Plasma ANP Levels Research Articles

Haemodynamic, hormonal and renal actions of osteocrin in normal sheep.

Osteocrin (OSTN) is an endogenous protein sharing structural similarities with the natriuretic peptides [NPs; atrial (ANP), B-type (BNP) and C-type (CNP) NP], which are hormones known for their crucial role in maintainingpressure/volume homeostasis. Osteocrin competes with the NPs for binding to the receptor involved in their clearance (NPR-C). In the present study, having identified, for the first time, the major circulating form of OSTN in human and ovine plasma, we examined the integrated haemodynamic, endocrine and renal effects of vehicle-controlled incremental infusions of ovine proOSTN (83-133) and its metabolism in eight conscious normal sheep. Incremental i.v. doses of OSTN produced stepwise increases in circulating concentrations of the peptide, and its metabolic clearance rate was inversely proportional to the dose. Osteocrin increased plasma levels of ANP, BNP and CNP in a dose-dependent manner, together with concentrations of their intracellular second messenger, cGMP. Increases in plasma cGMP were associated with progressive reductions in arterial pressure and central venous pressure. Plasma cAMP, renin and aldosterone were unchanged. Despite significant increases in urinary cGMP levels, OSTN administration was not associated with natriuresis or diuresis in normal sheep. These results support OSTN as an endogenous ligand for NPR-C in regulating plasma concentrations of NPs and associated cGMP-mediated bioactivity. Collectively, our findings support a role for OSTN in maintaining cardiovascular homeostasis.

Dapagliflozin Inhibits Ventricular Remodeling in Heart Failure Rats by Activating Autophagy through AMPK/mTOR Pathway.

Objective Heart failure (HF) is the end stage of heart disease caused by various factors which mainly involves ventricular remodeling (VR). In HF patients with reduced ejection fraction, dapagliflozin (DAPA) reduced the risk of worsening HF or cardiovascular death. Thus, we attempted to clarify the specific role of DAPA underlying HF progression. Methods The HF rat model was established to mimic characteristics of HF in vivo. HE staining assessed histopathological changes in left ventricular myocardial tissue of rats in each group. ELISA measured plasma ANP and BNP levels of rats in each group. M-mode echocardiography detected cardiac function of rats in each group. TUNEL staining detected apoptosis of infarct margin cells in myocardial tissue of rats in each group. Western blot detected levels of apoptosis-related proteins, autophagy-related proteins, and AMPK/mTOR-related proteins in myocardial tissue of rats in each group. Immunohistochemical staining detected caspase-3 or LC3B level in myocardial tissue of rats in each group. The HF cellular model was established to mimic characteristics of HF in vitro. Flow cytometry detected H9C2 cell apoptosis under different conditions. Western blot detected levels of apoptosis-related proteins, autophagy-related proteins, and AMPK/mTOR-related proteins in H9C2 cells under different conditions. Immunofluorescence detected caspase-3 or LC3B level in H9C2 cells under different conditions. Results DAPA attenuated left VR and improved cardiac function in HF rats. DAPA attenuated cardiomyocyte apoptosis in HF rats. DAPA facilitated cardiomyocyte autophagy in HF rats via the AMPK/mTOR pathway. DAPA repressed hypoxia-induced H9C2 cell apoptosis by facilitating autophagy. DAPA repressed hypoxia-induced H9C2 cell apoptosis via the AMPK/mTOR pathway. Conclusion DAPA suppresses ventricular remodeling in HF through activating autophagy via AMPK/mTOR pathway, which provides a potential novel insight for seeking therapeutic plans of HF.

Amelioration of Hypertension by Oryeongsan through Improvements of Body Fluid and Sodium Balance: Roles of the Renin-Angiotensin System and Atrial Natriuretic Peptide System.

