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Aims: The 2021 European Society of Cardiology prevention guidelines recommend the use of (lifetime) risk prediction models to aid decisions regarding initiation of prevention. We aimed to update and systematically recalibrate the LIFEtime-perspective CardioVascular Disease (LIFE-CVD) model to four European risk regions for the estimation of lifetime CVD risk for apparently healthy individuals., Methods and Results: The updated LIFE-CVD (i.e. LIFE-CVD2) models were derived using individual participant data from 44 cohorts in 13 countries (687 135 individuals without established CVD, 30 939 CVD events in median 10.7 years of follow-up). LIFE-CVD2 uses sex-specific functions to estimate the lifetime risk of fatal and non-fatal CVD events with adjustment for the competing risk of non-CVD death and is systematically recalibrated to four distinct European risk regions. The updated models showed good discrimination in external validation among 1 657 707 individuals (61 311 CVD events) from eight additional European cohorts in seven countries, with a pooled C-index of 0.795 (95% confidence interval 0.767-0.822). Predicted and observed CVD event risks were well calibrated in population-wide electronic health records data in the UK (Clinical Practice Research Datalink) and the Netherlands (Extramural LUMC Academic Network). When using LIFE-CVD2 to estimate potential gain in CVD-free life expectancy from preventive therapy, projections varied by risk region reflecting important regional differences in absolute lifetime risk. For example, a 50-year-old smoking woman with a systolic blood pressure (SBP) of 140 mmHg was estimated to gain 0.9 years in the low-risk region vs. 1.6 years in the very high-risk region from lifelong 10 mmHg SBP reduction. The benefit of smoking cessation for this individual ranged from 3.6 years in the low-risk region to 4.8 years in the very high-risk region., Conclusion: By taking into account geographical differences in CVD incidence using contemporary representative data sources, the recalibrated LIFE-CVD2 model provides a more accurate tool for the prediction of lifetime risk and CVD-free life expectancy for individuals without previous CVD, facilitating shared decision-making for cardiovascular prevention as recommended by 2021 European guidelines., Competing Interests: Conflict of interest: Due to the very long author list, these will be provided per author using ICMJE forms at the revision stage, if applicable., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aims: Individuals with or at high risk of cardiovascular disease (CVD) often receive long-term treatment with low-density lipoprotein cholesterol (LDL-C) lowering therapies, but whether the effects of LDL-C reduction remain stable over time is uncertain. This study aimed to establish the course of the effects of LDL-C reduction on cardiovascular risk over time., Methods: Randomized controlled trials (RCTs) of LDL-C lowering therapies were identified through a search in MEDLINE and EMBASE (1966-January 2023). The primary analyses were restricted to statins, ezetimibe, and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, with other therapies included in sensitivity analyses. Random-effects meta-analyses were performed to establish the hazard ratio (HR) for major vascular events (cardiovascular death, myocardial infarction, unstable angina, coronary revascularization, or stroke) per 1 mmol/L LDL-C reduction. Course of the effects over time was assessed using random-effects meta-regression analyses for the association between follow-up duration, age, and the HR for major vascular events per 1 mmol/L LDL-C reduction. Additionally, treatment-by-time interactions were evaluated in an individual participant data meta-analysis of six atorvastatin trials., Results: A total of 60 RCTs were identified (408,959 participants, 51,425 major vascular events). The HR for major vascular events per 1 mmol/L LDL-C reduction was 0.78 (95 % confidence interval [CI] 0.75-0.81). Follow-up duration was not associated with a change in the HR for major vascular events (HR for change per year 0.994; 95 % CI 0.970-1.020; p = 0.66). The HR attenuated with increasing age in primary prevention (HR for change per 5 years 1.097; 95 % CI 1.031-1.168; p = 0.003), but not secondary prevention (HR for change per 5 years 0.987; 95 % CI 0.936-1.040; p = 0.63). Consistent results were found for statin trials only, and all trials combined. In the individual participant data meta-analysis (31,310 participants, 6734 major vascular events), the HR for major vascular events did not significantly change over follow-up time (HR for change per year 0.983; 95 % CI 0.943-1.025; p = 0.42), or age (HR for change per 5 years 1.022; 95 % CI 0.990-1.055; p = 0.18)., Conclusions: Based on available RCT data with limited follow-up duration, the relative treatment effects of LDL-C reduction are stable over time in secondary prevention, but may attenuate with higher age in primary prevention., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Statin effects extend beyond low-density lipoprotein cholesterol reduction, potentially modulating the metabolism of bioactive lipids (BALs), crucial for biological signaling and inflammation. These bioactive metabolites may serve as metabolic footprints, helping uncover underlying processes linked to pleiotropic effects of statins and yielding a better understanding of their cardioprotective properties. This study aimed to investigate the impact of high-intensity statin therapy versus placebo on plasma BALs in the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; NCT00239681), a randomized primary prevention trial involving individuals with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein ≥2 mg/L., Methods: Using a nontargeted mass spectrometry approach, over 11 000 lipid features were assayed from baseline and 1-year plasma samples from cardiovascular disease noncases from 2 nonoverlapping nested substudies: JUPITER discovery (n=589) and JUPITER validation (n=409). The effect of randomized allocation of rosuvastatin 20 mg versus placebo on BALs was examined by fitting a linear regression with delta values (∆=year 1-baseline) adjusted for age and baseline levels of each feature. Significant associations in discovery were analyzed in the validation cohort. Multiple comparisons were adjusted using 2-stage overall false discovery rate., Results: We identified 610 lipid features associated with statin randomization with significant replication (overall false discovery rate, <0.05), including 26 with annotations. Statin therapy significantly increased levels of 276 features, including BALs with anti-inflammatory activity and arterial vasodilation properties. Concurrently, 334 features were significantly lowered by statin therapy, including arachidonic acid and proinflammatory and proplatelet aggregation BALs. By contrast, statin therapy reduced an eicosapentaenoic acid-derived hydroxyeicosapentaenoic acid metabolite, which may be related to impaired glucose metabolism. Additionally, we observed sex-related differences in 6 lipid metabolites and 6 unknown features., Conclusions: Statin allocation was significantly associated with upregulation of BALs with anti-inflammatory, antiplatelet aggregation and antioxidant properties and downregulation of BALs with proinflammatory and proplatelet aggregation activity, supporting the pleiotropic effects of statins beyond low-density lipoprotein cholesterol reduction., Competing Interests: Disclosures The parent JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) was funded by AstraZeneca (Wilmington, DE), which had no role in the current study. Quest Diagnostics and LabCorp (LipoScience) conducted assays at no additional charges. O.V. Demler received support from Kowa, not related to the current work. S. Mora has served as a consultant to Pfizer for work outside the current study. M. Jain is the founder and chief executive officer of Sapient, a private organization specialized in biotechnology research for biomarker profiling. P.M. Ridker received past investigator-initiated research grant support from AstraZeneca to conduct the JUPITER trial; has current investigator-initiated research grant support from Novartis, Novo Nordisk, Kowa, Amarin, Pfizer, Esperion, National Heart, Lung, and Blood Institute, Bristol Myers Squibb, and Operation Warp Speed; served as a consultant to Novartis, Flame, Agepha, Ardelyx, AstraZeneca, Janssen, Civi Biopharm, GlaxoSmithKline, SOCAR, Novo Nordisk, Health Outlook, Montai Health, Eli Lilly, New Amsterdam, Boehringer-Ingelheim, RTI, Cytokinetics, Horizon Therapeutics, and Cardio Therapeutics; has minority shareholder equity positions in Uppton, Bitteroot Bio, and Angiowave; received nonmonetary research support from the Pfizer Bristol Myers Squibb Alliance and from Quidel, Inc, to conduct federally funded COVID-19 research; and receives compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation, Paris FR, and the Baim Institute (Boston, MA). None of these conflicts relate to the current article. The other authors report no conflicts.

Background: Posttranslational glycosylation of IgG can modulate its inflammatory capacity through structural variations. We examined the association of baseline IgG N-glycans and an IgG glycan score with incident cardiovascular disease (CVD)., Methods: IgG N-glycans were measured in 2 nested CVD case-control studies: JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; NCT00239681; primary prevention; discovery; Npairs=162); and TNT trial (Treating to New Targets; NCT00327691; secondary prevention; validation; Npairs=397). Using conditional logistic regression, we investigated the association of future CVD with baseline IgG N-glycans and a glycan score adjusting for clinical risk factors (statin treatment, age, sex, race, lipids, hypertension, and smoking) in JUPITER. Significant associations were validated in TNT, using a similar model further adjusted for diabetes. Using least absolute shrinkage and selection operator regression, an IgG glycan score was derived in JUPITER as a linear combination of selected IgG N-glycans., Results: Six IgG N-glycans were associated with CVD in both studies: an agalactosylated glycan (IgG-GP4) was positively associated, while 3 digalactosylated glycans (IgG glycan peaks 12, 13, 14) and 2 monosialylated glycans (IgG glycan peaks 18, 20) were negatively associated with CVD after multiple testing correction (overall false discovery rate <0.05). Four selected IgG N-glycans comprised the IgG glycan score, which was associated with CVD in JUPITER (adjusted hazard ratio per glycan score SD, 2.08 [95% CI, 1.52-2.84]) and validated in TNT (adjusted hazard ratio per SD, 1.20 [95% CI, 1.03-1.39]). The area under the curve changed from 0.693 for the model without the score to 0.728 with the score in JUPITER (PLRT=1.1×10 -6 ) and from 0.635 to 0.637 in TNT (PLRT=0.017)., Conclusions: An IgG N-glycan profile was associated with incident CVD in 2 populations (primary and secondary prevention), involving an agalactosylated glycan associated with increased risk of CVD, while several digalactosylated and sialylated IgG glycans associated with decreased risk. An IgG glycan score was positively associated with future CVD., Competing Interests: Disclosures R.A. Hoshi, G. Lauc, O.V. Demler, S. Mora, and B. Plavša are co-inventors on a patent application for a Method for prediction of future cardiovascular disease risk via analysis of IgG glycome assigned to GENOS d.o.o. and the Brigham and Women’s Hospital Inc. O.V. Demler received support from Kowa, not related to the current work. S. Mora has served as consultant to Pfizer for work outside the current study. G. Lauc is the founder and chief executive officer of Genos Ltd, a private research organization that specializes in high-throughput glycomics analysis and has several patents in this field. I. Trbojević-Akmačić and Ivan Gudelj are employees of Genos Ltd. P.M. Ridker received past investigator-initiated research grant support from AstraZeneca to conduct the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) and has current investigator-initiated research grant support from Novartis, Novo Nordisk, Kowa, Amarin, Pfizer, Esperion, National Heart, Lung, and Blood Institute, Bristol Myers Squibb, and Operation Warp Speed; served as a consultant to Novartis, Flame, Agepha, Ardelyx, AstraZeneca, Janssen, Civi Biopharm, Glaxo Smith Kline, Socar, Novo Nordisk, Health Outlook, Montai Health, Eli Lilly, New Amsterdam, Boehringer-Ingelheim, RTI, Cytokinetics, Horizon Therapeutics, and Cardio Therapeutics; has minority shareholder equity positions in Uppton, Bitteroot Bio, and Angiowave; received nonmonetary research support from the Pfizer Bristol Myers Squibb Alliance and from Quidel Inc. to conduct federally funded COVID-19 research; and receives compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation, Paris France, and the Baim Institute (Boston, MA). The other authors report no conflicts.

