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Biomarkers in Congestive Heart Failure: ClinicalImportance
  JOHTN
MECHANISMS
Biomarkers in Congestive Heart Failure: Clinical
Importance
Amal K Banerjee
Consultant and Interventional Cardiologist
Institute of Cardiovascular Sciences, Institute of Post GraduateMedical Education & Research, SSKM Hospital, KolkataWest Bengal, India
Corresponding Author: Amal K Banerjee, 3/3, Padma BabuRoad, Bally, Howrah - 711201, West Bengal, India
Phone: +919831097167
e-mail: dramalcsi09@gmail.com
 
ABSTRACT
Congestive heart failure is a serious condition with highprevalence of morbidity and premature mortality. If not properlytreated, congestive heart failure (CHF) has the same adverseprognosis as a omalignancy. It is important to identify CHFearly so that its progression to end-stage heart disease canbe avoided. In addition to clinical suspicion, certain biomarkerscan be utilized in the diagnosis and management of CHF.Thus, appropriate management of CHF with require clinicaldiagnosis combined with rational utilization of biomarkers.Recent advances in biochemical technology have confirmedthe usefulness of certain biomarkers in the detection diagnosisand treatment of CHF.
Keywords: Biomarkers, Clinical diagnosis, Heart failure,Morbidity, Prognosis.
How to cite this article: Banerjee AK. Biomarkers in CongestiveHeart Failure: Clinical Importance. Hypertens J 2017;3(3):118-124.
Source of support: Nil
Conflict of interest: None
 
 

INTRODUCTION

Although heart failure (HF) remains a fundamentallyclinical diagnosis, substantial advances in the understandingof the underlying biology and pathophysiologyof this syndrome has led to a greater interest in objectivemeans to quantify its presence, severity, and potentialfuture progression. Among the most intensively studiedtools to achieve these goals are circulating biomarkers. Abiomarker is defined as a characteristic that is objectivelymeasured and evaluated as an indicator of normal biologicprocesses, pathogenic processes, or pharmacologicresponses to a therapeutic intervention.1 Although thisdefinition could encompass a wide array of assessments,conventionally speaking, the term "biomarker" is moreoften used to refer to substances detectable in blood,urine, or other bodily fluids. As clinical tools, biomarker measurements have the potential advantages of beingreadily available, quantitative, reproducible, generallyinexpensive, and without requiring specialized expertisefor interpretation.
 
Following the development, commercialization, andclinical successes of the natriuretic peptides as biomarkersof HF, there has been substantially increased interestin HF biomarker science. Biomarkers that are currentlyavailable reflect at least seven pathobiological processesoperative in HF (Fig. 1),2 help to identify the specificones involved in individual patients, and aid in guidingmanagement plans. In conjunction with advances inproteomics and clinical chemistry that have allowed forhigher throughput in identifying new potential biomarkers,a dizzying array of candidate markers have beenidentified that may have potential clinical applicationin HF (Table 1).3 This remarkable flurry of activity hasled to a metaphorical tsunami in the number of researchpublications focused on biomarkers in HF.

These biomarkers aid in the diagnosis of HF, providean estimate of prognosis, and help in the identification ofapparently healthy people who are at excessive risk for HF.In the assessment of the clinical value of any individualbiomarker, it is important to determine whether it providesindependent incremental information when added topreviously available information, which can be estimatedby determining whether it increases the c statistic, as wellas by calculating the net reclassification improvementindex and the integrated discrimination improvementindex. Despite the importance of these rigorous statisticaltests, measurements of biomarkers, even those that are notindependent predictors of risk on multivariate analysis, may nonetheless be of clinical importance because theyprovide information on the pathogenesis of HF and canhelp to direct treatment.