Oryeongsan (Wulingsan in China and Goreisan in Japan), a formula composed of five herbal medicines, has long been used for the treatment of imbalance of the body fluid homeostasis in Asian countries. However, the mechanism by which Oryeongsan (ORS) improves the impaired body fluid and salt metabolism is not clearly defined. The present study was performed to define the role of the cardiorenal humoral system in the ORS-induced changes in blood pressure and renal function in hypertension. Experiments were performed in normotensive and two-kidney, one-clip hypertensive rats. Changes in the fluid and salt balance were measured in rats individually housed in metabolic cages. Changes in the systemic and local renin-angiotensin system (RAS) and cardiac natriuretic peptide hormone system (NPS) were evaluated. ORS water extract was administered by oral gavage (100 mg/kg daily) for 3 weeks. ORS induced diuresis and natriuresis along with an increase in glomerular filtration rate and downregulation of the Na+/H+ exchanger 3 (NHE3) and aquaporin 2 expression in the renal cortex and medulla, respectively. Furthermore, treatment with ORS significantly decreased systolic blood pressure with contraction of body sodium and water accumulation in hypertensive rats. ORS-induced changes were accompanied by modulation of the RAS and NPS, downregulation of the systemic RAS and cardiorenal expression of angiotensin-converting enzyme (ACE) and angiotensin II subtype 1 (AT1) receptor, and upregulation of the plasma ANP concentration and cardiorenal expression of ANP, ACE2, Mas receptor, and AT2 receptor. These findings indicate that ORS induces beneficial effects on the high blood pressure through modulation of the RAS and NPS of the cardiorenal system, suppression of the prohypertensive ACE-AT1 receptor pathway and NHE3, accentuation of the antihypertensive ACE2-Mas axis/AT2 receptor pathway in the kidney, suppression of the systemic RAS, and elevation of the plasma ANP levels and its synthesis in the heart. The present study provides a biological basis for the use of ORS in the treatment of impaired volume and pressure homeostasis.

Kinetics of atrial and brain natriuretic peptides during hemodialysis are regulated in association with different cardiac functional changes.

The blood levels of atrial and brain natriuretic peptides (ANP and BNP) are both increased markedly in hemodialysis patients, but the kinetics of the two are not always parallel. The present study investigated the association of changes in ANP and BNP levels before and after dialysis with changes in cardiac function in hemodialysis patients. A total of 57 patients (mean age 64years, 47 males and 10 females) on maintenance hemodialysis with sinus rhythm were enrolled. Blood samples were taken at the beginning and end of dialysis, and plasma levels of ANP and BNP were measured. Changes in cardiac function during dialysis were examined by echocardiography performed just before and after dialysis. Both plasma ANP and BNP concentrations decreased significantly after hemodialysis, but the rate of decrease in BNP [mean ± SD, 555 ± 503 to 519 ± 477pg/mL (-6.4%), P = 0.011] was much smaller than that in ANP [233 ± 123 to 132 ± 83pg/mL (-43.4%), P < 0.001]. As for the relation to the changes in echocardiographic parameters before and after dialysis, the decrease in inferior vena cava diameter had a close correlation with the decrease in ANP (r = 0.528, P < 0.001), but not BNP. In contrast, the decrease in left ventricular end-diastolic volume index was correlated only with the decrease in BNP (r = 0.297, P = 0.035). The peak velocity ratio of early diastolic to atrial filling decreased with preload reduction by dialysis, and its decrease was more strongly correlated with the decrease in BNP (r = 0.407, P = 0.002) than that in ANP (r = 0.273, P = 0.040). These results demonstrated that in hemodialysis patients, the decrease in plasma ANP by a single dialysis was essentially caused by blood volume reduction, while BNP decrease was mainly induced by the reduction of left ventricular overload. Our findings indicate that the kinetics of both peptides during dialysis are regulated by different cardiac and hemodynamic factors.

The Protective Role of the Long Pentraxin PTX3 in Spontaneously Hypertensive Rats with Heart Failure.

