positioning of inflammatory biomarkers in the heart failure landscape

Positioning of Inflammatory Biomarkers in the HeartFailure Landscape

Justin Hartupee & Douglas L. Mann

Received: 4 April 2013 /Accepted: 23 April 2013 /Published online: 11 May 2013# Springer Science+Business Media New York 2013

Abstract The clinical syndrome of heart failure is charac-terized by a systemic inflammatory response that contributesto end organ damage in the heart and circulation and canthus lead to worsening heart failure. The ensemble of in-flammatory mediators that have been detected in heart fail-ure patients include pro-inflammatory cytokines and theircognate receptors, as well as molecules secreted/released bymacrophages (galectin-3 and pentraxin-3). Inflammatorybiomarkers correlate with disease severity and prognosisacross the broad spectrum of heart failure syndromes. Giventhe proliferation of new biomarkers that predict diseaseseverity and prognosis in heart failure, it is reasonable toask whether there is a current role for measuring inflamma-tory mediators in heart failure. This review will attempt toaddress this question, as well as review several novel ap-proaches that have utilized inflammatory biomarkers toenhance risk stratification and prognosis in heart failurepatients.

Keywords Inflammation . Heart failure . Biomarkers . Pro-inflammatory cytokines . Cytokine receptors . Tumornecrosis factor . Interleukins . C-reactive protein (CRP) .

sST2 . Galectin-3 . Pentraxin-3

Introduction

Heart failure is as progressive disorder that is initiated afteran index event that either damages the heart muscle, with a

resultant loss of functioning cardiac myocytes, or alterna-tively disrupts the ability of the myocardium to contractand/or relax normally. Although there have been repeatedattempts to define a unique pathophysiological mecha-nism that explains the progressive nature of heart failure,no single conceptual paradigm has withstood the test oftime. This statement notwithstanding, research from amultiple laboratories has shown consistently that heartfailure is accompanied by an inflammatory response,which is believed to occur as a response to the tissueinjury that occurs in the failing heart. Since the originalobservation by Levine et al. [17], who reported that heartfailure patients had elevated circulating levels of tumornecrosis factor (TNF), countless studies have confirmedand expanded upon this observation by demonstratingthat ensembles of pro-inflammatory cytokines, pro-inflammatory cytokine receptors, cell adhesion molecules,and chemokines are elevated in patients with heart failurewith a decreased ejection fraction (HFrEF). Moreover,elevated levels of inflammatory mediators have beenidentified in heart failure patients with a preserved ejec-tion fraction (HFpEF), as well as in the setting of acutedecompensated heart failure (ADHF). The observationthat elevated levels of inflammatory mediators can bedetected across the spectrum of heart failure syndromesraises important questions about whether elevated levelsof these proteins can be used as clinical biomarkers thatcan be used to provide diagnostic, prognostic, and/ortherapeutic information in heart failure patients. The fol-lowing review will attempt to provide a current overviewof what is known about inflammatory biomarkers in heartfailure, as well as discuss several novel analytic ap-proaches in which the serial measurement of inflamma-tory biomarkers has been used to increase the diagnosticaccuracy of traditional heart failure risk models.

J. Hartupee :D. L. Mann (*)Center for Cardiovascular Research, Division of Cardiology,Department of Medicine, Washington University School ofMedicine, 660 South Euclid Avenue, Campus Box 8086,St. Louis, MO 63110, USAe-mail: [email protected]

J. of Cardiovasc. Trans. Res. (2013) 6:485–492DOI 10.1007/s12265-013-9467-y

Overview of Inflammation in the Heart

Over the past two decades, research from multiple laborato-ries has shown that the heart possesses an intrinsic or “in-nate” stress response system that is activated in response totissue injury. This intrinsic stress response system is medi-ated, at least in part, by a family of pattern recognitionreceptors (PRRs), most notably the Toll-like receptors(TLRs), which are responsible for coordinating the initialresponse to tissue injury. TLRs serve as PRRs that recognizethe molecular patterns of endogenous host material that isreleased during cellular injury or death, the so-calleddamage-associated molecular patterns (DAMPs) [7, 10].DAMPs can be derived from dying or injured cells, dam-aged extracellular matrix proteins, or circulating oxidizedproteins. Pro-inflammatory cytokines serve as the down-stream “effectors” of the innate immune system and areresponsible for activating the cellular and molecular mech-anisms that facilitate tissue repair in the heart [20, 22].Although the innate immune system provides a short-termadaptive response to tissue injury, the beneficial effects ofthis phylogenetically ancient system are lost if innate im-mune signaling becomes sustained and/or excessive, inwhich case the salutary effects of the activation of thesepathways is contravened by the known deleterious effects ofinflammatory signaling.

