Recombinant Human B-type Natriuretic Peptide Research Articles

New pharmacological treatments for heart failure with reduced ejection fraction (HFrEF): A Bayesian network meta-analysis.

Background:Heart failure with reduced ejection fraction (HFrEF) has contributed to an increasing number of deaths and readmissions over the past few decades. Despite the appearance of standard treatments, including diuretics, β-receptor blockers and angiotensin-converting enzyme inhibitor (ACEI), there are still a large number of patients who have progressive deterioration of heart function and, inevitably, end-stage heart failure. In recent years, new medications for treating chronic heart failure have been clinically applied, but there is controversy surrounding drug selection and whether patients with HFrEF benefit from these medications. Therefore, we aimed to compare and rank different new pharmacological treatments in patients with HFrEF.Methods:We performed a network meta-analysis to identify both direct and indirect evidence from relevant studies. We searched MEDLINE, EMBASE, and PsycINFO through the OVID database and CENTRAL through the Cochrane Library for clinical randomized controlled trials investigating new pharmacological treatments in patients with HFrEF published up to September 30, 2018. We included trials of ivabradine, levosimendan, omega-3, tolvaptan, recombinant human B-type natriuretic peptide (rhBNP), isosorbide dinitrate and hydralazine (ISDN/HYD) and angiotensin-neprilysin inhibition (LCZ696). We extracted the relevant information from these trials with a predefined data extraction sheet and assessed the risk of bias with the Cochrane risk of bias tool. Based on these items, more than half of the entries were judged as having an overall low to moderate risk of bias; the remaining studies had a high or unclear risk of bias. The outcomes investigated were left ventricle ejection fraction (LVEF %), heart rate (HR) and serum level of B-type natriuretic peptide (BNP). We performed a random-effects network meta-analysis within a Bayesian framework.Results:We deemed 32 trials to be eligible that included 3810 patients and 32 treatments. Overall, 32 (94.1%) trials had a low to moderate risk of bias, while 2 (5.9%) trials had a high risk of bias. The quality of the included studies was rated as low in regard to allocation concealment and blinding and high in regard to other domains according to the Cochrane tools. As for increasing LVEF%, levosimendan was better than placebo (–3.77 (–4.96, –2.43)) and was the best intervention for improving ventricle contraction. As for controlling HR, n3-PUFA was better than placebo (4.01 (–0.44, 8.48)) and was the best choice for regulating HR. As for decreasing BNP, omega-3 was better than placebo (941.99 (–47.48, 1952.89) and was the best therapy for improving ventricle wall tension.Conclusions:Our study confirmed the effectiveness of the included new pharmacological treatments for optimizing the structural performance and improving the cardiac function in the management of patients with HFrEF and recommended several interventions for clinical practice.

Beneficial effects of early administration of recombinant human B-type natriuretic peptide in ST-elevation myocardial infarction patients receiving percutaneous coronary intervention treatment.

We aimed to evaluate the clinical performance of early administration of recombinant human B-type natriuretic peptide (rhBNP) to ST-elevation myocardial infarction (STEMI) patients receiving percutaneous coronary intervention (PCI) treatment. In total, 185 patients diagnosed with STEMI were enrolled and randomised into either the placebo-treated (n = 88) or rhBNP-treated (n = 97) group. Patients were given either saline or rhBNP ten minutes before PCI and monitored with various cardiac parameters, including accelerated idioventricular rhythm, frequent ventricular premature beat (FVPB), ventricular tachycardia, systolic blood pressure, thrombolysis in myocardial infarction (TIMI) 3 gradation, corrected TIMI frame count (cTFC) and myocardial blush grade (MBG) 3 classification. Our results revealed no difference in accelerated idioventricular rhythm between the two groups. However, FVPB and ventricular tachycardia were significantly decreased in rhBNP-treated patients compared to placebo-treated patients (p < 0.05). Moreover, the occurrence ratio of reperfusion-associated low blood pressure in rhBNP-treated patients was lower than in placebo-treated patients (p = 0.03), while no difference was observed in infarction-related arteries TIMI 3 blood flow between the two groups (p = 0.23). Importantly, measurement of post-reperfusion blood flow velocity via cTFC suggested that rhBNP treatment could significantly increase blood circulation (p = 0.003). After stent implantation, the acquisition rate of MBG 3 was higher in rhBNP-treated patients compared to placebo-treated patients (p = 0.071), although the difference was not significant. We concluded that early administration of rhBNP can ameliorate the severity of reperfusion injury for STEMI patients receiving PCI treatment.