Pentraxin 3 (PTX3) is synthesized locally and released into the circulation, reflecting local inflammation in the cardiovascular system. Therefore, we conducted a study to explore the effect of PTX3 in spontaneously hypertensive heart failure (SHHF) rats. Sprague Dawley (SD) and SHHF rats were treated with recombinant PTX3 protein, and the blood pressure (BP) and echocardiographic parameters were collected. Radioimmunoassay, enzyme immunoassay and enzyme-linked immunosorbent assay (ELISA) were applied to detect plasma levels of atrial/B-type natriuretic peptide (ANP/BNP) and PTX3. The pathological changes in the myocardial tissues were observed by hematoxylin and eosin (HE) and Masson stainings. The mRNA and protein expressions were detected by quantitative real-time reverse-transcription polymerase chain reaction (qPCR) and western blotting. Cardiomyocyte apoptosis was evaluated by TUNEL staining and DNA fragmentation test. Increased plasma concentrations of PTX3 were found in SHHF rats compared with SD rats, which was further enhanced by recombinant PTX3 protein. After injection with recombinant PTX3 protein, the heart function was improved in SHHF rats with the decreased systolic and diastolic BP, and the reduced plasma levels of ANP and BNP. Moreover, PTX3 improved the myocardial damage and interstitial fibrosis in SHHF rats with reduced cardiomyocyte apoptosis and decreased mRNA expressions of pro-inflammatory factors in myocardial tissues. PTX3 could decrease the BP and plasma levels of ANP and BNP in SHHF rats, as well as improve the inflammation, cardiomyocyte apoptosis, and pathological changes of myocardial tissues, suggesting it may be a useful intervention in the treatment of SHHF.

Cardiac Natriuretic Peptide Profiles in Chronic Hypertension by Single or Sequentially Combined Renovascular and DOCA-Salt Treatments.

The involvement of natriuretic peptides was studied during the hypertrophic remodeling transition mediated by sequential exposure to chronic hemodynamic overload. We induced hypertension in rats by pressure (renovascular) or volume overload (DOCA-salt) during 6 and 12 weeks of treatment. We also studied the consecutive combination of both models in inverse sequences: RV 6 weeks/DS 6 weeks and DS 6 weeks/RV 6 weeks. All treated groups developed hypertension. Cardiac hypertrophy and left ventricular ANP gene expression were more pronounced in single DS than in single RV groups. BNP gene expression was positively correlated with left ventricular hypertrophy only in RV groups, while ANP gene expression was positively correlated with left ventricular hypertrophy only in DS groups. Combined models exhibited intermediate values between those of single groups at 6 and 12 weeks. The latter stimulus associated to the second applied overload is less effective than the former to trigger cardiac hypertrophy and to increase ANP and BNP gene expression. In addition, we suggest a correlation of ANP synthesis with volume overload and of BNP synthesis with pressure overload-induced hypertrophy after a prolonged treatment. Volume and pressure overload may be two mechanisms, among others, involved in the differential regulation of ANP and BNP gene expression in hypertrophied left ventricles. Plasma ANP levels reflect a response to plasma volume increase and volume overload, while circulating BNP levels seem to be regulated by cardiac BNP synthesis and ventricular hypertrophy.

Recombinant Soluble Corin Improves Cardiac Function in Mouse Models of Heart Failure

BackgroundCorin is a transmembrane protease that activates ANP and BNP (atrial and B‐type natriuretic peptides). Impaired corin expression and function are associated with heart failure. In this study, we characterized a soluble form of corin (sCorin) and examined its effects on cardiac morphology and function in mouse heart failure models.Methods and ResultssCorin, consisting of the full‐length extracellular fragment of human corin with an engineered activation site, was expressed in Chinese hamster ovary cells, purified from the conditioned medium with affinity chromatography, and characterized in pro‐ANP processing assays in vitro and pharmacokinetic studies in mice. Effects of sCorin on mouse models of heart failure induced by left coronary artery ligation and transverse aortic constriction were assessed by ELISA analysis of plasma markers, histologic examination, and echocardiography. We showed that purified and activated sCorin converted pro‐ANP to ANP that stimulated cGMP production in cultured cells. In mice, intravenously and intraperitoneally administered sCorin had plasma half‐lives of 3.5±0.1 and 8.3±0.3 hour, respectively. In the mouse heart failure models, intraperitoneal injection of sCorin increased plasma ANP, BNP, and cGMP levels; lowered plasma levels of NT‐proANP (N‐terminal‐pro‐ANP), angiotensin II, and aldosterone; reduced cardiac hypertrophy and fibrosis; and improved cardiac function.ConclusionsWe show that sCorin treatment enhanced natriuretic peptide processing and activity, suppressed the renin‐angiotensin‐aldosterone system, and improved cardiac morphology and function in mice with failing hearts.

