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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.

Background: We hypothesize that Alzheimer's disease (AD)-related pathology may accelerate cognitive decline in patients with cardiovascular diseases., Objective: To investigate the association between blood-based biomarkers of AD, astrocyte activation, and neurodegeneration and cognitive decline., Methods: From the multi-center Heart-Brain study, we included 412 patients with heart failure, carotid occlusive disease or vascular cognitive impairment (age:68.6±9.0) and 128 reference participants (65.7±7.5). Baseline amyloid-β42/40 (Aβ42/40), phosphorylated-tau181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were determined using SiMoA (Quanterix). Memory, attention, language, and executive functioning were evaluated (follow-up:2.1±0.3 years). We applied linear mixed models with terms for biomarker, time and biomarker*time interactions, adjusted for age, sex, education, and site, to assess associations between biomarkers and cognitive decline., Results: Among patients, Aβ42/40 was not associated with cognitive performance at baseline. However, lower Aβ42/40 was associated with steeper decline in global cognition (β±SE:0.04±0.02). Higher pTau181 was associated with worse baseline performance on global cognition (-0.14±0.04) and memory (-0.31±0.09) and with steeper decline in global cognition (-0.07±0.02), memory (-0.09±0.04), attention (-0.05±0.02), and language (-0.10±0.03). Higher GFAP was associated with worse baseline performance on global cognition (-0.22±0.05), memory (-0.43±0.10), attention (-0.14±0.06), language (-0.15±0.05), and executive functioning (-0.15±0.05) and steeper decline in global cognition (-0.05±0.01). Higher NfL was associated with worse baseline performance on global cognition (-0.16±0.04), memory (-0.28±0.09), attention (-0.20±0.06), and executive functioning (-0.10±0.04), but was not associated with performance over time. In reference participants, no associations were found., Conclusions: Our findings suggest that blood-based biomarkers of AD-related pathology predict cognitive decline in patients with cardiovascular diseases.

Biological processes underlying decreased cerebral blood flow (CBF) in patients with cardiovascular disease (CVD) are largely unknown. We hypothesized that identification of protein clusters associated with lower CBF in patients with CVD may explain underlying processes. In 428 participants (74% cardiovascular diseases; 26% reference participants) from the Heart-Brain Connection Study, we assessed the relationship between 92 plasma proteins from the Olink® cardiovascular III panel and normal-appearing grey matter CBF, using affinity propagation and hierarchical clustering algorithms, and generated a Biomarker Compound Score (BCS). The BCS was related to cardiovascular risk and observed cardiovascular events within 2-year follow-up using Spearman correlation and logistic regression. Thirteen proteins were associated with CBF (ρ Spearman range: -0.10 to -0.19, p FDR-corrected <0.05), and formed one cluster. The cluster primarily reflected extracellular matrix organization processes. The BCS was higher in patients with CVD compared to reference participants (p FDR-corrected <0.05) and was associated with cardiovascular risk (ρ Spearman 0.42, p < 0.001) and cardiovascular events (OR 2.05, p < 0.01). In conclusion, we identified a cluster of plasma proteins related to CBF, reflecting extracellular matrix organization processes, that is also related to future cardiovascular events in patients with CVD, representing potential targets to preserve CBF and mitigate cardiovascular risk in patients with CVD., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: The Utrecht Cardiovascular Cohort-Second Manifestations of Arterial Disease (UCC-SMART) Study is an ongoing prospective single-centre cohort study with the aim to assess important determinants and the prognosis of cardiovascular disease progression. This article provides an update of the rationale, design, included patients, measurements and findings from the start in 1996 to date., Participants: The UCC-SMART Study includes patients aged 18-90 years referred to the University Medical Center Utrecht, the Netherlands, for management of cardiovascular disease (CVD) or severe cardiovascular risk factors. Since September 1996, a total of 14 830 patients have been included. Upon inclusion, patients undergo a standardised screening programme, including questionnaires, vital signs, laboratory measurements, an ECG, vascular ultrasound of carotid arteries and aorta, ankle-brachial index and ultrasound measurements of adipose tissue, kidney size and intima-media thickness. Outcomes of interest are collected through annual questionnaires and adjudicated by an endpoint committee., Findings to Date: By May 2022, the included patients contributed to a total follow-up time of over 134 000 person-years. During follow-up, 2259 patients suffered a vascular endpoint (including non-fatal myocardial infarction, non-fatal stroke and vascular death) and 2794 all-cause deaths, 943 incident cases of diabetes and 2139 incident cases of cancer were observed up until January 2020. The UCC-SMART cohort contributed to over 350 articles published in