Competing Interests: Disclosures J.H. Cornel reports membership on advisory boards for Amgen, Sanofi, Novo Nordisk en AstraZeneca. D. Gill and G.K. Hovingh are employed part-time by Novo Nordisk and own shares. A.L. Catapano reports consulting fees/lecturing fees from Akcea, Amgen, Amryt, Sanofi, Esperion, Kowa, Novartis, Ionis Pharmaceuticals, Mylan, Menarini, Merck, Recordati, Regeneron Daiichi Sankyo, Genzyme, Aegerion, and Sandoz. W. Koenig served on the Executive Steering Committee of SPIRE, which was funded by Pfizer. WK reports advisory board/lecturing fees from Novartis, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daiichi-Sankyo, Genentech, Novo Nordisk, Esperion, OMEICOS, Sanofi, New Amsterdam Pharma, TenSixteen Bio and Bristol-Myers Squibb, grants and nonfinancial support from Abbott, Roche Diagnostics, Beckmann, and Singulex, outside the submitted work. Ridker served as the Trial Co-Chair for SPIRE, which was funded by Pfizer. Unrelated to the current project, P.M. Ridker has received additional institutional research grant support from Novartis, Amarin, Pfizer, Esperion, Novo Nordisk, and the NHLBI; has served as a consultant to Novartis, Flame, Agepha, AstraZeneca, Janssen, Civi Biopharm, Glaxo Smith Kline, SOCAR, Novo Nordisk, Uptton, Pfizer, Health Outlook, Montai Health, New Amsterdam, Boehringer-Ingelheim, Angiowave, RTI; Zomagen, Cytokinetics, Horizon Therapeutics, and Cardio Therapeutics; and receives compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation, Paris FR, and the Baim Institute (Boston, MA). ESGS has received lecturing/advisory board fees from Amgen, Novartis, Esperion, Sanofi-Regenerion, and Akcea. NSN is co-founder of Lipid Tools. The other authors report no disclosures.

