physical activity and fluid intake [3], which may increase the chance of false-positive or false-negative results in each individual patient. Moreover, studies of different clinical populations identify different cut-off concentrations of Nt-proBNP [4, 5]; therefore, the optimal cut-off of plasma Nt-proBNP levels for assessing their negative predictive value for CTPH needs to be established, while the individual Nt-proBNP concentrations should be considered cautiously. In conclusion, the results of the study by Dentali et al. [1] are certainly useful in generating a hypothesis of a possible role for Nt-proBNP plasma levels in predicting long-term complications of PE, but they should be considered preliminary. This intriguing hypothesis deserves to be tested in well-designed and prospective studies to clarify whether the Nt-proBNP plasma levels could indeed be useful in clinical practice. F. Lussana (&) G. M. Podda M. Cattaneo Divisione di Medicina Generale III, Dipartimento di Medicina, Chirurgia e Odontoiatria, Azienda Ospedaliera San Paolo, Universita di Milano, Via A. di Rudini, 8, 20142 Milan, Italy e-mail: federico.lussana@ao-sanpaolo.it

Brain natriuretic peptide secretion in adult rat heart muscle cells: The role of calcium channels

The cellular mechanisms that regulate B-type natriuretic secretion are not well elicited. Intracellular fluctuation of calcium ions rate seems to be implicated. In this study, we evaluate the role of ventricular transmembrane calcium channels in the secretion of BNP in normal adult rats (group N) and pressure overload hypertrophied ones (group H). We measured plasma BNP concentration and BNP concentration in culture media of cardiomyocytes from N and H group in the presence and absence of calcium channels antagonists. Plasma BNP concentration was increased in H group in comparison to N group (0.630+/-0.008 ng/ml versus 0.106+/-0.004 ng/ml; p<0.01). This increase in BNP level was also obtained in culture media of H group in comparison to N group (3.45+/-0.7 ng/ml versus 0.53+/-0.22 ng/ml). However, the presence of calcium channels antagonists in the culture media of cardiomyocytes had decreased BNP concentration in both N (nifedipine: 0.22+/-0.04 ng/ml; verapamil: 0.19+/-0.05 ng/ml; diltiazem: 0.17+/-0.03 ng/ml; p<0.05) and H group (nifedipine: 0.18+/-0.05 ng/ml; verapamil: 0.23+/-0.04 ng/ml; diltiazem: 0.28+/-0.1 ng/ml; p<0.05). These results suggest that transmembrane calcium channels may have an important role in the regulation of BNP secretion.

Calcium-Calmodulin Kinase II Is the Common Factor in Calcium-Dependent Cardiac Expression and Secretion of A- and B-Type Natriuretic Peptides

Peptides derived from the precursor of A- and B-type natriuretic peptides (ANP and BNP) are powerful clinical markers of cardiac hypertrophy and dysfunction. It is known that many stimuli affecting the intracellular calcium concentration also induce ANP and BNP secretion. It was our intention to study the mechanisms by which calcium regulates the secretion of ANP and BNP. The effects of pacing and calcium-calmodulin kinase II activity on natriuretic peptide secretion were studied in isolated perfused rat atria and cultured rat neonatal cardiomyocytes. In isolated rat atrium pacing induced an increase in diastolic, systolic, and averaged intracellular free calcium concentration and a frequency-dependent increase in the secretion of both ANP and BNP. The molar ratio of the secreted natriuretic peptides (ANP to BNP) remained nearly constant ( approximately 1000) at all the pacing frequencies tested (1, 3, 6, and 8 Hz). Calmodulin kinase II inhibitor KN-93 (3 mum) did not affect intracellular free calcium concentration but showed a frequency-dependent inhibitory effect on ANP and BNP secretion without a change in ANP to BNP ratio. In the neonatal cardiomyocytes, KN-93 (3 mum) suppressed the secretion and gene expression of both ANP and BNP. Overexpression of constitutively active (T286D) or nuclear (delta(B)) calcium-calmodulin kinase II induced an increase in ANP and BNP gene expression. The results indicate that the calcium-dependent secretion and gene expression of A- and B-type natriuretic peptides are similarly regulated by calmodulin kinase II-dependent mechanisms. This is a plausible mechanism contributing to exercise-induced natriuretic peptide secretion and the augmented secretion in heart dysfunction due to impaired calcium handling.

