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Aims: To develop and externally validate the LIFE-T1D model for the estimation of lifetime and 10-year risk of cardiovascular disease (CVD) in individuals with type 1 diabetes., Materials and Methods: A sex-specific competing risk-adjusted Cox proportional hazards model was derived in individuals with type 1 diabetes without prior CVD from the Swedish National Diabetes Register (NDR), using age as the time axis. Predictors included age at diabetes onset, smoking status, body mass index, systolic blood pressure, glycated haemoglobin level, estimated glomerular filtration rate, non-high-density lipoprotein cholesterol, albuminuria and retinopathy. The model was externally validated in the Danish Funen Diabetes Database (FDDB) and the UK Biobank., Results: During a median follow-up of 11.8 years (interquartile interval 6.1-17.1 years), 4608 CVD events and 1316 non-CVD deaths were observed in the NDR (n = 39 756). The internal validation c-statistic was 0.85 (95% confidence interval [CI] 0.84-0.85) and the external validation c-statistics were 0.77 (95% CI 0.74-0.81) for the FDDB (n = 2709) and 0.73 (95% CI 0.70-0.77) for the UK Biobank (n = 1022). Predicted risks were consistent with the observed incidence in the derivation and both validation cohorts., Conclusions: The LIFE-T1D model can estimate lifetime risk of CVD and CVD-free life expectancy in individuals with type 1 diabetes without previous CVD. This model can facilitate individualized CVD prevention among individuals with type 1 diabetes. Validation in additional cohorts will improve future clinical implementation., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Unhealthy dietary habits are an important risk factor for cardiovascular disease (CVD) and adopting a healthy diet is a central recommendation in CVD prevention. This study assessed the dietary habits of patients with established CVD, their compliance to dietary guidelines, and the relationship between guideline-compliance and recurrent cardiovascular event risk., Methods: 2656 patients with established CVD from the Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease (UCC-SMART) prospective cohort study, were included between 1996 and 2022. Data on dietary intake was retrospectively collected for all participants in December 2022 using a 160-item food frequency questionnaire. Compliance with dietary guidelines was quantified using an amended version of the Dutch Healthy Diet 2015 (DHD-15) index (range: 0-135). Cox proportional hazard models were used to quantify the relationship with cardiovascular events (stroke and myocardial infarction)., Results: Among 2656 CVD patients (77% male, mean age 59 ± 9 years), median energy intake was 1922 [IQR: 1536-2351] kcal/day. The median DHD-15 index was 81.7 [IQR 71.2-92.0], with high compliance scores for recommendations on legumes and fish, and low scores for recommendations on whole grains, red meat, processed meat, and dairy. A higher DHD-15 score was associated with lower stroke risk (HR 0.78, 95% CI 0.66-0.92 per 10-point increase) but not with myocardial infarction., Conclusion: Compliance with dietary guidelines was suboptimal in patients with established CVD. High compliance was associated with a clinically significant reduction in stroke risk in patients with established CVD, emphasizing the importance of dietary counseling., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Mari Nordbø Gynnild,1,2 Steven HJ Hageman,3 Jannick AN Dorresteijn,3 Olav Spigset,4,5 Stian Lydersen,6 Torgeir Wethal,1,2 Ingvild Saltvedt,1,7 Frank LJ Visseren,3 Hanne Ellekjær1,2 1Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Science, NTNU – Norwegian University of Science and Technology, Trondheim, Norway; 2Department of Stroke, Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; 3Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands; 4Department of Clinical Pharmacology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; 5Department of Clinical and Molecular Medicine, NTNU – Norwegian University of Science and Technology, Trondheim, Norway; 6Department of Mental Health, Faculty of Medicine and Health Sciences, NTNU – Norwegian University of Science and Technology, Trondheim, Norway; 7Department of Geriatrics, Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, NorwayCorrespondence: Mari Nordbø GynnildDepartment of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, NTNU – Norwegian University of Science and Technology, Trondheim, NorwayEmail mari.nordbo.gynnild@ntnu.noPurpose: Suboptimal secondary prevention in patients with stroke causes a remaining cardiovascular risk desirable to reduce. We have validated a prognostic model for secondary preventive settings and estimated future cardiovascular risk and theoretical benefit of reaching guideline recommended risk factor targets.Patients and Methods: The SMART-REACH (Secondary Manifestations of Arterial Disease-Reduction of Atherothrombosis for Continued Health) model for 10-year and lifetime risk of cardiovascular events was applied to 465 patients in the Norwegian Cognitive Impairment After Stroke (Nor-COAST) study, a multicenter observational study with two-year follow-up by linkage to national registries for cardiovascular disease and mortality. The residual risk when reaching recommended targets for blood pressure, low-density lipoprotein cholesterol, smoking cessation and antithrombotics was estimated.Results: In total, 11.2% had a new event. Calibration plots showed adequate agreement between estimated and observed 2-year prognosis (C-statistics 0.63, 95% confidence interval 0.55– 0.71). Median estimated 10-year risk of recurrent cardiovascular events was 42% (Interquartile range (IQR) 32– 54%) and could be reduced to 32% by optimal guideline-based therapy. The corresponding numbers for lifetime risk were 70% (IQR 63– 76%) and 61%. We estimated an overall median gain of 1.4 (IQR 0.2– 3.4) event-free life years if guideline targets were met.Conclusion: Secondary prevention was suboptimal and residual risk remains elevated even after optimization according to current guidelines. Considerable interindividual variation in risk exists, with a corresponding variation in benefit from intensification of treatment. The SMART-REACH model can be used to identify patients with the largest benefit from more intensive treatment and follow-up.Keywords: secondary prevention, ischemic stroke, risk factors, risk assessment, risks and benefits, cardiovascular diseases

Aims: To assess whether implementation of the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) dyslipidaemia guidelines observed between 2020 and 2021 improved between 2021 and 2022 in the SANTORINI study., Methods and Results: Patients with high or very high cardiovascular (CV) risk were recruited across 14 European countries from March 2020 to February 2021, with 1-year prospective follow-up until May 2022. Lipid-lowering therapy (LLT) and 2019 ESC/EAS risk-based low-density lipoprotein (LDL) cholesterol (LDL-C) goal attainment (defined as <1.4 mmol/L for patients at very high CV risk and <1.8 mmol/L for patients at high CV risk) at 1-year follow-up were compared with baseline. Of 9559 patients enrolled, 9136 (2626 high risk and 6504 very high risk) had any available follow-up data, and 7210 (2033 high risk and 5173 very high risk) had baseline and follow-up LDL-C data. Lipid-lowering therapy was escalated in one-third of patients and unchanged in two-thirds. Monotherapy and combination therapy usage rose from 53.6 and 25.6% to 57.1 and 37.9%, respectively. Mean LDL-C levels decreased from 2.4 to 2.0 mmol/L. Goal attainment improved from 21.2 to 30.9%, largely driven by LLT use among those not on LLT at baseline. Goal attainment was greater with combination therapy compared with monotherapy at follow-up (39.4 vs. 25.5%)., Conclusion: Lipid-lowering therapy use and achievement of risk-based lipid goals increased over 1-year follow-up particularly when combination LLT was used. Nonetheless, most patients remained above goal; hence, strategies are needed to improve the implementation of combination LLT., Competing Interests: Conflict of interest: K.K.R. has received honoraria for consulting, lectures from Abbott Laboratories, Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim, Cargene, CRISPR, Daiichi Sankyo, Eli Lilly Company, Emendobio, Esperion, Kowa, New Amsterdam Pharma, Novartis Corporation, Nodthera, GSK, Novo Nordisk, Pfizer, Regeneron, Sanofi, SCRIBE, Silence Therapeutics, and VAXXINITY. In addition, he has received research grant support to his institution from Amgen, Daiichi Sankyo, Sanofi, Regeneron, and Ultragenyx, plus stock options from New Amsterdam Pharma, Scribe, and Pemi 31. A.L.C. received research grant support from Amryt Pharma, Menarini, Ultragenyx, and Viatris, and lecturing fees from Amarin, Amgen, Amryt Pharma, AstraZeneca, Daiichi Sankyo, Esperion, Ionis Pharmaceutical, Medscaper, Menarini, Merck, Novartis, Peervoice, Pfizer, Recordati, Regeneron, Sandoz, Sanofi, The Corpus, Ultragenyx, and Viatris. M.A. received research grant support and lecturing fees from Alfasigma, Amgen, Amryt, Daiichi Sankyo, Ionis Pharmaceuticals/Akcea Therapeutics, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi, Sobi, Viatris, and Ultragenyx. A.B., R.C., M.L., and J.S. are employees of Daiichi Sankyo. H.T. received grant support and lecturing fees from Daiichi Sankyo and participated in an advisory board run by Daiichi Sankyo. T.S. received consulting fees from Amgen, Novartis, Orion Pharma, and Valio, and lecturing fees from Amarin, Pfizer, and GSK. He is a patient on statin and ezetimibe therapy. U.L. received grant support from Daiichi Sankyo, Novartis, and Amgen and lecturing fees from Daiichi Sankyo, Novartis, Amgen, Sanofi, Boehringer, MSD, Pfizer, Lilly, and AstraZeneca. He has also been a member of advisory boards for Daiichi Sankyo, Novartis, Amgen, Sanofi, Boehringer, and MSD, in addition to donning leadership/fiduciary roles with EAS, ESC, DGK, and DACH., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aims: Pseudoxanthoma elasticum (PXE) patients have more arterial calcification due to lower levels of inorganic pyrophosphate, caused by mutations in the ABCC6 gene, but the relation with vascular complications is poorly understood. Because of the slow progressing nature of arterial disease in PXE patients, there is a need for a valid and reliable intermediate endpoint to be used in future clinical trials. Arterial calcification measured on computed tomography (CT) is a promising candidate, if associated with future cardiovascular events. We aimed to establish the relation between arterial calcification measured on CT and future cardiovascular events in patients with PXE., Methods: In this prospective cohort study, patients with PXE from the Dutch UMC Utrecht Expertise Center for PXE (UECP) were included. Arterial calcification volume was measured on low dose full body CT scans. Patient were followed for incident cardiovascular events. The relation between arterial calcification and the risk of cardiovascular events was analyzed using Cox proportional hazard models., Results: In 326 patients (median follow-up 6.0, IQR 3.8-8.2 years) 41 cardiovascular events were observed (21 events per 1000 person years). In patients with no cardiovascular history, there was a significant relation between the log arterial calcification volume at baseline and future cardiovascular events (adjusted HR: 1.87, 95 % CI: 1.14-3.09, per 1 log unit increase in arterial calcification). There was no relation in patients with clinical manifest cardiovascular disease at baseline between arterial calcification volume and future cardiovascular events., Conclusions: Higher arterial calcification volumes on CT in PXE patients are associated with a higher risk of a first cardiovascular event. This cohort study suggests that arterial calcification can be used as an intermediate endpoint in studies evaluating interventions to lower the risk of cardiovascular events., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: In post-myocardial infarction (MI) patients, we examined independent and combined associations of vitamin D status and physical activity (PA) with long-term mortality, including effect modification by health determinants., Methods: We conducted a prospective analysis of 4,837 MI patients from the Alpha Omega Cohort. Baseline blood samples (2002-2006) were assessed for plasma 25-hydroxyvitamin D (25[OH]D) levels using LC-MS/MS. PA was assessed using a validated