B-type natriuretic peptide enhances fibrotic effects via matrix metalloproteinase-2 expression in the mouse atrium in vivo and in human atrial myofibroblasts in vitro

B-type natriuretic peptide (BNP) was approved by the US Food and Drug Administration in 2001 for the treatment of heart failure. However, the effects of BNP in clinical applications are controversial and uncertain. Recently, study indicated that high BNP levels are associated with an increased risk of developing atrial fibrillation. In this study, we investigated the direct effects of BNP on TNF-α-induced atrial fibrosis mice, as well as its effects on human atrial myofibroblasts. We found that injecting TNF-α-induced mice with recombinant human BNP enhanced atrial fibrosis via matrix metalloproteinase-2 (MMP-2) expression and collagen accumulation. Furthermore, we found that BNP stimulated MMP-2 expression in human atrial myofibroblasts. Treatment of human atrial myofibroblasts with cycloheximide had no effect on this outcome; however, treatment of cells with MG132 enhanced BNP-induced MMP-2 expression, indicating that protein stability and inhibition of proteasome-mediated protein degradation pathways are potentially involved. Inhibition of SIRT1 significantly decreased BNP-induced MMP-2 expression. Additionally, confocal and coimmunoprecipitation data indicated that BNP-regulated MMP-2 expression are likely to be mediated through direct interaction with SIRT1, which is thought to deacetylate MMP-2 and to increase its protein stability in human atrial myofibroblasts. Finally, we confirmed that SIRT1 is expressed and cytoplasmically redistributed as well as colocalized with MMP-2 in mouse fibrotic atrial tissue. We suggest a possible fibrosis-promoting role of BNP in the atrium, although the antifibrotic properties of BNP in the ventricle have been reported in previous studies, and that the coordination between MMP-2 and SIRT1 in BNP-induced atrial myofibroblasts participates in atrial fibrosis.

Continuous administration of recombinant human B-type natriuretic peptide can improve heart and renal function in patients after cardiopulmonary bypass surgery.

Any cardiac surgery under cardiopulmonary bypass (CPB) will induce ischemia-reperfusion injury and systematic inflammatory response, which may lead to exacerbation. Conventional therapy strategy is to use inotropes, diuretics and vasodilator drugs, yet, the therapeutic effects of which need to be improved. Recombinant human B-type natriuretic peptide (rhBNP) has been shown to be efficacious in the treatment of acute decompensated heart failure and acute myocardial infarction. However, the effects of rhBNP on patients carried out CPB surgery is unknown. We retrospect 357 patients carried out CPB surgery between Jan 1st 2014 and Dec 31st 2015 of our department. And according the use of rhBNP, these patients were divided into two groups: rhBNP group and control group. Patients in rhBNP group were received continuous intravenous rhBNP (0.0075-0.01 µg/kg/min) in 6 hours after CPB surgery, for a period of 72 h. Hemodynamic parameters were measured immediately after CPB surgery, and then at 2, 4, 8, 12 and 24 h after surgery. Blood samples were obtained immediately after surgery and thereafter once a day at 6:00 AM within the first 3 days after surgery. The daily urine volume as well as the time of tracheal intubation, ICU stay and chest drainage were also recorded. The baseline characteristics and heart functions were well balanced between two groups, and no patient died in the surgery. It showed significant differences in time-dependent changes in both groups of MAP (P<0.0001, within groups), MPAP (P<0.0001, within groups), PAWP (P<0.0001, within groups), CI (P<0.0001, within groups), SVRI (P<0.0001, within groups), serum BNP (P<0.0001, within groups), CK-MB (P<0.0001, within groups), troponin (P<0.0001, within groups) and creatinine (P<0.0001, within groups). It also showed significant differences in time-dependent changes between the two groups of MAP (P=0.04, between groups), PAWP (P=0.04, between groups), serum troponin (P<0.0001, between groups), serum creatinine (P<0.0001, between groups) and urine volume (P<0.0001, between groups). Interestingly, our results showed that patients in rhBNP group tended to wean off the respirator half a day later than those in control group (P=0.05), while no significant difference showed in both the length of chest drainage time and intensive care unit stay between the two groups. The administration of rhBNP can improve heart and renal function in patients underwent CPB surgery as well as accelerating the recovery from myocardial injury. But the prognosis of the patients who were administrated rhBNP did not improve in our study.