peer-reviewed journals, including prediction models recommended by the 2021 European Society of Cardiology CVD prevention guidelines., Future Plans: The UCC-SMART Study guarantees an infrastructure for research in patients at high cardiovascular risk. The cohort will continue to include about 600 patients yearly and follow-up will be ongoing to ensure an up-to-date cohort in accordance with current healthcare and scientific knowledge. In the near future, UCC-SMART will be enriched by echocardiography, and a food frequency questionnaire at baseline enabling the assessment of associations between nutrition and CVD and diabetes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients with cardiovascular disease (CVD) are at higher risk of kidney function decline. The current study aimed to examine the association of lifestyle changes with kidney function decline in patients with manifest CVD., Methods: A total of 2260 patients from the Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease cohort with manifest CVD who returned for a follow-up visit after a median of 9.9 years were included. The relation between change in lifestyle factors (smoking, alcohol consumption, physical activity and obesity) and change in kidney function (eGFR and uACR) was assessed using linear regression models., Results: An increase in body mass index (β -2.81; 95% CI -3.98; -1.63 per 5 kg/m 2 ) and for men also an increase in waist circumference (β -0.87; 95% CI -1.28; -0.47 per 5 cm) were significantly associated with a steeper decline in eGFR over 10 years. Continuing smoking (β -2.44, 95% CI -4.43; -0.45) and recent smoking cessation during follow-up (β -3.27; 95% CI -5.20; -1.34) were both associated with a steeper eGFR decline compared to patients who remained as non- or previous smokers from baseline. No significant association was observed between physical exercise or alcohol consumption and kidney function decline. No significant relation between any lifestyle factor and change in uACR was observed., Conclusions: In patients with CVD, continuing smoking, recent smoking cessation and an increase in obesity markers were related to a steeper kidney function decline. Although no definite conclusions from this study can be drawn, the results support the importance of encouraging weight loss and smoking cessation in high-risk patients as a means of slowing down kidney function decline., (© 2022 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

The population of elderly with cardiovascular diseases and multimorbidity is rapidly growing. For decades, different antithrombotic therapies have been studied to find the most effective therapy in reducing the risk of cardiovascular events. Recently, large trials have investigated a new antithrombotic therapy consisting of a platelet aggregation inhibitor and a low-dose anticoagulant (aspirin plus rivaroxaban). This combination inhibits both primary and secondary haemostasis, and is therefore called 'dual pathway inhibition' (DPI). DPI leads to a further reduction of the risk of ischemic cardiovascular events as compared to aspirin monotherapy, but increases the risk of bleeding. The population at high risk of ischemic events, but without an increased bleeding risk, is expected to experience the highest risk reduction and therefore the highest net clinical benefit of DPI. This population consists of patients with polyvascular disease, heart failure, renal insufficiency, diabetes mellitus and other uncontrolled risk factors.

Background: Patients with cardiovascular disease (CVD) are at increased risk of end-stage kidney disease (ESKD). Insights into the incidence and role of modifiable risk factors for end-stage kidney disease may provide means for prevention in patients with cardiovascular disease., Methods: We included 8402 patients with stable cardiovascular disease. Incidence rates (IRs) for end-stage kidney disease were determined stratified according to vascular disease location. Cox proportional hazard models were used to assess the risk of end-stage kidney disease for the different determinants., Results: Sixty-five events were observed with a median follow-up of 8.6 years. The overall incidence rate of end-stage kidney disease was 0.9/1000 person-years. Patients with polyvascular disease had the highest incidence rate (1.8/1000 person-years). Smoking (Hazard ratio (HR) 1.87; 95% CI 1.10-3.19), type 2 diabetes (HR 1.81; 95% CI 1.05-3.14), higher systolic blood pressure (HR 1.37; 95% CI 1.24-1.52/10 mmHg), lower estimated glomerular filtration rate (eGFR) (HR 2.86; 95% CI 2.44-3.23/10 mL/min/1.73 m 2 ) and higher urine albumin/creatinine ratio (uACR) (HR 1.19; 95% CI 1.15-1.23/10 mg/mmol) were independently associated with elevated risk of end-stage kidney disease. Body mass index (BMI), waist circumference, non-HDL-cholesterol and exercise were not independently associated with risk of end-stage kidney disease., Conclusions: Incidence of end-stage kidney disease in patients with cardiovascular disease varies according to vascular disease location. Several modifiable risk factors for end-stage kidney disease were identified in patients with cardiovascular disease. These findings highlight the potential of risk factor management in patients with manifest cardiovascular disease., (© 2021. The Author(s).)