Background: Patients with established cardiovascular disease (CVD) are at high risk of incident heart failure (HF), which may in part reflect the impact of systemic inflammation., Objectives: The goal of this study was to determine the association between C-reactive protein (CRP) and incident HF in patients with established CVD., Methods: Patients from the prospective UCC-SMART (Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease) cohort with established CVD, but without prevalent HF were included (n = 8,089). Incident HF was defined as a first hospitalization for HF. The association between baseline CRP and incident HF was assessed using Cox proportional hazards models adjusted for established risk factors (ie, age, sex, myocardial infarction, smoking, diabetes mellitus, body mass index, blood pressure, cholesterol, and kidney function)., Results: During a median follow-up of 9.7 years (IQR 5.4-14.1 years), 810 incident HF cases were observed (incidence rate 1.01/100 person-years). Higher CRP was independently associated with an increased risk of incident HF: HR per 1 mg/L: 1.10 (95% CI: 1.07-1.13), and for last vs first CRP quartile: 2.22 (95% CI: 1.76-2.79). The association was significant for both HF with reduced (HR: 1.09; 95% CI: 1.04-1.14) and preserved ejection fraction (HR: 1.12; 95% CI: 1.07-1.18) (P for difference = 0.137). Additional adjustment for medication use and interim myocardial infarction did not attenuate the association, and the association remained consistent beyond 15 years after the CRP measurement., Conclusions: In patients with established CVD, CRP is an independent risk marker of incident HF. These data support ongoing trial efforts to assess whether anti-inflammatory agents can reduce the burden of HF., Competing Interests: Funding Support and Author Disclosures The UCC-SMART study was financially supported by a grant of the University Medical Center Utrecht. The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The authors did not receive any specific funding for the current study. Dr Ridker has received research grant support from Novo Nordisk, Novartis, Kowa, Amarin, Pfizer, Esperion, and the National Heart, Lung, and Blood Institute; has served as a consultant to Novartis, Flame, Agepha, AstraZeneca, Janssen, Civi Biopharm, GlaxoSmithKline, SOCAR, Novo Nordisk, Uptton, Health Outlook, Montai Health, New Amsterdam, Boehringer Ingelheim, Angiowave, RTI, Horizon Therapeutics, Cardio Therapeutics, SOCAR, and Zomagen; and receives compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation (Paris, France), and the Baim Institute (Boston, Massachusetts). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Anti-inflammatory drugs reduce the risk of cardiovascular events in patients with coronary artery disease (CAD), but less is known about the relation between inflammation and outcomes in patients with cerebrovascular disease (CeVD), peripheral artery disease (PAD), and abdominal aortic aneurysm (AAA). This study assessed the association between C-reactive protein (CRP) and clinical outcomes in patients with CAD (n = 4,517), CeVD (n = 2,154), PAD (n = 1,154), and AAA (n = 424) from the prospective Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease study. The primary outcome was recurrent cardiovascular disease (CVD), defined as myocardial infarction, ischemic stroke, or cardiovascular death. Secondary outcomes were major adverse limb events and all-cause mortality. Associations between baseline CRP and outcomes were assessed using Cox proportional hazards models adjusted for age, sex, smoking, diabetes mellitus, body mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, and glomerular filtration rate. Results were stratified by CVD location. During a median follow-up of 9.5 years, 1,877 recurrent CVD events, 887 major adverse limb events, and 2,341 deaths were observed. CRP was independently associated with recurrent CVD (hazard ratio [HR] per 1 mg/L 1.08, 95% confidence interval [CI] 1.05 to 1.10), and all secondary outcomes. Compared with the first quintile of CRP, HRs for recurrent CVD were 1.60 (95% CI 1.35 to 1.89) for the last quintile ≤10 mg/L and 1.90 (95% CI 1.58 to 2.29) for the subgroup with CRP >10 mg/L. CRP was associated with recurrent CVD in patients with CAD (HR per 1 mg/L 1.08, 95% CI 1.04 to 1.11), CeVD (HR 1.05, 95% CI 1.01 to 1.10), PAD (HR 1.08, 95% CI 1.03 to 1.13), and AAA (HR 1.08, 95% CI 1.01 to 1.15). The association between CRP and all-cause mortality was stronger for patients with CAD (HR 1.13, 95% CI 1.09 to 1.16) than for patients with other CVD locations (HRs 1.06 to 1.08; p = 0.002). Associations remained consistent beyond 15 years after the CRP measurement. In conclusion, greater CRP is independently associated with an increased risk of recurrent CVD and mortality, irrespective of previous CVD location., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Inflammation and hyperlipidaemia jointly contribute to atherothrombotic disease. However, when people are treated with intensive statin therapy, the relative contributions of inflammation and hyperlipidaemia to the risk of future cardiovascular events might change, which has implications for the choice of adjunctive cardiovascular therapeutics. We aimed to evaluate the relative importance of high-sensitivity C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDLC) as determinants of risk for major adverse cardiovascular events, cardiovascular death, and all-cause-death among patients receiving statins., Methods: We did a collaborative analysis of patients with-or at high risk of-atherosclerotic disease, who were receiving contemporary statins and were participants in the multinational PROMINENT (NCT03071692), REDUCE-IT (NCT01492361), or STRENGTH (NCT02104817) trials. Quartiles of increasing baseline high-sensitivity CRP (a biomarker of residual inflammatory risk) and of increasing baseline LDLC (a biomarker of residual cholesterol risk) were assessed as predictors of future major adverse cardiovascular events, cardiovascular death, and all-cause death. Hazard ratios (HRs) for cardiovascular events and deaths were calculated across quartiles of high-sensitivity CRP and LDLC in analyses adjusted for age, gender, BMI, smoking status, blood pressure, previous history of cardiovascular disease, and randomised treatment group assignment., Findings: 31 245 patients were included in the analysis from the PROMINENT (n=9988), REDUCE-IT (n=8179), and STRENGTH (n=13 078) trials. The observed ranges for baseline high-sensitivity CRP and LDLC, and the relationships of each biomarker to subsequent cardiovascular event rates, were almost identical in the three trials. Residual inflammatory risk was significantly associated with incident major adverse cardiovascular events (highest high-sensitivity CRP quartile vs lowest high-sensitivity CRP quartile, adjusted HR 1·31, 95% CI 1·20-1·43; p<0·0001), cardiovascular mortality (2·68, 2·22-3·23; p<0·0001), and all-cause mortality (2·42, 2·12-2·77; p<0·0001). By contrast, the relationship of residual cholesterol risk was neutral for major adverse cardiovascular events (highest LDLC quartile vs lowest LDLC quartile, adjusted HR 1·07, 95% CI 0·98-1·17; p=0·11), and of low magnitude for cardiovascular death (1·27, 1·07-1·50; p=0·0086) and all-cause death (1·16, 1·03-1·32; p=0·025)., Interpretation: Among patients receiving contemporary statins, inflammation assessed by high-sensitivity CRP was a stronger predictor for risk of future cardiovascular events and death than cholesterol assessed by LDLC. These data have implications for the selection of adjunctive treatments beyond statin therapy and suggest that combined use of aggressive lipid-lowering and inflammation-inhibiting therapies might be needed to further reduce atherosclerotic risk., Funding: Kowa Research Institute, Amarin, AstraZeneca., Competing Interests: Declaration of interests PMR has served as trial co-chair of PROMINENT, which was funded by an institutional research grant from Kowa; has received additional institutional research grant support from Novartis, Amarin, Pfizer, Esperion, NovoNordisk, and the National Heart, Lung, and Blood Institute; has served as a consultant to Novartis, Flame, Agepha, AstraZeneca, Janssen, Civi Biopharm, GlaxoSmithKline, SOCAR, NovoNordisk, Uptton, Omeicos, Health Outlook, Montai Health, New Amsterdam, Boehringer Ingelheim, Angiowave, Research Triangle Institute, Zomagen, Cytokinetics, Horizon Therapeutics, and Cardio Therapeutics; and receives compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation, Paris FR, and the Baim Institute (Boston, MA). DLB has served as Principal Investigator of REDUCE-IT with research funding from Amarin; has served on an advisory board for Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, NovoNordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; has served on the board of directors for Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, and TobeSoft; is inaugural chair of the American Heart Association Quality Oversight Committee; has served as a consultant for Broadview Ventures; has served on a data monitoring committee for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute, and Rutgers University (for the NIH-funded MINT Trial); has received honoraria from the American College of Cardiology, Arnold and Porter law firm, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute), Belvoir Publications, Canadian Medical and Surgical Knowledge Translation Research Group, Cowen and Company, Duke Clinical Research Institute, HMP Global, Journal of the American College of Cardiology, K2P, Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME, Piper Sandler, Population Health Research Institute, Slack Publications, Society of Cardiovascular Patient Care, WebMD, and Wiley; has received other fees for work from Clinical Cardiology, NCDR-ACTION Registry Steering Committee, and VA CART Research and Publications Committee; is named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon (does not receive any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, NovoNordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier; has served as site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; is a trustee of the American College of Cardiology; and has had a part in unfunded research for FlowCo and Takeda. ADP has served as trial co-chair of PROMINENT, which was funded by an institutional research grant from Kowa; has received research grants from Kowa Research Europe, Kowa Research Institute, and Denka; receives compensation for consultant services from Optum, NovoNordisk, and Reliant Medical Foundation; and receives compensation for lectures from Medtelligence and NACE. RJG has served as the academic biostatistician for PROMINENT, which was funded by an institutional research grant from Kowa; and has received additional research grant support from Amarin, Novartis, Pfizer, National Cancer Institute, National Eye Institute, National Heart Lung and Blood Institute, National Institute of Aging, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Child Health and Human Development, National Institute of Mental Health, United States Food and Drug Administration, and Patient-Centered Outcomes Research Institute. JGM has served as a data analyst on the PROMINENT trial, supported by Kowa. SEN has served as chair of the executive committee of STRENGTH, funded by an institutional research grant from AstraZeneca; reports that the Cleveland Clinic Center for Clinical Research has received funding to perform clinical trials from Abbvie, AstraZeneca, Amgen, Bristol Myers Squibb, Cerenis, Eli Lilly, Esperion, Medtronic, MyoKardia, Novartis, Pfizer, The Medicines Company, Silence Therapeutics, Takeda, and Orexigen, and is involved in these clinical trials but receives no personal remuneration for his participation; and consults for many pharmaceutical companies but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Recent large-scale randomised trials demonstrate that immunomodulators reduce cardiovascular (CV) events among the general population. However, it is uncertain whether these effects apply to rheumatoid arthritis (RA) and if certain treatment strategies in RA reduce CV risk to a greater extent., Methods: Patients with active RA despite use of methotrexate were randomly assigned to addition of a tumour necrosis factor (TNF) inhibitor (TNFi) or addition of sulfasalazine and hydroxychloroquine (triple therapy) for 24 weeks. Baseline and follow-up 18 F-fluorodeoxyglucose-positron emission tomography/CT scans were assessed for change in arterial inflammation, an index of CV risk, measured as an arterial target-to-background ratio (TBR) in the carotid arteries and aorta., Results: 115 patients completed the protocol. The two treatment groups were well balanced with a median age of 58 years, 71% women, 57% seropositive and a baseline disease activity score in 28 joints of 4.8 (IQR 4.0, 5.6). Baseline TBR was similar across the two groups. Significant TBR reductions were observed in both groups-ΔTNFi: -0.24 (SD=0.51), Δtriple therapy: -0.19 (SD=0.51)-without difference between groups (difference in Δs: -0.02, 95% CI -0.19 to 0.15, p=0.79). While disease activity was significantly reduced across both treatment groups, there was no association with change in TBR (β=0.04, 95% CI -0.03 to 0.10)., Conclusion: We found that addition of either a TNFi or triple therapy resulted in clinically important improvements in vascular inflammation. However, the addition of a TNFi did not reduce arterial inflammation more than triple therapy., Trial Registration Number: NCT02374021., Competing Interests: Competing interests: DHS receives research support through his institution from Abbvie, Amgen, CorEvitas and Moderna. He receives royalties from UpToDate on unrelated chapters. JTG has been a consultant for AbbVie, Pfizer, Eli Lilly and Company, Bristol Meyers Squibb, Gilead, Novartis in the last 3 years and received an unrestricted grant from Pfizer. Over the past 36 months, PMR received investigator-initiated research grant support from Novartis, Kowa, Amarin, Pfizer, Esperion, NHLBI, NCI and Operation Warp Speed; served as a consultant to Corvidia, Novartis, Flame, Agepha, Alynlam, IQVIA, R-Pharma, Horizon Therapeutics, Inflazome, AstraZeneca, Jannsen, Civi Biopharm, SOCAR, Novo Nordisk, Health Outlook, Omeicos, the Baim Institute, Boehringer-Ingelheim, Montai Health, Cardiol Therapeutics, the Peter Munk Institute (University of Toronto); and the Foundation Leducq (Paris, FR); and received non-monetary research support from the Pfizer Bristol Myers Squibb Alliance and from Quidel, Inc to conduct federally funded COVID-19 research. PMRo is also listed as a co-inventor on patents held by his institution, the Brigham and Women’s Hospital. None of these conflicts relate to the current manuscript. JMB has nothing to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Hyperlipidaemia and inflammation jointly contribute to atherosclerotic disease. Yet, after the initiation of statin therapy, the relative contributions of these processes may differ in patient groups, such as those with and without impaired kidney function., Methods and Results: Among 9151 stable statin-treated post-myocardial infarction patients participating in the CANTOS trial, the contributions of residual cholesterol risk and residual inflammatory risk were evaluated as determinants of recurrent major adverse cardiovascular events (MACE) and total mortality, stratified by baseline estimated glomerular filtration rate (eGFR) above or below 60 mL/min/1.73 m2 using the race agnostic CKD-EPI 2021 formula (all participants had eGFR > 30 mL/min/1.73 m2). Analyses of residual inflammatory risk focused on high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) while analyses of residual cholesterol risk focused on LDL-cholesterol (LDL-C) and non-HDL-cholesterol (non-HDL-C). Participants were followed for a period of up to 5 years (median 3.7 years). Median baseline levels of LDL-C and hsCRP were 81 mg/dL and 4.2 mg/L. Among participants with eGFR ≥ 60 mL/min/1.73 m2, increasing quartiles of plasma hsCRP, IL-6, LDL-C, and non-HDL-C all positively associated with risks of recurrent MACE [hazard ratios (HR) comparing the top to bottom quartile for hsCRP 1.45; for IL-6 2.48; for LDL-C 1.64; and for non-HDL-C 1.68] (all P < 0.0001). By contrast, among those with eGFR < 60 mL/min/1.73 m2, increasing quartiles of hsCRP and IL-6 significantly predicted recurrent MACE [HR comparing the top to bottom quartile for hsCRP 1.50 (P = 0.021); for IL-6 1.84 (P = 0.048)], whereas increasing quartiles of LDL-C and non-HDL-C did not [HR comparing the top to bottom quartile for LDL-C 1.04 (P = 0.80); for non-HDL-C 0.98 (P = 0.88)]. The predictive utility of hsCRP and IL-6 in the setting of eGFR < 60 mL/min/1.73 m2 remained significant after adjustment for a wide range of potential confounding factors including age, sex, smoking status, blood pressure, body mass index, and diabetes. For the endpoint of total mortality, both hsCRP (HR 1.77, P = 0.0021) and IL-6 (HR 2.15, P = 0.015) were significant predictors among those with eGFR < 60 mL/min/1.73 m2, whereas LDL-C (HR 0.91, P = 0.56) and non-HDL-C (HR 0.85, P = 0.31) were not. Similar effects were observed in analyses stratified by the albumin to creatinine ratio rather than eGFR., Conclusion: Among atherosclerosis patients with impaired kidney function already aggressively treated with statin therapy, residual inflammatory risk plays a substantial role in determining the risk of recurrent cardiovascular events. These data have implications for risk stratification of individuals with chronic kidney disease and for the development of novel agents that target inflammatory processes in this high-risk group of patients., Clinical Trial Registration: ClinicalTrials.gov: NCT01327846., Competing Interests: Conflict of interest: The analyses described in this manuscript derive from data obtained as part of the Canakinumab Anti-Inflammatory Thrombosis Inflammation Study (CANTOS), which was supported by Novartis, Inc. Dr Ridker has received research grant support from Novartis, Kowa, Amarin, Pfizer, Esperion, and the NHLBI; and has served as a consultant to Novartis, Flame, Agepha, AstraZeneca, Jannsen, Civi Biopharm, Glaxo Smith Kline, SOCAR, Novo Nordisk, Uptton, Omeicos, Health Outlook, Montai Health, New Amsterdam, Boehringer Ingelheim, Angiowave, RTI; Horizon Therapeutics, and Cardio Therapeutics; and receives compensation for service on the Peter Munk Advisory Bord (University of Toronto), the Leducq Foundation, Paris FR, and the Baim Institute (Boston, MA, USA). Dr Tuttle has received research grant support from the NIH through NIDDK, NCATS, and NIMHD; the CDC; and Goldfinch Bio, Bayer, and Travere, and has served as a consultant for Eli Lilly, Boehringer Ingelheim, Gilead, Astra Zeneca, Goldfinch Bio, Novo Nordisk, Bayer, Travere, and Janssen. Dr Perkovic reports scientific presentations and/or consultancy agreements with AbbVie, Bayer, Boehringer Ingelheim, Chinook, GlaxoSmithKline, Janssen, Pfizer; AstraZeneca, Baxter, Bristol-Myers Squibb, Eli Lilly, Gilead, GlaxoSmithKline, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Retrophin/Travere, Roche, Sanofi, Servier, and Vitae; research funding from Pfizer (supplied drug and seed funding for TESTING trial) and GlaxoSmithKline; serving on Steering Committees for trials funded by AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Novartis, Novo Nordisk, Otsuka, Retrophin/Travere and Tricida; is a Board Director for George Clinical, George Institute, Garvan Institute, Mindgardens Network, Childrens Cancer Institute, Victor Chang Cardiac Research Institute. Dr Libby is an unpaid consultant to, or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Cartesian, Esperion, Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Novo Nordisk, Merck, Novartis, Pfizer, Sanofi-Regeneron; a member of scientific advisory board for Amgen, Corvidia Therapeutics, Caristo, CSL Behring, DalCor Pharmaceuticals, Dewpoint, PlaqueTec, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, and XBiotech, Inc. Dr Libby’s laboratory has received research funding in the last 2 years from Novartis and research support from NHLBI, the American Heart Association, the RRM Charitable Fund, and the Simard Fund. Dr Libby is on the Board of Directors of XBiotech, Inc., a company developing therapeutic human antibodies., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Mortality among patients with chronic kidney disease (CKD) is largely a consequence of cardiovascular disease (CVD) and is a particular concern given the increasing prevalence of CKD. Sterile inflammation triggered by activation of the innate immune system is an important driver of both CKD and associated CVD. Several endogenous mediators, including lipoproteins, crystals such as silica, urate and cholesterol crystals, or compounds released from dying cells interact with pattern recognition receptors expressed on a variety of different cell types, leading to the release of pro-inflammatory cytokines. Disturbed regulation of the haematopoietic system by damage-associated molecular patterns, or as a consequence of clonal haematopoiesis or trained innate immunity, also contributes to the development of inflammation. In observational and genetic association studies, inflammation is linked to the progression of CKD and cardiovascular events. In 2017, the CANTOS trial of canakinumab provided evidence that inhibiting inflammation driven by NLRP3-IL-1-IL-6-mediated signalling significantly reduced cardiovascular event rates in individuals with and without CKD. Other approaches to target innate immune pathways are now under investigation for their ability to reduce cardiovascular events and slow disease progression among patients with atherosclerosis and stage 3 and 4 CKD. This Review summarizes current understanding of the role of inflammation in the pathogenesis of CKD and its associated CVD, and how this knowledge may translate into novel therapeutics., (© 2022. Springer Nature Limited.)

