Natriuretic Peptides in Congestive Heart Failure Publications (8427)
Natriuretic Peptides in Congestive Heart Failure Publications
Fifty one studies were identified. NP levels were lower in stable compared to exacerbation of COPD, and significantly increased with concomitant left ventricular systolic dysfunction or cor pulmonale. Elevation occurred in 16 to 60% of exacerbations and persisted in approximately one half of patients at discharge. Cardiovascular comorbidities were associated with increased levels. Levels consistently correlated with pulmonary artery pressure and left ventricular ejection fraction, but not pulmonary function or oxygen saturation. NP demonstrated high negative predictive values (0.80 to 0.98) to exclude left ventricular dysfunction in both stable and exacerbation of COPD, but relatively low positive predictive values. NP elevation predicted early adverse outcomes, but the association with long term mortality was inconsistent.
NP reflect diverse aspects of the cardiopulmonary continuum which limits utility when applied in isolation. Strategies integrating NP with additional variables, biomarkers and imaging require further investigation.
A total of 48 biomarkers, assessing multiple pathophysiological pathways, were measured in 2033 patients included in PROTECT (Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function), a trial comparing the effects of rolofylline to placebo in patients with acute heart failure. Patients were classified into 4 groups according to BMI (<25, 25-30, 30-35, and >35 kg/m(2)). Of 2003 patients with known weight and height, mean age was 70±12 years and 67% were men. Patients with a higher BMI (>35 kg/m(2)) had higher blood pressures, were younger, and were more often women. Median levels of brain natriuretic peptide were 550 pg/mL in patients with a BMI <25 kg/m(2) and 319 pg/mL in patients with a BMI >35 kg/m(2) (P<0.001). Multivariable regression revealed that brain natriuretic peptide (β=-0.250; P<0.001) and receptor for advanced glycation endproducts (β=-0.095; P<0.007) were inversely correlated to BMI, whereas higher levels of uric acid (β=0.164; P<0.001), proadrenomedullin (β=0.171; P<0.001), creatinine (β=0.118; P=0.003), sodium (β=0.101; P=0.006), and bicarbonate (β=0.094; P=0.009) were associated with higher BMI. No significant interaction was seen between these 7 biomarkers and BMI on 180-day mortality.
The plasma concentrations of several biomarkers are either positively or negatively influenced by BMI. These findings suggest that these markers should be interpreted with caution in patients with obesity. Although concentrations differ, their prognostic value for mortality up to 180 days did not differ.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00354458.
In a peripheral venous stress study, plasma concentrations of sCD146 and N-terminal probrain natriuretic-peptide (NT-proBNP) were measured in 44 HF patients at baseline and after 90 min of unilateral forearm venous congestion. In addition, sCD146 and NT-proBNP were measured in peripheral vein (PV) and coronary sinus (CS) blood samples of 137 HF patients and the transcardiac gradient was calculated. Those patients were followed for major adverse cardiovascular events (MACE) during 2 years.
The induction of venous stress was associated with a pronounced increase in circulating concentrations of sCD146 in the congested arm (+60 μg/L) compared to the control arm (+16 μg/L, P = 0.025), while no difference in NT-proBNP concentrations was seen. In contrast to positive transcardiac gradient for NT-proBNP, median sCD146 concentrations were lower in CS than in PV (396 vs 434, P < 0.001), indicating a predominantly extracardiac source of sCD146. Finally, increased PV concentrations of sCD146 were associated with higher risk of MACE at 2 years.
Soluble CD146 is released from the peripheral vasculature in response to venous stretch and may reflect systemic congestion in chronic HF patients.
There is a clear and urgent need to identify the glycosylation sites in the endogenously circulating peptides requested by the community to gain further insights into the different naturally occurring forms.
The glycosylation sites of (NT-) proBNP (NT-proBNP and/or proBNP) were characterized in leftovers of heparinized plasma samples of severe HF patients (NT-proBNP: >10000 ng/L) by using tandem immunoaffinity purification, sequential exoglycosidase treatment for glycan trimming, β-elimination and Michael addition chemistry, as well as high-resolution nano-flow liquid chromatography electrospray multistage mass spectrometry.
We describe 9 distinct glycosylation sites on circulating (NT-) proBNP in HF patients. Differentially glycosylated variants were detected based on highly accurate mass determination and multistage mass spectrometry. Remarkably, for each of the identified proteolytic glycopeptides, a nonglycosylated form also was detectable.
Our results directly demonstrate for the first time a rather complex distribution of the endogenously circulating glycoforms by mass spectrometric analysis in HF patients, and show 9 glycosites in human (NT-) proBNP. This information may also have an impact on commercial immunoassays applying antibodies specific for the central region of (NT-) proBNP, which detect mostly nonglycosylated forms.