Background: Recent treatment guidelines support the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes and cardiovascular disease based on the results of cardiovascular outcome trials (CVOTs). Applicability of these trials to everyday patients with type 2 diabetes and cardiovascular disease is however unknown. The aim of this study is to assess the external applicability of SGLT2i CVOTs in daily clinical practice type 2 diabetes patients with established cardiovascular disease., Methods: Trial in- and exclusion criteria from EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58 and VERTIS-CV were applied to 1389 type 2 diabetes patients with cardiovascular disease in the Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease (UCC-SMART). To evaluate the difference in cardiovascular risk (MACE) and all-cause mortality between trial eligible and ineligible patients, age and sex-adjusted Cox-regression analyses were performed., Results: After applying trial in- and exclusion criteria, 48% of UCC-SMART patients with type 2 diabetes and cardiovascular disease would have been eligible for DECLARE-TIMI 58, 35% for CANVAS, 29% for EMPA-REG OUTCOME and 21% for VERTIS-CV. Without the eligibility criteria of HbA 1c , eligibility was 58-88%. For all trials the observed risk for cardiovascular events and all-cause mortality was similar in eligible and ineligible patients after adjustment for age and gender., Conclusion: A large proportion of patients with type 2 diabetes and cardiovascular disease in daily clinical practice would have been eligible for participation in the SGLT2i CVOTs. Trial eligible and ineligible patients have the same risk for MACE and all-cause mortality., (© 2021. The Author(s).)

Aim: To quantify the relation between apparent treatment resistant hypertension (aTRH) and the risk of recurrent major adverse cardiovascular events (MACE including stroke, myocardial infarction and vascular death) and mortality in patients with stable vascular disease., Methods: 7455 hypertensive patients with symptomatic vascular disease were included from the ongoing UCC-SMART cohort between 1996 and 2019. aTRH was defined as an office blood pressure ≥140/90 mmHg despite treatment with ≥3 antihypertensive drugs including a diuretic. Cox proportional hazard models were used to quantify the relation between aTRH and the risk of recurrent MACE and all-cause mortality. In addition, survival for patients with aTRH was assessed, taking competing risk of non-vascular mortality into account., Results: A total of 1557 MACE and 1882 deaths occurred during a median follow-up of 9.0 years (interquartile range 4.8-13.1 years). Compared to patients with non-aTRH, the 614 patients (8%) with aTRH were at increased risk of cardiovascular mortality (HR 1.27; 95% CI 1.03-1.56) and death from any cause (HR 1.25; 95% CI 1.07-1.45) but not recurrent MACE (HR 1.13; 95% CI 0.95-1.34). At the age of 50 years, patients with aTRH after a first cardiovascular event on average had a 6.4 year shorter median life expectancy free of recurrent MACE than patients with non-aTRH., Conclusion: In hypertensive patients with clinically manifest vascular disease, aTRH is related to a higher risk of vascular death and death from any cause. Moreover, patients with aTRH after a first cardiovascular event have a 6.4 year shorter median life expectancy free of recurrent cardiovascular disease., Competing Interests: Conflicts of interest Folkert Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. The other authors report no conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Objective: Cerebral white matter lesions (WMLs) and lacunar infarcts are surrogates of cerebral small vessel disease (SVD). WML severity as determined by trained radiologists predicts post-operative stroke or death in patients undergoing carotid endarterectomy (CEA). It is unknown whether routine pre-operative brain imaging reports as part of standard clinical practice also predict short and long term risk of stroke and death after CEA., Methods: Consecutive patients from the Athero-Express biobank study that underwent CEA for symptomatic high degree stenosis between March 2002 and November 2014 were included. Pre-operative brain imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) reports were reviewed for reporting of SVD, defined as WMLs or any lacunar infarcts. The primary outcome was defined as any stroke or any cardiovascular death over three year follow up. The secondary outcome was defined as the 30 day peri-operative risk of stroke or cardiovascular