The initial interest in understanding the role of inflam-matory mediators in heart failure arose from the observationthat many aspects of the syndrome of heart failure could bemimicked by the known biological effects of pro-inflammatory cytokines. Although the disappointing resultswith targeted anti-cytokine therapies in heart failure damp-ened the initial enthusiasm for studying the role of inflam-mation in heart failure [21], continued progress in the fieldhas led to a deeper understanding of the role of inflamma-tion in the failing heart, as well as the identification of newinflammatory biomarkers such as soluble ST2 (sST2),galectin-3, and pentraxin-3, which have provided excitingnew information with respect to the diagnosis and prognosisof heart failure patients. In the sections that follow, we willreview the families of inflammatory mediators that havebeen identified across the spectrum of clinical heart failuresyndromes, with the intent of placing these observations in amore global perspective regarding the utility of measuringinflammatory mediators in heart failure.

Which Inflammatory Mediators are Best Suitedfor Use as Biomarkers?

Given the critical importance of innate immune responses tothe host, it is not surprising that nature has developed a myriadof pro-inflammatory and anti-inflammatory molecules that are

responsible for initiating and subsequently terminating in-flammatory responses, respectively. Unfortunately, there isno consensus in the literature with regard to which inflam-matory mediators are the most biologically relevant bio-markers to follow in different disease states. The familiesof molecules that have been evaluated in the setting ofheart failure thus far include pro-inflammatory cytokines,anti-inflammatory cytokines, soluble pro-inflammatory cy-tokine receptors, cell adhesion molecules, chemokines, che-mokine receptors, as well as molecules that aresecreted/released by macrophages and/or granulocytes. Inorder to better focus this review, we will limit the presentdiscussion to the literature on pro-inflammatory cytokinesand their receptors, as well as molecules that are releasedby macrophages. For recent reviews on chemokines inheart failure, the reader is referred to recent publications[2, 9].

The pro-inflammatory cytokines that are elaborated inheart failure include members of the TNF superfamily(TNFSF), members of the interleukin (IL)-1 family (IL1-F), and IL-6 (see Table 1) [2]. Pro-inflammatory cytokinesare expressed by all nucleated cell types residing in themyocardium, including the cardiac myocyte [36]. And in-deed, there is evidence that the failing heart releases pro-inflammatory “cardiokines” (e.g., TNF) into the circulation[5, 37]. However, the relative contribution of cardiacmyocytes, non-myocytes, and inflammatory cells to totalcytokine production in the heart is not known.

Cytokines exert their biological effects by binding to cog-nate cytokine receptors on cell membranes (Fig. 1). Oneinteresting aspect of the biology of cytokine receptors is thatthey can be proteolytically cleaved from cell membranes(referred to as “shedding”), thereby releasing the solubleextracellular ectodomain of the cytokine receptor into theextracellular space and/or circulation (Fig. 1). Receptor shed-ding occurs in response to exposure to inflammatory cyto-kines, mechanical stretch, and/or lipopolysaccharide. Solublecytokine receptors can also be generated through alternativesplicing of mRNA transcripts, which deletes the transmem-brane domain of membrane-associated receptors, or by dis-tinct genes that encode secreted cytokine-binding proteins thatcan function as decoy proteins [18]. Cleaved and/or secreted“soluble” cytokine receptors are quite stable in the circulationand retain their ability to bind ligand and to inhibit the bio-logical activities of cytokines by preventing cytokines frombinding to cognate receptors on target cells (Fig. 1). Becauseof their larger molecular weight, shed/secreted cytokine re-ceptors remain in the circulation longer than cytokines, whichhave a much lower molecular weight and a larger volume ofdistribution and, hence, are cleared from the circulation morerapidly. Accordingly, based on first principles, one wouldpredict that circulating levels of pro-inflammatory cytokinereceptors would integrate past and present inflammatory

486 J. of Cardiovasc. Trans. Res. (2013) 6:485–492

responses more precisely than pro-inflammatory cytokineswould and, hence, would be more accurate biomarkers ofinflammation.

