COMMENTARY

Inflammation, cardiovascular and cancer: moving toward predictive

Paul M. Ridker MD MPH

n Cite as: CMAJ 2017 March 13;189:E382-3. doi: 10.1503/cmaj.161033

See related article at www.cmaj.ca/lookup/doi/10.1503/cmaj.160313

n this issue, Singh-Manoux and colleagues1 report that mea- sures of low-grade systemic inflammation (e.g., C-reactive KEY POINTS protein [CRP] and interleukin-6 [IL-6]) in midlife were strong • Metabolomic and proteomic studies are furthering the Iindependent predictors of all-cause, cardiovascular and cancer- understanding of “predictive medicine.” related mortality in the Whitehall II study cohort. These findings • Inflammation is a biologic determinant of both cardiovascular support evidence from more than a dozen prior prospective disease and cancer and can be identified by measuring high- cohort studies with regard to CRP and all-cause mortality2 and sensitivity C-reactive protein or interleukin-6. more than 50 prior cohort studies showing that CRP and IL-6 pre- • Ongoing clinical trials will determine whether reducing dict future and stroke.3,4 Because CRP and inflammation reduces vascular event rates; if so, the clinical IL-6 are strongly correlated (both reflect upstream activation community will need to modify current concepts of residual risk to encompass residual cholesterol risk as well as the emerging from interleukin-1),5 there is no clinical need to measure both concept of residual inflammatory risk. factors, and of the two, CRP measured with a high-sensitivity assay (hs-CRP) is less expensive and has regulatory approval for clinical use. Following the multi-national JUPITER trial (Justifica- In this context, Singh-Manoux and colleagues report that all tion for the Use of Statins in Prevention: an Intervention Trial three inflammatory biomarkers were associated with all-cause as Evaluating Rosuvastatin), which showed large reductions in rela- well as cardiovascular and cancer-related mortality, both in uni- tive risk for first-ever cardiovascular events (myocardial infarc- variate analyses and in analyses controlling for traditional risk fac- tion, stroke and cardiovascular ) in the rosuvastatin­ group tors. Overall, these effects weakened over time, with stronger among participants with low levels of cholesterol but elevated associations in the first five years than in longer follow-up periods. hs-CRP, the 2009 Canadian Cardiovascular Society guideline However, when the authors controlled for all covariates and bio- endorsed hs-CRP screening for cardiovascular risk prediction, markers simultaneously, AGP was no longer predictive. By con- particularly among patients at intermediate risk.6 trast, the magnitude of effects for IL-6 and CRP were largely similar Surprisingly, the third inflammatory biomarker in the study by for both cancer-related and cardiovascular mortality in the fully

Singh-Manoux and colleagues — α1-acid glycoprotein (AGP) — did adjusted models (with small remaining differences between the not fare as well as either CRP or IL-6. This is important because the two likely reflecting intercorrelations between IL-6 and CRP). authors’ motivation to perform the new analyses using the White- The analysis from Singh-Manoux and colleagues is thus an im- hall II study cohort was to confirm or reject data from a recent portant reminder that data from metabolomics studies need to metabolomics study that found AGP to be the strongest predictor ensure that appropriate comparisons are made to established risk of mortality in a nuclear magnetic resonance spectroscopy evalua- markers. Indeed, the metabolomics field has suffered from low tion of 106 candidate biomarkers.7 That study, which used metabo- levels of external validation. In this regard, it is worth comparing lomic discovery data from the Estonian and validated the earlier Estonian Biobank data with those reported by Cheng important biomarkers in a population-based cohort from Finland, and colleagues8 from the Offspring Cohort of the Framingham suggested that four biomarkers predicted all-cause mortality: AGP, Heart Study, where higher concentrations of isocitrate, an inter- albumin, very-low-density lipoprotein particle size and citrate. mediate of the citric acid cycle, were associated with lower odds of However, because concomitant measures of CRP and IL-6 were not longevity. done in the Estonian and Finnish cohorts, clinical comparisons What are the clinical implications of the current data? Mea- could not be made. These kind of data are crucial because AGP and sure of inflammation as a tool for cancer screening has found albumin both correlate with systemic low-grade inflammation and limited clinical utility, although immune-modulating thus in turn with IL-6 and CRP. for cancer are a major new form of treatment. By contrast, since