Background: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels., Methods: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes., Results: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease., Conclusions: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.)., (Copyright © 2022 Massachusetts Medical Society.)

Objective: The inflammatory cytokine interleukin-6 (IL-6) is associated with cardiovascular (CV) and kidney outcomes in various populations. However, data in patients with type 2 diabetes are limited. We assessed the association of IL-6 with CV and kidney outcomes in the Canagliflozin Cardiovascular Assessment Study (CANVAS) and determined the effect of canagliflozin on IL-6., Research Design and Methods: Patients with type 2 diabetes at high CV risk were randomly assigned to canagliflozin or placebo. Plasma IL-6 was measured at baseline and years 1, 3, and 6. The composite CV outcome was nonfatal myocardial infarction, nonfatal stroke, or CV death; the composite kidney outcome was sustained ≥40% estimated glomerular filtration rate decline, end-stage kidney disease, or kidney-related death. Multivariable-adjusted Cox proportional hazards regression was used to estimate the associations between IL-6 and the outcomes. The effect of canagliflozin on IL-6 over time was assessed with a repeated-measures mixed-effects model., Results: The geometric mean IL-6 at baseline, available in 3,503 (80.2%) participants, was 1.7 pg/mL. Each doubling of baseline IL-6 was associated with 14% (95% CI 4, 24) and 21% (95% CI 1, 45) increased risk of CV and kidney outcomes, respectively. Over 6 years, IL-6 increased by 5.8% (95% CI 3.4, 8.3) in the placebo group. Canagliflozin modestly attenuated the IL-6 increase (absolute percentage difference vs. placebo 4.4% [95% CI 1.3, 9.9; P = 0.01]). At year 1, each 25% lower level of IL-6 compared with baseline was associated with 7% (95% CI 1, 22) and 14% (95% CI 5, 22) lower risks for the CV and kidney outcome, respectively., Conclusions: In patients with type 2 diabetes at high CV risk, baseline IL-6 and its 1-year change were associated with CV and kidney outcomes. The effect of IL-6-lowering therapy on CV, kidney, and safety outcomes remains to be tested., (© 2022 by the American Diabetes Association.)

Background: To clarify the mechanisms underlying physical activity (PA)-related cardioprotection, we examined the association of PA with plasma bioactive lipids (BALs) and cardiovascular disease (CVD) events. We additionally performed genome-wide associations., Methods: PA-bioactive lipid associations were examined in VITAL (VITamin D and OmegA-3 TriaL)-clinical translational science center (REGISTRATION: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT01169259; N=1032) and validated in JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)-NC (REGISTRATION: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT00239681; N=589), using linear models adjusted for age, sex, race, low-density lipoprotein-cholesterol, total-C, and smoking. Significant BALs were carried over to examine associations with incident CVD in 2 nested CVD case-control studies: VITAL-CVD (741 case-control pairs) and JUPITER-CVD (415 case-control pairs; validation)., Results: We detected 145 PA-bioactive lipid validated associations (false discovery rate <0.1). Annotations were found for 6 of these BALs: 12,13-diHOME, 9,10-diHOME, lysoPC(15:0), oxymorphone-3b-D-glucuronide, cortisone, and oleoyl-glycerol. Genetic analysis within JUPITER-NC showed associations of 32 PA-related BALs with 22 single-nucleotide polymorphisms. From PA-related BALs, 12 are associated with CVD., Conclusions: We identified a PA-related bioactive lipidome profile out of which 12 BALs also had opposite associations with incident CVD events.

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use 1 . Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels 2 , heart disease remains the leading cause of death worldwide 3 . Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS 4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns 24 . Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine 25 , we anticipate that increased diversity of participants will lead to more accurate and equitable 26 application of polygenic scores in clinical practice., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Low-dose methotrexate (LD-MTX) is contraindicated in advanced CKD, but kidney safety in normal kidney function or mild-to-moderate CKD is less clear., Methods: We performed a secondary analysis for eGFR and kidney AEs using the randomized double-blind, placebo-controlled Cardiovascular Inflammation Reduction Trial. Adults with cardiovascular disease and diabetes and/or metabolic syndrome were randomly allocated to oral LD-MTX (target dose 15-20 mg/week) or placebo. All participants took folic acid 1 mg 6 days/week. Exclusion criteria included systemic rheumatic disease and creatinine clearance <40 ml/min. The least-squares mean Δ eGFR from baseline was calculated at each study visit; the difference in eGFR between LD-MTX and placebo was compared. We used Cox proportional hazard models to compare rates of kidney AEs for LD-MTX versus placebo., Results: A total of 2391 participants were randomized to LD-MTX and 2395 to placebo. At baseline, the mean age was 66 years, 19% were female, and mean eGFR was 80.0 ml/min per 1.73 m 2 (54% had Stage 2 CKD and 18% had Stage 3 CKD). Median follow-up was 23 months. The LD-MTX group had less decline in eGFR than placebo (difference in least-squares mean ΔeGFR from baseline to on-treatment visits: 0.93 ml/min per 1.73 m 2 , 95% confidence interval [95% CI], 0.45 to 1.40, P <0.001). There were 138 (incidence rate [IR], 2.97 per 100 person-years) kidney AEs in the LD-MTX group and 184 (IR, 3.99 per 100 person-years) among placebo (hazard ratio [HR] 0.73, 95% confidence interval [95% CI], 0.59 to 0.91) during safety laboratory monitoring., Conclusions: These results demonstrate the kidney safety of LD-MTX among patients with normal kidney function or mild-to-moderate CKD at baseline., (Copyright © 2021 by the American Society of Nephrology.)

Chronic kidney disease (CKD) is associated with high cardiovascular risk. CKD patients exhibit a specific lipoprotein pattern termed 'uraemic dyslipidaemia', which is characterized by rather normal low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, and high triglyceride plasma levels. All three lipoprotein classes are involved in the pathogenesis of CKD-associated cardiovascular diseases (CVDs). Uraemia leads to several modifications of the structure of lipoproteins such as changes of the proteome and the lipidome, post-translational protein modifications (e.g. carbamylation) and accumulation of small-molecular substances within the lipoprotein moieties, which affect their functionality. Lipoproteins from CKD patients interfere with lipid transport and promote inflammation, oxidative stress, endothelial dysfunction as well as other features of atherogenesis, thus contributing to the development of CKD-associated CVD. While, lipid-modifying therapies play an important role in the management of CKD patients, their efficacy is modulated by kidney function. Novel therapeutic agents to prevent the adverse remodelling of lipoproteins in CKD and to improve their functional properties are highly desirable and partially under development., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

IL (interleukin)-6 is a pivotal cytokine of innate immunity, which enacts a broad set of physiological functions traditionally associated with host defense, immune cell regulation, proliferation, and differentiation. Following recognition of innate immune pathways leading from the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome to IL-1 to IL-6 and on to the hepatically derived clinical biomarker CRP (C-reactive protein), an expanding literature has led to understanding of the proatherogenic role for IL-6 in cardiovascular disease and thus the potential for IL-6 inhibition as a novel method for vascular protection. In this review, we provide an overview of the mechanisms by which IL-6 signaling occurs and how that impacts upon pharmacological inhibition; describe murine models of IL-6 and atherogenesis; summarize human epidemiological data outlining the utility of IL-6 as a biomarker of vascular risk; outline genetic data suggesting a causal role for IL-6 in systemic atherothrombosis and aneurysm formation; and then detail the potential role of IL-6 inhibition in stable coronary disease, acute coronary syndromes, heart failure, and the atherothrombotic complications associated with chronic kidney disease and end-stage renal failure. Finally, we review anti-inflammatory and antithrombotic findings for ziltivekimab, a novel IL-6 ligand inhibitor being developed specifically for use in atherosclerotic disease and poised to be tested formally in a large-scale cardiovascular outcomes trial focused on individuals with chronic kidney disease and elevated levels of CRP, a population at high residual atherothrombotic risk, high residual inflammatory risk, and considerable unmet clinical need.