questionnaire. Patients were followed for mortality through December 2022. HRs for CVD and all-cause mortality were obtained across sex-specific tertiles of 25(OH)D and four categories of PA using Cox models, adjusted for sociodemographic and lifestyle factors. Potential effect modification by health determinants was examined through stratification., Results: Patients were 69±5.6 years old, 78% was male, 21% had diabetes, and 10% used vitamin D-containing supplements. Over 14.4 years, 3,206 deaths occurred, including 1,244 from CVD. Median 25(OH)D was 21.1 ng/mL and 44% was vitamin D deficient (<20 ng/mL). Higher 25(OH)D levels were associated with lower CVD (HR:0.63, 95%CI:0.54,0.74) and all-cause mortality (HR:0.68, 95%CI:0.62,0.75). For PA levels (high vs. light), HRs were 0.72 (95%CI:0.61,0.85) for CVD mortality and 0.83 (95%CI:0.75,0.92) for all-cause mortality. Patients with low 25(OH)D and no PA had a threefold higher mortality risk than those with high 25(OH)D levels and high PA. The associations were not significantly modified by sex, comorbidities and other health determinants., Conclusions: Vitamin D status and PA were inversely and independently associated with long-term risk of CVD and all-cause mortality after MI, regardless of other health determinants., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Risk models to identify patients at high risk of asymptomatic carotid artery stenosis (ACAS) can help in selecting patients for screening, but long-term outcomes in these patients are unknown. We assessed the diagnostic and prognostic value of the previously published Prevalence of ACAS (PACAS) risk model to detect ACAS at baseline and to predict subsequent risk of stroke and cardiovascular disease (CVD) during follow-up., Methods: We validated the discrimination and calibration of the PACAS risk model to detect severe (≥70% narrowing) ACAS with patients from the Reduction of Atherothrombosis for Continued Health registry. We subsequently calculated the incidence rates of stroke and CVD (fatal and nonfatal stroke or myocardial infarction or vascular death) during follow-up in 4 risk groups (low, medium, high, and very high, corresponding to sum scores of ≤9, 10-13, 14-17, and ≥18, respectively)., Results: Among 26 384 patients, aged between 45 and 80 years, without prior carotid procedures, 1662 (6.3%) had severe baseline ACAS. During ≈70 000 patient-years of follow-up, 1124 strokes and 2484 CVD events occurred. Discrimination of the PACAS model was 0.67 (95% CI, 0.65-0.68), and calibration showed adequate concordance between predicted and observed risks of severe baseline ACAS after recalibration. Significantly higher incidence rates of stroke ( P trend <0.011) and CVD ( P trend <0.0001) during follow-up were found with increasing PACAS risk groups. Among patients with high PACAS sum score of ≥14 (corresponding to 27.7% of all patients), severe baseline ACAS prevalence was 11.4%. In addition, 56.6% of incident strokes and 64.9% of incident CVD events occurred in this group., Conclusions: The PACAS risk model can reliably identify patients at high risk of severe baseline ACAS. Incidence rates of stroke and CVD during follow-up were significantly higher in patients with high PACAS sum scores. Selective screening of patients with high PACAS sum scores may help to prevent future stroke or CVD., Competing Interests: Dr Bhatt discloses the following relationships: advisory board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; board of directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); consultant: Broadview Ventures, Hims, SFJ, and Youngene; data monitoring committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial [Portopulmonary Hypertension Treatment With Macitentan: A Randomized Clinical Trial], funded by St. Jude Medical, now Abbott), Boston Scientific (chair: the PEITHO trial [Pulmonary Embolism Thrombolysis]), Cleveland Clinic, Contego Medical (chair: PERFORMANCE 2 [Protection Against Emboli During Carotid Artery Stenting Using the Neuroguard IEP System]), 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; for ALLAY-HF [Safety and Efficacy of the Alleviant System for No-Implant Interatrial Shunt Creation in Patients With Chronic Heart Failure], funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the National Institutes of Health-funded MINT trial [Myocardial Ischemia and Transfusion]); honoraria: American College of Cardiology (senior associate editor: Clinical Trials and News, ACC.org; chair: ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; the RE-DUAL PCI [Evaluation of Dual Therapy With Dabigatran vs Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting] Clinical Trial Steering Committee funded by Boehringer Ingelheim; AEGIS-II [Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome] Executive Committee funded by CSL Behring), Belvoir Publications (editor-in-chief: Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial [A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease], funded by Ferring Pharmaceuticals), HMP Global (editor-in-chief: Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor, associate editor), K2P (co-chair: interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (Continuing Medical Education [CME] steering committees), MJH Life Sciences, Oakstone CME (course director: Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies] Operations Committee, Publications Committee, Steering Committee, and USA national coleader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee); other: Clinical Cardiology (deputy editor); patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital that assigned to Lexicon; neither he nor Brigham and Women’s Hospital receive any income from this patent); research funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, 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, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; royalties: Elsevier (editor: Braunwald’s Heart Disease); site coinvestigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; trustee: American College of Cardiology; and unfunded research: FlowCo. Dr Steg discloses the following relationships: employment: Assistance Publique-Hôpitaux de Paris and Université Paris-Cité; research grants: Bayer; consulting: Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, Pfizer, PhaseBio, Novartis, NovoNordisk, Regeneron, Sanofi, and Servier; and patent issued as coinventor of use of alirocumab to reduce cardiovascular risk (patent assigned to Sanofi). The other authors report no conflicts.

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.)

Aims: Identifying patients with established cardiovascular disease (CVD) who are at high risk of type 2 diabetes (T2D) may allow for early interventions, reducing the development of T2D and associated morbidity. The aim of this study was to develop and externally validate the CVD2DM model to estimate the 10-year and lifetime risks of T2D in patients with established CVD., Methods and Results: Sex-specific, competing risk-adjusted Cox proportional hazard models were derived in 19 281 participants with established CVD and without diabetes at baseline from the UK Biobank. The core model's pre-specified predictors were age, current smoking, family history of diabetes mellitus, body mass index, systolic blood pressure, fasting plasma glucose, and HDL cholesterol. The extended model also included HbA1c. The model was externally validated in 3481 patients from the UCC-SMART study. During a median follow-up of 12.2 years (interquartile interval 11.3-13.1), 1628 participants with established CVD were diagnosed with T2D in the UK Biobank. External validation c-statistics were 0.79 [95% confidence interval (CI) 0.76-0.82] for the core model and 0.81 (95% CI 0.78-0.84) for the extended model. Calibration plots showed agreement between predicted and observed 10-year risk of T2D., Conclusion: The 10-year and lifetime risks of T2D can be estimated with the CVD2DM model in patients with established CVD, using readily available clinical predictors. The model would benefit from further validation across diverse ethnic groups to enhance its applicability. Informing patients about their T2D risk could motivate them further to adhere to a healthy lifestyle., Competing Interests: Conflict of interest: M.W. has received consultancy fees from Amgen and Freeline. The other authors have nothing to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Icosapent ethyl lowers triglycerides and significantly reduces major adverse cardiovascular events (MACE), though treatment effects may vary between individuals. This study aimed to determine the relative and absolute effects of icosapent ethyl on MACE according to baseline cardiovascular disease (CVD) risk in patients with atherosclerotic cardiovascular disease (ASCVD)., Methods and Results: Participants from the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) with ASCVD were included (n = 5785). The primary outcome was 3-point MACE, i.e. non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. Baseline 5-year risk of MACE was estimated using the European Society of Cardiology (ESC) guideline-recommended SMART2 risk score. Modification of the relative treatment effects of icosapent ethyl by baseline risk was assessed using Cox proportional hazards models, including a treatment-by-risk interaction. Next, treatment effects were assessed stratified by quartiles of baseline risk. During a median follow-up of 4.8 years (interquartile range 3.2-5.3), MACE occurred in 361 vs. 489 patients in the icosapent ethyl vs. placebo group [95% confidence interval (CI)]; hazard ratio (HR) 0.72 (0.63-0.82), absolute risk reduction (ARR) 4.4% (2.6-6.2%), number needed to treat (NNT) 23 (16-38), and 5-year Kaplan-Meier estimated cumulative incidence reduction (CIR) 5.7% (3.5-7.9%). Icosapent ethyl significantly reduced MACE in all risk quartiles, with an HR (95% CI) of 0.62 (0.43-0.88), 0.66 (0.48-0.92), 0.69 (0.53-0.90), and 0.78 (0.63-0.96), respectively (P for treatment-by-risk interaction = 0.106). The ARR (95% CI) increased across risk quartiles, i.e. was 3.9% (1.0-6.8%), 4.3% (1.2-7.3%), 5.1% (1.4-8.7%), and 5.6% (1.3-10.0%), respectively. This translates to NNTs (95% CI) of 26 (15-98), 24 (14-84), 20 (11-70), and 18 (10-77). The 5-year CIR (95% CI) was 4.8% (1.3-8.2%), 5.0% (1.3-8.7%), 6.1% (1.7-10.5%), and 7.7% (2.3-13.2%), respectively. Consistent results were obtained for 5-point MACE, additionally including coronary revascularization and unstable angina., Conclusion: Among patients with ASCVD and elevated triglyceride levels, icosapent ethyl significantly reduces the risk of MACE irrespective of baseline CVD risk, though absolute benefits are largest for patients at the highest risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: After 3 months of anticoagulation for venous thromboembolism (VTE), the decision needs to be made whether to stop anticoagulation or extend treatment indefinitely. The VTE-PREDICT calculator can be used to estimate individual risks of VTE recurrence and bleeding to guide this decision., Objectives: To evaluate the impact of predicted individual risks of recurrence and bleeding on clinicians' decisions on anticoagulation duration and to assess usefulness of the VTE-PREDICT calculator., Methods: A randomized controlled trial and within-subject study was conducted among clinicians treating VTE patients. The clinicians were asked to complete an online survey containing 6 fictional case vignettes. Group A proposed anticoagulant duration for each case without additional information first and subsequently after seeing calculator-predicted risks (within-subject analysis). Group B was directly provided with calculator risks and proposed treatment duration for each case vignette (for comparison with group A results in a randomized controlled trial analysis). Then, group B received questions on usefulness and credibility of the calculator., Results: Forty-five clinicians were assigned to group A and 48 to B. Overall, group A did not propose different anticoagulation durations than group B. However, individual clinicians in group A changed proposed duration in 35% of the cases after seeing the calculator risks. The calculator was considered useful and credible by most clinicians., Conclusion: Overall, use of the VTE-PREDICT calculator did not affect proposed anticoagulation duration. However, individual clinicians frequently changed their proposed duration after using the calculator, especially for patients with high bleeding risk., (© 2024 The Authors.)