Hypoxia augments NaHS-induced ANP secretion via KATP channel, HIF-1α and PPAR-γ pathway

It has been reported that sodium hydrosulfide (NaHS) stimulated high stretch induced-atrial natriuretic peptide (ANP) secretion via ATP sensitive potassium (KATP) channel. KATP channel is activated during hypoxic condition as a compensatory mechanism. However, whether NaHS affects ANP secretion during hypoxia remains obscure. The purpose of the present study is to discover the impact of NaHS on ANP secretion during hypoxia and to unravel its signaling pathway. Isolated beating rat atria were perfused with buffer exposed to different O2 tension (to 100% O2, normoxia; to 20% O2, hypoxia). The ANP secretion increased negatively correlated with O2 tension. NaHS (50 μM) did not show any significant effect on low stretch induced-ANP secretion in normoxic condition but augmented low stretch induced-ANP secretion in hypoxic condition. The augmentation of NaHS-induced ANP secretion during hypoxia was blocked by the pretreatment with KATP channel blocker (glibenclamide) and was enhanced by the pretreatment with KATP channel activator (pinacidil). Hypoxia increased the expression of PPAR-γ protein but did not change the expression of HIF-1α protein and eNOS phosphorylation. The NaHS-induced ANP secretion during hypoxia was also blocked by the pretreatment with HIF-1α inhibitor (2-methoxy- estradiol), PPAR−γ inhibitor (GW9662) but not by NOS inhibitor (L-NAME) and endothelin receptor inhibitor (bosentan). The intravenous infusion of NaHS increased plasma ANP level in monocrotaline-treated rats but not in sham rats. These results suggest that hypoxia augmented NaHS-induced ANP secretion partly through KATP channel, HIF-1α, and PPAR−γ pathway.

Possible Enzymatic Downregulation of the Natriuretic Peptide System in Patients with Reduced Systolic Function and Heart Failure: A Pilot Study

Background In patients with reduced systolic function, the natriuretic peptide system affects heart failure (HF) progression, but the expression of key activating (corin) and degrading enzymes (neprilysin) is not well understood. Methods and Results This pilot study (n=48) compared plasma levels of corin, neprilysin, ANP, BNP, and cGMP in control patients with normal ejection fractions (mean EF 63 ± 3%) versus patients with systolic dysfunction, with (EF 24 ± 8%) and without (EF 27 ± 7%) decompensated HF (dHF), as defined by Framingham and BNP criteria. Mean ages, use of beta blockers, and ACE-inhibitors-angiotensin receptor blockers were similar between the groups. Corin levels were depressed in systolic dysfunction patients (797 ± 346 pg/ml) versus controls (1188 ± 549, p<0.02), but levels were not affected by dHF (p=0.77). In contrast, levels of neprilysin (p<0.01), cGMP (p<0.001), and ANP (p<0.001) were higher in systolic dysfunction patients than controls and were the highest in patients with dHF. Conclusions Levels of neprilysin, ANP, BNP, and cGMP increased in patients with reduced systolic function and were the highest in dHF patients. Conversely, corin levels were low in patients with reduced EF with or without dHF. This pattern suggests possible enzymatic downregulation of natriuretic peptide activity in patients with reduced EF, which may have diagnostic and prognostic implications.

Extracellular Volume Expansion Uncovers a Natriuretic Action of Glucagon-Like Peptide-1