death., Results: A total of 1038 patients were included (34% women), of whom 659 (63.5%) had CT images and 379 (36.5%) MRI images available. Of all patients, 697 (67%) had SVD reported by radiologists. Patients with SVD had a higher three year risk of cardiovascular death than those without (6.5% vs. 2.1%, adjusted HR 2.52 [95% CI 1.12-5.67]; p = .026) but no association was observed for the three year risk of stroke (9.0% vs. 6.7%, for patients with SVD vs. those without, adjusted HR 1.24 [95% CI 0.76-2.02]; p = .395). No differences in 30 day peri-operative risk were observed for stroke (4.4% vs. 2.9%, for patients with vs. those without SVD; adjusted HR 1.49 [95% CI 0.73-3.05]; p = .28), and for the combined stroke/cardiovascular death risk (4.4% vs. 3.5%, adjusted HR 1.20 [95% CI 0.61-2.35]; p = .59)., Conclusion: Presence of SVD in pre-operative brain imaging reports can serve as a predictor for the three year risk of cardiovascular death in symptomatic patients undergoing CEA but does not predict peri-operative or long term risk of stroke., (Copyright © 2020 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Aims: To quantify the relation between smoking cessation after a first cardiovascular (CV) event and risk of recurrent CV events and mortality., Methods: Data were available from 4,673 patients aged 61 ± 8.7 years, with a recent (≤1 year) first manifestation of arterial disease participating in the SMART-cohort. Cox models were used to quantify the relation between smoking status and risk of recurrent major atherosclerotic cardiovascular events (MACE including stroke, MI and vascular mortality) and mortality. In addition, survival according to smoking status was plotted, taking competing risk of non-vascular mortality into account., Results: A third of the smokers stopped after their first CV event. During a median of 7.4 (3.7-10.8) years of follow-up, 794 patients died and 692 MACE occurred. Compared to patients who continued to smoke, patients who quit had a lower risk of recurrent MACE (adjusted HR 0.66, 95% CI 0.49-0.88) and all-cause mortality (adjusted HR 0.63, 95% CI 0.48-0.82). Patients who reported smoking cessation on average lived 5 life years longer and recurrent MACE occurred 10 years later. In patients with a first CV event >70 years, cessation of smoking had improved survival which on average was comparable to former or never smokers., Conclusions: Irrespective of age at first CV event, cessation of smoking after a first CV event is related to a substantial lower risk of recurrent vascular events and all-cause mortality. Since smoking cessation is more effective in reducing CV risk than any pharmaceutical treatment of major risk factors, it should be a key objective for patients with vascular disease., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: To quantify the decline in recurrent major cardiovascular events (MCVE) risk in patients with clinically manifest vascular disease between 1996 and 2014 and to assess whether the improvements in recurrent MCVE-risk can be explained by reduced prevalence of risk factors, more medication use and less subclinical atherosclerosis., Methods and Results: The study was conducted in the Second Manifestations of ARTerial disease (SMART) cohort in patients entering the cohort in the period 1996-2014. The prevalence of risk factors and subclinical atherosclerosis was measured at baseline. Incidence rates per 100person-years for recurrent MCVE (including stroke, myocardial infarction, retinal bleeding, retinal infarction, terminal heart failure, sudden death, fatal rupture of abdominal aneurysm) were calculated, stratified by the year of study enrolment. For the attributable risk of changes in risk factors, risk factor treatment, and subclinical atherosclerosis on the incidence rates of recurrent MCVE, adjusted rate ratios were estimated with Poisson regression. 