Dennis W. Nilsen

Frederic Kontny

Hugo ten Cate

Frontiers in Cardiovascular Medicine

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EDITORIALpublished: 22 May 2019doi: 10.3389/fcvm.2019.00066Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 May 2019 | Volume 6 | Article 66Edited and reviewed by:Per Tornvall,Karolinska Institute (KI), Sweden*Correspondence:Hugo ten Cateh.tencate@maastrichtuniversity.nlFrederic Kontnyfkontny@usa.netDennis W. Nilsendnilsen1@getmail.noSpecialty section:This article was submitted toGeneral Cardiovascular Medicine,a section of the journalFrontiers in Cardiovascular MedicineReceived: 24 April 2019Accepted: 03 May 2019Published: 22 May 2019Citation:ten Cate H, Kontny F and Nilsen DW(2019) Editorial: Novel and potentialmarkers for prediction of outcome inpatients with acute and chroniccoronary heart disease.Front. Cardiovasc. Med. 6:66.doi: 10.3389/fcvm.2019.00066Editorial: Novel and potentialmarkers for prediction of outcome inpatients with acute and chroniccoronary heart diseaseHugo ten Cate 1*, Frederic Kontny 2,3* and Dennis W. Nilsen 2,4*1 Laboratory for Clinical Thrombosis and Hemostasis, Department of Internal Medicine, Cardiovascular Research InstituteMaastricht, Maastricht University Medical Center, Maastricht, Netherlands, 2Department of Cardiology, Stavanger UniversityHospital, Stavanger, Norway, 3Drammen Heart Center, Drammen, Norway, 4Department of Clinical Science, Faculty ofMedicine, University of Bergen, Bergen, NorwayKeywords: prognosis, chronic heart diseases (CHD), biomarker, acute heart disease, atherosclerosis, biomarkers,acute coronary heartdiseaseEditorial on the Research TopicNovel and potential markers for prediction of outcome in patients with acute and chroniccoronary heart diseaseCardiovascular disease (CVD) associated with atherosclerosis and/or atrial fibrillation form themain cause of death globally. Timely identification of patients at risk of CVD is thereforeparamount. Through early screening of risk conditions, like hypertension, hypercholesterolemia,or diabetes, primary prevention aimed at correcting such risk factors can be implemented (1).Smoking cessation can also be pursued through intervention programs early on. However, optimalprimary prevention is still limited; for instance, administration of aspirin to reduce the risk ofthrombosis in all subjects of certain age is useless and potentially harmful (bleeding), as againreiterated by recent large-scale clinical prevention studies [commented on in Song and French(2)]. Recommending aspirin prophylaxis needs to be stratified according to additional risk factors,such as diabetes (3) or coronary artery calcification (4), to reduce the number needed to treat toprevent CVD manifestations to acceptable levels. Similar arguments can be provided for the useof statins, and previous attempts to provide additional pharmacological prophylaxis against CVDby the “polypill” concept failed to become implemented. Assessment of vascular dysfunction mayhelp in selecting those at highest risk; we mentioned calcification, a strong marker of increasedcardiovascular (CV) risk. In this thematic series, Bonarjee discusses the relevance of anothermarkerof vascular dysfunction, arterial stiffness. This functional vascular marker is a predictor of CVevents and mortality, independent of traditional risk factors for CV disease. Gradually, vascularfunctional assessment and imaging tools for calcification and unstable plaque characteristics appearto become part of the workup by cardiologists and other specialists of patients suspected of CVD.There is still a substantial need for additional biomarkers that indicate CVD progression ata stage when, ideally, primary prevention would still be feasible. This topic has been addressedduring later decades and reliable applicable biomarkers are still lacking in clinical practice. Bloodbiomarkers other than lipids do not go beyond additional C-reactive protein (CRP) measurement,but even this indicator of inflammation is not linked to specific therapeutic consequences. A recentclinical trial aimed at reducing inflammation in at-risk for CVD subjects only showed a modestprotective effect upon lowering Il-6 levels (in those stratified for elevated CRP at baseline (5),but studies with methotrexate or colchicine, less specific anti-inflammatory drugs, were negative(6). Hence, determining CRP in all subjects of certain age or CVD risk profile does not seemwarranted yet.ten Cate et al. Biomarkers for Coronary Heart DiseaseDoes this mean that the laboratory biomarker perspective isbleak for CVD prediction? This does not seem to be the case.In fact, we may not yet have explored the possibilities