Biomarkers in Congestive Heart Failure: ClinicalImportance
Fig. 1: Seven major classes of biomarkers contributing to thebiomarker profile in HF2

 
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Biomarkers in Congestive Heart Failure: Clinical Importance

Table 1: Established and emerging biomarkers in HF3
Biomarkers in Congestive Heart Failure: ClinicalImportance
CA-125: Cancer antigen 125; Lp-PLA2: Lipoprotein-associated phospholipase; MB: Myocardial band; MR-proANP: Midregionalpro-atrial natriuretic peptide; PR3: Proteinase 3 antibodies; sFAS: Soluble FAS; sST2: Somatostatin receptor 2; TWEAK: Tumor necrosisfactor-like weak inducer of apoptosis; YKL-40: Chitinase-3-like protein; sTrail: TNF-related apoptosis-induced ligand

Natriuretic Peptides

Because the signs and symptoms of HF are so nonspecific,many patients with suspected HF referred forechocardiography are not found to have an importantcardiac abnormality. Where the availability of echocardiographyis limited, an alternative approach to diagnosisis to measure the blood concentration of a natriureticpeptide, a family of hormones secreted in increasedamounts when the heart is diseased or the load on anychamber is increased.4 Natriuretic peptide levels alsoincrease with age, but may be reduced in obese patients.A normal natriuretic peptide level in an untreated patientvirtually excludes significant cardiac disease, making an echocardiogram unnecessary.4,5 Multiple studies haveexamined the threshold concentration that excludes HFfor the two most commonly used natriuretic peptides,B-type natriuretic peptide (BNP) and N-terminal proB-type natriuretic peptide (NT-proBNP).6-8 The exclusionthreshold differs for patients presenting with acute onsetor worsening of symptoms (e.g., to a hospital emergencydepartment) and those presenting with a more gradualonset of symptoms.

 
For patients presenting with acute onset or worsening ofsymptoms, the optimal exclusion cutoff point is 300 pg/mLfor NT-proBNP and 100 pg/mL for BNP. In one otherstudy, midregional atrial (or A-type) natriuretic peptide(MR-proANP), at a cutoff point of 120 pmol/L, wasshown to be noninferior to these thresholds for BNPand NT-proBNP in the acute setting.9 For patientspresenting in a nonacute way, the optimum exclusion cutoff point is 125 pg/mL for NT-proBNP and 35 pg/mL for BNP. The sensitivity and specificity of BNPand NT-proBNP for the diagnosis of HF are lower innonacute patients.6-8
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The BNP and NT-proBNP levels improve with treatmentof chronic HF,10 with lowering of levels over timein general, correlating with improved clinical outcomes.Thus, BNP or NT-proBNP "guided" therapy has beenstudied against standard care without natriuretic peptidemeasurement to determine whether guided therapyrenders superior achievement of guideline-directedmedical therapy (GDMT) in patients with HF. However,randomized controlled trials have yielded inconsistentresults.

The positive and negative natriuretic peptide-guidedtherapy trials differ primarily in their study populations,with successful trials enrolling younger patients and onlythose with heart failure with reduced ejection fraction.In addition, a lower natriuretic peptide goal and/or asubstantial reduction in natriuretic peptides during treatmentare consistently present in the positive "guided"therapy trials.11 Although most trials examining the strategyof biomarker "guided" HF management were smalland underpowered, two comprehensive meta-analysesconcluded that BNP-guided therapy reduces all-causemortality in patients with chronic HF compared withusual clinical care,12,13 especially in patients < 75 years ofage. This survival benefit may be attributed to increasedachievement of GDMT. In some cases, BNP or NT-proBNPlevels may not be easily modifiable. If the BNP or NTproBNPvalue does not fall after aggressive HF care, riskfor death or hospitalization for HF is significant. On thecontrary, some patients with advanced HF have normalBNP or NT-proBNP levels or have falsely low BNP levelsbecause of obesity and heart failure with preserved ejectionfraction (HFpEF). All of these patients should stillreceive appropriate GDMT.