7216 patients had a median follow-up of 6.5years (IQR 3.4-9.9). The crude incidence of recurrent MCVE declined by 53% between 1996 and 2014 (from 3.68 to 1.73 events per 100person-years) and by 75% adjusted for age and sex. This improvement in vascular prognosis was 36% explained by changes in risk factors, medication use and subclinical atherosclerosis., Conclusion: The risk of recurrent MCVE in patients with clinically manifest vascular disease has strongly declined in the period between 1996 and 2014. This is only partly attributable to lower prevalence of risk factors, improved medication use and less subclinical atherosclerosis., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Diabetes mellitus is associated with an increased risk for cardiovascular morbidity and mortality. The vascular burden in terms of incidence of cardiovascular events (CVE) and vascular interventions is however poorly quantified. In this study we evaluated the incidence rates of CVE and vascular interventions in patients with type 2 diabetes (T2DM) with and without cardiovascular disease (CVD) in comparison to patients without type 2 diabetes., Research Design and Methods: In a cohort of 9.808 high-risk patients with and without cardiovascular disease and type 2 diabetes originated from the ongoing, single-center prospective SMART (Second Manifestations of ARTerial disease) cohort, the number and incidence rates of CVE and interventions were calculated. The incidence rates were adjusted for confounders using Poisson regression models. CVE were defined as vascular death, stroke and myocardial infarction (MI). Interventions were defined as percutaneous coronary intervention, coronary artery bypass grafting, percutaneous transluminal angioplasty or stenting of the peripheral arteries and amputation., Results: Patients with T2DM and CVD had a 4-fold higher incidence rate of CVE and a 8-fold higher incidence rate of vascular interventions compared to high-risk patients without T2DM and CVD after adjusting for confounders. The incidence rate for the composite of non-fatal MI, non-fatal stroke and vascular death was 5.8 per 1000person-years in patients without T2DM or CVD at baseline, 15.2 per 1000person-years in patients with T2DM but without CVD at baseline, 26.0 per 1000person-years in patients without T2DM but with CVD and 40.7 per 1000person-years in patients with both T2DM and CVD at baseline. A similar increasing incidence rate was seen for all vascular interventions from patients without T2DM or CVD to patients with both T2DM and CVD., Conclusions: Patients with type 2 diabetes or CVD are subject to an increased incidence of cardiovascular events and interventions compared to high-risk patients without type 2 diabetes or vascular disease. Patients with type 2 diabetes and CVD have the highest incidence of new cardiovascular diseases and vascular interventions when compared to patients without type 2 diabetes and CVD. These results underline the need for optimal risk factor treatment as well as the need for new prevention and treatment strategies in this very high risk population., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims: To validate and assess performance of the current ACC/AHA very high risk criteria in patients with clinically manifest arterial disease., Methods and Results: Data were used from the SMART study (n = 7216) and REACH Registry (n = 48 322), two prospective cohorts of patients with manifest atherosclerotic arterial disease. Prevalence and incidence rates of recurrent major adverse cardiovascular events (MACE) were calculated, according to the ACC/AHA VHR criteria (cardiovascular disease combined with diabetes, smoking, dyslipidaemia, and/or recent recurrent coronary events). Performance of the ACC/AHA criteria was compared with single very high risk factors in terms of C-statistics and Net Reclassification Index. All patients were at VHR according to the ESC guidelines (incidence of recurrent MACE in SMART was 2.4/100PY, with 95% CI 2.3-2.5/100PY and in REACH 5.1/100PY with 95% CI 5.0-5.3/100PY). In SMART 57% of the patients were at VHR according to the ACC/AHA criteria (incidence of recurrent MACE 2.7/100PY, 95% CI 2.5-2.9/100PY) and in REACH this was 64% (5.9/100PY, 95% CI 5.7-6.1/100PY). The C-statistic for the ACC/AHA VHR criteria was 0.53 in REACH and 0.54 in SMART. Very high risk factors with comparable or slightly better performance were eGFR < 45, polyvascular disease and age >70 years. Around two third of the patients meeting the ACC/AHA VHR criteria had a predicted 10-year risk of recurrent MACE <30%., Conclusion: The ACC/AHA VHR criteria have limited discriminative power. Identifying patients with clinically manifest arterial disease at VHR for recurrent vascular events using eGFR <45, polyvascular disease, or age >70 years performs as well as the ACC/AHA VHR criteria., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Background: Inter-arm systolic blood pressure difference (SBPD) is an easily obtained patient characteristic which relates to vascular disease. We aimed to identify determinants of large inter-arm SBPD and to investigate the relation between inter-arm SBPD and vascular events in patients with and without