In addition to cytokines and cytokine receptors, elevatedcirculating levels of a number of inflammatory mediatorsthat were originally identified in immune cells, most notablymacrophages, have also been observed in patients with heartfailure. The inflammatory mediators in this group that havegarnered the most attention include galectin-3 and pentraxin-3. Galectin-3, a member of the lectin family, is released bymacrophages in response to tissue injury, as well as bydamaged and/or dying cells. Galectin-3 has a number ofimportant biological roles, including fibroblast activationleading to the formation of tissue fibrosis. Pentraxin-3, a

novel inflammatory marker and member of the pentraxinsuperfamily of cytokines, has also recently been identifiedin patients with heart failure. Although the role of pentraxin-3 in heart failure is not known, this molecule is known tobind to C1q and initiate the classical pathway of complementactivation and to facilitate pathogen recognition by macro-phages. For want of a better description, in the presentreview, we will refer to pentraxin-3 and galectin-3 as mac-rophage biomarkers, recognizing that the precise source ofthese molecules in heart failure is not known and that mul-tiple cell types in the heart are capable of producing/releasingthese molecules. By way of review, C-reactive protein (CRP)is also a member of the pentraxin family that participates inthe systemic response to inflammation [11]. Although CRP

Table 1 Inflammatory biomarkers in heart failure

HFrEF HFpEF ADHF

Pro-inflammatory cytokines

TNF (TNFSF2), TWEAK (TNFSF12), FasL (TNFSF6), LIGHT(TNFSF12), IL-1β (IL-1F2), IL-2,IL-6, IL-18 (IL-1F8), IL-33 (IL-1F11)

TNF (TNFSF2), IL-6 (?) TNF (TNFSF2), IL-6, IL-18

Cytokine receptors

sTNFR1 (TNFRSF1A), sTNFR2 (TNFRSF1B), gp130 (IL6ST);IL-1ra (IL1F3), sST2 (IL-1RL1)

sST2 (IL-1RL1) sST2 (IL-1RL1)

Macrophage

Galectin-3, pentraxin-3 Galectin-3, pentraxin-3 Galectin-3, pentraxin-3

The parenthesis denotes the nomenclature for the TNF and IL-1 superfamily of cytokines and cytokine receptors

FasL Fas ligand, LIGHT homologous to lymphotoxins, inducible expression, competes with HSV glycoprotein D for HVEM, a receptor expressedon T lymphocytes, gp130 soluble gp130, IL-1β interleukin-1β, IL-2 interleukin-2, IL-6 interleukin-6, IL-18 interleukin-18, IL-33 interleukin 33,IL1-F interleukin-1 family, IL-1RL1 interleukin-1 receptor-like-1, sST2 soluble ST2 receptor, TNF tumor necrosis factor, sTNFR1 soluble TNF type1 receptor, sTNFR2 soluble TNF receptor type 2, TNFSF tumor necrosis factor superfamily, TNFSFR tumor necrosis factor superfamily receptor,TWEAK TNF-like weak inducer of apoptosis, ? conflicting data

Fig. 1 The biology of cytokines and cytokine receptors. Pro-inflam-matory cytokines are released by nucleated cell types residing in theheart, including cardiac myocytes. Cytokines exert their biologicaleffects by binding to cognate cytokine receptors on cell membranes(left side of the diagram). Cytokine receptors can be proteolyticallycleaved or “shed” from cell membranes, which releases the soluble

extracellular ectodomain of the cytokine receptor into the extracellularspace and/or circulation (middle of the diagram). Cytokine receptorsretain their ability to bind cytokine and to inhibit the biological activ-ities of cytokines by preventing cytokines from binding to cognatereceptors on target cells (right side of the diagram)

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was thought to be exclusively produced in the liver, morerecent studies have shown that CRP is produced by non-hepatic cells as well

The section that follows will review the literaturewhich suggests that pro-inflammatory cytokines andpro-inflammatory cytokine receptors, as well as inflam-matory mediators linked to immune activation can predictdisease severity, the transition to symptomatic heart fail-ure, as well as prognosis across the spectrum of heartfailure syndromes, including patients with HFrEF,HFpEF, and ADHF. For more in depth coverage of theseand other inflammatory mediators in heart failure, theinterested reader is referred to several more extensivereviews [2, 9].