Aims: The efficacy of a healthy lifestyle in secondary prevention of cardiovascular disease (CVD) is well established and a first-line recommendation in CVD prevention guidelines. The aim of this study was to assess whether Mediterranean diet and physical activity are also cost-effective in patients with established CVD., Methods and Results: A cost-utility analysis (CUA) was performed comparing a combined Mediterranean diet and physical activity intervention to usual care in patients with CVD. The CUA had a healthcare perspective and lifetime horizon. Costs and utilities were estimated using a microsimulation on a cohort of 100 000 patients with CVD sampled from the Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease study (n = 8947, mean age 62 ± 8.7 years, and 74% male). Cost-effectiveness was expressed as an incremental cost-effectiveness ratio (ICER), incremental net health benefit (INHB), and incremental net monetary benefit (INMB). Mediterranean diet and physical activity yielded 2.0 incremental quality-adjusted life years (QALYs) and cost reductions of €1236 per person compared with usual care, resulting in an ICER of €-626/QALY [95% confidence interval (CI) -1929 to 2673]. At a willingness-to-pay of €20 000/QALY, INHB was 2.04 (95% CI 0.99-3.58) QALYs and INMB was €40 757 (95% CI 19 819-71 605). The interventions remained cost-effective in a wide range of sensitivity analyses, including worst-case scenarios and scenarios with reimbursement for food and physical activity costs., Conclusion: In patients with established CVD, a combined Mediterranean diet and physical activity intervention was cost-saving and highly cost-effective compared with usual care. These findings strongly advocate for the incorporation of lifestyle interventions as integral components of care for all patients with CVD., Competing Interests: Conflicts of interest: none declared., (© 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: Cardiovascular disease (CVD) risk scores provide point estimates of individual risk without uncertainty quantification. The objective of the current study was to demonstrate the feasibility and clinical utility of calculating uncertainty surrounding individual CVD-risk predictions using Bayesian methods., Study Design and Setting: Individuals with established atherosclerotic CVD were included from the Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease (UCC-SMART). In 8,355 individuals, followed for median of 8.2 years (IQR 4.2-12.5), a Bayesian Weibull model was derived to predict the 10-year risk of recurrent CVD events., Results: Model coefficients and individual predictions from the Bayesian model were very similar to that of a traditional ('frequentist') model but the Bayesian model also predicted 95% credible intervals (CIs) surrounding individual risk estimates. The median width of the individual 95%CrI was 5.3% (IQR 3.6-6.5) and 17% of the population had a 95%CrI width of 10% or greater. The uncertainty decreased with increasing sample size used for derivation of the model. Combining the Bayesian Weibull model with sampled hazard ratios based on trial reports may be used to estimate individual estimates of absolute risk reduction with uncertainty measures and the probability that a treatment option will result in a clinically relevant risk reduction., Conclusion: Estimating uncertainty surrounding individual CVD risk predictions using Bayesian methods is feasible. The uncertainty regarding individual risk predictions could have several applications in clinical practice, like the comparison of different treatment options or by calculating the probability of the individual risk being below a certain treatment threshold. However, as the individual uncertainty measures only reflect sampling error and no biases in risk prediction, physicians should be familiar with the interpretation before widespread clinical adaption., Competing Interests: Declaration of competing interest The authors report no conflicts of interest relevant to the current study., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: Although trials have proven the group-level effectiveness of various therapies for heart failure with reduced ejection fraction (HFrEF), important differences in absolute effectiveness exist between individuals. We developed and validated the LIFEtime-perspective for Heart Failure (LIFE-HF) model for the prediction of individual (lifetime) risk and treatment benefit in patients with HFrEF., Methods and Results: Cox proportional hazards functions with age as the time scale were developed in the PARADIGM-HF and ATMOSPHERE trials (n = 15 415). Outcomes were cardiovascular death, heart failure (HF) hospitalization or cardiovascular death, and non-cardiovascular mortality. Predictors were age, sex, New York Heart Association class, prior HF hospitalization, diabetes mellitus, extracardiac vascular disease, systolic blood pressure, left ventricular ejection fraction, N-terminal pro-B-type natriuretic peptide, and glomerular filtration rate. The functions were combined in life-tables to predict individual overall and HF hospitalization-free survival. External validation was performed in the SwedeHF registry, ASIAN-HF registry, and DAPA-HF trial (n = 51 286). Calibration of 2- to 10-year risk was adequate, and c-statistics were 0.65-0.74. An interactive tool was developed combining the model with hazard ratios from trials to allow estimation of an individual's (lifetime) risk and treatment benefit in clinical practice. Applying the tool to the development cohort, combined treatment with a mineralocorticoid receptor antagonist, sodium-glucose cotransporter 2 inhibitor, and angiotensin receptor-neprilysin inhibitor was estimated to afford a median of 2.5 (interquartile range [IQR] 1.7-3.7) and 3.7 (IQR 2.4-5.5) additional years of overall and HF hospitalization-free survival, respectively., Conclusion: The LIFE-HF model enables estimation of lifelong overall and HF hospitalization-free survival, and (lifetime) treatment benefit for individual patients with HFrEF. It could serve as a tool to improve the management of HFrEF by facilitating personalized medicine and shared decision-making., (© 2023 European Society of Cardiology.)

Aim: To evaluate presence of treatment effect heterogeneity of intensive insulin therapy (INT) on occurrence of major adverse cardiovascular events (MACE) in individuals with type 1 diabetes., Methods: In participants from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, individual treatment effect of INT (≥3 daily insulin injections/insulin pump therapy) versus conventional therapy (once/twice daily insulin) on the risk of MACE was estimated using a penalized Cox regression model including treatment-by-covariate interaction terms., Results: In 1441 participants, 120 first MACE events were observed and 1279 individuals (89%) were predicted to benefit from INT with regard to MACE risk reduction. The study population was divided into four groups based on predicted treatment effect: one group with no predicted benefit and three tertiles with predicted treatment benefit. The median absolute reduction in 30-year risk of MACE across groups of predicted treatment effect ranged from -0.2% (i.e. risk increase; interquartile range [IQR] -0.1% to -0.3%) in the group with no predicted benefit to 6.6% (i.e. risk reduction; IQR 3.8%-10.9%; number needed to treat 15) in the highest tertile of predicted benefit. The observed benefit of preventing microvascular complications was stable across all subgroups of predicted MACE benefit., Conclusions: Although INT reduces the risk of MACE in the majority of individuals with type 1 diabetes, benefit varies substantially. These individual differences in the effect of INT underline the necessity for a better understanding of the individual response to intensive treatment., (© 2023 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Background: Current prediction models for mainland Europe do not include ethnicity, despite ethnic disparities in cardiovascular disease (CVD) risk. SCORE2 performance was evaluated across the largest ethnic groups in the Netherlands and ethnic backgrounds were added to the model., Methods: 11,614 participants, aged between 40 and 70 years without CVD, from the population-based multi-ethnic HELIUS study were included. Fine and Gray models were used to calculate sub-distribution hazard ratios (SHR) for South-Asian Surinamese, African Surinamese, Ghanaian, Turkish and Moroccan origin groups, representing their CVD risk relative to the Dutch group, on top of individual SCORE2 risk predictions. Model performance was evaluated by discrimination, calibration and net reclassification index (NRI)., Results: Overall, 274 fatal and non-fatal CVD events, and 146 non-cardiovascular deaths were observed during a median of 7.8 years follow-up (IQR 6.8-8.8). SHRs for CVD events were 1.86 (95 % CI 1.31-2.65) for the South-Asian Surinamese, 1.09 (95 % CI 0.76-1.56) for the African-Surinamese, 1.48 (95 % CI 0.94-2.31) for the Ghanaian, 1.63 (95 % CI 1.09-2.44) for the Turkish, and 0.67 (95 % CI 0.39-1.18) for the Moroccan origin groups. Adding ethnicity to SCORE2 yielded comparable calibration and discrimination [0.764 (95 % CI 0.735-0.792) vs. 0.769 (95 % CI 0.740-0.797)]. The NRI for adding ethnicity to SCORE2 was 0.24 (95 % CI 0.18-0.31) for events and - 0.12 (95 % CI -0.13-0.12) for non-events., Conclusions: Adding ethnicity to the SCORE2 risk prediction model in a middle-aged, multi-ethnic Dutch population did not improve overall discrimination but improved risk classification, potentially helping to address CVD disparities through timely treatment., Competing Interests: Declaration of competing interest All authors declare no conflicting interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Pseudoxanthoma elasticum (PXE), a rare genetic disorder presenting with slowly progressing calcification of various tissues, including the arteries, is caused by mutations in the ABCC6 gene that lead to the reduction of pyrophosphate, a natural inhibitor of calcification. We showed that, compared to a placebo, the cyclical administration of etidronate, a stable pyrophosphate analog, significantly reduced arterial calcification assessed by low-dose CT scans after one year. The aim of the present prospective, single center, observational cohort study was the assessment of the efficacy and safety of cyclical etidronate in patients treated for periods longer than one year. Methods: Seventy-three patients were followed for a median of 3.6 years without etidronate and 2.8 years with etidronate, and each patient served as their own control. Results: The median absolute yearly progression of total calcification volume during the period with etidronate (388 [83-838] µL) was significantly lower than that without etidronate (761 [362-1415] µL; p < 0.001). The rates of the relative progression of arterial calcification were 11.7% (95% CI: 9.6-13.9) without etidronate compared to 5.3% (95% CI: 3.7-7.0) with etidronate, after adjustment for confounders. Conclusions: The cyclical administration of etidronate for nearly 3 years significantly reduced the progression rate of arterial calcification in patients with PXE with pre-existing calcifications without any serious adverse effects.