manifest vascular disease., Methods: In a cohort of 7344 patients with manifest vascular disease or vascular risk factors alone enrolled in the Second Manifestations of ARTerial disease (SMART) study, single bilateral non-simultaneous blood pressure measurements were performed. Logistic and Cox regression was used to identify determinants of large inter-arm SBPD (≥15mmHg) and to investigate the relation between inter-arm SBPD and vascular events (composite of non-fatal myocardial infarction, stroke, and vascular mortality) and all-cause mortality., Results: In all patients the median inter-arm SBPD was 7mmHg (IQR 3-11) and 1182 (16%) patients had inter-arm SBPD ≥15mmHg. Higher age, higher systolic blood pressure, diabetes mellitus, peripheral artery disease, carotid artery stenosis, higher carotid intima-media thickness, and lower ankle-brachial indices were related to large inter-arm SBPD (≥15mmHg). Each 5mmHg increase in inter-arm SBPD was related to a 12% higher risk of vascular events in patients without manifest vascular disease (HR 1.12; 95% CI 1.00-1.27), whereas no relation was apparent in patients with manifest vascular disease (HR 0.98; 95% CI 0.93-1.04, interaction p-value 0.036). Inter-arm SBPD was not related to all-cause mortality (HR 1.05; 95% CI 0.93-1.19)., Conclusions: Inter-arm SBPD relates to a higher risk of vascular events in patients without manifest vascular disease, whereas this relation is not apparent in patients with manifest vascular disease., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The aim of this study was to quantify the relation between classical risk factors (smoking, diabetes, BMI, waist circumference, blood pressure, and lipids), risk factor targets, and risk of recurrent major atherosclerotic cardiovascular events (MACE). This was first done for recurrent MACE ≤65 years in patients aged <60 years and second for recurrent MACE ≤2.5 years after a first cardiovascular event. Data were used from the Second Manifestations of Arterial Disease study (n = 5,115), a prospective cohort of patients with a recent (≤1 year) first cardiovascular event. During follow-up, 746 recurrent MACE occurred. Smoking (hazard ratio [HR] 1.43, 95% CI 1.11 to 1.84), diabetes (HR 1.83, 95% CI 1.11 to 1.84), diastolic blood pressure (>90 vs 70 to 90 mm Hg, HR 1.54, 95% CI 1.15 to 2.07), and high-density lipoprotein cholesterol (≤1.0 vs >1.0 mmol/L, HR 1.34, 95% CI 1.03 to 1.76) were related to increased risk of recurrent MACE ≤65 years in patients aged <60 years. Smoking (HR 1.65, 95% CI 1.23 to 2.22), physical inactivity (highest vs lowest tertile, HR 1.48, 95% CI 1.05 to 2.09), body mass index (per kg/m 2 , HR 1.04, 95% CI 1.00 to 1.08), diastolic blood pressure (>90 vs 70 to 90 mm Hg, HR 1.61, 95% CI 1.17 to 2.21), low-density lipoprotein cholesterol (per mmol/L, HR 1.18, 95% CI 1.02 to 1.37), and non-high-density lipoprotein cholesterol (per mmol/L, HR 1.15, 95% CI 1.03 to 1.28) were related to recurrent MACE ≤2.5 years of follow-up. In conclusion, in patients with a recent cardiovascular event, smoking, blood pressure, and lipids are related to increased risk of recurrent cardiovascular events at young age or within a short time span, and intensive treatment of modifiable risk factors may contribute to prevent recurrent MACE in these patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Cerebral perivascular spaces (PVS) are small physiological structures around blood vessels in the brain. MRI visible PVS are associated with ageing and cerebral small vessel disease (SVD). 7 Tesla (7T) MRI improves PVS detection. We investigated the association of age, vascular risk factors, and imaging markers of SVD with PVS counts on 7 T MRI, in 50 persons aged ≥ 40. The average PVS count ± SD in the right hemisphere was 17 ± 6 in the basal ganglia and 71 ± 28 in the semioval centre. We observed no relation between age or vascular risk factors and PVS counts. The presence of microbleeds was related to more PVS in the basal ganglia (standardized beta 0.32; p = 0.04) and semioval centre (standardized beta 0.39; p = 0.01), and white matter hyperintensity volume to more PVS in the basal ganglia (standardized beta 0.41; p = 0.02). We conclude that PVS counts on 7T MRI are high and are related SVD markers, but not to age and vascular risk factors. This latter finding may indicate that due to the high sensitivity of 7T MRI, the correlation of PVS counts with age or vascular risk factors may be attenuated by the detection of "normal", non-pathological PVS., (© The Author(s) 2016.)