Biomarkers of Myocardial Injury: Cardiac
Troponin T or I


Abnormal concentrations of circulating cardiac troponinare found in patients with HF, often without obvious myocardialischemia and frequently in those without underlyingcoronary artery disease. This suggests ongoingmyocyte injury or necrosis in these patients. In chronicHF, elaboration of cardiac troponins is associated withimpaired hemodynamics, progressive left ventriculardysfunction, and increased mortality rates. Similarly, inpatients with acute decompensated HF, elevated cardiactroponin levels are associated with worse clinical outcomesand mortality; decrease in troponin levels overtime with treatment is associated with a better prognosis than persistent elevation in patients with chronic or acuteHF. Given the tight association with acute coronary syndrome(ACS) and troponin elevation as well as the linkbetween myocardial infarction and the development ofacute HF, the measurement of troponin I or T should beroutine in patients presenting with acutely decompensatedHF syndromes. With the introduction of highsensitivitycardiac troponin (hs-cTn) methods optimizedfor use at the troponin 99th percentile (corresponding tothe upper reference limit of a healthy, normal population),it is expected that elevated hs-cTn will be more frequentlydetected in HF.
 
Extracellular Matrix Markers

The extracellular matrix (ECM) of the heart is increasinglyrecognized to be important in the pathophysiologyof HF progression; deleterious remodeling of the ECMis an important process that takes place through thedegradation of collagen and other matrix proteins bycollagenases, matrix metalloproteinases (MMPs), andmediated by tissue inhibitors of metalloproteinases.Extracellular matrix is important in ventricular remodeling.Serum peptides derived from collagen metabolismreflect both the synthesis and degradation of collagenand thus, constitute a "window" on the ECM. Theratio of pro-collagen type I aminoterminal propeptide(PINP), a marker of collagen synthesis, to collagen typeI cross-linked carboxyterminal telopeptide, a marker ofcollagen breakdown, is a useful serum marker of collagenaccumulation. A multimarker panel consisting ofincreased levels of MMP-2, tissue inhibitor of MMP-4, andcollagen III N-terminal propeptide (PIIINP), accompaniedby decreased levels of MMP-8, has been reported to becharacteristic of HFpEF.14 Elevated ECM turnover hasalso been reported in patients with acute decompensatedheart failure (ADHF).15

Aldosterone

Aldosterone is a stimulant of collagen synthesis thatenhances cardiac fibrosis in HF and in ventricularhypertrophy secondary to pressure overload. Theadministration of the aldosterone receptor antagonistspironolactone in patients with chronic HF in RandomizedAldactone Evaluation Study (RALES) reducedelevated levels of markers of collagen synthesis (PINPand PIIINP) and was associated with clinical benefit.16 Inpatients with acute MI complicated by HF, levels of PINPand PIIINP rose.16 The administration of eplerenone, aspecific aldosterone antagonist, was reported to havereduced elevated levels of PINP and PIIINP, findingsassociated with reductions in mortality and hospitalizationfor HF.17
 
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Markers of Inflammation

The elevation of C-reactive protein (CRP), an inflammatorybiomarker, in HF has been confirmed and expandedon as assay methods have improved.18 The concentrationsof a number of proinflammatory cytokines, such as tumornecrosis factor-α and interleukin (IL)-6, have also beenreported to have been elevated in HF. In elderly subjectswithout HF, abnormal elevations in three inflammatorymarkers (CRP, tumor necrosis factor-α, and IL-6) werereported to have been associated with a significant,4-fold increase in the development of HF.19 The presenceand levels of these biomarkers were correlated with theseverity of HF; they appeared to have been independentpredictors of outcome and to have provided importantclues to the pathogenesis of HF. They could, in the future,become useful in testing novel anti-inflammatory therapiesin such patients.