Five BNP [Abbott, Abbott POC, Alere, Beckman Coulter, Siemens (Centaur)], 9 NT-proBNP [Ortho-Clinical Diagnostics, Roche, Response, bioMerieux, Siemens (Dimension, Immulite, Stratus CS), Mitsubishi] and 3 research-use-only proBNP immunoassays [Biosite (Alere), Bio-Rad, Goetze] were evaluated. Specificity was assessed by calculating the recovery between baseline and peptide-spiked human plasma pools at target concentrations of 100 ng/L BNP, 300 ng/L proBNP, or 450 ng/L NT-proBNP. All assays were performed in duplicate.
BNP and NT-proBNP assays demonstrated substantial cross-reactivity with proBNP peptides. NT-proBNP assays do not detect glycosylated forms of either NT-proBNP or proBNP. proBNP assays preferentially detect the BNP 1-32 peptide and have minimal cross-reactivity with BNP peptides and glycosylated proBNP.
BNP or NT-proBNP results are not transferable among the current existing immunoassays owing to their differences in cross-reactivity and ability to detect various glycosylated forms of proBNP-derived fragments. Opportunities remain to standardize and harmonize BNP and NT-proBNP assays, as well as to develop specific proBNP assays, to widen their clinical scope of use.
In this review we discuss novel biomarkers by dividing them into categories based on major pathophysiologic pathways they represent including myocardial stretch/stress, cardiac extracellular matrix remodeling, cardiomyocyte injury/death, oxidative stress, inflammation, neurohumoral activation, and renal dysfunction.
Given the limitations of NPs, along with the complex physiology in HF, it is logical to consider utilization of novel biomarkers providing orthogonal biological and clinical information. Several novel HF biomarkers have shown promise but have substantial expectations to meet before being used clinically. Nonetheless, it is reasonable to expect the future lies in the application of multibiomarker panels for the improvement in management of HF and the personalization of care.
More recently, B-type natriuretic peptide (BNP) or N-terminal-proBNP (NT-proBNP), 3'-5' cyclic guanosine monophosphate (cGMP), and soluble NEP as biomarkers have also been investigated in heart failure (HF) trials and their predictive value are beginning to be recognized.
The biological functions of NEP and NPs are discussed. Enhancing NPs through NEP inhibition combined with renin-angiotensin-aldosterone system (RAAS) antagonism has proved to be successful in HF treatment, although future surveillance studies will be required. Direct NP enhancement through peptide delivery may have fewer potentially hazardous effects compared to NEP inhibition. Strategies of combined inhibition on NEP with other cardiorenal pathophysiological pathways are promising. Finally, monitoring BNP/NT-proBNP/cGMP concentrations during NEP inhibition treatment may provide supplemental benefits to conventional biomarkers, and the identification of soluble NEP as a novel biomarker for HF needs further investigation.
In this review, the biology of NEP is summarized, with a focus on NP regulation. The degradation of NPs by NEP provides the rationale for NEP inhibition as a strategy for cardiorenal disease treatment. We also describe the current therapeutic strategies of NEP inhibition and NP therapeutics in cardiorenal diseases. Moreover, the discovery of its circulating form, soluble NEP, as a biomarker is also discussed.
The diversity of circulating forms of natriuretic peptides, the distinct expression of these forms in particular patients, and the heterogeneity of heart failure forms, along with specific assay-related and preanalytic issues, cause assays to be poorly harmonized.
This review presents the relevant issues related to the biology of natriuretic peptides and differences between assays with immediate implications for clinical practice.
Clinical and biological measurements as well as echocardiographic evaluations were performed at study entry for all patients. Severe AS was defined by a valve area <1cm(2). Asymptomatic patients were contacted every six months and seen every year. The occurrence of AS-related events (sudden death, congestive heart failure or new onset of symptoms) within two years was recorded prospectively.
We enrolled 809 patients. Nt-proBNP increased with AS severity (p<0.0001) and symptomatic status (p<0.0001) but there was a wide overlap between groups of AS severity or symptomatic status. Nt-proBNP was the result of complex interactions between multiple determinants, including AS severity and symptomatic status but also age (p=0.0008), history of coronary artery disease (p=0.03), rhythm (p=0.007) and diastolic function (p<0.0001). Consequently, in asymptomatic patients with moderate/severe AS, normal ejection fraction and in sinus rhythm, Nt-proBNP was associated with AS-related events in univariate analysis (p=0.009) but not after adjustment for AS severity (p=0.12). Repeated Nt-proBNP measurements at one year did not improve their predictive value (p=0.43).
This study highlights the limitations of Nt-proBNP in AS and raises caution regarding its use, at least as a single factor, in the decision-making process regarding asymptomatic patients with AS.