We have previously demonstrated that the gut hormone glucagon-like peptide-1 (GLP-1) does not affect renal hemodynamics or function at baseline conditions in healthy individuals and in patients with type 2 diabetes mellitus. However, it is possible that GLP-1 promotes renal NaCl excretion under conditions with addition of salt and water to the extracellular fluid (mimicking a mixed meal/daily NaCl load). The present study was designed to investigate whether GLP-1 induces natriuresis in healthy, volume overloaded individuals. Under fixed sodium intake, 8 healthy men were examined twice in random order during a 3-hour infusion of either GLP-1(1.5 pmol kg-1 min-1) or vehicle together with an intravenous infusion of 0.9% NaCl (750 ml/hour) given throughout both experiments. Timed urine collections were conducted throughout the experiments at voluntary voiding, and subjects remained supine during the experiments. Renal plasma flow (RPF), glomerular filtration rate (GFR), and uptake/release of hormones and ions were measured using Fick’s Principle after catheterization of a renal vein and an artery. During GLP-1 infusion, urinary sodium excretion increased compared to vehicle infusion (193 ± 40 mmol/180 min vs. 89 00B110 mmol/180 min, p&amp;lt;0.05), whereas GLP-1 had no significant effect on urine flow rate (1666 ± 284 ml/180 min vs. 1189 ± 132 ml/180 min, p=0.184). Plasma renin levels decreased similarly on both days, whereas angiotensin II levels decreased significantly only during GLP-1 infusion. During GLP-1 infusion, GLP-1 was extracted by the kidneys by about 50%. RPF and GFR remained unchanged on both days. Plasma proANP, ANP, and BNP levels remained unchanged on both days. This study shows that physiologically relevant changes in GLP-1 induce significant natriuresis independent of measurable changes in RPF and GFR in volume overloaded subjects. The natriuresis is likely brought about via a tubular mechanism secondary to suppression angiotensin II. Disclosure A. Asmar: None. P.K. Cramon: Employee; Spouse/Partner; Novo Nordisk A/S. L. Simonsen: None. M. Asmar: None. C.M. Sorensen: None. S. Madsbad: Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Eli Lilly and Company, Eli Lilly and Company. Advisory Panel; Self; Merck Sharp &amp; Dohme Corp., Sanofi-Aventis, Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. C. Moro: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. B.L. Jensen: None. J. Bülow: None.

Prediction of postoperative atrial fibrillation with left atrial mechanical functions and NT‐pro ANP levels after coronary artery bypass surgery: A three‐dimensional echocardiography study

Postoperative AF (POAF) is the most common cause of morbidity after coronary artery bypass surgery. In this study, we aimed to show the relationship between POAF and N-terminal pro-atrial natriuretic peptide (NT-pro ANP) levels and the relationship between mechanical functions and left atrial volume measured using preoperative three-dimensional echocardiography (3D ECHO) among patients that will undergo isolated coronary artery bypass grafting (CABG) in elective conditions. Sixty-six consecutive patients (51 male, 15 female) who were decided to undergo CABG and had normal sinus rhythm were involved in the study. Patients were followed by continuous electrocardiography monitoring and daily electrocardiogram. LA volume and mechanical functions were calculated with 3D ECHO. In addition, for the analysis of plasma levels of NT-pro ANP, blood samples were collected before the surgery. During follow-up after the operation, 15 patients (22.7%) had postoperative atrial fibrillation. LA Vmax, Vmin, VpreA values were higher (P<.001, P=.004, P<.001 respectively) Also in POAF-developed group and SR group, LAVI values were 27.56±4.2 and 20.7±4.64mL/m2 , respectively (P<.001). In POAF-developing group, NT-pro ANP levels were significantly higher (P<.001). In multiple logistic regression analysis, age (β=0.355, P=.007) and LAVI (β=0.668, P=.012) are independent predictors of POAF. It was found that 3D echocardiography can be used as a helping noninvasive method to show subclinical atrial volume and mechanical dysfunction in patients undergoing CABG. Also, blood levels of NT-pro ANP in POAF group were increased.

Plasma levels of heart failure biomarkers are primarily a reflection of extracardiac production

Plasma heart failure (HF) biomarkers, like natriuretic peptides, are important in diagnosis, prognosis and HF treatment. Several novel HF biomarkers have been identified, including Gal-3, GDF-15 and TIMP-1, but their clinical potential remains vague. Here we investigated plasma biomarker levels in relation to tissue expression and structural and functional cardiac changes.Methods: Cardiac remodeling, cardiac function, and plasma and tissue biomarker levels were investigated in mice after myocardial infarction induced by temporal and permanent LAD ligation (tLAD and pLAD). In addition, a pressure overload model induced by transverse aortic constriction (TAC) and an obese/hypertensive HFpEF-like mouse model were investigated.Results: Plasma levels of ANP and its cardiac expression were strictly associated with cardiac remodeling and function. Gal-3, GDF-15 and TIMP-1 cardiac expressions were also related to cardiac remodeling and function, but not their plasma levels. Only directly after myocardial infarction could elevated plasma levels of Gal-3 and TIMP-1 be detected. Eight weeks after infarction, plasma levels were not elevated despite enhanced cardiac expression and low EF (18.3±3.3%, pLAD). Plasma levels of TIMP-1 and GDF-15 were elevated after TAC, but this also correlated with increased lung expression and congestion. In obese-hypertensive mice, elevated plasma levels of Gal-3, GDF-15 and TIMP1 were associated with increased adipose tissue expression and not with cardiac function.Conclusions: The Gal-3, GDF-15 and TIMP-1 plasma pool levels are hardly influenced by dynamic changes in cardiac expression. These biomarkers are not specific for indices of cardiac remodeling, but predominantly reflect stress in other affected tissues and hence provide health information beyond the heart.

