Aimo, Alberto

Bayes‐Genis, Antoni

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Alberto Aimo

Antoni Bayes‐Genis

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Biomarkers of inflammation in heart failure: from risk prediction to possible treatment targets

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European Journal of Heart Failure (2023) 25, 161–162 INVITED EDITORIALdoi:10.1002/ejhf.2771Biomarkers of inflammation in heart failure:from risk prediction to possibletreatment targetsAlberto Aimo1,2* and Antoni Bayes-Genis3,4,51Scuola Superiore Sant’Anna, Pisa, Italy; 2Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy; 3Hospital Universitari Germans Trias i Pujol, Barcelona, Spain;4Universitat Autònoma de Barcelona, Barcelona, Spain; and 5CIBERCV, Carlos III Institute of Health, Madrid, SpainThis article refers to ‘Inflammation across universaldefinition of heart failure stages: the CASABLANCAstudy’ by R. Mohebi et al., published in this issue onpages 152–160.Inflammation is a response to tissue damage. As virtually all com-pensatory responses, it becomes maladaptive when sustained overtime, and may become itself a determinant of disease progression.Accordingly, anti-inflammatory therapies have been regarded withinterest as possible strategies for cardiovascular disorders rangingfrom stable coronary artery disease to myocardial infarction (MI),where the pathogenic role of inflammation is well established.1 Ourknowledge on inflammation in patients at risk for heart failure (HF)(besides the specific setting of MI) or with established HF is morelimited, the most established notions being that several comor-bidities elicit systemic inflammation, and this may contribute tothe development of HF with preserved ejection fraction (HFpEF),although it is not completely known whether inflammation playsa key role in HFpEF or is just a by-product of various comorbidi-ties.2,3 Further studies expanding the evidence on inflammation inHF are then welcome.In this issue of the Journal, Mohebi and co-workers investi-gated the inflammatory activation across the HF stages (A toC/D) through the use of an inflammatory panel and a machinelearning approach to assess the degree of inflammatory activa-tion.4 In a cohort of 1231 patients undergoing diagnostic coro-nary and/or peripheral angiography, those with stage C/D HF hadmore inflammatory activation. These was an independent associa-tion between moderate and high inflammatory activation and therisk of new-onset HF (in stage A/B) or HF decompensation (in stageC/D). The multivariable model in both cases included N-terminalpro-B-type natriuretic peptide (NT-proBNP) and high-sensitivitycardiac troponin T (hs-cTnT), and also soluble suppression oftumorigenesis-2 (sST2) in stage C/D.4The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Heart Failure or of the European Society of Cardiology. doi: 10.1002/ejhf.2742*Corresponding author. Scuola Superiore Sant’Anna and Fondazione Toscana Gabriele Monasterio, Piazza Martiri della Libertà 33, 56127 Pisa, Italy. Tel: +39 347 7084391,Email: a.aimo@santannapisa.it, albertoaimo@libero.it................................................................................................... The authors should be praised for their original approach, includ-ing the assessment of a panel of inflammatory biomarkers, theirevaluation through an unsupervised machine learning technique,and the assessment of the degree of inflammatory activation ontop of strong predictors of outcome such as NT-proBNP, hs-cTnTand sST2.5,6 This study provides a convincing demonstration thatthe degree of activation of the inflammatory response is associatedwith a higher risk of HF hospitalization across the whole pheno-typic spectrum of HF, from individuals at risk for this conditionto advanced HF. A study limitation, correctly acknowledged bythe authors,4 is the low number of individuals in stage A and thepooled assessment of patients with stages C and D HF (rangingfrom mildly symptomatic patients to those poorly responsiveto optimal treatment). Furthermore, it would be important todifferentiate patients from stage B onwards according to theirejection fraction, as the