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E382 CMAJ | MARCH 13, 2017 | VOLUME 189 | ISSUE 10 © 2017 Joule Inc. or its licensors COMMENTARY , et Eur . 40. 118:​ G 7 Can J E383 132- 234- 2016; Lowe , 375: 54: E 2010;​ 2008; . Circ Res 2 6791. : 6 Lancet 1720- 37: Clin Chem 2015; Di Angelantonio e1001606. , S 11: 2016;​ An analysis of calibration and discrim- An analysis of calibration and Distinct metabolomic signatures are are signatures metabolomic Distinct 2009 Canadian Cardiovascular Society/ 2009 Canadian Cardiovascular 2014; Biomarker profiling by nuclear magneticBiomarker profiling by nuclear Kaptoge - cytokines and risk of coro Inflammatory Nat Commun et al. 75. al. et et al. , Eur Heart J CJ, J et al. et al. 266- , , EL ,

PLoS Med P, P 162: Gao Frohlich Carrubba Würtz , 2015;​ McCabe , , R SR, , , R J 79. MG 567- Young 25: ISSUE 10 ISSUE Residual inflammatory risk: addressing the obverse side of the side of the Residual inflammatory risk: addressing the obverse From C-reactive protein to interleukin-6 to interleukin-1: moving interleukin-6 to interleukin-1: moving From C-reactive protein to Seshasai High sensitivity C-reactive protein as a predictor of all-cause mor- of all-cause as a predictor protein C-reactive High sensitivity | Kettunen AP, Larson McPherson , S, , , , K Ann Intern Med PM. J 2009;​ PM. S PM. 56. C-reactive protein concentration and risk of coronary heart disease, stroke, of coronary heart disease, concentration and risk C-reactive protein Kaptoge Emerging Risk Factors Collaboration ; Emerging Risk tality: implications for research and patient care. for research and patient tality: implications al. an individual participant meta-analysis. and mortality: 145- Genest and updated meta-analysis. new prospective study nary heart disease: :578-89. Heart J 2014;35 Ridker targets for atheroprotection. upstream to identify novel Cardiol Fischer Canadian guidelines for the diagnosis and treatment of dyslipidemia and pre- Canadian guidelines for the in the adult — 2009 recommendations. vention of cardiovascular disease DeFilippis Ridker associated with longevity in humans. associated with longevity in resonance spectroscopy for the prediction of all-cause mortality: an observa- resonance spectroscopy for tional study of 17 345 persons. Cheng risk scores in a modern multiethnic ination among multiple cardiovascular cohort. Ridker atherosclerosis prevention coin. - Competing interests: Paul Ridker is listed as a co-inventor on pat that relate to the useents held by the Brigham and Women’s Hospital disease and diabetesof inflammatory biomarkers in cardiovascular receivedhas He AstraZeneca. and Seimens to licensed been have that and Blood Instituteresearch grants from the US National Heart, Lung, Kowa. and from Amgen, Novartis, AstraZeneca, Pfizer and reviewed. This article was solicited and has not been peer BrighamAffiliation: Center for Cardiovascular Disease Prevention, Boston, Mass. and Women’s Hospital, Harvard , Correspondence to: Paul Ridker, [email protected] ...... 2 4. 3 8 6 5 7 9

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CMAJ MARCH 13, 2017 | ). This distinction leads 10 CMAJ Association between inflammatory between Association

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current concepts of residual risk to to risk of residual concepts current Bell , , MJ

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clonal antibody that targets interleukin-1β mortality. cancer-related and cardiovascular all-cause, and biomarkers Singh-Manoux 2017;189:E384-90. If the results of these trials are positive, then the clinical com- clinical the then positive, trials are these of the results If It is unusual for biomarker development programs to result in aIt is unusual for biomarker . 1 munity will need to modify ­ to modify need will munity but also the emerg- encompass not only residual cholesterol risk ing concept of residual inflammatory risk. tool useful for risk prediction. However, biomarker discovery is is discovery biomarker However, prediction. risk for useful tool to new treatment targets. With regard crucial for thinking about in- remains uncertain is whether reducing AGP, CRP and IL-6, what cardiovascular event rates. This importantflammation can reduce - up by several investigative groups world issue has been taken agents using way under are trials hard-outcome major and wide, - and colchicine (which are com such as low-dose methotrexate as respectively) gout, arthritis and to treat rheumatoid monly used (a human well as novel targeted agents such as canakinumab mono­ to different therapies being used for different patients and repre- to different therapies being used for different cardiovascular sents an important move toward .

References 2000, it has been clear that measure of inflammation can be can be of inflammation measure clear that it has been 2000, the for recently more and screening, cardiovascular for effective for risk prediction algorithms of statin . In fact, allocation (e.g., the data on inflammation that integrate primary prevention risk outperform traditional Risk Score) consistently Reynolds and the Framingham Risk Score scores such as the prediction from the American Heart Association Pooled Cohort Equations of . and American College