Inflammatory Mediators are Increased and Correlatedwith Disease Severity, Prognosis, and the Developmentof Symptomatic Heart Failure in Patientswith a Depressed Ejection Fraction

Disease Severity

Circulating levels of TNF and members of the TNF superfamily(TNFSF) [38], IL-1β, IL-6, IL-18, and IL-33 are elevated inheart failure patients (see Table 1; reviewed in [2]). Pro-inflammatory cytokines are activated in asymptomatic left ven-tricular (LV) dysfunction [40] and continue to rise in directrelation to worsening New York Heart Association (NYHA)functional class regardless of the etiology of heart failure [35].In addition to the pro-inflammatory cytokines, circulating levelsof pro-inflammatory cytokine receptors are elevated in heartfailure. These include the soluble type 1 and type 2 TNF re-ceptors (sTNFR1 and sTNFR2, respectively) and soluble trans-membrane glycoprotein 130 (gp130; one of the receptors for IL-6), which are increased in relation to worsening heart failurefunctional class [2]. Analogous to the findings with soluble TNFreceptor levels, IL-1 receptor antagonist levels are also elevatedin heart failure. Further, as discussed by Januzzi in this issue,there is growing interest in ST2, which is the receptor for IL-33,and is amember of the IL-1 superfamily (IL1-F) of cytokines. Ofnote, sST2 is secreted by cultured myocytes that are subjected tomechanical strain and is thus a marker of mechanical strain andinflammation [43]. In addition to pro-inflammatory cytokinesand cytokine receptors, molecules that are released bymacrophages/monocytes such as galectin-3 and pentraxin-3 alsocorrelate with disease severity and predict worse outcomes inheart failure [34, 39].

Transition to Symptomatic Heart Failure

Elevated levels of pro-inflammatory cytokines predicted thedevelopment of symptomatic heart failure in previously

asymptomatic older subjects in an analysis of Framingham data[40]. In this study, baseline levels of IL-6, as well as spontane-ous production of TNF by peripheral blood mononuclear cells(PBMCs), predicted the development of heart failure over a 5-year period. After adjustment for traditional risk factors, the riskof developing heart failure increased 1.6-fold to 1.7-fold pertertile increment in PBMC TNF and IL-6 levels, respectively,whereas patients with a CRP≥5 mg/dl had a 2.8-fold increasedrisk of developing heart failure. Of note, subjects with elevatedlevels of all three inflammatory mediators had a 4.1-fold riskfor developing heart failure. Unfortunately, baseline levels ofLV function were not measured, so it is possible that this studymay have identified patients with subclinical LV dysfunction. Itis noteworthy in this regard that very similar findings withrespect to the circulating levels of TNF, IL-6, and CRP andthe development of incident heart failure were observed inolder subjects enrolled in the Health, Aging, and Body Com-position study [13].

Prognosis

In addition to correlating with disease severity, elevated cir-culating levels of pro-inflammatory cytokines also correlatewith increased mortality in heart failure patients. Circulatinglevels of TNF, IL-6, sTNFR1, and sTNFR2 have beenreported to predict poorer survival [4, 29]. As shown inFig. 2a, there was a decline in survival as a function ofincreasing TNF levels in patients with moderate to severeheart failure in the Vesnarinone Trial (VEST), with the worstsurvival observed in patients with TNF levels >75th percentile[4]. Similar findings were observed with circulating levels of