of noveland promising biomarkers that include troponins for ischemicdamage, natriuretic peptides, growth differentiation factor 15(GDF-15) for cardiovascular stress and dysfunction, galectin-3 (fibrosis), cystatin (renal dysfunction) or specific cytokines(inflammation) or indices of coagulation activity (d-dimer) (7).In patients with acute coronary syndrome (ACS), NT-proBNP,and GDF-15 were found to be strong markers associated withall-cause death in a recent study (8).In this theme series additional biomarker approacheshave been reported, including circulating inflammation cellpopulations (Meeuwsen et al.; Gawdat et al.). Meeuwsen et al.review the importance of different leukocyte populations inrelation to atherosclerosis and its complications. Whereastraditionally, leukocytosis was associated with inflammationand also with specific features of atherosclerosis, more recentresearch provided substantial evidence for the important rolesof neutrophils, monocytes, and lymphocytes in distinct steps ofthe atherosclerosis process. Gwadat et al. provide in an originalstudy, data on the neutrophil-to-lymphocyte ratio (NLR) andspecific monocyte subsets (CD16) behavior following cardiacsurgery. These shifts in cell subsets and function, part of thepostoperative inflammatory response, may have consequencesfor the risks of CV events in such patients. For that reason,studies like the one from Gwadat et al. contribute knowledgethat may ultimately have clinical consequences. What aresuch possible consequences? For one, modifying the courseof inflammation by boosting the immune system could bea solution.Naesgaard et al. studied the potential benefit of a high doseof purified omega-3 as compared to corn oil on vitamin Dlevels in patients after having survived an acute myocardialinfarction. Previous work from this team led by Prof. DennisNilsen, showed that serum vitamin D levels were associated withtotal and CV mortality in patients with suspected acute chestsyndrome (9). The present study did not establish any favorableeffects of longterm omega-3 administered as a combination ofeicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA),on vitamin D levels. Given recent lack of evidence of anyfavorable effects of omega-3 supplementation at lower doseranges on outcomes in subjects at risk of CVD, the influence onprognosis of this type of intervention may be limited, with noeffect in healthy individuals with a high dietary background ofomega-3, as recently reported in the VITAL study (10), whereaspurified EPA given alone in a dose of 4 g per day (twice theamount of EPA as compared to that of the present study byNaesgaard et al.) may exert a beneficial impact on prognosis, asdemonstrated in the REDUCE-IT study (11). Furthermore, inthe VITAL study, cardiovascular endpoints were unaffected byvitamin D supplementation (12), suggesting that lower values ofvitamin D may be a result of established disease, rather than acausal factor.Finally, two studies addressed different aspects of thecoagulation system in patients with peripheral artery disease(PAD), a severe manifestation of atherosclerosis. In the hunt forbiomarkers, Kleinegris et al. provide evidence in albeit a smallcase control study, for differences in clot properties, generatedex vivo. An apparent increase in whole blood clotting derivedfrom PAD patients, possibly related to increased fibrinogenlevels, provide an indication for hypercoagulability in suchpatients. These data support the notion that in peripheralartery disease (PAD) not just platelets are involved in drivingatherothrombosis, but also clotting may contribute (13). Clotproperties also were a critical determinant in patients withACS (14). The latter lends support to some of the observedadvantages of the so-called COMPASS regimen comprising lowdose rivaroxaban (2.5mg bd) combined with aspirin in loweringCV mortality in high risk CAD and PAD patients (15). Thefinal study exploring a possible common thrombo-inflammatorynetwork in patients with PAD vs. those who have suffered deepvein thrombosis (DVT), evaluates additional biomarkers forneutrophil activation and clotting (Kremers et al.). Althoughcommon drivers of thrombosis risk were not clearly detected inthis study, it stimulates further research toward biomarkers thatcould pick up different stages of thrombo-inflammation in acuteor chronic CVD.Where does this leave us with respect to current biomarkerstatus in CVD? According to experts like Lars Wallentin, there ismuch hope for this field and we are just starting to explore thepotential (lecture at “Eurothrombosis”, Barcelona, 2018). Giventhe recent publications on above mentioned biomarkers, thismay indeed be