Systemic vascular inflammation plays multiple maladaptive roles which contribute to the progression and destabilization of atherosclerotic cardiovascular disease (ASCVD). These roles include: (i) driving atheroprogression in the clinically stable phase of disease; (ii) inciting atheroma destabilization and precipitating acute coronary syndromes (ACS); and (iii) responding to cardiomyocyte necrosis in myocardial infarction (MI). Despite an evolving understanding of these biologic processes, successful clinical translation into effective therapies has proven challenging. Realizing the promise of targeting inflammation in the prevention and treatment of ASCVD will likely require more individualized approaches, as the degree of inflammation differs among cardiovascular patients. A large body of evidence has accumulated supporting the use of high-sensitivity C-reactive protein (hsCRP) as a clinical measure of inflammation. Appreciating the mechanistic diversity of ACS triggers and the kinetics of hsCRP in MI may resolve purported inconsistencies from prior observational studies. Future clinical trial designs incorporating hsCRP may hold promise to enable individualized approaches. The aim of this Clinical Review is to summarize the current understanding of how inflammation contributes to ASCVD progression, destabilization, and adverse clinical outcomes. We offer forward-looking perspective on what next steps may enable successful clinical translation into effective therapeutic approaches-enabling targeting the right patients with the right therapy at the right time-on the road to more individualized ASCVD care., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Importance: It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk., Objective: To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk., Design, Setting, and Participants: A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa., Interventions: Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins., Main Outcomes and Measures: The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization., Results: When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil-treated patients (14.7%)., Conclusions and Relevance: Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients., Trial Registration: ClinicalTrials.gov Identifier: NCT02104817.

Background: Inflammation reduction with the interleukin (IL)-1β inhibitor canakinumab significantly reduces the first major adverse cardiovascular event in patients with prior myocardial infarction (MI) and residual inflammatory risk (high-sensitivity C-reactive protein ≥ 2 mg/l). However, the effect of canakinumab on the total number of cardiovascular events, including recurrent events collected after a first event, is unknown., Objectives: This study sought to determine whether randomly allocated canakinumab would reduce the total burden of serious cardiovascular events., Methods: We randomized 10,061 patients to placebo or canakinumab 50 mg, 150 mg, or 300 mg once every 3 months and compared the rates of the composite of all serious cardiovascular events (MI, stroke, coronary revascularization, and cardiovascular death) in active versus placebo groups. We used negative binomial regression to account for correlations among repeated events in the same person and to estimate rate ratios and 95% confidence intervals., Results: During a median of 3.7 years of follow-up, 3,417 total serious cardiovascular events occurred in 2,003 individuals among the 10,061 unique patients randomized. Canakinumab reduced the rates of total serious cardiovascular events, with rates per 100 person-years in the placebo, 50 mg, 150 mg, and 300 mg canakinumab groups of 10.4, 8.4, 8.3, and 8.2, respectively. The corresponding rate ratios (95% confidence intervals) compared with placebo were 0.80 (0.69 to 0.93) for 50 mg, 0.79 (0.68 to 0.92) for 150 mg, and 0.78 (0.67 to 0.91) for 300 mg., Conclusions: Anti-inflammatory therapy with canakinumab significantly reduced the total number of cardiovascular events in patients with prior MI and evidence of residual inflammatory risk. (Cardiovascular Risk Reduction Study [Reduction in Recurrent Major CV Disease Events] (CANTOS); NCT01327846., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background High-density lipoprotein (HDL) cholesterol has inverse association with cardiovascular disease. HDL possesses anti-inflammatory properties in vitro, but it is unknown whether this may be protective in individuals with inflammation. Methods and Results The functional capacity of HDL to inhibit oxidation of oxidized low-density lipoprotein (ie, the HDL inflammatory index; HII) was measured at baseline and 12 months after random allocation to rosuvastatin or placebo in a nested case-control study of the JUPITER (Justification for the Use of Statins in Prevention: An Intervention Evaluating Rosuvastatin) trial. There were 517 incident cases of cardiovascular disease and all-cause mortality compared to 517 age- and sex-matched controls. Multivariable conditional logistic regression was used to examine associations of HII with events. Median baseline HII was 0.54 (interquartile range, 0.50-0.59). Twelve months of rosuvastatin decreased HII by a mean of 5.3% (95% CI, -8.9% to -1.7%; P =0.005) versus 1.3% (95% CI, -6.5% to 4.0%; P =0.63) with placebo ( P =0.22 for between-group difference). HII had a nonlinear relationship with incident events. Compared with the reference group (HII 0.5-1.0) with the lowest event rates, participants with baseline HII ≤0.5 had significantly increased risk of cardiovascular disease/mortality (adjusted hazard ratio, 1.53; 95% CI, 1.06-2.21; P =0.02). Furthermore, there was significant ( P =0.002) interaction for HDL particle number with HII, such that having more HDL particles was associated with decreased risk only when HDL was anti-inflammatory. Conclusions In JUPITER participants recruited on the basis of chronic inflammation, HII was associated with incident cardiovascular disease/mortality, with an optimal anti-inflammatory HII range between 0.5 and 1.0. This nonlinear relationship of anti-inflammatory HDL function with risk may account in part for the HDL paradox. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00239681.

Importance: Migraine with aura is known to increase the risk of cardiovascular disease (CVD). The absolute contribution of migraine with aura to CVD incidence in relation to other CVD risk factors remains unclear., Objective: To estimate the CVD incidence rate for women with migraine with aura relative to women with other major vascular risk factors., Design, Setting, and Participants: Female health professionals in the US (the Women's Health Study cohort) with lipid measurements and no CVD at baseline (1992-1995) were followed up through December 31, 2018., Exposures: Self-reported migraine with aura compared with migraine without aura or no migraine at baseline., Main Outcomes and Measures: The primary outcome was major CVD (first myocardial infarction, stroke, or CVD death). Generalized modeling procedures were used to calculate multivariable-adjusted incidence rates for major CVD events by risk factor status that included all women in the cohort., Results: The study population included 27 858 women (mean [SD] age at baseline, 54.7 [7.1] years), among whom 1435 (5.2%) had migraine with aura and 26 423 (94.8%) did not (2177 [7.8%] had migraine without aura and 24 246 [87.0%] had no migraine in the year prior to baseline). During a mean follow-up of 22.6 years (629 353 person-years), 1666 major CVD events occurred. The adjusted incidence rate of major CVD per 1000 person-years was 3.36 (95% CI, 2.72-3.99) for women with migraine with aura vs 2.11 (95% CI, 1.98-2.24) for women with migraine without aura or no migraine (P < .001). The incidence rate for women with migraine with aura was significantly higher than the adjusted incidence rate among women with obesity (2.29 [95% CI, 2.02-2.56]), high triglycerides (2.67 [95% CI, 2.38-2.95]), or low high-density lipoprotein cholesterol (2.63 [95% CI, 2.33-2.94]), but was not significantly different from the rates among those with elevated systolic blood pressure (3.78 [95% CI, 2.76-4.81]), high total cholesterol (2.85 [95% CI, 2.38-3.32]), or family history of myocardial infarction (2.71 [95% CI, 2.38-3.05]). Incidence rates among women with diabetes (5.76 [95% CI, 4.68-6.84]) or who currently smoked (4.29 [95% CI, 3.79-4.79]) were significantly higher than those with migraine with aura. The incremental increase in the incidence rate for migraine with aura ranged from 1.01 additional cases per 1000 person-years when added to obesity to 2.57 additional cases per 1000 person-years when added to diabetes., Conclusions and Relevance: In this study of female health professionals aged at least 45 years, women with migraine with aura had a higher adjusted incidence rate of CVD compared with women with migraine without aura or no migraine. The clinical importance of these findings, and whether they are generalizable beyond this study population, require further research.