pathophysiological roles of inflammationmay differ. Figure 1 summarizes the main determinants of inflam-mation in HF with reduced ejection fraction (HFrEF) or HFpEF. Acrucial element is the cause–effect relationship between inflam-mation and cardiac damage. It is generally acknowledged that suchrelationship exists, but it is still unclear whether it is sufficientlystrong to make inflammation a possible treatment target. In otherwords, can we expect to obtain a meaningful impact on the naturalhistory of HF by giving anti-inflammatory therapies? To answerthis question, we must remember that inflammatory pathways aremultiple and partially overlapping, and that inflammatory responsemay be more or less intense in different conditions (HFrEF vs.HFpEF and in individual patients). Randomized clinical trials usingtumour necrosis factor inhibitors, almost two decades ago, wereterminated prematurely owing to lack of benefit, which became ahandicap for future analyses of anti-inflammatory drugs in HF.1The issues of inflammation as a determinant of disease and possi-ble therapeutic target in HF thus remain open. On the other hand,© 2023 European Society of Cardiology162 Invited editorialFigure 1 Possible determinants of inflammation and cardiacdamage in heart failure (HF). The main possible causes of inflam-matory activation and cardiac damage are reported, consider-ing separately HF with reduced or preserved ejection fraction(HFrEF/HFpEF). Both patients with HFrEF or HFpEF may havecomorbidities such as chronic obstructive pulmonary disease,obesity or chronic kidney disease, but their pathogenic role isthought to be more relevant in HFpEF. Lung congestion may pro-mote systemic inflammation by the release of soluble suppressionof tumorigenesis-2 (sST2). The cause–effect relationship betweeninflammation and the development or progression of HF (redarrow) may require further investigation.the degree of inflammation is at least an indicator of disease sever-ity, as demonstrated by the relationship between low inflammationlevels and earlier HF stages, and the strong, independent associ-ation between high inflammation levels and the graded increasein risk of HF hospitalization from low to high inflammation levels.Some elements of novelty in the paper by Mohebi et al. are the useof a panel of 24 biomarkers and their pooled assessment through anartificial intelligence (AI) approach.4 When dissecting the AI-basedclassification, high-sensitivity C-reactive protein (hs-CRP) emergedas the strongest determinant by far (coefficient> 20), followedby macrophage colony-stimulating factor-1 (M-CSF-1; coefficientlower than 10) and ferritin (coefficient of about 7.5).4 The prog-nostic value of hs-CRP is basically in agreement with previous data,reporting for example that hypertensive individuals with higherhs-CRP have an increased risk of developing HF,7 and that hs-CRPis predictive of outcome in HF regardless of ejection fraction.8Less evidence is available on M-CSF, reported to predict outcomein advanced HF,9 and on ferritin, whose relationship with outcomemight be confounded by the development of iron deficiency duringHF progression.10 The outstanding prognostic value of hs-CRPraises the question if we really need a panel of 24 inflammatorybiomarkers and the use of an AI approach to stratify inflammatorylevels into three categories (low, medium, or high) instead ofsimply measuring hs-CRP and using continuous hs-CRP levels foroutcome prediction. To clarify this point, we may envisage largerbiomarker studies, possibly also considering separately patientswith acute versus chronic presentations (who were instead pooledtogether in the present study). Besides confirming that hs-CRP isa strong predictor of outcome, it would be important to check if ....................................................................................................................................................................... a cause–effect relationship exists between elevated hs-CRP andHF development or progression. A few Mendelian randomizationstudies did not find evidence of a relationship between CRP andincident HF,11,12 and animal studies with direct modulation of thisprotein (much used to investigate the role of CRP in coronaryartery disease)13 would be important to clarify its causal role inHF. Should this role be confirmed, these findings would provide astrong rationale to target the innate immunity to prevent HF devel-opment or progression, particularly in patients with high hs-CRP.A specific inhibitor of CRP (1,6-bis[phosphocholine]-hexane) hasbeen developed and proved effective in preventing HF develop-ment following MI in rats,14 but we are not aware of furtherstudies on this compound as a possible HF therapy. Colchicineis a commonly available drug that can effectively reduce hs-CRP.1Colchicine therapy for 6 months did not improve the New YorkHeart Association class in a small randomized, placebo-controlledtrial, where the degree of inflammatory activation at baseline wasnot evaluated.15 To our knowledge, there is no further evidenceon colchicine for the prevention or treatment of HF, but this drugmight warrant consideration for future trials.Conflict of interest: none declared.References1. Aimo A, Pascual-Figal DA, Barison A, Cediel G, Vicente ÁH, Saccaro LF, et al.Colchicine for the treatment of coronary artery disease. Trends Cardiovasc Med.2021;31:497–504.2. Adamo L, Rocha-Resende C, Prabhu SD, Mann DL. Reappraising the role ofinflammation in heart failure. Nat Rev Cardiol. 2020;17:269–85.3. van Empel V, Brunner-La Rocca HP. Inflammation in HFpEF: key or circumstantial?Int J Cardiol. 2015;189:259–63.4. Mohebi R, Liu Y, van Kimmenade R, Gaggin H, Murphy S, Januzzi JL. Inflammationacross universal definition of heart failure stages: the CASABLANCA study. EurJ Heart Fail. 2023;25:152–60.5. Aimo A, Januzzi JL Jr, Vergaro G, Ripoli A, Latini R, Masson S, et al. Prognosticvalue of high-sensitivity troponin T in chronic heart failure: an individual patientdata meta-analysis. Circulation. 2018;137:286–97.6. Emdin M, Aimo A, Vergaro G, Bayes-Genis A, Lupón J, Latini R, et al. sST2predicts outcome in chronic heart failure beyond NT-proBNP and high-sensitivitytroponin T. J Am Coll Cardiol. 2018;72:2309–20.7. Maio R, Perticone M, Suraci E, Sciacqua A, Sesti G, Perticone F. Endothelialdysfunction and C-reactive protein predict the incidence of heart failure inhypertensive patients. ESC Heart Fail. 2021;8:399–407.8. Windram JD, Loh PH, Rigby AS, Hanning I, Clark AL, Cleland JG. Relationship ofhigh-sensitivity C-reactive protein to prognosis and other prognostic markers inoutpatients with heart failure. Am Heart J. 2007;153:1048–55.9. Hohensinner PJ, Rychli K, Zorn G, Hülsmann M, Berger R, Mörtl D, et al.Macrophage-modulating cytokines predict adverse outcome in heart failure.Thromb Haemost. 2010;103:435–41.10. Jankowska EA, Malyszko J, Ardehali H, Koc-Zorawska E, Banasiak W, vonHaehling S, et al. Iron status in patients with chronic heart failure. Eur Heart J.2013;34:827–34.11. Li X, Peng S, Guan B, Chen S, Zhou G, Wei Y, et al. Genetically determinedinflammatory biomarkers and the risk of heart failure: a Mendelian randomizationstudy. Front Cardiovasc Med. 2021;8:734400.12. Remmelzwaal S, van Oort S, Handoko ML, van Empel V, Heymans SRB, BeulensJWJ. Inflammation and heart failure: a two-sample Mendelian randomizationstudy. J Cardiovasc Med (Hagerstown). 2022;23:728–35.13. Fu Y, Wu Y, Liu E. C-reactive protein and cardiovascular disease: from animalstudies to the clinic (review). Exp Ther Med. 2020;20:1211–9.14. Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, et al.Targeting C-reactive protein for the treatment of cardiovascular disease. Nature.2006;440:1217–21.15. Deftereos S, Giannopoulos G, Panagopoulou V, Bouras G, Raisakis K, Kossy-vakis C, et al. Anti-inflammatory treatment with colchicine in stable chronic heartfailure: a prospective, randomized study. JACC Heart Fail. 2014;2:131–7.© 2023 European Society of Cardiology 18790844, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2771 by CochraneItalia, Wiley Online Library on [28/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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Biomarkers of inflammation in heart failure: from risk prediction to possible treatment targets

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