Effects of pretreatment with recombinant human B-type natriuretic peptide on infarct size in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention

To investigate whether the administration of recombinant human B-type natriuretic peptide (rhBNP) before primary percutaneous coronary intervention (PCI) could further limit the infract size, improve left ventricular function, and alleviate cardiac dilation in patients with acute ST-segment elevation myocardial infarction(STEMI). A total of 93 consecutive patients presenting chest pain within 12 hours from the onset, suspicious of first STEMI located at anterior wall undergoing primary PCI, were eligible for enrollment and randomly assigned to either rhBNP group (rhBNP administration starting at 5 min before PCI, 1.5 µg/kg bolus intravenous injection followed by 0.007 5-0.03 µg·kg(-1)·min(-1) for up to 120 hours, n=48) or nitroglycerin (NIT) group (NIT treatment starting at 5 min before PCI, 10-100 µg/min intravenous infusion for 120 hours, n=45). Primary PCI was performed in both groups using post-conditioning (PC) technique. TIMI flow grade, corrected TIMI frame count, and TIMI myocardial perfusion grade were compared between the two groups at the time of infarct related artery (IRA) re-patency. The levels of serum creatine kinase MB isoenzyme (CK-MB) and troponin I (TnI) were measured. Echocardiography was performed at baseline 7 days and 6 months later. Baseline characteristics were similar between the two groups. The percentage of TIMI grade 3 and TIMI myocardial perfusion grade 3 after PCI both tended to be higher in rhBNP group than those in NIT group (95.8%(46/48) vs. 86.7%(39/45), P=0.162) and (72.9%(35/48) vs. 62.2%(28/45), P=0.500). The corrected TIMI frame count was significantly decreased in rhBNP group (21.0±8.7 vs. 28.2±14.8, P=0.005). The myocardial infarct size expressed as the AUC of CK-MB ((3 249±1 101) U/L vs. (4 474±1 661)U/L, P=0.010) or AUC of TnI ((3 670±942) µg/L vs. (4 541±1 098) µg/L, P=0.021) was significantly decreased in rhBNP group compared with those in NIT group. At 7 days after primary PCI, the left ventricular ejection fraction (LVEF) tended to be higher (P>0.05), while the E/e' index and wall motion score index (WMSI) ((11.95±3.31 vs. 14.60±4.09, P=0.030) and (1.74±0.17 vs. 2.40±0.55, P<0.001)) were significantly improved in rhBNP group compared with those in NIT group. BNP level was also significantly lower in rhBNP group compared that in NIT group ((68.3±37.8) ng/L vs. (129.4±64.4) ng/L, P<0.001). During 6-month follow-up, LVEF and WMSI were significantly improved in rhBNP group compared those in NIT group(51.7%±12.7% vs. 46.9%±9.6%, P=0.024 and 1.69±0.35 vs. 1.92±0.47, P=0.020). Administration of rhBNP before PCI with post-conditioning procedure can further improve myocardial perfusion, limit myocardial infarct size, ameliorate cardiac dysfunction and postpone left ventricular early-stage and long-term remodeling in STEMI patients undergoing primary PCI.

Increased yield of high purity recombinant human brain natriuretic peptide by acid hydrolysis of short fusion partner in Escherichia coli

Recombinant human B-type natriuretic peptide (rhBNP) is a 32-amino acid peptide used to treat congestive heart failure. In this paper, we report a method for the increased production of rhBNP in Escherichia coli with high purity. hBNP was cloned with a short growth hormone fusion partner coupled with a unique acid-labile dipeptide linker to cleave the fusion protein to release the rhBNP. The recombinant fusion protein was expressed as an inclusion body (IB) and the fermentation process was optimized to produce on large scale. The IBs were recovered by cell lysis, and the pure IBs were directly treated with diluted acid to get the target peptide from the fusion protein and the resultant peptide was purified by reversed phase chromatography. The final purity of the rhBNP was more than 99% with yield of 50mg per liter of culture, which is ten times higher than the previous reports. The purified rhBNP exhibited specific biological activity similar to the standard peptide in producing cyclic-guanosine monophosphate.

