A new score to predict recurrent cardiovascular events?
2015; Elsevier BV; Volume: 240; Issue: 1 Linguagem: Inglês
10.1016/j.atherosclerosis.2015.02.042
ISSN1879-1484
Autores Tópico(s)Lipoproteins and Cardiovascular Health
ResumoAs a consequence of global aging, with its associated chronic diseases, and thanks to improved care after a first cardiovascular event, the number of people at risk for recurrent major cardiovascular events (MACE) is steadily increasing [[1]van der Heijden A.A. Van't Riet E. Bot S.D. Cannegieter S.C. Stehouwer C.D. Baan C.A. Dekker J.M. Nijpels G. Risk of a recurrent cardiovascular event in individuals with type 2 diabetes or intermediate hyperglycemia: the Hoorn study.Diabetes Care. 2013; 36: 3498-3502Crossref PubMed Scopus (31) Google Scholar]. International guidelines recommend regular follow-up of this group of individuals at increased risk with imaging of major atherosclerosis sites, including coronary, carotid, abdominal aortal and lower-extremity vascular tree [2Lim L.S. Haq N. Mahmood S. Hoeksema L. ACPM prevention practice Committee; American college of preventive Medicine. Atherosclerosis cardiovascular disease screening in adults. 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SVS position statement on vascular screening, www.vascularweb.org/patients/screenings/SVSPositionStatementonVascular Screening.html.Google Scholar]. In recent years imaging techniques have significantly improved, allowing to study with great precision unstable or vulnerable plaques [[7]Saba L. Anzidei M. Sanfilippo R. Montisci R. Lucatelli P. Catalano C. Passariello R. Mallarino G. Imaging of the carotid artery.Atherosclerosis. 2012; 220: 294-309Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar]; however the widespread use of these advanced techniques is currently still impractical; considerable research efforts are thus being devoted to the identification of serological biomarkers that may be helpful in the recognition of patients at increased risk of plaques rupture and consequently of MACE. In the paper published by Rizza et al. in the previous issue of Atherosclerosis [[8]Rizza S. Copetti M. Cardellini M. Menghini R. Pecchioli C. Luzi A. Di Cola G. Porzio O. Ippoliti A. Romeo F. Pellegrini F. Federici M. A score including ADAM17 substrates correlates to recurring cardiovascular event in subjects with atherosclerosis.Atherosclerosis. 2015; 239: 459-464Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar], the Authors tested the predictive potential of three endothelial activation/inflammatory biomarkers and, more importantly, combined them in a novel risk score, which they called “ADAM-17 risk score”. ADAM-17 (A Disintegrin and Metallo Protease Domain 17), also known as TACE (TNF-alpha Converting Enzyme), is a zinc-dependent metalloprotease, that regulates the release from cellular membranes of several cytokines, chemokines, and adhesion molecules as well as of growth factors and their receptors [[9]Gooz M. ADAM-17: the enzyme that does it all.Crit. Rev. Biochem. Mol. Biol. 2010; 45: 146-169Crossref PubMed Scopus (288) Google Scholar]. Increased activity of ADAM-17 has been demonstrated to be associated with adverse clinical outcomes of acute myocardial infarction [[10]Satoh M. Ishikawa Y. Itoh T. Minami Y. Takahashi Y. Nakamura M. The expression of TNF-alpha converting enzyme at the site of ruptured plaques in patients with acute myocardial infarction.Eur. J. Clin. Invest. 2008; 38: 97-105Crossref PubMed Scopus (44) Google Scholar] and an altered balance between ADAM-17 and its native inhibitor TIMP-3 (tissue inhibitor of metalloproteinase 3) is characteristic of unstable carotid plaques in diabetic and non diabetic subjects [11Müller A. Krämer S.D. Meletta R. et al.Gene expression levels of matrix metalloproteinases in human atherosclerotic plaques and evaluation of radiolabeled inhibitors as imaging agents for plaque vulnerability.Nucl. Med. Biol. 2011; 41: 562-569Abstract Full Text Full Text PDF Scopus (32) Google Scholar, 12Cardellini M. Menghini R. Luzi A. Davato F. Cardolini I. D'Alfonso R. Gentileschi P. Rizza S. Marini M.A. Porzio O. Lauro D. Sbraccia P. Lauro R. Federici M. Decreased IRS2 and TIMP3 expression in monocytes from offspring of type 2 diabetic patients is correlated with insulin resistance and increased intima-media thickness.Diabetes. 