Natriuretic Peptides and Cardiovascular Events

IN PATIENTS WITH KNOWN OR SUSPECTED CARDIOVASCUlar disease, biomarkers are increasingly being explored as indicators of disease presence, severity, or activity; prognosis; and therapeutic efficacy. A biomarker may be a by-product of the disease state and may also directly participate in its pathogenesis or modulation. The cardiac natriuretic peptides (secreted in response to myocardial stretch) promote vasodilation and natriuresis and are believed to mitigate adverse cardiovascular remodeling. Circulating levels of these peptides have proved useful in gauging the severity of heart failure and in assessing the differential diagnosis of acute dyspnea. N-terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP) is an inactive cleavage product with much slower clearance than the biologically active BNP. Its plasma concentration, therefore, principally reflects myocardial secretion over a prolonged time. Prior investigations have identified plasma BNP and NT-proBNP levels as independent predictors of mortality or cardiovascular events in populations with chronic heart failure, acute coronary syndromes, prior myocardial infarction, established vascular disease or elevated coronary risk, and in community-based samples. In this issue of JAMA, the study by Bibbins-Domingo and colleagues extends these observations within a population of patients with stable coronary artery disease (CAD) and further clarifies the utility of NT-proBNP level as a predictor of a variety of subsequent cardiovascular events. The authors observe that plasma NT-proBNP concentration remains an independent predictor of all-cause mortality, CAD mortality, stroke, and events related to heart failure, even after sequentially adjusting for known measures of cardiac risk, left ventricular remodeling and function, inducible ischemia, functional capacity, inflammation, myocyte necrosis, and symptoms. Furthermore, plasma NT-proBNP concentration approaches significance as an independent predictor of myocardial infarction. These findings challenge the conventional view of the natriuretic peptide levels as mere hemodynamic markers of worsening heart failure or left ventricular dysfunction. Furthermore, these findings provoke reconsideration of the value of these markers as diagnostic tools and potentially as triggers for therapeutic intervention. How can a marker of myocardial stretch, measured at a single time point within a stable population, predict such a wide variety of cardiovascular events? Levels of NTproBNP may reflect a variety of adverse factors, all potentially resulting in increased hormonal release from stretched myocardium. However, to the extent that levels denote myocardial stretch, it seems likely that their value in predicting cardiovascular events would diminish after accounting for numerous known biochemical, echocardiographic, and functional markers of myocardial injury, ventricular remodeling, and active or inducible ischemia. The value of NTproBNP in predicting stroke, also observed for BNP in an analysis of the Framingham cohort, could be linked to its role as a marker of cardiac dilation with a predisposition to atrial fibrillation. However, the preserved predictive value for stroke after correction for multiple covariates, including echocardiographic measures of left ventricular function, supports consideration of alternative mechanisms responsible for the linkage between NT-proBNP levels and vascular events, including stroke. Along with myocardial stretch, a variety of other factors have been found to stimulate or enhance secretion of BNP in vitro, including myocardial ischemia and paracrine or endocrine agents such as endothelin A, angiotensin II, and tumor necrosis factor . Cardiac fibroblasts, as well as cardiac myocytes, secrete BNP, and its secretion modulates fibrosis through induction of matrix metalloproteinases. These observations suggest that the predictive value of plasma NT-proBNP concentration, particularly in a stable population without clinical heart failure, results not merely from its relationship with acute myocardial stretch but to

Effect of Myocardial Ischemia itself on N-terminal Pro Brain Natriuretic Peptide (NT-proBNP) and Brain Natriuretic Peptide (BNP) Secretion

Background: Whether myocardial ischemia increases the secretion of NT-proBNP and BNP from the heart independent of ventricular dysfunction remains unknown. To evaluate the relation among BNP and NT-proBNP secretion, plasma levels and the severity of coronary artery stenosis in patients with ischemic heart disease (IHD).