Oleanolic acid modulates the renin-angiotensin system and cardiac natriuretic hormone concomitantly with volume and pressure balance in rats

Oleanolic acid is known to possess beneficial effects on the regulation of the cardiovascular homeostasis. However, the exact nature of the role of oleanolic acid on the regulation of body fluid balance and blood pressure homeostasis and its mechanisms involved are not well defined. Experiments were performed to identify the effects of oleanolic acid on the renin-angiotensin system and cardiac natriuretic hormone (ANP) system, and also renal function and blood pressure in normotensive and renovascular hypertensive rats. The change in the plasma levels of hormones and the expressions of renin, angiotensin II receptors, ANP, natriuretic peptide receptor-C, M2 muscarinic receptor and GIRK4 were determined in the kidney, heart and aorta. Oleanolic acid was administered orally for 1 or 3 weeks. Here, we found that oleanolic acid suppressed plasma levels of renin activity and aldosterone and intrarenal levels of renin and angiotensin II type 1 receptor expression and increased angiotensin II type 2 receptor in normotensive and hypertensive rats. Also, oleanolic acid increased plasma levels of ANP. Further, oleanolic acid suppressed angiotensin II type 1 receptor and natriuretic peptide receptor-C expression and increased angiotensin II type 2 receptor and ANP expression in the heart and aorta. Along with these changes, oleanolic acid accentuated urinary volume, electrolyte excretion and glomerular filtration rate in normotensive rats and suppressed arterial blood pressure in hypertensive rats. These findings suggest that beneficial effects of oleanolic acid on the cardiorenal system are closely associated with its roles on the renin-angiotensin system and cardiac natriuretic hormone system.

Plasma levels of natriuretic peptides and year-by-year blood pressure variability: a population-based study.

Augmented blood pressure (BP) variability over various time periods has been recognized as a risk factor for cardiovascular diseases. Both atrial and B-type natriuretic peptides (ANP and BNP) are secreted in response to volume or pressure overload to the heart, exerting natriuretic and vasodilator actions. In this study, we examined the relationships between year-by-year BP variability and plasma levels of ANP and BNP in the general population. Study subjects were local residents receiving an annual heath checkup, who had an estimated glomerular filtration rate of >30 ml min-1 per 1.73 m2 and no history of heart disease. Of those, we selected 314 subjects that received checkups at least five times over the past 6 years. BP variability year-by-year was retrospectively evaluated by s.d., coefficient of variation, average real variability and variation independent of the mean of BP values of 6 or 7 time points. The four parameters of BP variability were each found to significantly correlate with logarithmically transformed ANP and BNP levels by simple regression. When classified by quartiles of s.d. of systolic BP, the highest quartile group showed significantly higher levels of the natriuretic peptides compared with other groups. Multivariate analyses revealed that BP variability was an independent determinant for the ANP and BNP levels. In conclusion, augmented year-by-year BP variability over the past 6 years was associated with elevation of plasma levels of ANP and BNP, suggesting a possible relationship between the BP variability and cardiac load, in the general population.

Changes in Plasma Levels of Atrial Natriuretic Peptide and B-Type Natriuretic Peptide after Surgical Therapy of Atrial Fibrillation

Objective: In patients undergoing surgical therapy of atrial fibrillation (AF), left atrial appendage (LAA) amputation is discussed controversially, because the LAA is a hormone-producing organ. We examined patients after surgical AF therapy with or without LAA amputation to determine the influence of LAA amputation on ANP and BNP plasma levels.

ANP and BNP plasma levels in patients with rheumatic mitral stenosis after percutaneous balloon mitral valvuloplasty.