Genetic and Nongenetic Factors Influencing Pharmacokinetics of B-Type Natriuretic Peptide

BackgroundNatriuretic peptides (NPs) represent a critical pathway in heart failure (HF). However, there is wide individual variability in NP system activity, which could be partly genetic in origin. We explored genetic and nongenetic contributions to B-type natriuretic peptide (BNP) inactivation. MethodsChronic HF patients (n = 95) received recombinant human BNP (nesiritide) at standard doses, and BNP levels were measured at baseline, after 2 hours of infusion, and 30 minutes after discontinuation. Genomic DNA was genotyped for 91 single-nucleotide polymorphisms (SNP) in 2 candidate genes. We tested the association of patient characteristics and genotype with 5 pharmacokinetics (PK) parameters: elimination rate constant, ΔBNP, BNP clearance, adjusted BNP clearance, and half-life. Linear regression with pleiotropic analysis was used to test genotype associations with PK. ResultsParticipants’ mean age was 63 years, 44% were female, and 46% were African American. PK parameters varied widely, some >10-fold. HF type (preserved vs reduced) was associated with PK (P < .01), whereas renal function, demographics, and body mass index and were not. Two SNPs in MME (rs989692, rs6798179) and 2 in NPR3 (rs6880564, rs2062708) also had associations with PK (P < .05). ConclusionsThe pharmacokinetics of BNP varies greatly in HF patients, differs by HF type, and possibly by MME or NPR3 genotype. Additional study is warranted.

Atorvastatin Attenuates Atrial Remodeling by Its Anti-Oxidant and Anti-Inflammatory Action

Introduction: Infusion of nesiritide (recombinant human B-type natriuretic peptide (BNP)) lowers blood pressure and may cause natriuresis, but these effects are highly variable between individuals. How much of this variability is genetic is unknown. Hypothesis: Genetic variants in BNP clearance mechanisms will affect drug elimination rate and may thus impact its clinical effects. Methods: Patients with heart failure (n537, 24 men, 19 African Americans) who received nesiritide infusion at standard doses (0.005-0.01 mcg/kg/min) were studied. Subjects were closely monitored during a 1 hour baseline period and a 2 hour infusion period. BNP levels were measured during the baseline and infusion periods, as was urine sodium (Na) excretion and mean arterial pressure (MAP). DNA was extracted from blood and genotyped for 71 sequence variants in membrane metallo-endopeptidase (MME) and natriuretic peptide receptor 3 (NPR3), the two key clearance mechanisms for BNP. Elimination rate constant (K) was calculated using the difference in BNP level from baseline to 2-hours of infusion (C), the infusion rate (k0), and the estimated volume of distribution (0.073 L/kg, V) according to the equation K5k0/(C*V). We first tested the association of NPR3 and MME genotypes (additive model) with K, then examined changes in Na excretion and MAP for variants of interest. P!0.01 was considered significant. Results: Two NPR3 sites, rs11749133 and rs16890196 were associated K (p50.0055, 0.0092, respectively) with O4 fold difference in K between homozygous genotype groups (median K 5 0.06 vs. 0.3 for AA vs. GG). These genotypes were also associated with differences in sodium excretion (p50.0017, 0.0096, respectively); While Na excretion declined overall with nesiritide, it was better preserved in the AA group (slower elimination) compared to GG group (rapid elimination) with median decline in Na excretion of 3,300meq/hr vs. 13,000meq/hr. There was no significant difference in MAP changes between genotype groups. Conclusions: This small pilot study suggests that NPR3 genotype affects BNP elimination, and possibly natriuresis during BNP infusion. Further investigation with larger cohorts is needed to illuminate genetic sources of variability in BNP response.

