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Contains fulltext : 291889.pdf (Publisher’s version ) (Open Access) BACKGROUND: Angina without angiographic evidence of obstructive coronary artery disease (ANOCA) is a highly prevalent condition with insufficient pathophysiological knowledge and lack of evidence-based medical therapies. This affects ANOCA patients prognosis, their healthcare utilization and quality of life. In current guidelines, performing a coronary function test (CFT) is recommended to identify a specific vasomotor dysfunction endotype. The NetherLands registry of invasive Coronary vasomotor Function testing (NL-CFT) has been designed to collect data on ANOCA patients undergoing CFT in the Netherlands. METHODS: The NL-CFT is a web-based, prospective, observational registry including all consecutive ANOCA patients undergoing clinically indicated CFT in participating centers throughout the Netherlands. Data on medical history, procedural data and (patient reported) outcomes are gathered. The implementation of a common CFT protocol in all participating hospitals promotes an equal diagnostic strategy and ensures representation of the entire ANOCA population. A CFT is performed after ruling out obstructive coronary artery disease. It comprises of both acetylcholine vasoreactivity testing as well as bolus thermodilution assessment of microvascular function. Optionally, continuous thermodilution or Doppler flow measurements can be performed. Participating centers can perform research using own data, or pooled data will be made available upon specific request via a secure digital research environment, after approval of a steering committee. CONCLUSION: NL-CFT will be an important registry by enabling both observational and registry based (randomized) clinical trials in ANOCA patients undergoing CFT.

Histopathological studies have revealed key processes of atherosclerotic plaque thrombosis. However, the diversity and complexity of lesion types highlight the need for improved sub- phenotyping. We hypothesized that unbiased clustering of plaques based on gene expression results in an alternative categorization of late-stage atherosclerotic lesions.We analyzed the gene expression profiles of 654 advanced human carotid plaques. The unsupervised, transcriptome-driven clustering revealed five dominant plaque types. These novel plaque phenotypes associated with clinical presentation (pIn conclusion, the definition of the plaque at risk for a thrombotic event can be fine-tuned by in- depth transcriptomic based phenotyping. These differential plaque phenotypes prove clinically relevant for both carotid and coronary artery plaques and point to differential underlying biology of symptomatic lesions.

Background Performing sex-stratified analyses in medical research can lead to new insights. Artificial intelligence is increasingly used on electrocardiograms (ECGs) for prediction of mortality, risk and diagnosis. ECG-based deep neural networks (DNN) have shown to be able to distinguish women from men. This classification inevitably leads to a misclassified group. It is unknown what ECG characteristics account for sex classification, and how these variables affect mortality. We hypothesize that misclassification of sex by a DNN on ECGs can lead to new insights on ECG variables and mortality in women and men. Aim To study if DNN-based sex classification and misclassification identifies new ECG features associated with mortality in women and in men. Methods All ECGs spanning three decades from our University Medical Center were selected (n=1.136.113). A DNN was trained to classify sex based on 12-lead ECG using 131.673 normal ECGs of 68.500 subjects (48.6% women). Validation was performed on the other half of the population (68.500 ECGs, 49.5% women). Correctly classified and misclassified women and men were grouped. Discriminatory performance of the DNN was assessed using the AUC. The DNN was used to assess which characteristics influenced classification. We post-hoc tested their association with misclassification. To assess the association between sex-classification and mortality, time-to-event analysis was done with Kaplan-Meier curves. All individuals from 18 to 85 years, with at least 1 year follow-up were selected. To assess which ECG characteristics explain differences in mortality between the groups, sex-specific mediation analysis was performed using Weibull regression. Results DNN classification could distinguish women and men based on ECG (AUC: 0.97, 95% CI: 0.9789–0.9806). However, still 2.589 (8.1%) men and 2.368 (7.5%) women were misclassified. During a median follow-up of 8 years and 10 months, 4066 (13.0%) men died and 3055 (10.2%) women died, of whom, respectively 380 (9.3%) and 318 (9.9%) were misclassified. Misclassified individuals had worse survival than their correctly classified biological peers (misclassified vs correct classified women HR: 1.31, 95% CI: 1.17–1.48, misclassified vs correct classified men HR: 1.36, 95% CI: 1.22–1.51, figure 1). Mediation analysis showed that in men known ECG variables could partly explain the association between misclassification of sex and mortality. In women this was less so (figure 2). Moreover, this study revealed a new causal relation between QRS-shortening and mortality in women (figure 2). Conclusion A DNN can accurately classify women and men based on ECGs. Misclassification of sex is associated with worse survival in both sexes, and explained by sex-specific ECG features such as QRS shortening in women. This novel finding underscores the importance of integrating sex in AI to uncover previously unknown associations with mortality, and to prevent bias in algorithms. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): CVON-AIZonMW