Competing Interests: Funding Support and Author Disclosures Dr Marinho is supported by the Lemann Foundation Cardiovascular Research Fellowship. Dr Everett has received grants from PCORI and Novo Nordisk; has received royalties from UpToDate; and has been a consultant for Circulation/American Heart Association, Eli Lilly and Company, U.S. Food and Drug Administration, Novo Nordisk, Gilead Pharmaceuticals, Ipsen Biosciences Inc, Johnson & Johnson, Provention Bio, and Roche Diagnostics. Dr Aday has received compensation for consultant services from Aeglea. Ms MacFadyen has received salary support from a research grant to BWH from Kowa Research Institute. Dr Santos has received honoraria related to consulting and/or speaker activities from Aché, Abbott, Amryt, Amgen, Biolab, EMS, Eli Lilly, Getz Pharma, Pfizer, PTC Therapeutics, Novartis, Novo Nordisk, and Sanofi/Regeneron; and has received research grants from Amgen, Esperion, Kowa, Novartis, and Sanofi/Regeneron. Dr Libby is an unpaid consultant to or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa, Medimmune, Merck, Moderna, Novo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron; and is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Elucid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, Soley Therapeutics, and XBiotech, Inc. Dr Libby’s laboratory has received research funding in the last 2 years from Novartis, Novo Nordisk, and Genentech; is on the Board of Directors of XBiotech, Inc; and has a financial interest in Xbiotech (a company developing therapeutic human antibodies), in TenSixteen Bio (a company targeting somatic mosaicism and clonal hematopoiesis of indeterminate potential to discover and develop novel therapeutics to treat age-related diseases), and in Soley Therapeutics (a biotechnology company that is combining artificial intelligence with molecular and cellular response detection for discovering and developing new drugs, currently focusing on cancer therapeutics). Dr Fruchart is a consultant to Kowa. Dr Ridker has received institutional research grant support from Kowa Research Institute, Novartis, Amarin, Pfizer, Esperion, Novo Nordisk, and the National Heart, Lung, and Blood Institute; has served as a consultant to Novartis, Flame, Agepha, Ardelyx, AstraZeneca, Janssen, CiVi Biopharma, GlaxoSmithKline, SOCAR, Novo Nordisk, Health Outlook, Montai Health, Eli Lilly, New Amsterdam, Boehringer Ingelheim, RTI, Zomagen, Cytokinetics, Horizon Therapeutics, and Cardiol Therapeutics; has minority shareholder equity positions in Uppton, Bitterroot Bio, and ANGIOWave; and receives compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation, Paris FR, and the Baim Institute. Dr Pradhan has received research grants from Kowa Research Europe and Denka, LTD; has received compensation for consultant services from Optum, Novo Nordisk, and Reliant Medical Foundation; receives compensation for lectures from Medtelligence and NACE; and is currently employed by Bristol Myers Squibb. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Cardiovascular (CV) disease is the most common cause of death in Europe. Despite proven benefits, use of lipid-lowering therapy remains suboptimal. Treatment goals are often not achieved, even in patients at high risk with atherosclerotic CV disease (ASCVD). The occurrence of CV events in patients on lipid-lowering drugs is defined as "residual risk", and can result from inadequate control of plasma lipids or blood pressure, inflammation, diabetes, and environmental hazards. Assessment of CV risk factors and vascular imaging can aid in the evaluation and management decisions for individual patients. Lifestyle measures remain the primary intervention for lowering CV risk. Where drug therapies are required to reach lipid treatment targets, their effectiveness increases when they are combined with lifestyle measures delivered through formal programs. However, lipid drug dosage and poor adherence to treatment remain major obstacles to event-free survival. This article discusses guideline-supported treatment algorithms beyond statin therapy that can help reduce residual risk in specific patient profiles while also likely resulting in substantial healthcare savings through better patient management and treatment adherence., Competing Interests: Declaration of competing interest Mach: Research grants from Amgen, Daiichi-Sankyo, Novartis, and Sanofi; participation on a data safety monitoring board or advisory board for Amgen, Daiichi-Sankyo, Novartis, and Sanofi. Visseren: None. Cater: Employment with and stock or stock options from Pfizer. Salhi: Employment with and stock or stock options from Amgen. Soronen: Employment with and stock or stock options from Daiichi Sankyo. Ray: Unrestricted institutional research grants from Amgen, Daiichi-Sankyo, Regeneron, and Sanofi; consulting fees for participation in a steering committee, executive committee, or advisory board for Novartis, Esperion, Daiichi Sankyo, Abbott, Bayer, Eli Lilly, Silence Therapeutics, CSL Behring, New Amsterdam Pharma, Sanofi, Amgen, Novo Nordisk, Boehringer Ingelheim, Scribe, Vaxxinity, CRISPR, AstraZeneca, Kowa Pharmaceuticals, Cargene Therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for CME and non-CME materials from Novartis, Novo Nordisk, Boehringer Ingelheim, AstraZeneca, Daiichi Sankyo, Amgen, Sanofi; leadership role (President) of European Atherosclerosis Society (EAS); and stock or stock options from Pemi-31 Therapeutics. Delgado: Consulting fees from Edwards Lifesciences, Novo Nordisk; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbott Vascular, Edwards Lifescience, GE Healthcare, Medtronic, Novartis, and Philips. Jukema: Research grants from and/or was speaker (with or without lecture fees) on CME accredited meetings sponsored by Amarin, Amgen, Athera, Biotronik, Boston Scientific, Dalcor, Daiichi-Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, the Netherlands Heart Foundation, CardioVascular Research the Netherlands (CVON), the Netherlands Heart Institute, and the European Community Framework KP7 Programme. Laufs: Support for the present manuscript from the European Society of Cardiology (ESC); grants or contracts from Amgen, Daiichi-Sankyo, and Novartis; consulting fees from Amgen, Boehringer Ingelheim, Daiichi-Sankyo, and Novartis; payment for public lectures from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, Novo Nordisk, Pfizer, and Sanofi; leadership roles with ESC, DGK, DACH, and EAS. Zamorano: Grants or contracts from Abbott and Edwards Lifesciences; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, Amgen, Daiichi-Sankyo, and Pfizer. Ros: Honoraria for a lecture at the Sociedad Española de Arteriosclerosis (SEA), for participation in an EAS Task Force Expert Panel on Dyslipidaemia Guidelines, for manuscript writing for the California Walnut Commission, and for participation in an educational seminar for the Fundación Dieta Mediterránea; and participation on an advisory board for Alexion. Plat: Travel reimbursement for the meeting relating to the present manuscript from the ESC; institutional grants from Raisio to evaluate effects of plant stanol esters on vaccinations; honoraria paid directly to the institution for lectures at the EAS 2020 annual meeting, the EAS 2021 annual meeting, and at the BASF Day of Science Symposium 2022. Gesztes: None. Tokgozoglu: Consulting fees Astra Zeneca, Abbott, Amgen, Bayer, MSD, Mylan, Novartis, Sanofi, Novo Nordisk, and Daiichi-Sankyo; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbott, Amgen, Daiichi-Sankyo, MSD, Mylan, Novartis, Novo Nordisk, Sanofi, Servier, Pfizer, Recordati, and Janssen; participation on a data safety monitoring board or advisory board for Abbott, Amgen, Novartis, Sanofi, Daiichi-Sankyo, Mylan, and Pfizer; and leadership roles with the EAS (past president) and Turkish Society of Cardiology (past president). Packard: Institutional research grant from Pfizer; consulting fees from Amgen, Amarin, Daiichi-Sankyo, MSD, Novartis, and Response therapeutics; and payment or honoraria for manuscript preparation from Novartis and for lectures for Amgen and Amarin. Libby: Support for the present manuscript from the National Heart, Lung, and Blood Institute (NHLBI) (grant nos. 1R01HL134892, 1R01HL163099-01), the American Heart Association (grant no. 18CSA34080399), the RRM Charitable Fund, and the Simard Fund; payment or honoraria for lectures and educational events from Pri-Med and Medtelligence; Research support from Novartis, Novo Nordisk, and Genentech, a US patent application for the use of canakinumab (application no. 20200239564) and a US provisional patent application for the treatment of brain ischemia-reperfusion injury (application no. 5409-0001); participation on a data safety monitoring board or advisory board for Amgen, Novartis, DalCor, and XBiotech, Inc; a leadership role (Director) for XBiotech, Inc; stock or stock options from XBiotech, Inc, TenSixteen Bio, and Soley Therapeutics; receipt of drugs from Novartis and Regeneron; consultancies (unpaid) for Amgen, Kowa Pharmaceuticals, Medimmune, AstraZeneca, Bain Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Merck, Moderna, Kancera, Novo Nordisk, Pfizer, Sanofi-Regeneron, participation on scientific advisory boards (unpaid) for Amgen, Kowa Pharmaceuticals, Olatec Pharmaceuticals, Medimmune, Caristo, Cartesian, CSL Behring, Dewpoint, Plaquetec, TenSixteen Bio, Soley Therapeutics, and Eulicid., (Copyright © 2024. Published by Elsevier Inc.)

Aim: To quantify the relationship of neutrophil-to-lymphocyte ratio (NLR) with cardiovascular events and all-cause mortality in patients with type 2 diabetes (T2D), independent of C-reactive protein (CRP)., Methods: Patients with T2D from the UCC-SMART-cohort were studied using multivariable-adjusted Cox regression. The relationship of NLR and CRP with vascular events (cerebrovascular events, myocardial infarction and vascular death) and all-cause mortality was quantified., Results: During 10,833 person-years, 232 vascular events and 302 deaths occurred in 1,239 patients with T2D. Risk of vascular events and all-cause mortality increased per standard deviation (SD) in NLR (hazard ratio (HR) 1.27; 95 % confidence interval (CI):1.11-1.46) and 1.15; 95 % CI:1.02-1.30) after adjustment for CRP. CRP was not associated with vascular events after adjustment for NLR, (HR per SD 1.03; 95 % CI: 0.90-1.19), but was associated with all-cause mortality (HR per SD 1.18; 95 % CI: 1.04-1.33). Notably, NLR was related to vascular events in patients with CRP < 2 mg/L (HR per unit 1.45; 95 % CI: 1.19-1.77)., Conclusion: In patients with T2D, NLR is related to higher risk of CVD and all-cause mortality, independently from CRP. NLR is related to CVD even when CRP is low, indicating that NLR is a marker of CVD-risk in addition to CRP. Both NLR and CRP are independently related to all-cause mortality in T2D patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Risk factors for stroke differ between women and men in general populations. However, little is known about sex differences in secondary prevention. We investigated if sex interacted with modifiable risk factors for stroke in a large arterial disease cohort., Methods: Within the prospective UCC-SMART study, 13,898 patients (35% women) with atherosclerotic disease or high-risk factor profile were followed up to 23 years for stroke incidence or recurrence. Hypertension, smoking, diabetes, overweight, dyslipidemia, high alcohol use, and physical inactivity were studied as risk factors. Association between these factors and ischemic and hemorrhagic stroke incidence or recurrence was studied in women and men using Cox proportional hazard models and Poisson regression models. Women-to-men relative hazard ratios (RHR) and rate differences (RD) were estimated for each risk factor. Left-truncated age was used as timescale., Results: The age-adjusted stroke incidence rate was lower in women than men (3.9 vs 4.4 per 1000 person-years), as was the age-adjusted stroke recurrence rate (10.0 vs 11.7). Hypertension and smoking were associated with stroke risk in both sexes. HDL cholesterol was associated with lower stroke incidence in women but not in men (RHR 0.49; CI 0.27-0.88; and RD 1.39; CI - 1.31 to 4.10). Overweight was associated with a lower stroke recurrence in women but not in men (RHR 0.42; CI 0.23-0.80; and RD 9.05; CI 2.78-15.32)., Conclusions: In high-risk population, sex modifies the association of HDL cholesterol on stroke incidence, and the association of overweight on stroke recurrence. Our findings highlight the importance of sex-specific secondary prevention., (© 2024. The Author(s).)