IntroductionAtrial (ANP) and B-type (BNP) natriuretic peptides are hormones secreted by the heart as a response to volume expansion and pressure overload.AimTo assess the changes of ANP and BNP after percutaneous balloon mitral valvuloplasty (PBMV) and to investigate factors associated with endpoints.Material and methodsThe study included 96 patients (90.7% females, age 51.6 ±12.2 years) with rheumatic mitral valve stenosis (mitral valve area (MVA) 1.18 (1.01–1.33) cm2, mean mitral gradient (MMG) 8.2 (7.1–9.2) mm Hg, NYHA 2.09 (1.9–2.5)). Patients were followed up for 29.1 months for the search of endpoints.ResultsThe PBMV was successful in all cases. After the procedure MVA increased (1.18–1.78 cm2, p < 0.01) and pulmonary capillary wedge pressure (PCWP) decreased (29.8–21.8 mm Hg, p < 0.01). Concentration of ANP significantly rose 30 min after the PBMV (79.2 vs. 134.2 pg/ml, p = 0.012) and dropped significantly after 24 h (134.2 vs. 70.4 pg/ml, p = 0.01). Furthermore, after 36 months concentration of ANP did not differ from the baseline value (p = NS). BNP concentration at day 1 was lower than at baseline (94.5 vs. 80.2 pg/ml, p = 0.032). Moreover, during the follow-up period BNP continued to fall at all time points. In univariate analysis parameters associated with endpoint occurrence were baseline PAP (p = 0.023), baseline PCWP (p = 0.022), baseline NYHA (p = 0.041) and increase in 6-minute walk test (6MWT) (p = 0.043). In multivariate analysis the only factor associated with endpoint occurrence was baseline NYHA (HR = 1.52, 95% CI: –1.3–1.91, p = 0.022).ConclusionsPatients with MS had increased levels of both BNP and ANP. Baseline NYHA class was found to be associated with outcomes after the procedure.

Immune-Inflammatory and Metabolic Effects of High Dose Furosemide plus Hypertonic Saline Solution (HSS) Treatment in Cirrhotic Subjects with Refractory Ascites.

IntroductionPatients with chronic liver diseases are usually thin as a result of hypermetabolism and malnutrition expressed by reduced levels of leptin and impairment of other adyponectins such as visfatin.AimsWe evaluated the metabolic and inflammatory effects of intravenous high-dose furosemide plus hypertonic saline solutions (HSS) compared with repeated paracentesis and a standard oral diuretic schedule, in patients with cirrhosis and refractory ascites.Methods59 consecutive cirrhotic patients with refractory ascites unresponsive to outpatient treatment. Enrolled subjects were randomized to treatment with intravenous infusion of furosemide (125–250mg⁄bid) plus small volumes of HSS from the first day after admission until 3 days before discharge (Group A, n:38), or repeated paracentesis from the first day after admission until 3 days before discharge (Group B, n: 21). Plasma levels of ANP, BNP, Leptin, visfatin, IL-1β, TNF-a, IL-6 were measured before and after the two type of treatment.ResultsSubjects in group A were observed to have a significant reduction of serum levels of TNF-α, IL-1β, IL-6, ANP, BNP, and visfatin, thus regarding primary efficacy endpoints, in Group A vs. Group B we observed higher Δ-TNF-α, Δ-IL-1β, Δ-IL-6, Δ-ANP, Δ-BNP, Δ-visfatin, Δ-Leptin at discharge.DiscussionOur findings underline the possible inflammatory and metabolic effect of saline overload correction in treatment of cirrhosis complications such as refractory ascites, suggesting a possible role of inflammatory and metabolic-nutritional variables as severity markers in these patients.

Abstract 423: Potential Role of Natriuretic Peptides in Atherosclerosis and Inflammation