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IL-6

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sTNFR1 sTNFR2

Weeks0 20 40 60 80

00.60.70.80.91.0

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Fig. 2 Kaplan–Meier survival analysis. The circulating levels of TNF(a), IL-6 (b), sTNFR1 (c), and sTNFR2 (d) were examined in relationto patient survival during follow-up (mean duration, 55 weeks; maxi-mum duration, 78 weeks). For this analysis, the circulating levels ofcytokines and cytokine receptors were arbitrarily divided into quartiles.Reproduced with permission from Deswal et al. [4]


IL-6 (Fig. 2b) and levels of sTNFR1 and sTNFR2 (Fig. 2c, d).When each cytokine and/or cytokine receptor was separatelyentered into a multivariate Cox proportional hazards modelthat included age, sex, etiology of heart failure, NYHA class,ejection fraction, and serum sodium, TNF, IL-6, sTNFR1, andsTNFR2 remained significant independent predictors of mor-tality, along with NYHA class and ejection fraction. However,when all the cytokines and receptors were entered into themodel together, only sTNFR2 remained a significant predictorof mortality [4]. In a smaller study of 152 heart failure patients,Rauchhaus et al. reported that sTNFR1 was the strongest andmost accurate prognosticator [29]. More recent studies haveshown that elevated levels of sST2 correlate with heart failureoutcomes (see also the article by Januzzi in this issue). Wein-berg and colleagues demonstrated that increased sST2 levelspredicted increased mortality or cardiac transplantation, inde-pendent of circulating levels of BNP or ProANP [43]. Similarfindings were reported by Ky et al., who demonstrated thatelevated levels of sST2 predicted adverse outcomes in patientswith chronic heart failure [15]. Elevated levels (fifth quintile)of soluble gp130 were associated with all-cause mortality,cardiovascular mortality, and death from worsening heartfailure in the Controlled Rosuvastatin Multinational Trial inHeart Failure (CORONA) trial, whereas elevated levels of IL-6 were not associated with adverse outcomes [1].

In addition to pro-inflammatory cytokines and pro-inflammatory cytokine receptors, inflammatory moleculesthat are secreted by macrophages have been shown to pre-dict untoward outcomes in HFrEF patients. In a substudy ofthe CORONA trial, elevated levels of galectin-3 were sig-nificantly associated with the primary end point of cardio-vascular death, nonfatal myocardial infarction, or stroke, aswell as all-cause and cardiovascular mortality. However,when NT-proBNP was added to the statistical model, theassociation of galectin-3 with the aforementioned clinicalend points was no longer significant [8]. In contrast, elevat-ed baseline levels of pentraxin-3 were associated with ahigher risk of all-cause mortality, cardiovascular mortality,or hospitalization for worsening heart failure in the GISSI(Gruppo Italiano per lo Studio della Streptochinasinell'Infarto Miocardico) Heart Failure and CORONA trials,even after adjusting for hsCRP or NT-proBNP levels [16].

Elevated Levels of Inflammatory Mediators Correlatewith Disease Severity and Prognosis in Patientswith Heart Failure with a Preserved Ejection Fraction

Disease Severity

Although most studies have focused on the role of inflam-matory biomarkers in the setting of HFrEF, there is anemerging body of literature which suggests that elevated

levels of inflammatory biomarkers are associated with in-creased risk of mortality in patients with HFpEF [6, 23].Thus far, the extant literature suggests that TNF, sST2,galectin-3, and pentraxin-3 are elevated across the spectrumof heart failure syndromes, regardless of ejection fraction[24, 39]. Moreover, pentraxin-3 has been show to be pro-duced within the heart of patients with HFrEF, as measuredby differences in pentraxin-3 levels in the aorta and coro-nary sinus [24]. However, the data with respect to IL-6 andCRP in HFpEF patients are conflicting [24–26]. Whereassome studies found these markers to be elevated to a similarextent in all patients with heart failure, regardless of LVejection fraction, other studies have reported lower levels inpatients with HFpEF. These discrepant findings may be due,at least in part, to small numbers of patients with differingseverities of illness.