Background and Aims: Body adiposity is known to affect mortality risk in patients with coronary artery disease (CAD). We examined associations of body mass index (BMI) and waist circumference (WC) with long term mortality in Dutch CAD patients, and potential and effect modification of these associations by lifestyle and health determinants., Methods: 10,370 CAD patients (mean age ∼65 y; 20% female; >80% on cardiovascular drugs) from the prospective Alpha Omega Cohort and Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease study were included. Cox models were used to estimate categorical and continuous associations (using restricted cubic splines) of measured BMI and WC with all-cause and cardiovascular mortality risk, adjusting for age, sex, smoking, alcohol, physical activity and educational level. Analyses were repeated in subgroups of lifestyle factors (smoking, physical activity, diet quality), education and health determinants (diabetes, self-rated health)., Results: During ∼10 years of follow-up (91,947 person-years), 3,553 deaths occurred, including 1,620 from cardiovascular disease. U-shaped relationships were found for BMI and mortality risk, with the lowest risk for overweight patients (BMI ∼27 kg/m2). For obesity (BMI ≥30), the HR for all-cause mortality was 1.31 (95% CI: 1.11, 1.41) in male patients and 1.10 (95% CI: 0.92, 1.30) in female patients, compared to BMI 25-30 kg/m2. WC was also non-linearly associated with mortality, and HRs were 1.18 (95%CI:1.06, 1.30) in males and 1.31 (95%CI:1.05, 1.64) in females for the highest vs. middle category of WC. Results for cardiovascular mortality were mostly in line with the results for all-cause mortality. U-shaped associations were found in most subgroups, associations were moderately modified by physical activity, smoking and educational level., Conclusions: CAD patients with obesity and a large WC were at increased risk of long-term CVD and all-cause mortality, while mildly overweight patients had the lowest risk. These associations were consistent across subgroups of patients with different lifestyles and health status., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Cruijsen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims/hypothesis: Continuous glucose monitoring (CGM) is increasingly used in the treatment of type 2 diabetes, but the effects on glycaemic control are unclear. The aim of this systematic review and meta-analysis is to provide a comprehensive overview of the effect of CGM on glycaemic control in adults with type 2 diabetes., Methods: We performed a systematic review using Embase, MEDLINE, Web of Science, Scopus and ClinicalTrials.gov from inception until 2 May 2023. We included RCTs investigating real-time CGM (rtCGM) or intermittently scanned CGM (isCGM) compared with self-monitoring of blood glucose (SMBG) in adults with type 2 diabetes. Studies with an intervention duration <6 weeks or investigating professional CGM, a combination of CGM and additional glucose-lowering treatment strategies or GlucoWatch were not eligible. Change in HbA 1c and the CGM metrics time in range (TIR), time below range (TBR), time above range (TAR) and glycaemic variability were extracted. We evaluated the risk of bias using the Cochrane risk-of-bias tool version 2. Data were synthesised by performing a meta-analysis. We also explored the effects of CGM on severe hypoglycaemia and micro- and macrovascular complications., Results: We found 12 RCTs comprising 1248 participants, with eight investigating rtCGM and four isCGM. Compared with SMBG, CGM use (rtCGM or isCGM) led to a mean difference (MD) in HbA 1c of -3.43 mmol/mol (-0.31%; 95% CI -4.75, -2.11, p<0.00001, I 2 =15%; moderate certainty). This effect was comparable in studies that included individuals using insulin with or without oral agents (MD -3.27 mmol/mol [-0.30%]; 95% CI -6.22, -0.31, p=0.03, I 2 =55%), and individuals using oral agents only (MD -3.22 mmol/mol [-0.29%]; 95% CI -5.39, -1.05, p=0.004, I 2 =0%). Use of rtCGM showed a trend towards a larger effect (MD -3.95 mmol/mol [-0.36%]; 95% CI -5.46 to -2.44, p<0.00001, I 2 =0%) than use of isCGM (MD -1.79 mmol/mol [-0.16%]; 95% CI -5.28, 1.69, p=0.31, I 2 =64%). CGM was also associated with an increase in TIR (+6.36%; 95% CI +2.48, +10.24, p=0.001, I 2 =9%) and a decrease in TBR (-0.66%; 95% CI -1.21, -0.12, p=0.02, I 2 =45%), TAR (-5.86%; 95% CI -10.88, -0.84, p=0.02, I 2 =37%) and glycaemic variability (-1.47%; 95% CI -2.94, -0.01, p=0.05, I 2 =0%). Three studies reported one or more events of severe hypoglycaemia and macrovascular complications. In comparison with SMBG, CGM use led to a non-statistically significant difference in the incidence of severe hypoglycaemia (RR 0.66, 95% CI 0.15, 3.00, p=0.57, I 2 =0%) and macrovascular complications (RR 1.54, 95% CI 0.42, 5.72, p=0.52, I 2 =29%). No trials reported data on microvascular complications., Conclusions/interpretation: CGM use compared with SMBG is associated with improvements in glycaemic control in adults with type 2 diabetes. However, all studies were open label. In addition, outcome data on incident severe hypoglycaemia and incident microvascular and macrovascular complications were scarce., Registration: This systematic review was registered on PROSPERO (ID CRD42023418005)., (© 2024. The Author(s).)

Aims: This study aimed to evaluate the stepwise approach for cardiovascular (CV) risk factor treatment as outlined by the European Society for Cardiology 2021 guidelines on CV disease (CVD) prevention in patients with established atherosclerotic CVD (ASCVD)., Methods and Results: In patients with ASCVD, included in UCC-SMART (n = 8730) and European parts of the REACH registry (n = 18 364), the 10-year CV risk was estimated using SMART2. Treatment effects were derived from meta-analyses and trials. Step 1 recommendations were LDL cholesterol (LDLc) < 1.8 mmol/L, systolic blood pressure (SBP) < 140 mmHg, using any antithrombotic medication, sodium-glucose co-transporter 2 (SGLT2) inhibition, and smoking cessation. Step 2 recommendations were LDLc < 1.4 mmol/L, SBP < 130 mmHg, dual-pathway inhibition (DPI, aspirin plus low-dose rivaroxaban), colchicine, glucagon-like peptide (GLP)-1 receptor agonists, and eicosapentaenoic acid. Step 2 was modelled accounting for Step 1 non-attainment. With current treatment, residual CV risk was 22%, 32%, and 60% in the low, moderate, and pooled (very) high European risk regions, respectively. Step 2 could prevent up to 198, 223 and 245 events per 1000 patients treated, respectively. Intensified LDLc reduction, colchicine, and DPI could be applied to most patients, preventing up to 57, 74, and 59 events per 1000 patients treated, respectively. Following Step 2, the number of patients with a CV risk of <10% could increase from 20%, 6.4%, and 0.5%, following Step 1, to 63%, 48%, and 12%, in the respective risk regions., Conclusion: With current treatment, residual CV risk in patients with ASCVD remains high across all European risk regions. The intensified Step 2 treatment options result in marked further reduction of residual CV risk in patients with established ASCVD., Key Findings: Guideline-recommended intensive treatment of patients with cardiovascular disease could prevent additional 198-245 new cardiovascular events for every 1000 patients treated., Competing Interests: Conflict of interest: D.L.B.: advisory board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; board of directors: American Heart Association New York City, Angiowave (stock options), Bristol-Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); consultant: Broadview Ventures, GlaxoSmithKline, Hims, SFJ, and Youngene; data monitoring committees: 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, 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; for ALLAY-HF, funded by Alleviant Medical), Novartis, and Population Health Research Institute; Rutgers University (for the NIH-funded MINT trial); honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee); other: Clinical Cardiology (Deputy Editor); Patent: sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital who assigned to Lexicon; neither I nor Brigham and Women’s Hospital receive any income from this patent); research funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, 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, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; royalties: Elsevier (Editor, Braunwald’s Heart Disease); site co-investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; trustee: American College of Cardiology; and unfunded research: FlowCo. K.K.R. has received grants from Amgen, Sanofi, Regeneron, Daiichi Sankyo, and Ultragenyx; consulting fees from Novartis, Daiichi Sankyo, Kowa, Esperion, Novo Nordisk, MSD, Lilly, Silence Therapeutics, AZ, NewAmsterdam Pharma, Bayer, Beren Therapeutics, CLEERLY, EMENDOBIO, SCRIBE, CRISPR, VAXXINITY, Amarin, Regeneron, Ultragenyx, Cargene, and Resverlogix; and speaking fees from Novartis, BI, AZ, Novo Nordisk, Viatris, Amarin, Biologix Pharma, Sanofi, Amgen, Esperion, Daiichi Sankyo, and Macleods Pharma, is president of the EAS, and hold stocks in NewAmsterdam Pharma and PEMI31. P.G.S. has received grants from Amarin and Sanofi; was involved in clinical trials (steering committee, CEC, DSMB): Amarin, Amgen, AstraZeneca, Bayer, BMS, Idorsia, Janssen, Novartis, and Sanofi; has received consulting/speaking fees from Amarin, Amgen, BMS, Novartis, and Novo Nordisk; and is a Senior Associate Editor at Circulation. The other authors have nothing to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aims: Guidelines no longer recommend low-fat diets and currently recommend more plant-based diets to reduce atherosclerotic cardiovascular disease (ASCVD) risk. Furthermore, these guidelines have consistently recommended salt-reduced diets. This article describes current self-reported use and time-trends in the self-reported use of low-fat, low-salt and vegetarian diets in ASCVD patients and examines patient characteristics associated with each diet., Methods and Results: 9005 patients with ASCVD included between 1996 and 2019 in the UCC-SMART cohort were studied. The prevalence of self-reported diets was assessed and multi-variable logistic regression was used to identify the determinants of each diet. Between 1996-1997 and 2018-2019, low-fat diets declined from 22.4 % to 3.8 %, and low-salt diets from 14.7 % to 4.6 %. The prevalence of vegetarian diets increased from 1.1 % in 1996-1997 to 2.3 % in 2018-2019. Patients with cerebrovascular disease (CeVD) and peripheral artery disease or an abdominal aortic aneurysm (PAD/AAA) were less likely to report a low-salt diet than coronary artery disease (CAD) patients (OR 0.62 [95%CI 0.49-0.77] and 0.55 [95%CI 0.41-0.72])., Conclusion: In the period 1996 to 2019 amongst patients with ASCVD, the prevalence of self-reported low-fat diets was low and decreased in line with changes in recommendations in major guidelines. The prevalence of self-reported vegetarian diets was low but increased in line with societal and guideline changes. The prevalence of self-reported low-salt diets was low, especially in CeVD and PAD/AAA patients compared to CAD patients, and decreased over time. Renewed action is needed to promote low-salt diets in ASCVD patients., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Assessment of generalisability of guideline-informing trials on antithrombotic treatment intensification to real-world patients with cardiovascular disease (CVD)., Methods: Inclusion and exclusion criteria