Background: Brain natriuretic peptide (BNP) is currently recognized as one of the important markers of Congestive heart failure (CHF). BNP levels are simple and objective measures of cardiac function in patients with ischemic injury. These measurements can be used to diagnose HF, including diastolic dysfunction and inflammation. Plasma levels of BNP and ANP are elevated in CHF, especially after myocardial infarction (MI). Furthermore, within the heart tissue, gene expression of BNP and ANP is reportedly up-regulated in animal models with MI and CHF, and in human heart disease. In this study, we tested the natriuretic peptides ability in reduction of peroxides as well as inflammation Methods: BNP and ANP were commercially synthesized and their ability to reduce lipid peroxides (LOOH) was measured using 13-hydroperoxyoctadecadienoic acid (13-HPODE). Low density lipoprotein (LDL) was isolated from human plasma and its oxidation was performed using copper in the presence or absence of the peptides. The ability of these peptides to neutralize charges of modified lipoproteins, as well as attenuate inflammation, were analyzed. Oxidized LDL (Ox-LDL)/Ac-LDL was pretreated with increasing concentrations of peptides to evaluate charge neutralizing properties of the peptides. RAW cells were incubated with LPS pretreated with peptides. RNA was isolated from treated cells and real time PCR was performed using mouse IL-1α and IL-6 primers. Results: Natriuretic peptides reduced 13-HPODE and inhibited the oxidation of LDL. Reduced IL-1α and IL-6 gene expression was observed in the presence of LPS. Conclusion: The results of our studies suggest that these peptides a) inhibit the oxidation of LDL and b) have an inhibitory effect on inflammatory cytokine/gene production in the presence of LPS. Based on these results, we predict that natriuretic peptides could have therapeutic potential in reducing CVD/atherosclerosis-associated inflammation.

Depressed Corin Levels Indicate Early Systolic Dysfunction Before Increases of Atrial Natriuretic Peptide/B-Type Natriuretic Peptide and Heart Failure Development

Dilated cardiomyopathy is a major cause of heart failure (HF) that affects millions. Corin cleaves and biologically activates pro-atrial natriuretic peptide (pro-ANP) and pro-B-type natriuretic peptide (pro-BNP). High corin levels reduce the development of systolic dysfunction and HF in experimental dilated cardiomyopathy. Yet, patients with significant HF unexpectedly show low corin levels with high plasma ANP/BNP levels. Therefore, we examined the relationship between cardiac corin expression, ANP/BNP levels, and the stages of HF. We used a well-established, dilated cardiomyopathy model to evaluate gene and protein expression as mice longitudinally developed Stages A-D HF. Cardiac systolic function (ejection fraction) continuously declined over time (P<0.001). Cardiac corin transcripts were decreased at early Stage B HF and remained low through Stages C and D (P<0.001). Cardiac corin levels were positively correlated with systolic function (r=0.96, P=0.003) and inversely with lung water (r=-0.92, P=0.001). In contrast, cardiac pro-ANP/BNP transcripts increased later (Stages C and D) and plasma levels rose only with terminal HF (Stage D, P<0.001). Immunoreactive plasma ANP and BNP levels were positively associated with plasma cyclic guanosine monophosphate levels (r=0.82, P=0.01 and r=0.8, P=0.02, respectively). In experimental dilated cardiomyopathy, corin levels declined early with progressive systolic dysfunction before the development of HF, whereas significant increases in plasma ANP, BNP, and cyclic guanosine monophosphate levels were found only in later stage (C and D) HF. This dyssynchrony in expression of corin versus ANP/BNP may impair cleavage activation of pro-natriuretic peptides, and thereby promote the transition from earlier to later stage HF.

Plasma levels of natriuretic peptides and development of chronic kidney disease.

BackgroundPlasma levels of atrial and brain natriuretic peptides (ANP and BNP) are increased in patients with chronic kidney disease (CKD) complicated with deteriorated kidney function, but the relationship between the plasma level of ANP or BNP and the future development of CKD is unclear.MethodsWe measured the plasma ANP and BNP levels of 294 local residents without CKD in a Japanese community (56.5 ± 10.4 years, mean ± S.D.), who were followed up for the development of CKD over the next 7 years.ResultsSixty-three residents developed CKD during the follow-up period, and the baseline level of plasma ANP of these residents was significantly higher than in those without CKD development. Kaplan-Meier analysis showed that the residents with higher ANP than the median value developed CKD more frequently than those with lower ANP. The association between plasma ANP level and CKD development was found to be independent of baseline estimated glomerular filtration rate by a Cox proportional hazards model, while this association became insignificant when adjusted by age; plasma ANP was significantly correlated with age. Compared with ANP, the relationship between plasma BNP and CKD development was unclear in these analyses.ConclusionsAge-related elevation of plasma ANP levels preceded the development of CKD in the general population of Japan, raising a possibility for ANP being involved in the development of CKD.