Transition to Symptomatic Heart Failure

At the time of this writing, there are scant data to suggestthat elevated levels of inflammatory mediators predict thetransition to symptomatic heart failure in patients withHFpEF. Low-grade inflammation as evidenced by elevatedurinary levels of TNF has been shown to identify a hyper-tensive population at higher risk of developing LV hyper-trophy, which is a known risk factor for the development ofsymptomatic HFpEF [27]. Moreover, given that inflamma-tory mediators are elevated in patients with hypertension, aswell as in older subjects, it is likely that elevated levels ofinflammatory mediators will predict the transition to symp-tomatic heart failure in HFpEF patients [19].

Prognosis

Surprisingly, there are relatively few studies with respect tothe prognostic importance of elevated pro-inflammatorycytokine levels in HFpEF patients. Thus far, only TNFlevels have been shown to correlate with increased mortalityin HFpEF [6, 23].

Elevated Levels of Inflammatory Mediators Correlatewith Disease Severity and Prognosis in AcuteDecompensated Heart Failure

Prognosis

Elevated levels of CRP, ST-2, galectin-3, and IL-6 have allbeen correlated with increased rates of mortality in patientsdiagnosed with ADHF [3, 12, 26, 28, 30, 32, 39, 41]. Ofnote, the majority of these studies compared the utility ofinflammatory biomarkers to natriuretic peptides with respectto the predictive accuracy for diagnosing heart failure in


dyspneic patients. The aggregate data suggest that, whencompared to natriuretic peptides, inflammatory biomarkersare less accurate in terms of diagnosing heart failure inpatients who present with acute dyspnea [12, 31]. Thedecreased diagnostic accuracy of inflammatory mediatorsin this setting is not at all surprising given the wide rangeof inflammatory diseases that present with dyspnea (e.g.,asthma, chronic obstructive lung disease, and pneumonia).Importantly, all of the aforementioned inflammatory bio-markers independently predicted increased mortality in thesetting of ADHF, even after adjusting for BNP levels. Inter-estingly, in pooled data sets when sST2 levels were includedin the statistical model, NT-proBNP was not a predictor ofdeath in patients with HFrEF [23]. Viewed together, thepreviously discussed findings have led to the notion thatrisk stratification may be best accomplished using modelsthat incorporate multiple biomarkers, including both inflam-matory cytokines and natriuretic peptides, as will bediscussed in the next section.

Positioning of Inflammatory Biomarkers in the HeartFailure Landscape

Given the striking rise in the number of biomarkers current-ly available or in development, as well as the understandingthat high-throughput proteomic approaches will likely con-tribute to proliferation of new biomarkers, it is reasonable toquestion whether measuring inflammatory biomarkers is ofadded value in heart failure patients. Since different bio-markers reflect different aspects of the many aspects of heartfailure and since ongoing tissue injury contributes to theinexorable progression of heart failure, it is likely that in-flammatory biomarkers will have the most immediate clin-ical utility in heart failure when they are incorporated intomultimarker biomarker panels, rather than being used as asingle biomarker. And indeed, incorporation of sST2 into astepwise risk model with NT-proBNP resulted in improvedrisk stratification in the ProBNP Investigation of Dyspnea inthe Emergency Department (PRIDE) study. Remarkably,elevated levels of CRP were not meaningful prognosticallywhen sST2 was added to the model, which may reflect thefact that CRP is an indirect marker of inflammation in heartfailure, whereas sST2 integrates both inflammation andmechanical stress. Similar findings were observed with re-spect to galectin-3 in the PRIDE study, wherein galectin-3was a better univariate predictor of 60-day mortality thanNT-proBNP and was the best predictor of 60-day mortalityin a multivariable model that included NT-proBNP andapelin [39]. A multimarker strategy that included sST2, tro-ponin I, and growth differentiation factor-14 predicted in-creased risk of heart failure when added to traditionalclinical factors in a study from the Framingham cohort [42].

Similarly, a multimarker panel that included sST2, along withbiomarkers that detected myocyte injury (TnI), neurohormon-al activation (BNP), vascular growth and remodeling (sFlt-134), inflammation (CRP), oxidative stress (uric acid, MPO),and renal dysfunction (creatinine), resulted in increased abilityto predict 1 year risk that was superior to the Seattle HeartFailure Model [14]. Furthermore, adding the multimarkerscore to the Seattle Heart Failure Model risk score reclassified~24 % of the patients to a higher risk category [14]. Whether amore parsimonious multimarker strategy would have yieldedsimilar results is unclear but is not likely, insofar as many ofthe biomarkers correlated with one another and likely provid-ed similar and/or overlapping prognostic information.