of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS), Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA), Prevention of Cardiovascular events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction (PEGASUS-TIMI) and Dual Antiplatelet Therapy (DAPT) study were applied to coronary artery disease (CAD) and/or peripheral artery disease (PAD) patients from Utrecht Cardiovascular Cohort-Second Manifestations of Arterial Disease (UCC-SMART) to determine real-world eligibility. Eligible and ineligible patients were compared on baseline characteristics, cardiovascular events, major bleeding and mortality., Results: Eligibility ranged from 11%-94% for CAD to 75%-90% for patients with PAD. Cardiovascular, bleeding and mortality risks were higher in COMPASS-eligible patients with CAD (rate ratios (RR) 1.98 (95% CI 1.74 to 2.26), 2.02 (95% CI 1.47 to 2.78) and 3.11 (95% CI 2.71 to 3.57), respectively) and CHARISMA-eligible patients (RR 1.51 (95% CI 1.12 to 2.06), 2.25 (95% CI 1.01 to 6.21) and 4.43 (95% CI 2.79 to 7.51), respectively), and lower in COMPASS-eligible patients with PAD (RR 0.45 (95% CI 0.36 to 0.56), 0.29 (95% CI 0.18 to 0.46) and 0.45 (95% CI 0.38 to 0.54), respectively) and DAPT-eligible patients with CAD (RR CVD 0.49 (95% CI 0.34 to 0.69) and mortality 0.67 (95% CI 0.48 to 0.94)) than ineligible patients. After adjustment for trial eligibility criteria, only higher cardiovascular and mortality risks in COMPASS-eligible patients with CAD and lower cardiovascular risks in CHARISMA-eligible and DAPT-eligible patients persisted with CAD., Conclusion: A large proportion of contemporary CVD patients would be eligible for intensified antithrombotic treatment trials, with mostly similar adjusted event risks to ineligible patients. Trial-based guideline recommendations are largely applicable to real-world patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Improving dietary habits is a first-line recommendation for patients with cardiovascular disease (CVD). It is unclear which dietary pattern most effectively lowers cardiovascular risk factors and what the short- and long-term effects are. Therefore, this network meta-analysis compared the effects of popular dietary patterns on cardiovascular risk factors in patients with established CVD., Methods: A systematic search of PubMed, Embase, the Cochrane library, SCOPUS and Web of Science was conducted up to 1 April 2023. Randomized controlled trials (RCTs) comparing the effect of popular dietary patterns (Mediterranean, moderate carbohydrate, low glycemic index, low-fat and minimal dietary intervention) on cardiovascular risk factors (body weight, systolic blood pressure, lipids) in CVD populations were selected. A random-effects network meta-analysis was performed., Results: Seventeen RCTs comprising 6,331 participants were included. The moderate carbohydrate diet had the most beneficial effect on body weight (-4.6 kg, 95%CrI -25.1; 15.8) and systolic blood pressure (-7.0 mmHg 95%CrI -16.8; 2.7) compared to minimal intervention. None of the included dietary patterns had a favorable effect on low-density lipoprotein cholesterol. After 12 months, the effects were attenuated compared to those at < 6 months., Conclusions: In this network meta-analysis of 17 randomized trials, potentially clinically relevant effects of dietary interventions on CV risk factors were observed, but there was considerable uncertainty due to study heterogeneity, low adherence, or actual diminished effects in the medically treated CVD population. It was not possible to select optimal dietary patterns for secondary CVD prevention. Given recent clinical trials demonstrating the potential of dietary patterns to significantly reduce cardiovascular event risk, it is likely that these effects are effectuated through alternative physiological pathways., (© 2024. The Author(s).)

Aims: The European Systematic Coronary Risk Evaluation 2 (SCORE2) and SCORE2-Older Persons (OP) models are recommended to identify individuals at high 10-year risk for cardiovascular disease (CVD). Independent validation and assessment of clinical utility is needed. This study aims to assess discrimination, calibration, and clinical utility of low-risk SCORE2 and SCORE2-OP., Methods and Results: Validation in individuals aged 40-69 years (SCORE2) and 70-79 years (SCORE2-OP) without baseline CVD or diabetes from the European Prospective Investigation of Cancer (EPIC) Norfolk prospective population study. We compared 10-year CVD risk estimates with observed outcomes (cardiovascular mortality, non-fatal myocardial infarction, and stroke). For SCORE2, 19 560 individuals (57% women) had 10-year CVD risk estimates of 3.7% [95% confidence interval (CI) 3.6-3.7] vs. observed 3.8% (95% CI 3.6-4.1) [observed (O)/expected (E) ratio 1.0 (95% CI 1.0-1.1)]. The area under the curve (AUC) was 0.75 (95% CI 0.74-0.77), with underestimation of risk in men [O/E 1.4 (95% CI 1.3-1.6)] and overestimation in women [O/E 0.7 (95% CI 0.6-0.8)]. Decision curve analysis (DCA) showed clinical benefit. Systematic Coronary Risk Evaluation 2-Older Persons in 3113 individuals (58% women) predicted 10-year CVD events in 10.2% (95% CI 10.1-10.3) vs. observed 15.3% (95% CI 14.0-16.5) [O/E ratio 1.6 (95% CI 1.5-1.7)]. The AUC was 0.63 (95% CI 0.60-0.65) with underestimation of risk across sex and risk ranges. Decision curve analysis showed limited clinical benefit., Conclusion: In a UK population cohort, the SCORE2 low-risk model showed fair discrimination and calibration, with clinical benefit for preventive treatment initiation decisions. In contrast, in individuals aged 70-79 years, SCORE2-OP demonstrated poor discrimination, underestimated risk in both sexes, and limited clinical utility., Competing Interests: Conflict of interest: S.H.J.H., J.A.N.D., and F.L.J.V. are part of the SCORE2 working group and ESC cardiovascular risk collaboration. H.T.J. received unrestricted research grants to institution from Bayer, Amgen, and Sanofi and is a member of the national advisory board Amgen (The Netherlands). These funders had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To quantify the relationship between self-reported, long-term lifestyle changes (smoking, waist circumference, physical activity, and alcohol consumption) and clinical outcomes in patients with established cardiovascular disease (CVD)., Methods and Results: Data were used from 2011 participants (78% male, age 57 ± 9 years) from the Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease cohort who returned for a re-assessment visit (SMART2) after ∼10 years. Self-reported lifestyle change was classified as persistently healthy, improved, worsened, or persistently unhealthy. Cox proportional hazard models were used to quantify the relationship between lifestyle changes and the risk of (cardiovascular) mortality and incident Type 2 diabetes (T2D). Fifty-seven per cent of participants was persistently healthy, 17% improved their lifestyle, 8% worsened, and 17% was persistently unhealthy. During a median follow-up time of 6.1 (inter-quartile range 3.6-9.6) years after the SMART2 visit, 285 deaths occurred, and 99 new T2D diagnoses were made. Compared with a persistently unhealthy lifestyle, individuals who maintained a healthy lifestyle had a lower risk of all-cause mortality [hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.36-0.63], cardiovascular mortality (HR 0.57, 95% CI 0.38-0.87), and incident T2D (HR 0.46, 95% CI 0.28-0.73). Similarly, those who improved their lifestyle had a lower risk of all-cause mortality (HR 0.52, 95% CI 0.37-0.74), cardiovascular mortality (HR 0.46, 95% CI 0.26-0.81), and incident T2D (HR 0.50, 95% CI 0.27-0.92)., Conclusion: These findings suggest that maintaining or adopting a healthy lifestyle can significantly lower mortality and incident T2D risk in CVD patients. This study emphasizes the importance of ongoing lifestyle optimization in CVD patients, highlighting the potential for positive change regardless of previous lifestyle habits., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Low-dose colchicine reduces cardiovascular risk in patients with coronary artery disease (CAD), but absolute benefits may vary between individuals. This study aimed to assess the range of individual absolute benefits from low-dose colchicine according to patient risk profile., Methods and Results: The European Society of Cardiology (ESC) guideline-recommended SMART-REACH model was combined with the relative treatment effect of low-dose colchicine and applied to patients with CAD from the Low-Dose Colchicine 2 (LoDoCo2) trial and the Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease (UCC-SMART) study (n = 10 830). Individual treatment benefits were expressed as 10-year absolute risk reductions (ARRs) for myocardial infarction, stroke, or cardiovascular death (MACE), and MACE-free life-years gained. Predictions were also performed for MACE plus coronary revascularization (MACE+), using a new lifetime model derived in the REduction of Atherothrombosis for Continued Health (REACH) registry. Colchicine was compared with other ESC guideline-recommended intensified (Step 2) prevention strategies, i.e. LDL cholesterol (LDL-c) reduction to 1.4 mmol/L and systolic blood pressure (SBP) reduction to 130 mmHg. The generalizability to other populations was assessed in patients with CAD from REACH North America and Western Europe (n = 25 812). The median 10-year ARR from low-dose colchicine was 4.6% [interquartile range (IQR) 3.6-6.0%] for MACE and 8.6% (IQR 7.6-9.8%) for MACE+. Lifetime benefit was 2.0 (IQR 1.6-2.5) MACE-free years, and 3.4 (IQR 2.6-4.2) MACE+-free life-years gained. For LDL-c and SBP reduction, respectively, the median 10-year ARR for MACE was 3.0% (IQR 1.5-5.1%) and 1.7% (IQR 0.0-5.7%), and the lifetime benefit was 1.2 (IQR 0.6-2.1) and 0.7 (IQR 0.0-2.3) MACE-free life-years gained. Similar results were obtained for MACE+ and in American and European patients from REACH., Conclusion: The absolute benefits of low-dose colchicine vary between individual patients with chronic CAD. They may be expected to be of at least similar magnitude to those of intensified LDL-c and SBP reduction in a majority of patients already on conventional lipid-lowering and blood pressure-lowering therapy., Competing Interests: Conflict of interest: J.W.E. reported receiving grants from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Janssen, and Sanofi-Aventis; and honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myer Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Merck, Pfizer, Janssen, Sanofi-Aventis, and Servier. P.L.T. reported receiving institutional research grants from the National Health Medical Research Council of Australia and Sir Charles Gairdner Research Advisory Committee; and the provision of colchicine and a matching placebo from Aspen Pharma Australia. J.H.C. reported receiving institutional research grants from the Withering Foundation Netherlands, The Netherlands Heart Foundation, The Netherlands Organization for Health Research and Development, and a consortium of Teva, Disphar, and Tiofarma; and consulting fees from Amgen and Sanofi. P.G.S. reported receiving research grants from Bristol Myers Squibb/Sanofi, Amarin, Bayer, and Servier; and consulting fees from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Myokardia, Idorsia, Merck, Novartis, Novo Nordisk, Regeneron, PhaseBio, Pfizer, Sanofi, and Servier; and honoraria from AstraZeneca, Novartis, and Novo Nordisk; and support for attending meetings from AstraZeneca; and participating in advisory boards for Monash University, PHRI, Sanofi, and