Low-density lipoprotein cholesterol (LDL-C) only partly represents the atherogenic lipid burden, and a growing body of evidence suggests that non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides, and apolipoprotein B (apoB) are more accurate in estimating lipid-related cardiovascular disease risk. Our objective was to compare the relation among LDL-C, non-HDL-C, triglycerides, and apoB and the occurrence of future vascular events and mortality in patients with manifest arterial disease. This is a prospective cohort study of 7,216 patients with clinically manifest arterial disease in the Secondary Manifestations of Arterial Disease Study. Cox proportional hazard models were used to quantify the risk of major cardiovascular events (MACE; i.e., stroke, myocardial infarction, and vascular mortality) and all-cause mortality. Interaction was tested for type of vascular disease at inclusion. MACE occurred in 1,185 subjects during a median follow-up of 6.5 years (interquartile range 3.4 to 9.9 years). Adjusted hazard ratios (HRs) of MACE per 1 SD higher were for LDL-C (HR 1.15, 95% confidence interval [CI] 1.09 to 1.22), for non-HDL-C (HR 1.17, 95% CI 1.11 to 1.23), for log(triglycerides) (HR 1.12, 95% CI 1.06 to 1.19), and for apoB HR (1.12, 95% CI 0.99 to 1.28). The relation among LDL-C, non-HDL-C, and cardiovascular events was comparable in patients with cerebrovascular disease, coronary artery disease, or polyvascular disease and absent in those with aneurysm of abdominal aorta or peripheral artery disease. In conclusion, in patients with a history of cerebrovascular, coronary artery, or polyvascular disease, but not aneurysm of abdominal aorta or peripheral artery disease, higher levels of LDL-C and non-HDL-C are related to increased risk of future MACE and of comparable magnitude., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To investigate the development of vascular risk factor levels at four points over 15 years in relation to late-life cognitive functioning., Design: Longitudinal population-based study., Setting: The Hoorn Study, a community-based cohort study of glucose metabolism and cardiovascular risk., Participants: Three hundred eighty individuals without dementia (mean baseline age 57.7 ± 5.5)., Measurements: Four extensive medical examinations were conducted over 15 years. Cognition was assessed in detail at the fourth examination. The time course of vascular risk factors across the examinations was compared between individuals in the highest tertile (good performance) and those in the lowest tertile (poor performance) of cognitive functioning on three cognitive domains (memory, information processing speed, and attention and executive functioning (A&EF))., Results: Individuals with poor information processing speed had higher levels of systolic blood pressure at baseline (mean difference (standard error) 11.6 (2.6) mmHg, P < .001) than those with good information processing speed. Individuals with poor A&EF had a higher waist:hip ratio (3.03 (1.15), P = .009), glycosylated hemoglobin (0.29% (0.10%), P = .005) and total cholesterol:high-density lipoprotein cholesterol ratio (0.38 (0.19), P = .04) at baseline than individuals with good A&EF, although the differences in vascular risk factor levels between the poor and good cognition group diminished with increasing age., Conclusion: High blood pressure, adiposity, hypercholesterolemia, and hyperglycemia at midlife are associated with late-life cognitive dysfunction, but for most risk factors, this relationship gradually attenuates with increasing age. These results suggest that timing of vascular treatment strategies to prevent cognitive impairment is critical., (© 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.)

Background: The metabolic syndrome (MetS) is associated with cognitive deficits and atherosclerotic vascular disease. We examined whether the relation between the MetS and cognitive dysfunction is mediated by measures of atherosclerosis or the presence of clinically manifest cardiovascular disease., Methods: In 380 individuals (153 with MetS; 60-87 years) from the population based Hoorn Study, measures of atherosclerosis including carotid intima-media thickness (c-IMT), flow mediated dilation (FMD), ankle-brachial index and the presence of clinically manifest cardiovascular disease were assessed at baseline and 7 later years at follow-up. Cognitive functioning (information processing speed, memory, and attention and executive functioning) was assessed at follow-up. The relation between the MetS, atherosclerosis and cognitive functioning was assessed with linear regression analysis., Results: Individuals with MetS showed worse performance on information processing speed (adjusted mean difference z-score ± SE: -0.22 ± 0.6; p = 0.01) and attention and executive functioning (-0.32 ± 0.07; p < 0.001), but not on the domain memory. The affected cognitive domains were also associated with measures of atherosclerosis (standardised B (95%CI) c-IMT: -0.14 (-0.24; -0.05); p < 0.01; FMD: 0.13 (0.02; 0.24), p < 0.05) and a history of clinically manifest cardiovascular disease: (-0.29 (-0.47; -0.11); p < 0.01). However, the relation between the MetS and cognitive functioning did not change after adjustment for c-IMT, FMD or a history of clinically manifest cardiovascular disease (p > 0.05)., Conclusion: In this population based cohort, the relation between the MetS and cognitive dysfunction was not mediated by atherosclerosis or a history of cardiovascular disease. These findings should stimulate future studies to elucidate alternative mechanisms underlying cognitive deficits in individuals with MetS., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Aims: Atherosclerosis causes coronary artery disease (CAD), cerebrovascular disease (CVD) or peripheral arterial obstructive disease (PAOD). The risk of new vascular events and mortality is high. Direct comparisons of vascular event rates are scarce., Methods and Results: Vascular risk factors and outcome events of 3563 patients from a university hospital presenting with nondisabling CAD, CVD or PAOD were compared with regression analyses, adjusted for age and sex (median follow-up, 3.9 years). The primary outcome was the composite of myocardial infarction, stroke and vascular death. The risk among the three groups of outcomes was compared using the Cox regression analysis. At baseline, CAD patients were the most obese; PAOD patients smoked the most and suffered more often from hypertension and hyperlipidaemia. The average rate of vascular events was 2.5% per year; the hazard ratio (HR) of CVD/CAD was 1.7 [95% confidence interval (CI): 1.3-2.2] and PAOD/CAD was 1.8 (95% CI: 1.5-2.0). PAOD patients had a higher risk for coronary events than CAD (HR: 1.6; 95% CI: 1.2-2.1). Patients with CVD or PAOD had a higher risk for major bleeding than CAD patients (HR: 2.1; 95% CI: 1.4-3.2)., Conclusion: Patients with a recent CVD or PAOD have almost twice the risk for future vascular events than those with CAD.

