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Biomarkers in Heart Failure

List of key references prepared and regularly updated by the Heart Failure Association (HFA)


 

B-Type Natriuretic Peptides and Cardiovascular Risk. Systematic Review and Meta-Analysis of 40 Prospective Studies.

Di Angelantonio E, Chowdhury R, Sarwar N, Ray KK, Gobin G, Saleheen D, Thompson A, Gudnason V, Sattar V, Danesh S. 

Circulation 2009;120:2177-2187. 

Synopsis

The meta-analysis included >80 000 subjects from a general population and >10 000 patients with vascular disease from 40 long-term prospective studies that have investigated the strength and consistency of associations between levels of BNP and/or NT-proBNP with qsubsequent CVD outcome (defined as any fatal or nonfatal myocardial infarction, stroke, transient ischemic attack, or heart failure).  Overall, there was an almost 3-fold increase in risk of CVD in people in the top third of baseline natriuretic peptide values compared with those in the bottom third, even after an adjustment for co-variables.  The relationships were similar in essentially general populations, subjects with CV risk factors and in those with prevalent CVD, in studies with both shorter and longer-term average follow-up, and apparently irrespective of inclusion of heart failure as an event.

Commentary

Although the measurement of circulating natriuretic peptides has an established role in the diagnosis of heart dysfunction and risk stratification in a broad spectrum of heart pathologies, the significance of these markers in a general population remains unclear.  The presented meta-analysis provides evidence that the applicability of measurements of natriuretic peptides could be much broader and become a potential universal measure for CV risk stratification across a variety of populations.

Neuregulin-1beta is associated with disease severity and adverse outcomes in chronic heart failure.

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Ky B, Kimmel SE, Safa RN, Putt ME, Sweitzer NK, Fang JC, Sawyer DB, Cappola TP.

Circulation. 2009 Jul 28;120(4):310-7.

Synopsis

Neuregulin-1β (NRG-1β) is a member of the epidermal growth factor family that exerts cardioprotective effects in animal models of cardiomyopathy.  The authors demonstrated that among 899 outpatients from the Penn Heart Failure Study representing a broad range of chronic systolic heart failure, increased circulating levels of NRG-1β were independently associated with disease severity and higher risk of death or cardiac transplantation over a median follow-up of 2.4 years.  Circulating NRG-1β was a prognosticator independent of B-type natriuretic peptide (BNP), and its predictive value was the greatest in patients with NYHA class III-IV.  Moreover, the combined assessment of NRG-1β and BNP improved a risk stratification beyond a separate assessment of each biomarker.

Commentary

Neuregulin-1β (NRG-1β) is a member of the epidermal growth factor family released from cardiac microvascular endothelial cells that acts via a set of tyrosine kinase receptors (ErbB2, ErbB3, ErbB4) to promote growth, differentiation, and survival of cardiomyocytes.  NRG-1/ErbB signaling is indispensable both in the cardiac development and in the adult heart.  It regulates myocardial performance and sympatovagal balance, and may exert beneficial cardioprotective effects.  In animal studies, the depletion of this pathway can induce heart failure, whereas an administration of recombinant NRG-1β can improve cardiac function and increase survival in different experimental models of cardiomyopathy.  The presented study is the first to explore the significance of circulating NRG-1β in human heart disease, and provides evidence on the role of NRG-1/ErbB signaling in human heart failure, indicating that circulating NRG-1β might serve as a novel biomarker to assess prognosis in patients with heart failure.  There is a need for further evidence on the usefulness of NRG-1β measurements in clinical practice.  Future studies should also investigate the pharmacological activation of NRG-1/ErbB signaling as a potential novel therapeutic approach in heart failure.

Resistin, adiponectin, and risk of heart failure the Framingham offspring study.

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Frankel DS, Vasan RS, D'Agostino RB Sr, Benjamin EJ, Levy D, Wang TJ, Meigs JB.

J Am Coll Cardiol. 2009 Mar 3;53(9):754-62.

Synopsis

During the 6-year prospective follow-up, among 2 739 subjects without heart failure at baseline (participants oth the Framingham Offspring Study) high circulating resistin was shown to predict the new onset of heart failure, independently of the presence of coronary artery disease, body mass index, insulin resistance, C-reactive protein, and B-type natriuretic peptide.  There was no association between adiponectin level and the risk of the development of heart failure in this cohort.