Servier. D.L.B. discloses the following relationships: Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; Board of Directors: 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; Chair: Inaugural chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures, Hims; Data Monitoring Committee: 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); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, and ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee, funded by Boehringer Ingelheim; AEGIS-II executive committee, funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor, Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and US national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), and Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), and VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, 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, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo, and Takeda. A.M. reported institutional research grants from the Withering Foundation The Netherlands, The Netherlands Heart Foundation, The Netherlands Organization for Health Research and Development, Novartis, and a consortium of Teva, Disphar, and Tiofarma; A.M. will not accept personal fees from pharma. Other authors reported no disclosures., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: - Pseudoxanthoma elasticum (PXE) is a rare genetic disease caused by pathogenic mutations in the ABCC6 gene, resulting in low values of inorganic pyrophosphate (PPi). While low PPi is thought to contribute to arterial calcification, it remains unclear whether this fully explains premature calcification in PXE. It has been hypothesized that the ABCC6 gene could be related to dyslipidemia, which could contribute to vascular calcification seen in PXE. The aim of this study is to evaluate the relation between PXE and plasma lipid concentrations in a large cohort of PXE patients compared with reference values for the general population and compared with non-PXE controls., Methods: - The plasma concentrations of total cholesterol, HDL-cholesterol, tiglycerides, and LDL-cholesterol of 312 PXE patients were compared to age- and sex-matched modeled data of the general Dutch population. Differences in median lipid levels were compared with Mann-Whitney-U test. Secondly, plasma lipid concentrations of 44 PXE patients were compared to 44 not-genetically related relatives (spouses or friends), with linear models adjusted for age, sex and BMI., Results: - Total cholesterol in PXE patients was 5.6 [IQR 4.6-6.4] mmol/L versus 5.3 [IQR 4.7-6.0] mmol/L (p < 0.01) in the general population; triglycerides were 1.1 [IQR 0.9-1.7] mmol/L versus 1.0 [0.7-1.4] mmol/L (p < 0.01); HDL-c was 1.4 [IQR 1.2-1.7] mmol/L versus 1.5 [IQR 1.2-1.8] mmol/L (p = 0.03) and LDL-c was 3.3 [IQR 2.7-4.1] mmol/L versus 3.2 [IQR 2.7-3.8] mmol/L (p = 0.01). In the patient control analysis with 44 pairs and age, sex and BMI adjusted, comparison with the non-PXE controls only triglycerides were significantly different (mean difference: 0.38 (0.13-0.63))., Conclusion: -The lipid profiles of PXE patients are marginally different from the general population or compared to a matched control group, but the differences are unlikely to be clinically relevant . It is therefore unlikely that plasma lipids contribute to the premature vascular calcifications in PXE patients., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Purpose: To evaluate the validity of spot urine assay methods in estimating the 24-h urinary sodium, potassium and sodium-to-potassium ratio during three different sodium diets., Materials and Methods: Twelve healthy volunteers were asked to adhere to 3 dietary sodium targets (3.3-5.0g/day,<3.3 g/day and >5.0 g/day) for three consecutive weeks and to measure salt excretion daily in spot urine samples using a self-monitoring device. On day 7 of each week, 24-h urine was collected to compare measured with estimated 24-h salt excretion (by the Kawasaki, Tanaka and INTERSALT equations)., Results: Correlation coefficients relating measured and estimated 24-h sodium excretion were low and not significant for Kawasaki and INTERSALT and moderate for the Tanaka equation (τ 0.56-0.64, p <.05). Bland-Altman plots showed considerable differences between estimated and measured sodium excretion across all salt diets. Over 40% of the participants showed an absolute difference between measured and estimated 24-h sodium of more than 1000 mg/day. The correlation coefficients between 24-h and spot Na/K ratio were 0.67, 0.94 and 0.85( p <.05), and mean differences were 0.59, 0.06 and 0.48 for the intermediate, low and high sodium diets, respectively., Conclusion: These findings do not support estimation of individual 24-h salt excretion from spot urine by the Kawasaki, Tanaka, or INTERSALT formula. Plain language summaryAccurate monitoring of salt intake is essential to improve BP control. At present, measurement of sodium and potassium excretion in multiple non-consecutive 24-h urinary collections is considered the gold standard for measuring dietary sodium intake. However, this method is burdensome, time-consuming and error prone.Therefore, we assessed and compared the validity of three formula-based approaches to estimate 24-h urinary sodium and potassium excretion and the Na/K ratio from spot urine samples measured by a self-monitoring device under three different sodium diets using 24-h urine collections as the reference.We conclude that use of three commonly used equations that estimate 24-h urinary sodium and potassium excretion result in substantial bias, poor precision and poor accuracy and are therefore not recommended. The Na/K ratio based on multiple casual urine samples may be a useful, low-burden, low-cost alternative method to 24-h urine collection for monitoring daily salt intake.

Aims: Population-wide impacts of new guidelines in the primary prevention of atherosclerotic cardiovascular disease (ASCVD) should be explored in independent cohorts. Assess and compare the lipid-lowering therapy eligibility and predictive classification performance of 2016 and 2021 European Society of Cardiology (ESC), 2019 American Heart Association/American College of Cardiology (AHA/ACC), and 2022 US Preventive Services Task Force (USPSTF) guidelines., Methods and Results: Participants from the CoLaus|PsyCoLaus study, without ASCVD and not taking lipid-lowering therapy at baseline. Derivation of 10-year risk for ASCVD using Systematic COronary Risk Evaluation (SCORE1), SCORE2 [including SCORE2-Older Persons (SCORE2-OP)], and pooled cohort equation. Computation of the number of people eligible for lipid-lowering therapy based on each guideline and assessment of discrimination and calibration metrics of the risk models using first incident ASCVD as an outcome. Among 4,092 individuals, 158 (3.9%) experienced an incident ASCVD during a median follow-up of 9 years (interquartile range, 1.1). Lipid-lowering therapy was recommended or considered in 40.2% (95% confidence interval, 38.2-42.2), 26.4% (24.6-28.2), 28.6% (26.7-30.5), and 22.6% (20.9-24.4) of women and in 62.1% (59.8-64.3), 58.7% (56.4-61.0), 52.6% (50.3-54.9), and 48.4% (46.1-50.7) of men according to the 2016 ESC, 2021 ESC, 2019 AHA/ACC, and 2022 USPSTF guidelines, respectively. 43.3 and 46.7% of women facing an incident ASCVD were not eligible for lipid-lowering therapy at baseline according to the 2021 ESC and 2022 USPSTF, compared with 21.7 and 38.3% using the 2016 ESC and 2019 AHA/ACC, respectively., Conclusion: Both the 2022 USPSTF and 2021 ESC guidelines particularly reduced lipid-lowering therapy eligibility in women. Nearly half of women who faced an incident ASCVD were not eligible for lipid-lowering therapy., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Many models developed for predicting the risk of cardiovascular disease (CVD) are adjusted for the competing risk of non-CVD mortality, which has been suggested to reduce potential overestimation of cumulative incidence in populations where the risk of competing events is high. The objective was to evaluate and illustrate the clinical impact of competing risk adjustment when deriving a CVD prediction model in a high-risk population., Methods and Results: Individuals with established atherosclerotic CVD were included from the Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease (UCC-SMART). In 8355 individuals, followed for a median of 8.2 years (IQR 4.2-12.5), two similar prediction models for the estimation of 10-year residual CVD risk were derived: with competing risk adjustment using a Fine and Gray model and without competing risk adjustment using a Cox proportional hazards model. On average, predictions were higher from the Cox model. The Cox model predictions overestimated the cumulative incidence [predicted-observed ratio 1.14 (95% CI 1.09-1.20)], which was most apparent in the highest risk quartiles and in older persons. Discrimination of both models was similar. When determining treatment eligibility on thresholds of predicted risks, more individuals would be treated based on the Cox model predictions. If, for example, individuals with a predicted risk > 20% were considered eligible for treatment, 34% of the population would be treated according to the Fine and Gray model predictions and 44% according to the Cox model predictions., Interpretation: Individual predictions from the model unadjusted for competing risks were higher, reflecting the different interpretations of both models. For models aiming to accurately predict absolute risks, especially in high-risk populations, competing risk adjustment must be considered., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background We tested the potential of the Secondary Manifestations of Arterial Disease (SMART2) risk score for use in patients undergoing coronary artery bypass grafting. Methods and Results We conducted an external validation of the SMART2 score in a racially diverse high-risk national cohort (2010-2019) that underwent isolated coronary artery bypass grafting. We calculated the preoperative SMART2 score and modeled the 5-year major adverse cardiovascular event (cardiovascular mortality+myocardial infarction+stroke) incidence. We evaluated SMART2 score discrimination at 5 years using c-statistic and calibration with observed/expected ratio and calibration plots. We analyzed the potential clinical benefit using decision curves. We repeated these analyses in clinical subgroups, diabetes, chronic kidney disease, and polyvascular disease, and separately in White and Black patients. In 27 443 (mean age, 65 years; 10% Black individuals) US veterans undergoing coronary artery bypass grafting (2010-2019) nationwide, the 5-year major adverse cardiovascular event rate was 25%; 27% patients were in high predicted risk (>30% 5-year major adverse cardiovascular events). SMART2 score discrimination (c-statistic: 64) was comparable to the original study (c-statistic: 67) and was best in patients with chronic kidney disease (c-statistic: 66). However, it underpredicted major adverse cardiovascular event rates in the whole cohort (observed/expected ratio, 1.45) as well as in all studied subgroups. The SMART2 score performed better in White than Black patients. On decision curve analysis, the SMART2 score provides a net benefit over a wide range of risk thresholds. Conclusions The SMART2 model performs well in a racially diverse coronary artery bypass grafting cohort, with better predictive capabilities at the upper range of baseline risk, and can therefore be used to guide secondary preventive pharmacotherapy.