Background: Elevated triglyceride-rich lipoprotein (TRL) and small-dense low-density lipoprotein (sdLDL) particles are hallmarks of atherogenic dyslipidemia, and their cholesterol content is hypothesized to drive atherosclerotic risk. Prospective epidemiological data pertaining to cholesterol content of TRLs and sdLDL in primary prevention populations are mostly limited to coronary heart disease., Objectives: The purpose of this study was to prospectively evaluate whether triglyceride-rich lipoprotein cholesterol (TRL-C) and small-dense low-density lipoprotein cholesterol (sdLDL-C) concentrations associate with composite and individual incident cardiovascular disease (CVD) outcomes including myocardial infarction (MI), ischemic stroke (IS), and peripheral artery disease (PAD)., Methods: In a prospective case-cohort study within the Women's Health Study, TRL-C and sdLDL-C (mg/dl) were directly measured in baseline blood specimens of case subjects (n = 480) and the reference subcohort (n = 496). Risk associations were evaluated for total CVD (MI, IS, PAD, and CVD death), coronary and cerebrovascular disease (MI, IS, CVD death), and individual outcomes (MI, IS, and PAD). Models were adjusted for traditional risk factors, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein., Results: The risk of both composite outcomes significantly increased across quartiles of TRL-C and sdLDL-C. TRL-C was significantly associated with MI and PAD (MI hazard ratio [HR] Q4 : 3.05 [95% confidence interval (CI): 1.46 to 6.39]; p trend  = 0.002; PAD HR Q4 : 2.58 [95% CI: 1.18 to 5.63]; p trend  = 0.019), whereas sdLDL-C was significantly associated with MI alone (HR Q4 : 3.71 [95% CI: 1.59 to 8.63]; p trend  < 0.001). Both markers weakly associated with IS. Association patterns were similar for continuous exposures and, for TRL-C, among subjects with low atherogenic particle concentrations (apolipoprotein B <100 mg/dl)., Conclusions: TRL-C strongly associates with future MI and PAD events, whereas sdLDL-C strongly associates with MI alone. These findings signal that the cholesterol content of TRLs and sdLDL influence atherogenesis independently of low-density lipoprotein cholesterol, and high sensitivity C-reactive protein, with potentially different potency across vascular beds. (Women's Health Study; NCT00000479)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Pharmacological lowering of inflammation has proven effective in reducing recurrent cardiovascular event rates. Aim of the current study is to evaluate lifestyle changes (smoking cessation, weight loss, physical activity level increase, alcohol moderation, and a summary lifestyle improvement score) in relation to change in plasma C-reactive protein (CRP) concentration in patients with established cardiovascular disease., Methods: In total, 1794 patients from the UCC-SMART cohort with stable cardiovascular disease and CRP levels ≤10 mg/L, who returned for a follow-up study visit after median 9.9 years (IQR 5.4-10.8), were included. The relation between changes in smoking status, weight, physical activity, alcohol consumption, a summary lifestyle improvement score and change in plasma CRP concentration was evaluated with linear regression analyses., Results: Smoking cessation was related to a 0.40 mg/L decline in CRP concentration (β-coefficient -0.40; 95%CI -0.73,-0.07). Weight loss (per 1SD = 6.4 kg) and increase in physical activity (per 1 SD = 48 MET hours per week) were related to a decrease in CRP concentration (β-coefficients -0.25; 95%CI -0.33,-0.16 and -0.09; 95%CI -0.17,-0.01 per SD). Change in alcohol consumption was not related to CRP difference. Every point higher in the summary lifestyle improvement score was related to a decrease in CRP concentration of 0.17 mg/L (β-coefficient -0.17; 95%CI -0.26,-0.07)., Conclusions: Smoking cessation, increase in physical activity, and weight loss are related to a decrease in CRP concentration in patients with stable cardiovascular disease. Patients with the highest summary lifestyle improvement score have the most decrease in CRP concentration. These results may indicate that healthy lifestyle changes contribute to lowering systemic inflammation, potentially leading to a lower cardiovascular risk in patients with established cardiovascular disease., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: P.M. Ridker, has received investigator initiated research grants from Kowa, Novartis, Pfizer, AstraZeneca, NHLBI, NCI. Dr Ridker has served as a consultant to Corvidia, Inflammazome, Novartis, Amgen, Merck, and Civi Bio. Dr Ridker is listed as co-inventor on patents related to the use of inflammatory biomarkers in CVD and diabetes that are no longer active. F.W. Asselbergs reports grants from UCL Hospitals NIHR Biomedical Research Centre, outside the submitted work. The other authors have nothing to declare., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis. Despite extensive clinical use for more than 30 years, few data on adverse event (AE) rates derive from randomized, placebo-controlled trials, where both causality and magnitude of risk can be inferred., Objective: To investigate AE rates, risk, and risk differences comparing LD-MTX versus placebo., Design: Prespecified secondary analyses of a double-blind, placebo-controlled, randomized trial. (ClinicalTrials.gov: NCT01594333)., Setting: North America., Participants: Adults with known cardiovascular disease and diabetes or metabolic syndrome., Intervention: Random allocation to LD-MTX (≤20 mg/wk) or placebo. All participants received folic acid, 1 mg/d, 6 days per week., Measurements: Risks for specific AEs of interest, as well as for all AEs, were compared across treatment groups after blinded adjudication., Results: After an active run-in period, 6158 patients were enrolled and 4786 randomly assigned to a group; median follow-up was 23 months and median dosage 15 mg/wk. Among the randomly assigned participants, 81.2% were male, median age was 65.7 years, and median body mass index was 31.5 kg/m2. Of 2391 participants assigned to LD-MTX, 2080 (87.0%) had an AE of interest, compared with 1951 of 2395 (81.5%) assigned to placebo (hazard ratio [HR], 1.17 [95% CI, 1.10 to 1.25]). The relative hazards of gastrointestinal (HR, 1.91 [CI, 1.75 to 2.10]), pulmonary (HR, 1.52 [CI, 1.16 to 1.98]), infectious (HR, 1.15 [CI, 1.01 to 1.30]), and hematologic (HR, 1.15 [CI, 1.07 to 1.23]) AEs were elevated for LD-MTX versus placebo. With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs. Renal AEs were reduced in the LD-MTX group (HR, 0.85 [CI, 0.78 to 0.93])., Limitation: The trial was done in patients without rheumatic disease who tolerated LD-MTX during an active run-in period., Conclusion: Use of LD-MTX was associated with small to moderate elevations in risks for skin cancer and gastrointestinal, infectious, pulmonary, and hematologic AEs, whereas renal AEs were decreased., Primary Funding Source: National Institutes of Health.

Current evidence supports the use of low-dose aspirin for secondary cardiovascular prevention. By contrast, the benefit-to-risk ratio of aspirin use in primary prevention is debated: three contemporary randomized control trials have been conflicting, and meta-analyses have concluded for an unclear clinical benefit, based on the consideration that the reduction in thromboembolic events is counterbalanced by increased bleeding. The primary prevention setting is, however, a heterogeneous mix of subjects at highly variable cardiovascular risk. One possible explanation for the uncertainty of data interpretation is the progressive reduction in risk of major adverse cardiovascular events (MACEs) in primary prevention that has accompanied global education programs, leading patients to smoke less, exercise more, and increasingly take lipid-lowering therapies. Based on a meta-regression of the benefits and harm of aspirin therapy in primary prevention as a function of the 10-year risk of MACE, we favor a nuanced approach still, however, based on the evaluation of cardiovascular risk, acknowledging differences between patients and emphasizing an individualized assessment of both benefits and harm. After optimal control of cardiovascular risk factors, and when patients are less than 70 years of age, clinicians should assess the risk of MACE and base decision on such stratification, considering the risk of bleeding and patient preferences. Clinicians would then advise the use of aspirin in primary prevention patients at the highest risk of MACE who do not have a prohibitive risk of bleeding, and in the majority of cases after initiation of properly titrated statin therapy., Competing Interests: R.D.C. declares having received fees and honoraria from Bayer related to the topic. A.A. and P.M.R. have no conflict of interest to disclose., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To assess the risk of major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis (RA) treated with tocilizumab compared to those treated with the tumor necrosis factor inhibitor etanercept., Methods: This randomized, open-label, parallel-group trial enrolled patients with active seropositive RA (n = 3,080) who had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs and who had at least 1 cardiovascular (CV) risk factor. Patients were randomly assigned 1:1 to receive open-label tocilizumab at 8 mg/kg/month or etanercept at 50 mg/week. All patients were followed up for a mean of 3.2 years. The primary end point was comparison of time to first occurrence of MACE. The trial was powered to exclude a relative hazard ratio for MACE of 1.8 or higher in the tocilizumab group compared to the etanercept group., Results: By week 4 of treatment, the serum low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were a median 11.1%, 5.7%, and 13.6% higher, respectively, in patients receiving tocilizumab compared to those receiving etanercept (each P < 0.001). During follow-up, 83 MACE occurred in the tocilizumab group compared to 78 MACE in the etanercept group. The estimated hazard ratio for occurrence of MACE in the tocilizumab group relative to the etanercept group was 1.05 (95% confidence interval 0.77-1.43). Results were similar in sensitivity analyses and in the on-treatment population analysis. Adverse events occurred more frequently in the tocilizumab group, including serious infection and gastrointestinal perforation., Conclusion: The results of this trial, which provide insights into the CV safety of tocilizumab as compared to etanercept, ruled out a risk for occurrence of MACE of 1.43 or higher in patients treated with tocilizumab. This result should be interpreted in the context of the clinical efficacy and non-CV safety of tocilizumab., (© 2019, American College of Rheumatology.)

Aims: Low-grade inflammation, measured by elevated plasma concentrations of high-sensitive C-reactive protein (CRP), is a risk factor for cardiovascular disease (CVD). There is evidence that low-grade inflammation is also related to a higher risk of cancer. The present prospective cohort study evaluates the relation between low-grade systemic inflammation and risk of cancer in patients with stable CVD., Methods and Results: In total, 7178 patients with stable CVD and plasma CRP levels ≤10 mg/L were included. Data were linked to the Dutch national cancer registry. Cox regression models were fitted to study the relation between CRP and incident CVD and cancer. After a median follow-up time of 8.3 years (interquartile range 4.6-12.3) 1072 incident cancer diagnoses were observed. C-reactive protein concentration was related to total cancer [hazard ratio (HR) 1.35; 95% confidence interval (CI) 1.10-1.65] comparing last quintile to first quintile of CRP. Especially lung cancer, independent of histopathological subtype, was related to CRP (HR 3.39; 95% CI 2.02-5.69 comparing last to first quintile of CRP). Incidence of epithelial neoplasms and especially squamous cell neoplasms were related to CRP concentration, irrespective of anatomical location. Sensitivity analyses after excluding patients with a cancer diagnosis within 1, 2, and 5 years of follow-up showed similar results. No effect modification was observed by smoking status or time since smoking cessation (P-values for interaction > 0.05)., Conclusion: Chronic systemic low-grade inflammation, measured by CRP levels ≤10 mg/L, is a risk factor for incident cancer, markedly lung cancer, in patients with stable CVD. The relation between inflammation and incident cancer is seen in former and current smokers and is uncertain in never smokers., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background Genetic variation in catechol-O-methyltransferase ( COMT ), a key enzyme in estrogen and catecholamine metabolism, has plausible physiological links to cardiovascular disease (CVD) and its risk factors. In WHS (Women's Health Study), COMT variants rs4818 and rs4680 were associated with a lower risk of CVD among women receiving placebo but not aspirin, suggesting a possible role of COMT in thrombosis. Methods and Results To evaluate potential pathways linking COMT with CVD, and COMT effect modification of aspirin in prevention, we examined COMT association with CVD risk and subclinical measures, coronary artery calcium, and carotid intima-media thickness in MESA (Multi-Ethnic Study of Atherosclerosis). In 65 957 person-years of follow-up, during which 498 events occurred, COMT rs4818 was associated with lower CVD risk (hazard ratio, 0.85; 95% CI, 0.74-0.97 [ P =0.02]). This association remained virtually unchanged after adjusting for common CVD risk factors. Fibrinogen was the only risk factor associated with rs4818 (β, -3.65; SE, 1.35 mg/dL [ P =0.007]). Results were directionally similar but not significant for rs4680. Adjusted hazard ratios for COMT rs4818 CVD association were 0.79 (95% CI, 0.65-0.95; P =0.02) among individuals who used aspirin <3 days per week and 0.89 (95% CI, 0.71-1.13; P =0.34) among more frequent users ( P interaction =0.39). Neither intima-media thickness nor coronary artery calcium was associated with COMT . Conclusions In a multiethnic prospective cohort of men and women, the COMT rs4818G allele was associated with lower CVD risk and lower fibrinogen levels but not with radiographic measures of subclinical atherosclerosis. These results suggest a plausible role of COMT in the latter stages of CVD.

Aims: Efficacy of aspirin in primary prevention of cardiovascular disease (CVD) may be influenced by a common allele in guanylate cyclase GUCY1A3, which has been shown to modify platelet function and increase CVD risk., Methods and Results: We investigated whether homozygotes of the GUCY1A3 rs7692387 risk (G) allele benefited from aspirin in two long-term, randomized placebo-controlled trials of aspirin in primary CVD prevention: the Women's Genome Health Study (WGHS, N = 23 294) and a myocardial infarction (MI, N = 550) and stroke (N = 382) case-control set from the Physician's Health Study (PHS, N = 22 071). Bleeding risk was evaluated in the WGHS. In the placebo group of the WGHS, the GUCY1A3 risk (G) allele was confirmed to increase CVD risk [hazard ratio 1.38; 95% confidence interval (CI) 1.08-1.78; P = 0.01]. Random-effects meta-analysis of the WGHS and PHS revealed that aspirin reduced CVD events among risk allele homozygotes [G/G: odds ratio (OR) 0.79; 95% CI 0.65-0.97; P = 0.03] but increased CVD events among non-risk allele carriers (e.g. G/A: OR 1.39; 95% CI 1.03-1.87; P = 0.03) thus implying an interaction between genotype stratum and aspirin intake (Pinteraction = 0.01). Bleeding associated with aspirin increased in all genotype groups, with higher risks in heterozygotes., Conclusion: In two randomized placebo-controlled trials in the setting of primary prevention, aspirin reduced the incidence of CVD events in individuals homozygous for the GUCY1A3 risk (G) allele, whereas heterozygote individuals had more events when taking aspirin., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.