Commentary

Adipose tissue is no longer considered as only energy storage, but there is increasing evidence that adipocytes and other accompanying cells secrete a variety of biologically active molecules, including those involved in the regulation of immune response and metabolism and among others providing a pathophysiological link between inflammation and insulin resistance.  Among the so-called adipokines, there are leptin and adiponectin improving insulin sensitivity, and resistin and retinol-binding protein 4 promoting insulin resistance.  The previous studies have demonstrated links between body composition, fatness, obesity and the development of heart failure, whereas in the presented prospective study the authors revealed that high circulating resistin can also be considered as a novel risk factor for new-onset heart failure.  Potential therapeutic approaches targeting the metabolic pathways including resistin might be considered as future prevention strategies.

Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure.

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Rehman SU, Mueller T, Januzzi JL Jr.
J Am Coll Cardiol. 2008 Oct 28;52(18):1458-65.

Synopsis

In this study, the authors analysed the associations between circulating ST2, a novel biomarker in HF, and demographics, severity of heart failure and other biomarkers, and also evaluated its prognostic significance in 346 patients with acute heart failure.  ST2 levels correlated with the severity of heart failure, ejection fraction, creatinine clearance, circulating natriuretic peptides and C-reactive protein.  Circulating ST2 provided an additional prognostic power to a survival model with circulating natriuretic peptides and clinical prognosticators in the studied group.

Commentary

ST2 is a cardiomyocyte protein belonging to an interleukin-1 receptor family with transmembrane and soluble isoforms.  Together with its functional ligand, interleukin 33, they form a mechanically activated, cardioprotective paracrine system, which is involved in the myocardial response to overload.  This is the first study providing the evidence that circulating ST2 may be a useful prognosticator in patients with acute heart failure.

Serum Neutrophil Gelatinase-Associated Lipocalin as a Marker of Renal Function in Patients with Chronic Heart Failure and Coronary Artery Disease.

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Poniatowski B, Malyszko J, Bachorzewska-Gajewska H, Malyszko JS, Dobrzycki S.
Kidney Blood Press Res. 2009 Mar 14;32(2):77-80.

Synopsis

The authors investigated the utility of serum and urinary neutrophil gelatinase-associated lipocalin (NGAL) as a potential sensitive marker of kidney function in patients with ischaemic chronic heart failure and normal serum creatinine.  Serum NGAL correlated to NYHA class, haemoglobin level, estimated GFR and cystatin C, whereas urinary NGAL correlated to age, hemoglobin, and estimated GFR.

Commentary

Renal dysfunction is common in patients with heart failure.  The diagnosis of renal failure and monitoring of It is usually diagnosed by measuring serum creatinine concentrations which is, however, an unreliable indicator of acute changes in kidney function. NGAL is rapidly and massively induced in renal failure, hence its blood and urine levels may be the real-time indicators of active kidney damage. The present study provides data supporting these statements and indicating that NGAL may represent a novel early marker of kidney impairment in HF patients.

Increased systemic and myocardial expression of neutrophil gelatinase-associated lipocalin in clinical and experimental heart failure.

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Yndestad A, Landrø L, Ueland T, Dahl CP, Flo TH, Vinge LE, Espevik T, Frøland SS, Husberg C, Christensen G, Dickstein K, FESC, Kjekshus J, FESC, Øie E, Gullestad L, FESC, Aukrust P.

Eur Heart J. 2009 May;30(10):1229-36.

Synopsis

The study demonstrated enhanced systemic and myocardial expression of neutrophil gelatinase-associated lipocalin (NGAL) in clinical and experimental heart failure.  Serum NGAL was increased in patients with heart failure following acute myocardial infarction and chronic heart failure, and correlated with clinical and neurohormonal deterioration.  In patients with heart failure following acute myocardial infarction high baseline NGAL predicted unfavourable outcome during the mean 27-month follow-up.

Commentary

NGAL was initially found in activated neurophiles as it has several antibacterial properties.  Later, NGAL was demonstrated to be produced by different cells (including kidneys and myocardium) in response to injury.  The study provided preliminary data indicating that NGAL may be a novel biomarker of renal injury in cardiovascular disease, but also may reflect the injury of cardiomyocytes.  Its precise role in the pathogenesis of heart dysfunction needs to be further investigated.