Natriuretic Peptides in Congestive Heart Failure Publications (8427)


Natriuretic Peptides in Congestive Heart Failure Publications

BMC Pulm Med
BMC Pulm Med 2017 Jan 10;17(1):11. Epub 2017 Jan 10.
Division of Respiratory Medicine, University of British Columbia and Institute for Heart and Lung Health, Vancouver, Canada.
Circ Heart Fail
Circ Heart Fail 2017 Jan;10(1)
From the Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (K.W.S., J.M.t.M., H.L.H., D.J.v.V., A.A.V., P.v.d.M.); National Heart and Lung Institute, Royal Brompton and Harefield Hospitals, Imperial College, London, United Kingdom (J.G.C.); Inova Heart and Vascular Institute, Falls Church, VA (C.M.O'C.); Momentum Research, Durham, NC (B.A.D.); University of Brescia, Italy (M.M.); Brigham and Women's Hospital, Boston, MA (M.M.G.); University of California at San Francisco and San Francisco Veterans Affairs Medical Center (J.R.T.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); Merck Research Laboratories, Rahway, NJ (D.M.B.); and University of Iowa Carver College of Medicine Cardiovascular Research Center (H.C.D.).

Plasma concentrations of natriuretic peptides decline with obesity in patients with heart failure. Whether this is true for other biomarkers is unknown. We investigated a wide range of biomarker profiles in acute heart failure across the body mass index (BMI) spectrum. Read More

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: Unique identifier: NCT00354458.

Soluble CD146 (sCD146), is an endothelial marker with similar diagnostic power as natriuretic peptides in decompensated heart failure (HF). While natriuretic peptides are released by the failing heart, sCD146 may be released by veins in response to stretch induced by systemic congestion in HF. This study investigated the source, effects of vascular stress on release and prognostic properties of sCD146 in HF. Read More

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.

Clin. Chem.
Clin Chem 2017 Jan 8;63(1):359-368. Epub 2016 Nov 8.
Division of Clinical Biochemistry and Protein Micro-Analysis Facility, Biocenter, Innsbruck Medical University, Innsbruck, Austria;

Currently, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and its physiologically active counterpart, BNP, are most frequently used as biomarkers for diagnosis, prognosis, and disease monitoring of heart failure (HF). Commercial NT-proBNP and BNP immunoassays cross-react to varying degrees with unprocessed proBNP, which is also found in the circulation. ProBNP processing and immunoassay response are related to O-linked glycosylation of NT-proBNP and proBNP. Read More

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.

Clin. Chem.
Clin Chem 2017 Jan 15;63(1):351-358. Epub 2016 Nov 15.
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN;

B-type natriuretic peptides (BNPs) are used clinically to diagnose and monitor heart failure and are present in the circulation as multiple proBNP-derived fragments. We investigated the specificity of BNP immunoassays with glycosylated and nonglycosylated BNP, N-terminal proBNP (NT-proBNP), and proBNP peptides to probe the cross-reactivity of each assay.
Nine B-type natriuretic peptides were studied,including synthetic and recombinant BNP (Shionogi, Scios, Mayo), human and synthetic glycosylated and nonglycosylated NT-proBNP (HyTest, Roche Diagnostics), and human glycosylated and nonglycosylated proBNP (HyTest, Scios). Read More

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.

Clin. Chem.
Clin Chem 2017 Jan 10;63(1):211-222. Epub 2016 Oct 10.
Cardiology Division, Massachusetts General Hospital, Boston, MA;

Heart failure (HF) is a complex syndrome with an enormous societal burden in terms of cost and morbidity and mortality. Natriuretic peptide (NP) testing is now widely used to support diagnosis, prognostication, and management of patients with HF, but NPs come with limitations, including vulnerability to the presence of obesity, atrial fibrillation, and renal dysfunction, for example. Beyond the NPs, novel biomarkers may supplement traditional clinical and laboratory testing to improve understanding of the complex disease process of HF, and possibly to personalize care for those affected through better individual phenotyping. Read More

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.

Clin. Chem.
Clin Chem 2017 Jan 15;63(1):108-115. Epub 2016 Nov 15.
Cardiorenal Research Laboratory, Department of Cardiovascular Diseases, Mayo Clinic, Rochester MN.

Neprilysin (NEP) is a membrane-bound neutral endopeptidase that degrades a variety of bioactive peptides. The substrates include natriuretic peptides (NPs), which are important regulating mediators for cardiovascular and renal biology. Inhibition of NEP activity and exogenous NP administration thus have emerged as potential therapeutic strategies for treating cardiorenal diseases. Read More

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.

Clin. Chem.
Clin Chem 2017 Jan 10;63(1):50-58. Epub 2016 Oct 10.
Division of Cardiovascular Diseases, Department of Medicine, Rochester, MN;

The natriuretic peptide system is an endocrine, autocrine and paracrine system that plays an important role in the maintenance of cardiovascular homeostasis. Biomarkers based on these peptides are important diagnostic and prognostic tools for myocardial function.
Although natriuretic peptides were discovered more than 2 decades ago, their intricate and complex biology is associated with important questions not yet elucidated. Read More

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.

Int. J. Cardiol.
Int J Cardiol 2017 Mar 24;230:371-377. Epub 2016 Dec 24.
Department of Cardiology, Bichat Hospital, Paris, France; INSERM U1148, Bichat Hospital, Paris, France; University Paris 7, Paris, France. Electronic address:

The prognostic value of N-terminal fragment of pro B-type natriuretic peptide (Nt-proBNP) in aortic stenosis (AS) is still being debated. We sought to evaluate the determinants of Nt-proBNP in AS and its prognostic value in asymptomatic patients.
Patients with pure isolated at least mild degenerative AS enrolled in our prospective cohort (2006-2013) constituted our population. Read More

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.

Vitam. Horm.
Vitam Horm 2017 5;103:131-145. Epub 2016 Oct 5.
University of Göttingen Medical Centre, Göttingen, Germany; German Centre for Cardiovascular Research, University of Göttingen, Göttingen, Germany.

Natriuretic peptides exert pleiotropic effects on the cardiovascular system, including natriuresis, diuresis, vasodilation, and lusitropy, by signaling through membrane-bound guanylyl cyclases. In addition to their use as diagnostic and prognostic markers for heart failure, accumulating behavioral evidence suggests that these hormones also modulate anxiety symptoms and panic attacks. This review summarizes our current knowledge of the role of natriuretic peptides in animal and human anxiety and highlights some novel aspects from recent clinical studies on this topic. Read More