Natriuretic Peptide Receptor 3 Genotype Is Associated with Altered Pharmacokinetics during Nesiritide Infusion

Infusion of nesiritide (recombinant human B-type natriuretic peptide (BNP)) lowers blood pressure and may cause natriuresis, but these effects are highly variable between individuals. How much of this variability is genetic is unknown. Genetic variants in BNP clearance mechanisms will affect drug elimination rate and may thus impact its clinical effects. Patients with heart failure (n=37, 24 men, 19 African Americans) who received nesiritide infusion at standard doses (0.005-0.01 mcg/kg/min) were studied. Subjects were closely monitored during a 1 hour baseline period and a 2 hour infusion period. BNP levels were measured during the baseline and infusion periods, as was urine sodium (Na) excretion and mean arterial pressure (MAP). DNA was extracted from blood and genotyped for 71 sequence variants in membrane metallo-endopeptidase (MME) and natriuretic peptide receptor 3 (NPR3), the two key clearance mechanisms for BNP. Elimination rate constant (K) was calculated using the difference in BNP level from baseline to 2-hours of infusion (C), the infusion rate (k0), and the estimated volume of distribution (0.073 L/kg, V) according to the equation K=k0/(C*V). We first tested the association of NPR3 and MME genotypes (additive model) with K, then examined changes in Na excretion and MAP for variants of interest. P<0.01 was considered significant. Two NPR3 sites, rs11749133 and rs16890196 were associated K (p=0.0055, 0.0092, respectively) with >4 fold difference in K between homozygous genotype groups (median K = 0.06 vs. 0.3 for AA vs. GG). These genotypes were also associated with differences in sodium excretion (p=0.0017, 0.0096, respectively); While Na excretion declined overall with nesiritide, it was better preserved in the AA group (slower elimination) compared to GG group (rapid elimination) with median decline in Na excretion of 3,300meq/hr vs. 13,000meq/hr. There was no significant difference in MAP changes between genotype groups. This small pilot study suggests that NPR3 genotype affects BNP elimination, and possibly natriuresis during BNP infusion. Further investigation with larger cohorts is needed to illuminate genetic sources of variability in BNP response.

The use of B-type natriuretic peptide in the management of perioperative heart failure

Background The relative deficiency and/or resistance of B-type natriuretic peptide (BNP) may in severe heart failure, BNP has attracted more attention because of its special clinical value in diagnosis,prognosis and treatment of heart failure.Nesiritide is a recombinant human BNP (rhBNP) and is a new drug to treat heart failure. Purpose This paper is to elucidate the relationship between BNP and perioperative heart failure, and the clinical using of nesiritide. Content We will review the relationship between BNP and perioperative heart failure, and the clinical application of the recombinant human BNP-nesiritide. Trend BNP has special clinical value in diagnosis, prognosis and treatment of heart failure because of its close correlation with the soverity of heart failure. The definite therapeutic effect of nesiritide maks it a promising agent for the treatment of perioperative heart failure. Key words: B-type natriuretic peptide ; Heart failure ; Nesiritide ; Perioperative ;

The use of recombinant human B-type natriuretic peptide for the protection of cardiac and renal functions in heart failure patients with acute anterior myocardial infarction in peri-operative period of primary percutaneous coronary intervention

To evaluate the protective effect of recombinant human B-type natriuretic peptide (rhBNP) on cardiac and renal functions in heart failure (HF) patients as a result of acute anterior myocardial infarction (AAMI) in peri-operative period of primary percutaneous coronary intervention (pPCI). One hundred and twenty-six patients with AAMI-HF were enrolled into this study. All patients undertaken pPCI were randomly assigned to the rhBNP group (n=62) or the control group (n=64). rhBNP or nitroglycerin was intravenously administered on the basis of conventional treatment from first day of admission to 24 hours after pPCI in both groups. Heart rate (HR), systolic blood pressure (SBP), B-type natriuretic peptide (BNP), estimated glomerular filtration rate (eGFR) and heart function were observed. All patients were followed up for 30 days for the observation of main adverse cardiac events (MACE). The HR was significantly decreased compared with that at admission in rhBNP group, but such condition was not found in the control group. The SBP was reduced obviously in both groups. The plasma level of BNP, left ventricular ejection fraction (LVEF) and left ventricular end-diastolic dimension (LVEDD) were improved significantly at different time points compared with those before administration in both groups. The improvement of above parameters in rhBNP group was more significant than that in the control group [BNP (ng/L) 30 hours after pPCI: 303.5±128.4 vs. 354.0±133.6, 14 days after pPCI: 157.8±78.6 vs. 201.1±91.7; LVEF 1 day after pPCI: 0.420±0.052 vs. 0.378±0.055, 14 days after pPCI : 0.444±0.050 vs. 0.393±0.055, 30 days after pPCI: 0.469±0.053 vs. 0.413±0.052; LVEDD (mm) 1 day after pPCI: 53.5±4.4 vs. 57.6±4.4, 14 days after pPCI : 49.6±5.1 vs. 53.4±4.6, 30 days after pPCI: 46.5±4.4 vs. 50.2±4.8, P<0.05 or P<0.01]. The eGFR was reduced obviously 1 day after pPCI than that at admission in both groups, and eGFR recovered to baseline 3 days after pPCI. The level of eGFR was significantly increased 7 days and 14 days after pPCI than that at admission, but there was no difference between rhBNP group and control group. The incidence of contrast-induced nephropathy showed a lowering tendency in the rhBNP group than that in the control group [19.4% (12/62) vs. 29.7% (19/64), P=0.178]. The incidence of ventricular arrhythmias was obviously lowered 7 days after pPCI in the rhBNP group than that in the control group [48.4% (30/62) vs. 75.0% (48/64), P<0.01]. The rate of MACE was lower in rhBNP group than that in control group in 30 days [12.9% (8/62) vs. 26.6% (17/64), P<0.05]. Administration of rhBNP can effectively improve the heart function in AAMI-HF patients undergoing pPCI, and it lowered the incidence of MACE in 30 days, without influence on renal function, and it can reduce the incidence of contrast-induced nephropathy.