Amino-Terminal Pro-B-Type Natriuretic Peptide and B-Type Natriuretic Peptide in the General Community: Determinants and Detection of Left Ventricular Dysfunction

This study sought to characterize factors influencing amino-terminal pro-B-type natriuretic peptide (NT-proBNP) and to evaluate the ability of NT-proBNP to detect left ventricular (LV) dysfunction in a large community sample. Secretion of BNP increases in cardiac disease, making BNP an attractive biomarker. Amino-terminal proBNP, a fragment of the BNP prohormone, is a new biomarker. We evaluated factors influencing NT-proBNP in normal patients and compared the ability of NT-proBNP and BNP to detect LV dysfunction in a large community sample. Amino-terminal pro-BNP was determined in plasma samples of a previously reported and clinically and echocardiographically characterized random sample (n = 1,869, age > or =45 years) of Olmsted County, Minnesota. In normal patients (n = 746), female gender and older age were the strongest independent predictors of higher NT-proBNP. Test characteristics for detecting an LV ejection fraction < or =40% or < or =50% were determined in the total sample with receiver operating characteristic curves. Amino-terminal pro-BNP had significantly higher areas under the curve for detecting an LV ejection fraction < or =40% or < or =50% than BNP in the total population and in several male and age subgroups, whereas areas were equivalent in female subgroups. Age- and gender-adjusted cutpoints improved test characteristics of NT-proBNP. Both assays detected patients with systolic and/or moderate to severe diastolic dysfunction to a similar degree, which was less robust than the detection of LV systolic dysfunction alone. Amino-terminal pro-BNP in normal patients is affected primarily by gender and age, which should be considered when interpreting values. Importantly, in the entire population sample NT-proBNP performed at least equivalently to BNP in detecting LV dysfunction and was superior in some subgroups in detecting LV systolic dysfunction.

Tachycardia-induced myocardial ischemia and diastolic dysfunction potentiate secretion of ANP, not BNP, in hypertrophic cardiomyopathy

The aim of this study was to investigate what factor determines tachycardia-induced secretion of atrial and brain natriuretic peptides (ANP and BNP, respectively) in patients with hypertrophic cardiomyopathy (HCM). HCM patients with normal left ventricular (LV) systolic function and intact coronary artery (n = 22) underwent rapid atrial pacing test. The cardiac secretion of ANP and BNP and the lactate extraction ratio (LER) were evaluated by using blood samples from the coronary sinus and aorta. LV end-diastolic pressure (LVEDP) and the time constant of LV relaxation of tau were measured by a catheter-tip transducer. These parameters were compared with normal controls (n = 8). HCM patients were divided into obstructive (HOCM) and nonobstructive (HNCM) groups. The cardiac secretion of ANP was significantly increased by rapid pacing in HOCM from 384 +/- 101 to 1,268 +/- 334 pg/ml (P < 0.05); however, it was not significant in control and HNCM groups. In contrast, the cardiac secretion of BNP was fairly constant and rather significantly decreased in HCM (P < 0.01). The cardiac ANP secretion was significantly correlated with changes in LER (r = -0.57, P < 0.01) and tau (r = 0.73, P < 0.001) in HCM patients. Tachycardia potentiates the cardiac secretion of ANP, not BNP, in patients with HCM, particularly when it induces myocardial ischemia and LV diastolic dysfunction.