Aim Stroke prevention and rate or rhythm control are crucial parts of the treatment of atrial fibrillation (AF). There is limited evidence for the efficacy or safety of rate and rhythm control in elderly or very elderly patients, although this population is rapidly increasing. Therefore, we analyzed electronic health record data from outpatient cardiology clinics to give insight in prescribing patterns and mortality of both treatment strategies in the elderly patients. Methods and results We extracted data from all patients with AF who were aged >75 years, used a pharmacological rate or rhythm control strategy and visited one of the independent outpatient cardiology clinics in the Netherlands between 2007 and February 2018. This resulted in 1,497 selected patients (54% women), of whom 316 (21%) were prescribed rhythm control (consisting of class 1 or 3 antiarrhythmic drugs) and 1,181 (79%) rate control (beta blockers, calcium antagonists or digoxin). Patients aged >85 years (OR: 2.28) and those with permanent AF (OR: 2.71) were more likely to receive rate control (OR: 2.28, OR: 2.71 respectively), whereas those with paroxysmal AF were more likely to receive rhythm control (OR: 0.42). After correcting for relevant confounders, the mortality risk for patients using rhythm control was similar to patients using rate control (HR: 0.89; 95% CI: 0.70; p=0.31). Conclusion Considering the similar mortality risks in both groups, a more liberal approach in prescribing a rhythm control strategy to the healthier elderly patient with AF seems safe. Our data underscores the need for a non-inferiority trial to provide definite answers on safety of rhythm control in elderly patients with AF. Funding Acknowledgement Type of funding sources: None.

Background/Purpose Heart failure with preserved ejection fraction (HFpEF) is currently hard to treat, and more prevalent in women as compared to men. Therefore, focus on prevention is key. Concentric remodelling is considered a pre-stage of HFpEF, yet knowledge on distributions and risk factor relations are scarce. Therefore, we identified the prevalence of early remodelling in women and men, and studied risk factors for early remodelling in women and men at risk for heart failure. Methods Clinical and echocardiographic data from 880 individuals, included in the HELPFul cohort were analysed (mean age 62.9 ±SD 9.3 years, 68.6% women). Relative wall thickness was calculated with the formula (2*LVPWD)/LVEDD and expressed as percentage. Concentric remodelling was defined as a relative wall thickness >42%. The relationship of classical cardiovascular risk factors, anthropometric -, lifestyle -, and pregnancy factors with relative wall thickness was tested using uni- and multivariable analyses for women and men separately. The association of continuous variables with relative wall thickness was analysed per standard deviation (SD) increase. Results Relative wall thickness was similar for both men (mean 43.2 ±SD 9.5) and women (mean 42.6 ±SD 8.1). Concentric remodelling (RWT >42%) was present in 49.1% of the population. Multivariable analyses showed that age, heart rate, systolic blood pressure, hypertension, and the usage of antihypertensive medication were independently associated with relative wall thickness in women. In men, heart rate and hypertension were independently associated with relative wall thickness. No associations were found for lifestyle factors such as smoking and alcohol intake. In women, there was no significant association of hypertensive pregnancy disorders and gestational diabetes with relative wall thickness. When relative wall thickness was dichotomized with >42% as cut-off for concentric remodelling the same risk factors remained independently associated in women. Per SD increase age, systolic blood pressure, heart rate, a diagnosis of hypertension and usage of antihypertensive medication were associated with an increased risk of concentric remodelling (OR=1.39 (95% CI: 1.18–1.64), 1.27 (95% CI: 1.05–1.53), 1.32 (95% CI: 1.10–1.58), 1.61 (95% CI: 1.09–2.36) and 1.67 (95% CI: 1.16–2.43), respectively) (Figure 1). In men, only a diagnosis of hypertension was a risk factor for concentric remodelling (OR=1.80 (95% CI: 1.05–3.06)). Conclusion Left ventricular concentric remodelling was as common in women as in men visiting outpatient cardiology clinics and found in half of the population. No sex-specific -, or lifestyle related risk factors could be identified. A relation with hypertension was evident in both sexes, but surprisingly no association of hypertensive pregnancy disorders was found. Concentric remodelling in women and men remains a common, but poorly understood, phenomenon that warrants further attention. Funding Acknowledgement Type of funding sources: None.