Adrenomedullin

Adrenomedullin is a vasodilator peptide derived in partfrom the heart, but also synthesized in vascular smoothmuscle and endothelial cells. Because of its short half-lifeand instability, an assay for the MR sequence of its precursor[mid-regional pro-adrenomedullin (MR-proADM)]has been developed and reported to be an independentpredictor of mortality in ADHF and of adverse outcomesin chronic HF.20 While this marker has excellent sensitivityin detecting HF, its specificity has been questionedbecause of reported elevations in sepsis, glomerulonephritis,and chronic renal failure-perhaps not surprisinggiven its synthesis in multiple tissues. While promisingfor predicting short-term prognosis, more data areneeded before MR-proADM is to be considered ready forprime-time clinical use. For example, considerable depthof understanding regarding the clinical response to anelevated MR-proADM is required before testing wouldbe justified.

Copeptin

The concentration of circulating arginine vasopressinis elevated in patients with severe HF, but as is the casewith ANP and adrenomedullin, its direct measurement isfraught with difficulties. Instead, copeptin, the C-terminalsegment of pre-provasopressin, has been reported to bean excellent surrogate highly predictive of adverse outcomesin patients with ADHF.21

Neutrophil Gelatinase-associated Lipocalin

Neutrophil gelatinase-associated lipocalin, a polypeptidemarker of renal injury,22 is elevated in patients withADHF and renal failure, i.e., with the cardiorenal syndrome.Its elevation at the time of hospital discharge is a strong indicator of renal tubular damage and of adverseprognosis.

 
Kidney Injury Molecule-1

Kidney injury molecule-1 is a glycoprotein expressed inthe proximal tubule in renal injury and both its presencein patients with HF and its correlation with NT-proBNPsuggest that renal involvement occurs in many patientswith severe HF.23

Quiescin Q6

The field of proteomics is likely to provide distinct "fingerprints"of circulating proteins in a variety of disorders,including HF.24 Just as genome-wide association studiesrepresent an unbiased (i.e., not hypothesis-driven) searchfor genetic variants, liquid chromatography combined withmass spectroscopy has been used to carry out a search forplasma proteins in the proteome of patients with ADHF.25This approach revealed that quiescin Q6 (QSOX1), a proteininvolved in the formation of disulfide bridges, was (alongwith BNP) associated with ADHF. After the discoveryand isolation of QSOX1, its association with ADHF wasvalidated in a second group of patients. Then, QSOX1was reported to have been induced in the hearts of ratswith HF following thoracic aortic constriction, lendingcredence to the specificity of this marker.25 The challengenow is to determine its biological significance and whetherit provides information that could be useful to clinicians.

High-sensitivity ST2

Soluble ST2 reflects activity of an IL-33-dependentcardioprotective signaling axis and is a diagnostic andprognostic marker in acute HF and ST2 is a potent indicatorof prognosis in chronic HF and offers a moderateimprovement in risk stratification when used in combinationwith conventional markers.

The ST2 is an IL-1 receptor family member expressedin cardiomyocytes, fibroblasts, and vascular endothelialcells. The ST2 is part of a cardioprotective signalingsystem composed of paracrine interactions betweenIL-33 produced by cardiac fibroblasts and transmembraneST2 receptors on cardiac myocytes. The ST2 existsin both transmembrane and soluble forms, and solubleST2 is a candidate biomarker in cardiovascular disease.In response to inflammation and cardiac stress, IL-33/ST2 signaling becomes activated, and the soluble formof ST2 is released into the circulation. The soluble form ofST2 acts as a decoy receptor, sequestering and inhibitingIL-33, potentially explaining why higher circulating levelsreflect increased cardiac risk.26 Compared with otherbiomarkers, such as natriuretic peptides, advantages ofsomatostatin receptor 2 (sST2) include that its concentra-tion is not affected by age, renal function, or body massindex. Prognostically speaking, sST2 represents a validcontender to be added to the natriuretic peptides. Withpreliminary data suggesting benefit of therapies thatmitigate ventricular remodeling among patients withelevated sST2 concentrations, the potential of its useto "guide" therapy for prevention of HF complicationsappears promising.