The physiological and pathophysiological modulation of the endocrine function of the heart

Under physiological conditions, the endocrine heart contributes to the maintenance of cardiovascular homeostasis through the polypeptide hormones ANF and BNP, which are members of the natriuretic peptide (NP) family. Given that NPs are of interest from the basic and clinical points of view, the genetic expression and secretion of ANF and BNP as well as the nature of the interaction of these hormones with their receptors has been the subject of extensive studies since the discovery of ANF in 1980. Following hemodynamic overload, increased secretion of NPs by the heart can be seen. This change may occur without an increase in gene expression as observed for atrial NPs following acute volume expansion, or it can occur with an increase in both ANF and BNP gene expression in atria only as seen in mineralocorticoid escape during which it is obvious that a critical decrease in hormone stores must be reached before transcriptional activation occurs. Chronic hemodynamic pressure or volume overload results in increased expression of NPs in atria and ventricles. Under these circumstances, the increased production of BNP by hypertrophic ventricles changes the normal plasma concentration ratio of ANF to BNP, a fact that has clinical diagnostic and prognostic implications. There are exceptions to this rule: chronic, severe L-NAME hypertension, which may occur without left ventricular hypertrophy, does not cause this effect and increased ventricular NP gene expression can occur in mineralocorticoid hypertension before detectable ventricular hypertrophy. Atrial and ventricular NP gene expression appears to be under different transcriptional control because pharmacological treatments such as chronic ACE inhibition or ET(A) receptor blockade can reverse the increased ventricular NP expression but has no detectable effect on atrial NP gene expression. This is not unlike the myosin heavy chain switch that is observed in certain pathologies, and can be pharmacologically reversed in a manner similar to NPs in the ventricles but it does not occur in atrial muscle. These observations made in vivo or using isolated adult atria often differ strikingly from results obtained using the mixed phenotype afforded by cardiocytes in culture, indicating that the kinds of questions addressed by each approach must be judiciously chosen. G-protein coupled receptor-mediated actions of neurohumors such as endothelin and phenylephrine are normally used to stimulate NP gene expression and release in different in vitro models. The main physiological stimulus for increased ANF release, atrial muscle stretch, also appears to rely on G-protein-coupled mechanisms. Alternative agonists and receptor types at play are suggested by the finding that circulating levels of BNP are selectively increased before and during overt cardiac allograft rejection episodes in human patients. The data suggest that enhanced BNP plasma levels could form a basis for a noninvasive test for cardiac allograft rejection. However, the molecular mechanism by which expression of NPs are regulated in the transplanted heart is not well understood. Conditioned medium from mixed lymphocyte reaction cultures, considered an in vitro model of transplantation immunity, induces specific upregulation of BNP as do individual pro-inflammatory cytokines. Findings such as these suggest that the study of NPs will continue to produce a wealth of information relevant to basic and clinical scientists.

Pathophysiological significance and clinical application of ANP and BNP in patients with heart failure

Plasma levels of ANP and BNP increase in accordance with the severity of the heart failure. In severe cases, the amount of BNP secreted surpasses that of ANP. The main secretion site of BNP is the ventricles, and that of ANP is the atria. However, ANP is also secreted from the ventricles as heart failure advances, and thus the ventricles are important sites for both BNP and ANP. It is well known that myocardial stretch is a key factor in the stimulation of the secretion of ANP and BNP, although neurohumoral factors also play a role in the secretion mechanism. The major physiological effects of ANP and BNP are vasodilation, natriuresis, and inhibition of the renin-angiotensin-aldosterone (RAA) and the sympathetic nervous systems; all of which are supposed to suppress the progression of heart failure. The inhibitory action of ANP and BNP on the RAA system has been considered to be an extra-cardiac effect. We recently reported the activation of an angiotensin-converting enzyme and aldosterone production in failing human hearts. ANP and BNP, however, would inhibit aldosterone production, not only in the adrenal cortex but also in cardiac tissue. ANP, and especially BNP, are useful markers of the heart's status during treatment for heart failure. The infusion of synthetic ANP (hANP) or BNP (Nesiritide®) is effective in the treatment of acute heart failure. In Japan, BNP occupies an important position in the diagnosis of chronic heart failure, as ANP does in the treatment of acute heart failure.Key words: natriuretic peptide, heart failure, myocardial infarction, cardiomyopathy, aldosterone.