2011; 60: 3265-3270Crossref PubMed Scopus (22) Google Scholar]. Furthermore, several well known cardiovascular risk factors, including hyperglycemia, inflammation, and oxidized low-density lipoprotein have been suggested to increase ADAM-17 activity and/or expression [9Gooz M. ADAM-17: the enzyme that does it all.Crit. Rev. Biochem. Mol. Biol. 2010; 45: 146-169Crossref PubMed Scopus (288) Google Scholar, 13Gutwein P. Abdel-Bakky M.S. Schramme A. Doberstein K. Kämpfer-Kolb N. Amann K. Hauser I.A. Obermüller N. Bartel C. Abdel-Aziz A.A. El Sayed el S.M. Pfeilschifter J. CXCL16 is expressed in podocytes and acts as a scavenger receptor for oxidized low-density lipoprotein.Am. J. Pathol. 2009; 174: 2061-2072Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar]. Rizza and coworkers thus reasoned that assessing ADAM-17 activity should give a inclusive view of different aspects involved in the weakening and rupture of atherosclerotic plaques. To comprehensively assess ADAM-17 activity they constructed a score based on circulating levels of ADAM-17 substrates that were previously suggested to be independently implicated in severity or complications of atherosclerosis, including soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble intercellular cell adhesion molecule 1 (sICAM-1), and soluble tumor necrosis factor (TNF) alpha receptor I [[9]Gooz M. ADAM-17: the enzyme that does it all.Crit. Rev. Biochem. Mol. Biol. 2010; 45: 146-169Crossref PubMed Scopus (288) Google Scholar]. Surprisingly, one of the apparently most likely candidates as a CV risk factor among ADAM-17 substrates, soluble inteleukin-6 (IL-6) receptor, was excluded from the score, since its circulating levels were not significantly associated with events in the cohort under study. This may at first seem unexpected since IL-6 has a fairly established role in inflammation and CV pathogenesis [[14]Ridker P.M. Rifai N. Stampfer M.J. Hennekens C.H. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men.Circulation. 2000; 101: 1767-1772Crossref PubMed Scopus (1986) Google Scholar]; however it has been quite recently described that the most common functional variant in IL-6 receptor may actually play a protective role in inflammation [[15]The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.Lancet. 2012; 379: 1214-1224Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar]. This recent independent observation suggests that the role of IL-6 and its receptor in inflammatory process is far more complex than previously thought. The simultaneous detection of the three substrates is not only likely to give a realistic assessment of ADAM-17 activation state, but offers also concrete advantages, that may be particularly relevant in the light of possible clinical applications of the score. In fact, the levels of three circulating factors included in the score can be quite easily measured with routine ELISA assays, while the direct measurement of ADAM-17 activity requires a far more cumbersome fluorescence assay [[16]Moreira-Tabaka H. Peluso J. Vonesch J.L. Hentsch D. Kessler P. Dumont S. Muller C.D. Unlike for human monocytes after LPS activation, release of TNF-α by THP-1 cells is produced by a TACE catalytically different from constitutive TACE.PLoS One. 2012; 7: e34184Crossref PubMed Scopus (15) Google Scholar]. Rizza and colleagues tested the ability of the newly generated score to predict recurring MACE on a cohort of 298 consecutively recruited subjects, participating to the Athero-Vascular Diabetes (AVD) Study. This follow-up study was specifically designed by the Researchers at the University of Rome-Tor Vergata to investigate the pathophysiology of recurrent MACE in a well characterized cohort of adult subjects with previous cardiovascular disease [[17]Rizza S. Copetti M. Cardellini M. Porzio O. Luzi A. Pecchioli C. Martelli E. Valentini A. Ippoliti A. Romeo F. Pellegrini F. Lauro D. Lauro R. Federici M. Atherosclerosis severity but not undiagnosed diabetes predicts new cardiovascular events of subjects in secondary cardiovascular prevention.Atherosclerosis. 2012; 223: 448-453Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. To generate the ADAM-17 risk score Rizza et al. applied the RECPAM (RECursive Partitioning and AMalgamation) method, a tree-based statistical approach, that integrates statistical discrete event modeling with decision tree analysis [[18]Ciampi A. Negassa A. Lou Z. Tree-structured prediction for censored survival data and the Cox model.J. Clin. Epidemiol. 