Background: Type 2 diabetes mellitus (T2DM) is associated with mild decrements in cognitive functioning, but the relation of these decrements to metabolic and vascular risk factors is unclear. The present study compared the vascular risk factor profile over the preceding 16 years between T2DM patients with good cognitive functioning and those with poor cognitive functioning., Methods: The Hoorn study is a population-based cohort study on glucose metabolism and vascular disease initiated in 1989, with follow-up examinations in 1996-1998, 2000-2001 and 2005-2007. Cognitive functioning was assessed in 2005-2007. Patients who developed T2DM between 1989 and 2000-2001 (n = 64) were divided in tertiles (lowest tertile = 'poor cognition', highest tertile = 'good cognition') according to a sum score for performance across cognitive domains (SUM) and the domain score for information-processing speed (IPS). The time course of vascular risk factors from 1989 to 2005-2007 was compared between these tertiles with linear mixed models adjusted for age, sex and estimated IQ., Results: Present levels (2005-2007) of vascular risk factors did not differ between patients with relatively poor or good cognition. However, patients with poor cognition had a 14-18 mmHg higher systolic blood pressure in 1989 than patients with good cognition. There were no differences in lipid profile and body weight at any time during the study between the groups. For IPS the T2DM patients with poor cognition even had a lower baseline HbA(1c) level than patients with good cognition., Conclusions: Cognitive dysfunction in T2DM is related to the cumulative effects of long-term exposure to hypertension, even in pre-DM stages., ((c) 2009 John Wiley & Sons, Ltd.)

BackgroundCerebral atrophy on brain magnetic resonance imaging (MRI) has been associated with vascular risk factors including hypertension. Progression of cerebral atrophy and its risk factors have not been studied in vascular disease patients. This study aimed to assess the progression of cerebral atrophy and to evaluate possible associations with blood pressure (BP) in patients with pre-existing vascular disease.MethodsA total of 331 patients with manifest vascular disease from the Second Manifestations of ARTerial Disease (SMART) Study underwent baseline and follow-up MRI scanning (mean follow-up 4.1 ± 0.3 years). The annual change in brain and ventricular volume was calculated with an automated quantitative volumetric method. Associations between BP and change in brain and ventricular volumes and between BP and the occurrence of lacunar infarcts were analyzed.ResultsAt baseline mean age was 58 ± 9 years and mean BP was 138/80 mm Hg. Mean annual decrease in brain tissue volume was 6.5 ± 3.8 ml and mean annual increase in ventricular volume was 1.0 ± 1.0 ml. There was no association observed between BP and annual change in brain or ventricular volume, but a clear association was found between BP and incident lacunar infarcts (odds ratio 1.57; 1.11–2.22 per s.d. increase in systolic BP (SBP)).ConclusionsThe magnitude of changes in brain tissue and ventricular volume in patients with vascular disease was comparable to the physiological changes described in normal people at a much higher age. Progression of cerebral atrophy in this population may be associated with advanced physiological aging, but is probably not caused by elevated BP.American Journal of Hypertension 2009; doi:10.1038/ajh.2009.166 [ABSTRACT FROM AUTHOR]