The physiological and pathophysiological modulation of the endocrine function of the heart

Under physiological conditions, the endocrine heart contributes to the maintenance of cardiovascular homeostasis through the polypeptide hormones ANF and BNP, which are members of the natriuretic peptide (NP) family. Given that NPs are of interest from the basic and clinical points of view, the genetic expression and secretion of ANF and BNP as well as the nature of the interaction of these hormones with their receptors has been the subject of extensive studies since the discovery of ANF in 1980. Following hemodynamic overload, increased secretion of NPs by the heart can be seen. This change may occur without an increase in gene expression as observed for atrial NPs following acute volume expansion, or it can occur with an increase in both ANF and BNP gene expression in atria only as seen in mineralocorticoid escape during which it is obvious that a critical decrease in hormone stores must be reached before transcriptional activation occurs. Chronic hemodynamic pressure or volume overload results in increased expression of NPs in atria and ventricles. Under these circumstances, the increased production of BNP by hypertrophic ventricles changes the normal plasma concentration ratio of ANF to BNP, a fact that has clinical diagnostic and prognostic implications. There are exceptions to this rule: chronic, severe L-NAME hypertension, which may occur without left ventricular hypertrophy, does not cause this effect and increased ventricular NP gene expression can occur in mineralocorticoid hypertension before detectable ventricular hypertrophy. Atrial and ventricular NP gene expression appears to be under different transcriptional control because pharmacological treatments such as chronic ACE inhibition or ETA receptor blockade can reverse the increased ventricular NP expression but has no detectable effect on atrial NP gene expression. This is not unlike the myosin heavy chain switch that is observed in certain pathologies, and can be pharmacologically reversed in a manner similar to NPs in the ventricles but it does not occur in atrial muscle. These observations made in vivo or using isolated adult atria often differ strikingly from results obtained using the mixed phenotype afforded by cardiocytes in culture, indicating that the kinds of questions addressed by each approach must be judiciously chosen. G-protein coupled receptor-mediated actions of neurohumors such as endothelin and phenylephrine are normally used to stimulate NP gene expression and release in different in vitro models. The main physiological stimulus for increased ANF release, atrial muscle stretch, also appears to rely on G-protein-coupled mechanisms. Alternative agonists and receptor types at play are suggested by the finding that circulating levels of BNP are selectively increased before and during overt cardiac allograft rejection episodes in human patients. The data suggest that enhanced BNP plasma levels could form a basis for a noninvasive test for cardiac allograft rejection. However, the molecular mechanism by which expression of NPs are regulated in the transplanted heart is not well understood. Conditioned medium from mixed lymphocyte reaction cultures, considered an in vitro model of transplantation immunity, induces specific upregulation of BNP as do individual pro-inflammatory cytokines. Findings such as these suggest that the study of NPs will continue to produce a wealth of information relevant to basic and clinical scientists.Key words: atrial natriuretic factor, hypertension, hypertrophy, heart failure, cytokines.

Pathophysiological significance and clinical application of ANP and BNP in patients with heart failure

Plasma levels of ANP and BNP increase in accordance with the severity of the heart failure. In severe cases, the amount of BNP secreted surpasses that of ANP. The main secretion site of BNP is the ventricles, and that of ANP is the atria. However, ANP is also secreted from the ventricles as heart failure advances, and thus the ventricles are important sites for both BNP and ANP. It is well known that myocardial stretch is a key factor in the stimulation of the secretion of ANP and BNP, although neurohumoral factors also play a role in the secretion mechanism. The major physiological effects of ANP and BNP are vasodilation, natriuresis, and inhibition of the renin-angiotensin-aldosterone (RAA) and the sympathetic nervous systems; all of which are supposed to suppress the progression of heart failure. The inhibitory action of ANP and BNP on the RAA system has been considered to be an extra-cardiac effect. We recently reported the activation of an angiotensin-converting enzyme and aldosterone production in failing human hearts. ANP and BNP, however, would inhibit aldosterone production, not only in the adrenal cortex but also in cardiac tissue. ANP, and especially BNP, are useful markers of the heart's status during treatment for heart failure. The infusion of synthetic ANP (hANP) or BNP (Nesiritide) is effective in the treatment of acute heart failure. In Japan, BNP occupies an important position in the diagnosis of chronic heart failure, as ANP does in the treatment of acute heart failure.