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Galectin-3 (Gal-3)

Galectin-3 (Gal-3) is a beta-galactoside-binding lectinthat appears to be a mediator of cardiac fibrosis. Higherconcentrations of Gal-3 are markers of cardiac fibrosis.Gal-3 is an indicator not only of myocardial fibrosis, butalso other fibrotic conditions, including liver cirrhosisand pulmonary fibrosis, all of which could increase therisk for overall mortality. Beyond the association withall-cause mortality, a recent case-control study demonstratedan association of Gal-3 with HF risk after ACSs.27It is associated with increased risk for incident HF andmortality. Gal-3 has been related to mortality in patientswith acute and chronic HF. The potential clinical roleof Gal-3 may be pathobiological rather than prognosticin nature. Future studies evaluating the role of Gal-3 incardiac remodeling may provide further insights into therole of Gal-3 in the pathophysiology of HF. In patients withchronic, ambulatory HF, concentrations of galectin-3 arefound to be prognostic; interestingly, consistent with thepossibility that biomarkers of fibrosis, such as galectin-3are particularly important in HFpEF (where diastolicnoncompliance is the primary mechanism of HF).

Multimarker Approaches

There has recently been an interest in multimarker strategiesto examine panels of biomarkers that assess differentpathophysiologic pathways. An early study in patientswith HF with reduced ejection fraction reported that acombination of proBNP, high-sensitivity CRP (hsCRP),and myeloperoxidase (a marker of oxidative stress)provided greater predictive accuracy than did any ofthese markers individually.28 Subsequently, multimarkerapproaches to predict the risk for mortality in patientswith ADHF,29 the development of HF,30 and cardiovasculardisease-related death in community-based cohorts31have been described.

In a recent study of ambulatory patients with chronicHF, Ky et al32 tested the hypothesis that a group of sevenbiomarkers, each reflecting a different pathophysiologicpathway, could be combined into a multimarker score thatwould predict the risk for an adverse outcome, defined asdeath, cardiac transplantation, or placement of a ventricularassistdevice. Each of these seven biomarkers and their pathways were reported to have been independentlyassociated with such an outcome. These biomarkers wereBNP (neurohormonal activation), soluble fms-like tyrosinekinase receptor (vascular remodeling), hsCRP (inflammation),ST2 (myocyte stretch), cTnI (myocyte injury), uricacid (oxidative stress), and creatinine (renal function).The combined multimarker integer score provided anexcellent assessment of risk, with the hazard ratios of theintermediate- and higher-risk tertiles (adjusted for clinicalrisk) significantly elevated, to 3.5 and 6.8 respectively,compared with that of the lowest-risk tertile.

 
Guidelines

The American College of Cardiology Foundation/American Heart Association (AHA) HF guidelines33 havegiven BNP and NT-proBNP a Class I recommendation forboth diagnosis and prognosis of HF (level of evidence:A). The use of these natriuretic peptides for guiding HFmanagement received a Class IIa recommendation forchronic HF (level of evidence: B) and IIb for acute HF(level of evidence: C). The TnT or TnI received Class Irecommendation (level of evidence: A) for prognosisand in detection of acute myocardial infarction as theprecipitant of acute HF, while biomarkers of myocardialfibrosis, soluble ST2, and galectin-3 received Class IIbrecommendations (level of evidence: B for chronic andA for acute HF).

European Society of Cardiology recommends natriureticpeptides as IIa (C).34

CONCLUSION

The applications of biomarkers in HF, particularly theNPs, have revolutionized HF management. The next stagein biomarker evolution is taking the insight of underlyingphysiologic mechanisms that biomarkers provide andapplying this knowledge to better understand complexdisease mechanisms. Biomarkers can be used to identifypathologic processes in patients with HF and, thereby, tohelp direct specific therapy. This enhanced understandingcan then be integrated into disease management,which will lead to better therapies and ultimately toimproved patient outcomes.

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