true. Combining several very promising markersof different elements of CVD (ischemia, necrosis, thrombo-inflammation, clot lysis, and fibrosis) may increase the diagnosticyield in patients at risk of CV complications and death. The fieldsof proteomics and genomics (e.g., miRNAs) are also movingand it is a matter of time before phenotyping patients basedon biomarker cluster analysis will become clinically useful. Howmuch time? That is anybody’s guess, but we would say one decadeahead, biomarkers will be embedded in the diagnostic toolbox ofmost practicing physicians dealing with patients at risk of CVD.AUTHOR CONTRIBUTIONSAll authors listed have made a substantial, direct and intellectualcontribution to the work, and approved it for publication.REFERENCES1. Leong DP, Joseph PG, McKee M, Anand SS, Teo KK, Schwalm JD,et al. Reducing the global burden of cardiovascular disease, part 2:prevention and treatment of cardiovascular disease. Circ Res. (2017)121:695–710. doi: 10.1161/CIRCRESAHA.117.3118492. Song N, French JK. Aspirin for primary cardiovascular diseaseprevention: what we know and what we don’t know. Int Med J. (2019)49:12–14. doi: 10.1111/imj.141903. The ASCEND Study Collaborative Group. Effects of aspirin for primaryprevention in persons with diabetes mellitus. N Engl J Med. (2018)379:1529–39. doi: 10.1056/NEJMoa1804988Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 May 2019 | Volume 6 | Article 66ten Cate et al. Biomarkers for Coronary Heart Disease4. Miedema MD, Huguelet J, Virani SS. Aspirin for the primary preventionof cardiovascular disease: in need of clarity. Curr Atheroscler Rep. (2016)18:4. doi: 10.1007/s11883-015-0555-05. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C,et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease.N Engl J Med. (2017) 377:1119–31. doi: 10.1056/NEJMoa17079146. Ridker PM. Anticytokine agents. Circ Res. (2019)124:437–50. doi: 10.1161/CIRCRESAHA.118.3131297. Hijazi Z, Oldgren J, Siegbahn A, Wallentin L. Application of biomarkersfor risk stratification in patients with atrial fibrillation. Clin Chem. (2017)63:152–64. doi: 10.1373/clinchem.2016.2551828. Lindholm D, James SK, Gabrysch K, Storey RF, Himmelmann A,Cannon CP et al. Association of multiple biomarkers with risk ofall-cause and cause-specific mortality after acute coronary syndromes:a secondary analysis of the PLATO biomarker study. JAMA Cardiol.(2018). doi: 10.1001/jamacardio.2018.38119. Naesgaard PA, León De La Fuente RA, Nilsen ST, Woie L, AarslandT, Brede C, et al. Serum 25(OH)D is a 2-year predictor of all-causemortality, cardiac death and sudden cardiac death in chest pain patients fromNorthern Argentina. PLoS ONE. (2012) 7:e43228. doi: 10.1371/journal.pone.004322810. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. MarineN-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl JMed. (2019) 380:23–32. doi: 10.1056/NEJMoa181140311. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, KetchumSB, et al. REDUCE-IT Investigators. Cardiovascular risk reductionwith icosapent ethyl for hypertriglyceridemia. N Engl J Med. (2019)380:11–22. doi: 10.1056/NEJMoa181279212. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, MoraS, et al. Vitamin D supplements and prevention of cancer andcardiovascular disease. N Engl J Med. (2019) 380:33–44. doi: 10.1056/NEJMoa180994413. Narula N, Dannenberg AJ, Olin JW, Bhatt DL, Johnson KW, NadkarniG, et al. Pathology of peripheral artery disease in patients with criticallimb ischemia. J Am Coll Cardiol. (2018) 72:2152–63. doi: 10.1016/j.jacc.2018.08.00214. Sumaya W, Wallentin L, James SK, Siegbahn A, Gabrysch K,Bertilsson M, et al. Fibrin clot properties independently predictadverse clinical outcome following acute coronary syndrome: a PLATOsubstudy. Eur Heart J. (2018) 39:1078–85. doi: 10.1093/eurheartj/ehy01315. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O,et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. NEngl J Med. (2017) 377:1319–1330.Conflict of Interest Statement: The authors declare that the research wasconducted in the absence of any commercial or financial relationships that couldbe construed as a potential conflict of interest.Copyright © 2019 ten Cate, Kontny and Nilsen. This is an open-access articledistributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 May 2019 | Volume 6 | Article 66

Editorial: Novel and potential markers for prediction of outcome in patients with acute and chronic coronary heart disease

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Editorial: Novel and potential markers for prediction of outcome in patients with acute and chronic coronary heart disease

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