E0657 The perioperation effects of recombinant human B-type natriuretic peptide for heart failure patients with primary percutaneous coronary intervention

ObjectiveTo study the efficacy and safety of recombinant human B-type natriuretic peptide (rhBNP) in AMI-ADHF patients undergoing PCI, especially changes in renal function and the impact of short-term outcome during...

E0627 The perioperation effect of recombinant human B-type natriuretic peptide for heart failure patients with primary percutaneous coronary intervention

ObjectiveTo study the efficacy and safety of recombinant human B-type natriuretic peptide (rhBNP) in AMI-ADHF patients undergoing PCI, especially changes in renal function and the impact of short-term outcome during...

E0539 B-type natriuretic peptide on preventing of contrast-induced nephropathy in patients with heart failure undergoing primary percutaneous coronary intervention

BackgroundContrast-induced nephropathy (CIN) is one of the leading causes of hospital-acquired renal failure and increase in the mortality and length of hospital stay after percutaneous coronary intervention (PCI).PurposeTo evaluate the...

B-type natriuretic peptide for prevention of contrast-induced nephropathy in patients with heart failure undergoing primary percutaneous coronary intervention

Contrast-induced nephropathy (CIN) is one of the leading causes of hospital-acquired renal failure and increase in the mortality and length of hospital stay after percutaneous coronary intervention (PCI). To evaluate the protective effect of B-type natriuretic peptide (BNP) on CIN in patients with heart failure undergoing PCI. In the prospective, placebo-controlled, randomized trial, 149 consecutive acute myocardial infarction (AMI) patients with heart failure undergoing primary PCI received recombinant human BNP (rhBNP) or placebo from the time of admission to 24 h after PCI. Serum creatinine (SCr) levels were measured to evaluate the protective effect of rhBNP on renal function. Estimated glomerular filtration rate (eGFR) was calculated by the simplified modification of diet in renal disease study equation. CIN was defined as a postprocedure peak increase in SCr of >0.5 mg/dl or >25% from baseline. The baseline characteristics were similar in the two groups. The SCr significantly increased after PCI, with the peak value at 48 h, and then began to decrease. At day 7 after PCI, the SCr had lowered to the baseline level in the BNP group, but it failed to do so in the control group. At 24, 48, and 72 h and 7 days after PCI, the SCr was lower in the BNP group than that in the control group. The eGFR decreased significantly after PCI, with the lowest value at 48 h, and then it began to increase. The eGFR after PCI was higher in the rhBNP group than that in the control group. The occurrence of CIN was significantly lower in the rhBNP group than in the control group. Periprocedural use of BNP could further promote the recovery of renal function and decrease the occurrence of CIN compared with routine treatment alone in patients with heart failure undergoing primary PCI.