Deconvolution analysis of cardiac natriuretic peptides during acute volume overload.

Cardiac natriuretic peptides, especially amino terminal pro-Brain Natriuretic Peptide (NT-proBNP), are emerging as powerful circulating markers of cardiac function. However, the in vivo secretion and elimination (t1/2) of these peptides during acute volume overload have not been studied. We present the first report of the secretion and elimination of cardiac natriuretic peptides, based on deconvolution analysis of endogenous ovine plasma levels measured by specific radioimmunoassay. Four normal, conscious sheep underwent rapid right ventricular pacing (225 bpm) for 1 hour to stimulate acute cardiac natriuretic peptide release. Plasma samples and right atrial pressure measurements were taken at regular intervals 30 minutes before, during, and 4 hours after pacing. Baseline right atrial pressure significantly increased (P:=0.02) during the 1 hour of pacing in association with a prompt increase in plasma BNP (P:=0.03), atrial natriuretic peptide (P:=0.01), and NT-proBNP (P:=0.02). Deconvolution analysis showed that the t1/2 of NT-proBNP (69.6+/-10.8 minutes) was 15-fold longer than BNP (4.8+/-1. 0 minutes). Despite sustained increases in atrial pressure, cardiac secretion of natriuretic peptides (particularly atrial natriuretic peptide) fell during the pacing period, suggesting a finite source of peptide for secretion. Size-exclusion high-performance liquid chromatography revealed NT-proBNP to be a single immunoreactive peak, whereas BNP comprised at least 2 immunoreactive forms. These findings, especially the prompt secretion of BNP and the prolonged t1/2 of NT-proBNP, clarify the metabolism of BNP forms and help to explain the diagnostic value of NT-proBNP measurement as a sensitive marker of ventricular function.

Amino-terminal proBNP in ovine plasma: evidence for enhanced secretion in response to cardiac overload.

We have recently identified a novel amino-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) in the circulation of humans, the concentration of which increases progressively as the left ventricle fails. To clarify the origins of NT-proBNP in experimental animals, we have developed an RIA for NT-proBNP based on residues 52-71 of ovine proBNP-(1-103) and used it to study cardiac processing, secretion, and metabolism of BNP in sheep with cardiac overload induced by coronary artery ligation (CAL) or rapid left ventricular pacing (rLVP). The concentration of NT-proBNP in left atrial plasma extracts drawn from normal control sheep was threefold that of mature BNP. Size-exclusion and reverse-phase HPLC analyses of plasma extracts coupled to RIA revealed a single peak of immunoreactive (ir) NT-proBNP [ approximately 8,000 relative molecular weight (Mr)], quite distinct from a single peak of ir-mature BNP ( approximately 3,000 Mr). In contrast, ovine cardiac tissue contained only a single immunoreactive peak of high-molecular-weight BNP ( approximately 11,000 Mr), consistent in size with proBNP-(1-103). Sampling from the cardiac coronary sinus in normal control sheep (n = 5) and sheep with CAL (n = 5) revealed that the molar ratio of NT-proBNP to mature BNP was similar. There was a significant gradient of both mature and NT-proBNP across the heart in normal sheep, whereas after CAL the gradient was significant for mature BNP only. In both forms of cardiac overload (CAL and rLVP), left atrial plasma levels of NT-proBNP were significantly increased above normal levels, in contrast with mature BNP levels, which were raised only in the rLVP group of animals. Blockade of natriuretic peptide metabolism in sheep with heart failure (induced by rLVP) raised mature BNP levels threefold but did not affect levels of NT-proBNP. In conclusion, these studies show that NT-proBNP is formed from proBNP stores during secretion and, compared with mature BNP, accumulates in plasma because metabolism of NT-proBNP appears to differ from that of mature BNP. Although its function, if any, remains unclear, plasma NT-proBNP may prove to be a sensitive marker of cardiac overload and/or decompensation.