1995; 48: 675-689Abstract Full Text PDF PubMed Scopus (65) Google Scholar]. At each partitioning step the method chooses the covariate and its best binary split to maximize the difference, the algorithm then stops when user defined conditions (stopping rules) are met. In the present report, an increased risk for incident events was observed among subjects with the highest value of the ADAM-17 score both in univariable (HR 19.20, 95% CI 15.82–63.36, p < 0.001) and multivariable analysis (HR 3.42, 95% CI 1.55–7.54, p < 0.001), after adjustment for age, sex and body mass index. The potential clinical relevance of this newly proposed score is supported by the observation that its addition to the Framingham Recurring-Coronary-Heart-Disease-Score [[19]D'Agostino R.B. Russell M.W. Huse D.M. Ellison R.C. Silbershatz H. Wilson P.W. Hartz S.C. Primary and subsequent coronary risk appraisal: new results from the Framingham study.Am. Heart J. 2000; 139: 272-281Abstract Full Text PDF PubMed Scopus (471) Google Scholar] significantly increases the prediction accuracy of this validated score, with a significant improvement in discrimination (integrated discrimination improvement = 9%, p = 0.012) and a correct reclassification of 10% of events and 41% of non-events (cNRI = 0.51, p = 0.005). As the Authors themselves acknowledge, the statistical significance of their results is rather weak; this should not however be considered as a real limit of the study since it has proven widely difficult to enhance the predictive power of the Framingham risk score and even when this aim has been achieved the improvement has been modest, even with biomarkers for which a firm demonstration of association with cardiovascular risk existed [[20]Yousuf O. Mohanty B. Martin S. Joshi P.H. Blaha M.J. Nasir K. Blumenthal R.S. Budoff M.J. High-sensitivity C-reactive protein and cardiovascular disease: a resolute belief or an elusive link?.J. Am. Coll. Cardiol. 2013; 5: 397-408Abstract Full Text Full Text PDF Scopus (325) Google Scholar]. It could indeed be of great interest to compare the predictive power of the ADAM-17 score with that of a score comprising well established inflammatory markers, such as C-reactive protein, fibrinogen, and white blood cell counts. An additional limit of the study that it is worth underlying is that the Authors employed a composite end-point encompassing different cardiovascular events that may have different pathogenic backgrounds, and thus not necessarily always be related to the rupture of vulnerable plaques; future studies using unique clinical events as independent endpoints should be carried out to validate the present results. Finally, even if the application of a permutation analysis for RECPAM model and of a bootstrap approach for the reclassification metrics allowed the Investigators to obtain a robust internal validation of the data, an external validation on a independent, desirably larger, cohort is needed. In conclusion, the Results from Rizza et al. appear promising and suggest that an approach based on carefully designed scores, generated with statistically sound methods, may be employed to achieve a more accurate risk prediction, especially in specific groups in whom classical scores have proven less satisfactory, such as older patients [[21]Freitas W.M. Carvalho L.S. Moura F.A. Sposito A.C. Atherosclerotic disease in octogenarians: a challenge for science and clinical practice.Atherosclerosis. 2012; 225: 281e9Abstract Full Text Full Text PDF Scopus (22) Google Scholar] or subjects with previous cardiovascular disease. None. A score including ADAM17 substrates correlates to recurring cardiovascular event in subjects with atherosclerosisAtherosclerosisVol. 239Issue 2PreviewAtherosclerosis disease is a leading cause for mortality and morbidity. The narrowing/rupture of a vulnerable atherosclerotic plaque is accountable for acute cardiovascular events. However, despite of an intensive research, a reliable clinical method which may disclose a vulnerable patient is still unavailable. Full-Text PDF
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