Objective- Inflammation is a causal risk factor for cardiovascular disease (CVD). sPLA 2 -IIA (group IIA secretory phospholipase A 2 ) plays an integral role in regulating vascular inflammation. Although studies investigated sPLA 2 -IIA in secondary prevention, we prospectively evaluated sPLA 2 -IIA mass and genetic variants with CVD events in a primary prevention population with chronic inflammation. Approach and Results- The JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) randomized participants with LDL (low-density lipoprotein) <130 mg/dL and hsCRP (high-sensitivity C-reactive protein) ≥2 mg/L to high-intensity rosuvastatin versus placebo. Baseline and 1-year plasma sPLA 2 -IIA mass was measured (N=11 269 baseline; N=9620 1 year). We also identified genetic variants influencing sPLA 2 -IIA using genome-wide association and examined them with CVD. Three hundred thirteen incident CVD events occurred during follow-up. Baseline sPLA 2 -IIA mass (median, 25th-75th percentile: 3.81, 2.49-6.03 ng/mL) was associated with increased risk of CVD: risk factor-adjusted hazard ratio (95% CI; P) per SD increment: 1.22 (1.08-1.38; P=0.002). This remained significant (1.18; 1.04-1.35; P=0.01) after incrementally adjusting for hsCRP. Similar estimates were observed in rosuvastatin and placebo groups ( P treatment interaction>0.05). The rs11573156C variant in PLA2G2A (encoding sPLA 2 -IIA) had the strongest effect on sPLA 2 -II: median (25th-75th percentile, ng/mL) for CC and GG genotypes: 2.79 (1.97-4.01) and 7.38 (5.38-10.19), respectively; and had nonsignificant trend for higher CVD risk (hazard ratio, 1.11; 95% CI, 0.89-1.38; P=0.34). Conclusions- In the JUPITER population recruited on chronic inflammation, sPLA 2 -IIA mass was associated with CVD risk relating to vascular inflammation not fully reflected by hsCRP. Additional studies, including larger functional genetic and clinical studies, are needed to determine whether sPLA 2 -IIA may be a potential pharmacological target for primary prevention of CVD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00239681.

Background: Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1β, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit., Methods: We conducted a randomized, double-blind trial of low-dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome. All participants received 1 mg of folate daily. The primary end point at the onset of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Near the conclusion of the trial, but before unblinding, hospitalization for unstable angina that led to urgent revascularization was added to the primary end point., Results: The trial was stopped after a median follow-up of 2.3 years. Methotrexate did not result in lower interleukin-1β, interleukin-6, or C-reactive protein levels than placebo. The final primary end point occurred in 201 patients in the methotrexate group and in 207 in the placebo group (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). The original primary end point occurred in 170 patients in the methotrexate group and in 167 in the placebo group (incidence rate, 3.46 vs. 3.43 per 100 person-years; hazard ratio, 1.01; 95% CI, 0.82 to 1.25). Methotrexate was associated with elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non-basal-cell skin cancers than placebo., Conclusions: Among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of interleukin-1β, interleukin-6, or C-reactive protein and did not result in fewer cardiovascular events than placebo. (Funded by the National Heart, Lung, and Blood Institute; CIRT ClinicalTrials.gov number, NCT01594333.)., (Copyright © 2018 Massachusetts Medical Society.)

Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied., Methods and Results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms., Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The recognition that atherosclerosis is a complex chronic inflammatory disorder mediated through both adaptive and innate immunity has led to the hypothesis that anticytokine therapies targeting specific IL (interleukin) signaling pathways could serve as powerful adjuncts to lipid lowering in the prevention and treatment of cardiovascular disease. Cytokines involved in human atherosclerosis can be broadly classified as proinflammatory and proatherogenic (such as IL-1, IL-6, and TNF [tumor necrosis factor]) or as anti-inflammatory and antiatherogenic (such as IL-10 and IL-1rA). The recent CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) has shown that specific targeting of IL-1β can significantly reduce cardiovascular event rates without lipid or blood pressure lowering. In CANTOS, the magnitude of benefit of this cytokine-targeted approach to atherosclerosis treatment was associated to the magnitude of reduction of the central signaling cytokine IL-6 and the downstream clinical biomarker high-sensitivity CRP (C-reactive protein). By contrast, in the recent CIRT (Cardiovascular Inflammation Reduction Trial), low-dose methotrexate neither reduced IL-1β, IL-6, or high-sensitivity CRP nor lowered cardiovascular event rates. Taken together, these 2 contemporary trials provide proof of principle that focused cytokine inhibition, not broad-spectrum anti-inflammatory therapy, is likely to be crucial for atheroprotection. This review provides an overview of cytokines in atherosclerosis, the potential benefits and risks associated with targeted anticytokine therapies, and a look to the future of clinical practices addressing residual inflammatory risk.

Importance: Higher Mediterranean diet (MED) intake has been associated with lower risk of cardiovascular disease (CVD), but limited data are available about the underlying molecular mechanisms of this inverse disease association in human populations., Objective: To better characterize the relative contribution of traditional and novel factors to the MED-related risk reduction in CVD events in a US population., Design, Setting, and Participants: Using a prospective cohort design, baseline MED intake was assessed in 25 994 initially healthy US women in the Women's Health Study who were followed up to 12 years. Potential mediating effects of a panel of 40 biomarkers were evaluated, including lipids, lipoproteins, apolipoproteins, inflammation, glucose metabolism and insulin resistance, branched-chain amino acids, small-molecule metabolites, and clinical factors. Baseline study information and samples were collected between April 30, 1993, and January 24, 1996. Analyses were conducted between August 1, 2017, and October 30, 2018., Exposures: Intake of MED is a 9-category measure of adherence to a Mediterranean dietary pattern. Participants were categorized into 3 levels based on their adherence to the MED., Main Outcomes and Measures: Incident CVD confirmed through medical records and the proportion of CVD risk reduction explained by mediators., Results: Among 25 994 women (mean [SD] age, 54.7 [7.1] years), those with low, middle, and upper MED intakes composed 39.0%, 36.2%, and 24.8% of the study population and experienced 428 (4.2%), 356 (3.8%), and 246 (3.8%) incident CVD events, respectively. Compared with the reference group who had low MED intake, CVD risk reductions were observed for the middle and upper groups, with respective HRs of 0.77 (95% CI, 0.67-0.90) and 0.72 (95% CI, 0.61-0.86) (P for trend < .001). The largest mediators of the CVD risk reduction of MED intake were biomarkers of inflammation (accounting for 29.2% of the MED-CVD association), glucose metabolism and insulin resistance (27.9%), and body mass index (27.3%), followed by blood pressure (26.6%), traditional lipids (26.0%), high-density lipoprotein measures (24.0%) or very low-density lipoprotein measures (20.8%), with lesser contributions from low-density lipoproteins (13.0%), branched-chain amino acids (13.6%), apolipoproteins (6.5%), or other small-molecule metabolites (5.8%)., Conclusions and Relevance: In this study, higher MED intake was associated with approximately one-fourth relative risk reduction in CVD events, which could be explained in part by known risk factors, both traditional and novel.

Purpose of Review: We aim to outline the importance and the clinical implications of using predicted individual therapy-benefit in making patient-centered treatment decisions in cardiovascular disease (CVD) prevention. Therapy-benefit concepts will be illustrated with examples of patients undergoing lipid management., Recent Findings: In both primary and secondary CVD prevention, the degree of variation in individual therapy-benefit is large. An individual's therapy-benefit can be estimated by combining prediction algorithms and clinical trial data. Measures of therapy-benefit can be easily integrated into clinical practice via a variety of online calculators. Lifetime estimates (e.g., gain in healthy life expectancy) look at therapy-benefit over the course of an individual's life, and are less influenced by age than short-term estimates (e.g., 10-year absolute risk reduction). Lifetime estimates can thus identify people who could substantially benefit from early initiation of CVD prevention. Compared with current guidelines, treatment based on predicted therapy-benefit would increase eligibility for therapy among young people with a moderate risk-factor burden and individuals with a high residual risk., Summary: The estimation of individual therapy-benefit is an important part of individualized medicine. Implementation tools allow for clinicians to readily estimate both short-term and lifetime therapy-benefit.