Clinical Implications of Defective B‐Type Natriuretic Peptide

Our understanding of the natriuretic peptide system continues to evolve rapidly. B-type natriuretic peptide (BNP), originally thought to be a simple volume-regulating hormone that is produced in response to cardiac stretch, has been shown to also play important roles in modulating bronchodilation, endothelial function, and cardiac remodeling. Recent data demonstrate that elevated levels of BNP in patients with heart failure do not represent a simple ratcheting up of normal production in response to increased stimulus. Instead, we now know that chronic stimulation of BNP synthesis induces a reversion to fetal gene expression, resulting in production of high molecular weight forms of BNP that are functionally deficient. Standard point-of-care BNP assays are immunoassays that will detect any molecule containing the target epitopes. Consequently, these assays cannot distinguish between defective, high molecular weight forms of BNP and normal, physiologically active BNP. In 2 separate evaluations, mass spectroscopy detected little, if any, normal BNP in patients with heart failure, despite the appearance of high circulating levels of immunoreactive BNP (iBNP) using commercial assays. Therefore, these commercial assays should be considered to be only an indication of myocardial stress. They do not measure physiologic BNP activity. This accounts for the "BNP paradox," namely, that administration of exogenous recombinant human BNP (rhBNP, nesiritide) has substantial clinical and hemodynamic impact in the presence of high levels of circulating iBNP using commercial assays. In addition to its short-term hemodynamic impact, rhBNP may have other important effects in this setting, and further investigation is warranted.

Acute Hemodynamic Effects of Intravenous Nesiritide on Left Ventricular Diastolic Function in Heart Failure Patients

Background Nesiritide is recombinant human B-type natriuretic peptide with vasodilatory effects used in patients with decompensated congestive heart failure. We sought to evaluate the effects of nesiritide on left ventricular diastolic function in heart failure patients. Methods and Results Twenty-five heart failure patients underwent left heart catheterization (using a pressure-volume conductance catheter) and echocardiography at baseline and 30 minutes after an intravenous bolus and infusion of nesiritide. Invasive and noninvasive measurements of load-dependent (deceleration time, echocardiographic diastolic function classification, negative dP/dt, left ventricular diastolic pressure, tau) parameters of diastolic function were assessed. The nonlinear slope of the end-diastolic pressure volume relationship (EDPVR) using 2 single-beat methods for measuring left ventricular end-diastolic elastance was calculated to assess load-independent parameters of diastolic function. Nesiritide reduced biventricular diastolic pressure and systemic vascular resistance. Tau and negative dP/dt showed modest improvement. Deceleration time, isovolumetric relaxation time, diastolic stiffness indices (E/E′/stroke volume (SV) and E/E′/left ventricular end-diastolic volume index (LVEDVI)), and the echocardiographic diastolic filling pattern classification did not change. Furthermore, there was no change in the EDPVR. Conclusions Although nesiritide is an effective vasodilator resulting in decreased left ventricular preload and afterload in heart failure patients, intrinsic left ventricular diastolic function did not change acutely, suggesting that nesiritide has no significant acute lusitropic effect.

Nesiritide Enhances Myocardial Protection during the Revascularization of Acutely Ischemic Myocardium

Nesiritide, a recombinant human B-type natriuretic peptide, has been used in conjunction with inotropic agents in the management of low cardiac output and pulmonary hypertension following cardiac surgery. However, its independent effects on intraoperative myocardial protection are unknown. This study was, therefore, undertaken to determine whether nesiritide alone could enhance myocardial protection when given intraoperatively in a porcine model simulating urgent coronary artery bypass graft surgery. Twenty pigs underwent occlusion of the second and third diagonal coronary arteries using snares for 90 minutes followed by 45 minutes of antegrade, cold blood cardioplegic arrest and 180 minutes of reperfusion on cardiopulmonary bypass during which the snares were released. Ten animals received an IV bolus of Nesiritide (2 microg per kg) at the initiation of coronary occlusion followed by a 0.01-microg/kg per min IV infusion during coronary occlusion, cardioplegic arrest, and reperfusion. Ten other animals underwent the same protocol without Nesiritide (placebo). Infarct size was assessed by the area of necrosis/area of risk using histochemical staining, endothelial function by the % change in coronary vasodilation using ring chamber methodology, and lung edema using % change in wet/dry weights. Nesiritide-treated animals had significantly decreased infarct size (23.44% 3.13 SD% vs. 37.95%+/- 1.05%; p < 0.003), better preservation of endothelial function (70.1%+/- 12.3% vs. 38.9%+/- 10.3%; p < 0.001), and less lung edema (3.39%+/- 2.13% vs. 4.72 +/- 1.14%; p = 0.23). In a porcine model of acute coronary occlusion simulating urgent CABG surgery, the intraoperative infusion of nesiritide limits myocardial injury.