Background and Aims: Despite lipid lowering therapy (LLT), reaching LDL-C targets in patients with familial hypercholesterolemia (FH) remains challenging. Our aim was to determine attainment of LDL-C target levels and reasons for not reaching these in female and male FH patients., Methods: We performed a cross-sectional study of heterozygous FH patients in five hospitals in the Netherlands and Norway. Clinical characteristics and information about LLT, lipid levels and reasons for not being on LDL-C treatment target were retrospectively collected from electronic medical records., Results: We studied 3178 FH patients (53.9% women), median age 48.0 (IQR 34.0-59.9) years. Median LDL-C before treatment and on-treatment was higher in women compared to men (6.2 (IQR 5.1-7.3) and 6.0 (IQR 4.9-7.2) mmol/l (p=0.005) and 3.0 (IQR 2.4-3.8) and 2.8 (IQR 2.3-3.5) mmol/L (p<0.001)), respectively. A minority of women (26.9%) and men (28.9%) reached LDL-C target. In patients with CVD, 17.2% of women and 25.8% of men reached LDL-C target. Women received less often high-intensity statins and ezetimibe. Most common reported reasons for not achieving the LDL-C target were insufficient effect of maximum LLT (women 17.3%, men 24.3%) and side effects (women 15.2%, men 8.6%)., Conclusions: In routine practice, only a minority of women and men with FH achieved their LDL-C treatment target. Extra efforts have to be made to provide FH patients with reliable information on the safety of statins and their long-term effects on CVD risk reduction. If statin treatment is insufficient, alternative lipid lowering therapies such as ezetimibe or PCSK9-inhibitors should be considered., Competing Interests: Declaration of competing competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: In clinical practice, factors associated with cardiovascular disease (CVD) like albuminuria, education level, or coronary artery calcium (CAC) are often known, but not incorporated in cardiovascular risk prediction models. The aims of the current study were to evaluate a methodology for the flexible addition of risk modifying characteristics on top of SCORE2 and to quantify the added value of several clinically relevant risk modifying characteristics., Methods and Results: Individuals without previous CVD or DM were included from the UK Biobank; Atherosclerosis Risk in Communities (ARIC); Multi-Ethnic Study of Atherosclerosis (MESA); European Prospective Investigation into Cancer, The Netherlands (EPIC-NL); and Heinz Nixdorf Recall (HNR) studies (n = 409 757) in whom 16 166 CVD events and 19 149 non-cardiovascular deaths were observed over exactly 10.0 years of follow-up. The effect of each possible risk modifying characteristic was derived using competing risk-adjusted Fine and Gray models. The risk modifying characteristics were applied to individual predictions with a flexible method using the population prevalence and the subdistribution hazard ratio (SHR) of the relevant predictor. Risk modifying characteristics that increased discrimination most were CAC percentile with 0.0198 [95% confidence interval (CI) 0.0115; 0.0281] and hs-Troponin-T with 0.0100 (95% CI 0.0063; 0.0137). External validation was performed in the Clinical Practice Research Datalink (CPRD) cohort (UK, n = 518 015, 12 675 CVD events). Adjustment of SCORE2-predicted risks with both single and multiple risk modifiers did not negatively affect calibration and led to a modest increase in discrimination [0.740 (95% CI 0.736-0.745) vs. unimproved SCORE2 risk C-index 0.737 (95% CI 0.732-0.741)]., Conclusion: The current paper presents a method on how to integrate possible risk modifying characteristics that are not included in existing CVD risk models for the prediction of CVD event risk in apparently healthy people. This flexible methodology improves the accuracy of predicted risks and increases applicability of prediction models for individuals with additional risk known modifiers., Competing Interests: Conflict of interest: Dr. Matsushita received funding from the National Institutes of Health during the study and personal fees from Fukuda Denshi, Kowa Company, and the American Medical Group Association outside of the submitted work. L.P. is funded by a BHF Programme Grant (RG/18/13/33946) S.K. is funded by a BHF Chair award (CH/12/2/29428)., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Importance: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US., Objective: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes., Design, Setting, and Participants: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021., Exposures: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR)., Main Outcomes and Measures: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses., Results: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years])., Conclusions and Relevance: In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.

Aims: Current guidelines recommend measuring carotid intima-media thickness (IMT) at the far wall of the common carotid artery (CCA). We aimed to precisely quantify associations of near vs. far wall CCA-IMT with the risk for atherosclerotic cardiovascular disease (CVD, defined as coronary heart disease or stroke) and their added predictive values., Methods and Results: We analysed individual records of 41 941 participants from 16 prospective studies in the Proof-ATHERO consortium {mean age 61 years [standard deviation (SD) = 11]; 53% female; 16% prior CVD}. Mean baseline values of near and far wall CCA-IMT were 0.83 (SD = 0.28) and 0.82 (SD = 0.27) mm, differed by a mean of 0.02 mm (95% limits of agreement: -0.40 to 0.43), and were moderately correlated [ r = 0.44; 95% confidence interval (CI): 0.39-0.49). Over a median follow-up of 9.3 years, we recorded 10 423 CVD events. We pooled study-specific hazard ratios for CVD using random-effects meta-analysis. Near and far wall CCA-IMT values were approximately linearly associated with CVD risk. The respective hazard ratios per SD higher value were 1.18 (95% CI: 1.14-1.22; I ² = 30.7%) and 1.20 (1.18-1.23; I ² = 5.3%) when adjusted for age, sex, and prior CVD and 1.09 (1.07-1.12; I ² = 8.4%) and 1.14 (1.12-1.16; I ²=1.3%) upon multivariable adjustment (all P < 0.001). Assessing CCA-IMT at both walls provided a greater C-index improvement than assessing CCA-IMT at one wall only [+0.0046 vs. +0.0023 for near ( P < 0.001), +0.0037 for far wall ( P = 0.006)]., Conclusions: The associations of near and far wall CCA-IMT with incident CVD were positive, approximately linear, and similarly strong. Improvement in risk discrimination was highest when CCA-IMT was measured at both walls., Competing Interests: Conflict of interest: M.J.S. is a full-time employee of AstraZeneca. The other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibodies (mAbs) reduce fasting and post fat load cholesterol in non-HDL and intermediate density lipoprotein (IDL) in familial dysbetalipoproteinemia (FD). However, the effect of PCSK9 mAbs on the distribution and composition of atherogenic lipoproteins in patients with FD is unknown., Objective: To evaluate the effect of the PCSK9 mAb evolocumab added to standard lipid-lowering therapy in patients with FD on fasting and post fat load lipoprotein distribution and composition., Methods: Randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. Patients received an oral fat load at the start and end of each treatment period. Apolipoproteins (apo) were measured with ultracentrifugation, gradient gel electrophoresis, retinyl palmitate and SDS-PAGE., Results: PCSK9 mAbs significantly reduced particle number of all atherogenic lipoproteins, with a stronger effect on smaller lipoproteins than on larger lipoproteins (e.g. IDL-apoB 49%, 95%confidence interval (CI) 41-59 and very low-density lipoprotein (VLDL)-apoB 33%, 95%CI 16-50). Furthermore, PCSK9 mAbs lowered cholesterol more than triglyceride (TG) in VLDL, IDL and low-density lipoprotein (LDL) (e.g. VLDL-C 48%, 95%CI 29-63%; and VLDL-TG 20%, 95%CI 6.3-41%). PCSK9 mAbs did not affect the post fat load response of chylomicrons., Conclusion: PCSK9 mAbs added to standard lipid-lowering therapy in FD patients significantly reduced lipoprotein particle number, in particular the smaller and more cholesterol-rich lipoproteins (i.e. IDL and LDL). PCSK9 mAbs did not affect chylomicron metabolism. It seems likely that the observed effects are achieved by increased hepatic lipoprotein clearance, but the specific working mechanism of PCSK9 mAbs in FD patients remains to be elucidated., Competing Interests: Declaration of Competing Interest BEH declares no conflicts of interest ADM declares no conflict of interest MM declares no conflicts of interest FV declares no conflict of interest JRvL has received a research grant by Amryt Ad-board speaker fees have been paid to institution of ES by: Amgen, Sanofi, Esperion, Novo-Nordisk, Akcea/Ionis, Regeneron NR declares no conflict of interest LvZ declares no conflicts of interest DMB declares no conflict of interest CK declares no conflicts of interest, (Copyright © 2023. Published by Elsevier Inc.)

Objective: To determine the role of waist circumference and metabolic dysfunction in the risk of cancer in individuals with type 2 diabetes (T2D) and to compare this to individuals without T2D., Methods: Individuals with (n = 1925) and without T2D (n = 10,204) were included from the UCC-SMART cohort. Incident cancer diagnoses were obtained by linkage with the Netherlands Cancer Registry. Metabolic dysfunction was defined as ≥ 3 adapted NCEP ATP-III metabolic syndrome criteria. The effects of waist circumference and metabolic dysfunction on cancer were assessed using Cox proportional hazards models, adjusted for confounders., Results: During a median follow-up of 8.3 years (IQR 4.2-13.1), 1740 individuals were diagnosed with cancer. Incidence rates of total cancer were 19.3 and 15.5/1000 person-years for individuals with and without T2D, respectively. In individuals without T2D, a higher waist circumference was associated with an increased risk of colorectal (per standard deviation: HR 1.23; 95%CI 1.03-1.46), urinary tract (HR 1.28; 95%CI 1.05-1.56) and total cancer (HR 1.06; 95%CI 1.02-1.13). Metabolic dysfunction was related to an increased risk of colorectal (HR 1.35; 95%CI 1.01-1.82), lung (HR 1.37; 95%CI 1.07-1.75) and total cancer (HR 1.13; 95%CI 1.01-1.25) in individuals without T2D. In individuals with T2D, no significant associations were found., Conclusion: Incidence rates of cancer are higher among individuals with T2D. However, higher waist circumference and metabolic dysfunction are only associated with an increased cancer risk in patients without T2D. These findings provide novel insights into the role of metabolic dysfunction in the occurrence of cancer., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest. The UCC-SMART study was financially supported by a grant of the University Medical Center Utrecht, the Netherlands. The supporting sources had no involvement in study design, analysis, interpretation, writing of the results, or the decision to submit for publication., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.)