Observational, genetic, and experimental data indicate that triglyceride rich lipoproteins (TRLs) likely participate causally in atherothrombosis. Yet, robust clinical trial evidence that triglyceride (TG) lowering therapy reduces cardiovascular events remains elusive. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARM-α), pemafibrate, will be used to target residual cardiovascular risk remaining after treatment to reduce low-density lipoprotein cholesterol (LDL-C) in individuals with the dyslipidemia of type 2 diabetes mellitus (T2). The PROMINENT study will randomly allocate approximately 10,000 participants with T2D, mild-to-moderate hypertriglyceridemia (TG: 200-499 mg/dl; 2.26-5.64 mmol/l) and low high-density lipoprotein cholesterol levels (HDL-C: ≤40 mg/dl; 1.03 mmol/l) to either pemafibrate (0.2 mg twice daily) or matching placebo with an average expected follow-up period of 3.75 years (total treatment phase 5 years; 24 countries). At study entry, participants must be receiving either moderate-to-high intensity statin therapy or meet specified LDL-C criteria. The study population will be one-third primary and two-thirds secondary prevention (established cardiovascular disease). The primary endpoint is a composite of nonfatal myocardial infarction, nonfatal ischemic stroke, hospitalization for unstable angina requiring urgent coronary revascularization, and cardiovascular death. This event-driven study will complete when 1092 adjudicated primary endpoints have accrued with at least 200 occurring in women. Statistical power is at least 90% to detect an 18% reduction in the primary endpoint. Pre-specified secondary and tertiary endpoints include all-cause mortality, hospitalization for heart failure, new or worsening peripheral artery disease, new or worsening diabetic retinopathy and nephropathy, and change in biomarkers including select lipid and non-lipid biomarkers, inflammatory and glycemic parameters., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Elevated lipoprotein(a) is a genetic risk factor for cardiovascular disease in general population studies. However, its contribution to risk for cardiovascular events in patients with established cardiovascular disease or on statin therapy is uncertain., Methods: Patient-level data from seven randomised, placebo-controlled, statin outcomes trials were collated and harmonised to calculate hazard ratios (HRs) for cardiovascular events, defined as fatal or non-fatal coronary heart disease, stroke, or revascularisation procedures. HRs for cardiovascular events were estimated within each trial across predefined lipoprotein(a) groups (15 to <30 mg/dL, 30 to <50 mg/dL, and ≥50 mg/dL, vs <15 mg/dL), before pooling estimates using multivariate random-effects meta-analysis., Findings: Analyses included data for 29 069 patients with repeat lipoprotein(a) measurements (mean age 62 years [SD 8]; 8064 [28%] women; 5751 events during 95 576 person-years at risk). Initiation of statin therapy reduced LDL cholesterol (mean change -39% [95% CI -43 to -35]) without a significant change in lipoprotein(a). Associations of baseline and on-statin treatment lipoprotein(a) with cardiovascular disease risk were approximately linear, with increased risk at lipoprotein(a) values of 30 mg/dL or greater for baseline lipoprotein(a) and 50 mg/dL or greater for on-statin lipoprotein(a). For baseline lipoprotein(a), HRs adjusted for age and sex (vs <15 mg/dL) were 1·04 (95% CI 0·91-1·18) for 15 mg/dL to less than 30 mg/dL, 1·11 (1·00-1·22) for 30 mg/dL to less than 50 mg/dL, and 1·31 (1·08-1·58) for 50 mg/dL or higher; respective HRs for on-statin lipoprotein(a) were 0·94 (0·81-1·10), 1·06 (0·94-1·21), and 1·43 (1·15-1·76). HRs were almost identical after further adjustment for previous cardiovascular disease, diabetes, smoking, systolic blood pressure, LDL cholesterol, and HDL cholesterol. The association of on-statin lipoprotein(a) with cardiovascular disease risk was stronger than for on-placebo lipoprotein(a) (interaction p=0·010) and was more pronounced at younger ages (interaction p=0·008) without effect-modification by any other patient-level or study-level characteristics., Interpretation: In this individual-patient data meta-analysis of statin-treated patients, elevated baseline and on-statin lipoprotein(a) showed an independent approximately linear relation with cardiovascular disease risk. This study provides a rationale for testing the lipoprotein(a) lowering hypothesis in cardiovascular disease outcomes trials., Funding: Novartis Pharma AG., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aims: Canakinumab, a monoclonal antibody targeting interleukin (IL)-1β, reduces rates of recurrent cardiovascular events without lowering lipids. It is uncertain, however, to what extent these beneficial cardiovascular outcomes are mediated through interleukin-6 (IL-6) signalling, an issue with substantial pathophysiologic consequences and therapeutic implications., Methods and Results: A total of 4833 stable atherosclerosis patients in the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) had IL-6 levels measured before randomization and after treatment with placebo or one of three doses of canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. Participants were followed for up to 5 years (median follow-up 3.7 years). Compared with those allocated to placebo, CANTOS participants receiving canakinumab who achieved on-treatment IL-6 levels below the study median value of 1.65 ng/L experienced a 32% reduction in major adverse cardiovascular events [MACE, multivariable adjusted hazard ratio (HRadj) 0.68, 95% confidence interval (CI) 0.56-0.82; P < 0.0001], a 30% reduction in MACE plus the additional endpoint of hospitalization for unstable angina requiring urgent revascularization (MACE+, HRadj 0.70, 95% CI 0.59-0.84; P < 0.0001), a 52% reduction in cardiovascular mortality (HRadj 0.48, 95% CI 0.34-0.68; P < 0.0001), and a 48% reduction in all-cause mortality (HRadj 0.52, 95% CI 0.40-0.68; P < 0.0001) with prolonged treatment. In contrast, those with on-treatment IL-6 levels equal to or above 1.65 ng/L after taking the first dose of canakinumab had no significant benefit for any of these endpoints. These differential findings based on the magnitude of IL-6 response were seen in analyses alternatively based on tertiles of on-treatment IL-6 levels, and in analyses using a statistical inference approach to estimate the effect of treatment among individuals who would achieve a targeted IL-6 level., Conclusion: CANTOS provides proof of concept evidence in humans that modulation of the IL-6 signalling pathway, at least with canakinumab, associates with reduced cardiovascular event rates, independent of lipid lowering., Clinical Trial Registration: ClinicalTrials.gov NCT01327846.

It is uncertain whether omega-3 fatty acids are beneficial in statin-treated patients. Epanova is a mix of omega-3 free fatty acids, not requiring co-ingestion with food, which can lower triglycerides by up to 31%. STRENGTH will examine whether Epanova 4 g daily reduces the rate of cardiovascular events in statin-treated patients with hypertriglyceridemia and low levels of HDL-C at high risk for developing cardiovascular events. STRENGTH is a randomized, double-blind, placebo-controlled trial. Patients had a triglyceride level ≥ 180 to <500 mg/dL and HDL-C < 42 mg/dL (men) or < 47 mg/dL (women) in the presence of either (1) established atherosclerotic cardiovascular disease, (2) diabetes with one additional risk factor, or (3) were other high-risk primary prevention patients, based on age and risk factor assessment. Patients should be treated with a statin, for >4 weeks, and have LDL-C < 100 mg/dL, but were also eligible if LDL-C was ≥100 mg/dL while on maximum tolerated statin therapy. The study will extend from October 30, 2014 to October 30, 2019. 13 086 patients were randomized to Epanova 4 g or placebo daily in addition to standard medical therapy. The primary efficacy outcome is time to first event of cardiovascular death, myocardial infarction, stroke, coronary revascularization or hospitalization for unstable angina. The trial will continue until 1600 patients reach the primary endpoint, with a median duration of therapy of 3 years. STRENGTH will determine whether Epanova 4 g daily will reduce cardiovascular events in statin-treated high-risk patients with hypertriglyceridemia and low HDL-C levels., (© 2018 Wiley Periodicals, Inc.)

Importance: Atherosclerotic cardiovascular disease (ASCVD) kills approximately 1 in every 3 US women. Current cholesterol, hypertension, and aspirin guidelines recommend calculating 10-year risk of ASCVD using the 2013 Pooled Cohort Equations (PCE). However, numerous studies have reported apparent overestimation of risk with the PCE, and reasons for overestimation are unclear., Objective: We evaluated the predictive accuracy of the PCE in the Women's Health Initiative (WHI), a multiethnic cohort of contemporary US postmenopausal women. We evaluated the effects of time-varying treatments such as aspirin and statins, and ascertainment of additional ASCVD events by linkage with the Centers for Medicare and Medicaid Services (CMS) claims., Design, Setting, and Participants: The WHI recruited the largest number of US women (n = 161 808) with the racial/ethnic, geographic, and age diversity of the general population (1993-1998). For this study, we included women aged 50 to 79 (n = 19 995) participating in the WHI with data on the risk equation variables at baseline and who met the guideline inclusion and exclusion criteria. Median follow-up was 10 years., Main Outcomes and Measures: For this study, ASCVD was defined as myocardial infarction, stroke, or cardiovascular death., Results: Among the 19 995 women (mean [SD] age, 64 [7.3] years; 8305 [41.5%] white, 7688 [38.5%] black, 3491 [17.5%] Hispanic, 103 [0.5%] American Indian, 321 [1.6%] Asian/Pacific Islander, and 87 [0.4%] other/unknown), a total of 1236 ASCVD events occurred in 10 years and were adjudicated through medical record review by WHI investigators. The WHI-adjudicated observed risks were lower than predicted. The observed (predicted) risks for baseline 10-year risk categories less than 5%, 5% to less than 7.5%, 7.5% to less than 10%, and 10% or more were 1.7 (2.8), 4.4 (6.2), 5.3 (8.7), and 12.4 (18.2), respectively. Small changes were noted after adjusting for time-dependent changes in statin and aspirin use. Among women 65 years or older enrolled in Medicare, WHI-adjudicated risks were also lower than predicted, but observed (predicted) risks became aligned after including events ascertained by linkage with CMS for additional surveillance for events: 3.8 (4.3), 7.1 (6.4), 8.3 (8.7), and 18.9 (18.7), respectively. Similar results were seen across ethnic/racial groups. Overall, the equations discriminated risk well (C statistic, 0.726; 95% CI, 0.714-0.738)., Conclusions and Relevance: Without including surveillance for ASCVD events using CMS, observed risks in the WHI were lower than predicted by PCE as noted in several other US cohorts, but risks were better aligned after including CMS events., Trial Registration: ClinicalTrials.gov identifier: NCT00000611.

Background: Although lipoprotein(a) [Lp(a)] is associated with incident cardiovascular disease (CVD), its contribution to prediction remains controversial., Objectives: This study examined the association and clinical utility of Lp(a) with incident CVD in women., Methods: A turbidimetric assay assessed Lp(a) in 3 cohorts of women (the WHS [Women's Health Study] [N = 24,558], a case-cohort sample from the WHI [Women's Health Initiative] Observational Study [n = 1,815 cases, subcohort n = 1,989], and the JUPITER [Justification for Use of Statins in Prevention] trial [n = 2,569]) and in men from JUPITER (n = 5,161). A WHS derivation sample (n = 16,400) determined the form of association with incident CVD. This was tested in WHS validation data (n = 8,158) and the other study samples. Models including traditional CV risk factors but with and without Lp(a) were compared using risk reclassification., Results: In the WHS, there was a curvilinear association, with increased CVD risk among those with Lp(a) >50 mg/dl, but only among women with total cholesterol (TC) >220 mg/dl. In the WHS test sample, there was a small but significant change in the C-statistic (0.790 to 0.797; p = 0.035) but no improvement in measures of reclassification. This pattern was replicated among women in the WHI and JUPITER trial. In contrast, there was a strong association of Lp(a) with CVD among men with low TC levels in JUPITER., Conclusions: In 3 cohorts of women, Lp(a) was associated with CVD only among those with high TC, and improvement in prediction was minimal. These data have implications for Lp(a) in clinical practice among women and for trials of Lp(a)-lowering agents., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)