Assessment of Renal Hemodynamic Effects of Nesiritide in Patients With Heart Failure Using Intravascular Doppler and Quantitative Angiography

We evaluated the magnitude and site of action of the nesiritide mediated renal vasodilatory effect in patients with heart failure (HF). Nesiritide, a recombinant human B-type natriuretic peptide is approved for the treatment of acute decompensated HF and has been shown to exert favorable hemodynamic, neurohormonal, and symptomatic effects. The renal effect of nesiritide in HF patients has not been well defined. In 15 patients with acute decompensated HF, intravascular Doppler and quantitative angiography of the renal artery were used to assess the effect of nesiritide on renal artery diameter and velocity time integral as well as renal blood flow and vascular resistance. Nesiritide was administered intravenously at a standard dose of 2 microg/kg bolus followed by a continuous infusion at a rate of 0.01 microg/kg/min. Assessment of nesiritide effect was made at 15 min. Nesiritide infusion was associated with a significant central hemodynamic effect including a fall in mean pulmonary artery pressure (36 +/- 12 mm Hg to 31 +/- 13 mm Hg, p < 0.001), mean pulmonary capillary wedge pressure (21 +/- 2 mm Hg to 15 +/- 10 mm Hg, p < 0.001), and systemic vascular resistance (1,995 +/- 532 dynes s cm(-5) to 1,563 +/- 504 dynes s cm(-5), r < 0.001), and an increase in cardiac output from 3.9 +/- 1.2 l/min to 4.6 +/- 1.6 l/min (p = 0.001). Nesiritide was also associated with a significant vasodilatory effect on the large conductance renal arteries resulting in an increase in renal artery diameter from 6.2 +/- 0.7 mm to 6.7 +/- 0.8 mm (p < 0.001). At the same time, there was a concomitant fall in mean renal artery pressure (99 +/- 17 mm Hg to 89 +/- 13 mm Hg, p = 0.002) and renal blood flow velocity time integral (27 +/- 15 cm/beat to 23 +/- 15 cm/beat, p = 0.008) and, therefore, no significant change in renal blood flow or renal vascular resistance. The nesiritide effect on the renal circulation in patients with HF is complex, with a marked vasodilatory action on the large, conductance renal arteries but a concomitant fall in velocity time integral and no effect on renal vascular resistance or renal blood flow. Lack of increase in renal blood flow may be due to a fall in renal blood pressure or an intrarenal vasoconstrictive effect.

Abstract 2890: Nesiritide Enhances Myocardial Protection during the Revascularization of Acutely Ischemic Myocardium

Nesiritide, a recombinant human B-type natriuretic peptide, has been used in conjunction with inotropic agents in the postoperative management of low cardiac output and pulmonary hypertension. However, its effects on intraoperative myocardial protection are unknown. This study was therefore undertaken to determine whether Nesiritide could enhance myocardial protection when given intraoperatively in a porcine model simulating urgent CABG surgery. Twenty pigs underwent occlusion of the second and third diagonal coronary arteries using snares for 90 minutes followed by 45 minutes of antegrade, cold blood cardioplegic arrest and 180 minutes of reperfusion on cardiopulmonary bypass(CPB) during which time the snares were released. Ten animals received an IV bolus of Nesiritide(2ug/kg) at the initiation of coronary occlusion followed by a 0.01ug/kg/min IV infusion during coronary occlusion, cardioplegic arrest, and reperfusion on CPB. Ten other animals underwent the same protocal without Nesiritide(placebo). Infarct size was assessed by the area of necrosis/area of risk(AN/AR) using histochemical staining, endothelial function by the % change in coronary vasodilation using ring chamber methodology, and lung edema using % change in wet/dry weights. The data is expressed as the mean+/− standard deviation. Nesiritide treated hearts had significantly decreased infarct size, better preservation of endothelial function, and less lung edema. In a porcine model of acute coronary occlusion simulating urgent CABG surgery, the intraoperative infusion of Nesiritide limited myocardial damage. These data suggest that IV Nesiritide infusions may afford increased myocardial protection when administered intraoperatively during the revascularization of acutely ischemic myocardium. RESULTS