More recently, serial measurement of inflammatory bio-markers has been shown to improve the predictive accuracy of1 year mortality in heart failure patients, above and beyondwhat can be obtained through multimarker strategiesperformed at a single time point. As noted previously, inclu-sion of a multimarker approach to a clinical heart failuremodel resulted in a modest but significant improvement inthe C statistic from 0.76 to 0.80 (P<0.001). In a recentanalysis of the VESTcytokine database, a multivariate logisticregression model of mortality that employed baseline andserial measurements of cytokine and cytokine receptors levelspredicted 1 year mortality that was significantly better than alogistic regression model of mortality without the serial mea-surements of cytokines and cytokine receptors (C statistic 0.81versus 0.73, respectively; P=0.001) (Fig. 3). Thus, significant

Fig. 3 Serial measurements of pro-inflammatory cytokines and pro-inflammatory cytokine receptors in the VEST trial. Receiver operatingcurves are for three logistic regression models for 1 year mortality inthe VEST trial. The three models use standard clinical variables only(no cytokines, C statistic of 0.73), standard variables and baselinecytokines only (C statistic of 0.74), and standard variables and serialcytokine measurements at baseline and 8, 16, and 24 weeks (C statisticof 0.81). Reproduced with permission from Subramanian et al. [33]


gains in predictive accuracy of 1 year mortality in chronicheart failure can be obtained by using serial measurements ofinflammatory biomarkers rather than baseline values alone.Changes observed with serial measurements are more likely tolead to improved prognostic capability because they reflectboth ongoing changes in the underlying disease process, aswell as the individual response (i.e., responder ornonresponder) of a patient to a given form of therapy. More-over, when the data from the VESTstudy were analyzed usinga well-established method of statistical machine learningtermed “ensemble modeling,” ensemble models performedsignificantly better when compared to standard logistic regres-sion models that employed time series data alone (C statistic=0.84 versus 0.81, respectively; P=0.04). One potential reasonfor the significant increase in predictive accuracy with ensem-ble modeling is that this statistical method may better adjustfor the biological variability inherent in clinical studies. Theresults of this study support the point of view that clinicalmodels that predict mortality can be improved significantly bymoving away from obtaining a large series of measurements ata single point in time and focusing instead on a smaller set ofrelevant measurements that are measured serially. Given thatinflammatory biomarkers are surrogate markers for ongoingtissue injury, it is likely that these biomarkers will continue tocontribute to prognostic assessments obtained using time se-ries measurements.

Conclusions

In the foregoing review, we have discussed the utility ofmeasuring inflammatory biomarkers in the setting of HFrEF,HFpEF, and ADHF. As noted, the extant literature suggeststhat inflammatory biomarkers provide important diagnosticand prognostic information across the entire spectrum ofheart failure syndromes. What is less clear at the time ofthis writing is whether these biomarkers are directly in-volved in the pathogenesis and/or progression of heart fail-ure or whether the elevated levels of these inflammatorybiomarkers reflect an intrinsic adaptive response toongoing/incessant tissue damage in the failing heart. Thisdistinction is important, insofar as the former possibilitysuggests that elevated levels of inflammatory biomarkermay represent potential therapeutic targets, whereas thelatter possibility suggests that not all inflammatory bio-markers that are elevated in heart failure are necessarilyharmful and may, therefore, not represent appropriate ther-apeutic targets. With that said, the totality of the datareviewed herein suggests that the measurement of inflam-matory biomarkers continues to provide important informa-tion with respect to prognosis and risk stratification acrossthe entire spectrum of heart failure syndromes. Moreover,given that inflammatory mediators are surrogate markers for

ongoing tissue injury and/or mechanical strain, it is likelythat measurements of inflammatory biomarkers will contin-ue to contribute to our understanding of the pathogenesis ofheart failure now and for the foreseeable future.

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positioning of inflammatory biomarkers in the heart failure landscape

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