Background Machine learning (ML) allows the exploration and progressive improvement of very complex high-dimensional data patterns that can be utilised to optimise specific classification and prediction tasks, outperforming traditional statistical approaches. An enormous acceleration of ready-to-use tools and artificial intelligence (AI) applications, shaped by the emergence, refinement, and application of powerful ML algorithms in several areas of knowledge, is ongoing. Although such progress has begun to permeate the medical sciences and clinical medicine, implementation in cardiovascular medicine and research is still in its infancy. Objectives To lay out the theoretical framework, purpose, and structure of a novel AI consortium. Methods We have established a new Dutch research consortium, the CVON-AI, supported by the Netherlands Heart Foundation, to catalyse and facilitate the development and utilisation of AI solutions for existing and emerging cardiovascular research initiatives and to raise AI awareness in the cardiovascular research community. CVON-AI will connect to previously established CVON consortia and apply a cloud-based AI platform to supplement their planned traditional data-analysis approach. Results A pilot experiment on the CVON-AI cloud was conducted using cardiac magnetic resonance data. It demonstrated the feasibility of the platform and documented excellent correlation between AI-generated ventricular function estimates as compared to expert manual annotations. The resulting AI solution was then integrated in a web application. Conclusion CVON-AI is a new consortium meant to facilitate the implementation and raise awareness of AI in cardiovascular research in the Netherlands. CVON-AI will create an accessible cloud-based platform for cardiovascular researchers, demonstrate the clinical applicability of AI, optimise the analytical methodology of other ongoing CVON consortia, and promote AI awareness through education and training.

Background Heart failure (HF) guidelines recommend equal target doses for women and men. Recently, these recommendations have been challenged as research suggested that women with HF with reduced Ejection Fraction (HFrEF) may reach optimal treatment effect at half of the guideline-recommended dose while men may require the full dose. However, it is unclear how often women and men reach guideline-recommended target doses in daily practice. Purpose To evaluate whether women and men with HF reach guideline-recommended target doses for Angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blocker (ARB), β-blockers (BB) and mineralocorticoid receptor antagonists (MRA) in daily practice. Methods We extracted data from 13 outpatient cardiology clinics for all individuals diagnosed with HF within 14 days leading up to their visit who were prescribed at least one guideline-recommended HF medication. HF was defined based on a combination of the cardiologist's diagnosis and left ventricular systolic or diastolic dysfunction determined during echocardiography. Guideline-recommended medication groups and target doses were taken from the 2016 ESC HF guidelines or from literature for medications not mentioned in the guidelines. To enable comparison between medications and medication groups, daily dose was converted to percentage of target dose. Mean change in percentage of target dose over consecutive medication prescriptions was modelled for men and women using natural cubic splines. Results We included 1254 patients with HF (48% women). Women were on average older at diagnosis (71 vs 67 years) and more often had hypertension (54.9 vs 44.3%), but less often had diabetes mellitus (13.5 vs 19.4%), a history of coronary heart disease (7.8 vs 19.6%,) or past cardiovascular interventions (8.7 vs 23.0%) than men. In total, 1069 patients were prescribed an ACEI/ARB (46% women), 920 a BB (48% women) and 243 an MRA (43% women). Women were more often prescribed only one medication than men (39.6 vs 33.2%, p=0.014). Approximately 14% of first prescriptions for all medications were at 100% of target dose or higher for both women and men, with the majority of prescriptions being either at 1–49% of target dose (47.2 vs 45.5%, respectively) or 50–99% of target dose (39.1 vs 40.8%, respectively). The natural cubic splines showed that this distribution did not change over consecutive drug prescriptions in either women or men. Only MRA prescriptions for men showed an upward trend and reached 100% of target dose. Conclusion In daily practice, both women and men were unlikely to reach guideline-recommended target doses for both ACEI/ARBs and BBs. For MRAs, women were less likely to reach target dose than men. Optimal dosing in HF is difficult for both sexes, but in light of recent evidence, the challenge in daily practice seems to lie more in undertreatment of men than overtreatment of women. Figure 1 (women in red, men in blue) Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): ZonMw

Introduction High-sensitivity cardiac troponin (hs-cTn) assays have enhanced sensitivity for myocardial injury and may lead to an increase in the diagnosis of myocardial infarction. Few real-world studies have investigated the transition from conventional cardiac troponin (cTn) to hs-cTn. We evaluated the impact of implementing hs-cTn assays and sex-specific thresholds in the Netherlands on the diagnosis of myocardial infarction in women and men. Methods Twelve Dutch hospitals were included (hs-cTnI assay [sex-specific thresholds], n=4; hs-cTnT assay [uniform threshold], n=8). Data from the health insurance claims of consecutive patients with anginal symptoms were collected before (cTn period) and after (hs-cTn period) implementation from January 2008 to December 2017. The proportion of patients with a diagnosis of myocardial infarction overall, and in men and women separately, and one-year mortality was compared before and after implementation of the hs-cTn assay. Results Across twelve hospitals, a total number of 77,464 patients presenting with anginal symptoms were included (cTn period: 35,409 [36.6% women]; hs-cTn period: 42,055 [34.6% women]). Following implementation of hs-cTn testing the proportion of patients with anginal symptoms diagnosed with myocardial infarction doubled from 24% (3,111/12,970) to 48% (7,014/14,560) in women, and from 25% (5,712/22,439) to 51% (13,912/27,495) in men, with similar increases in sites implementing hs-cTnI and hs-cTnT. The proportion of patients diagnosed with myocardial infarction who were women increased in sites implementing sex-specific thresholds (from 36.4% [1,435/3,941] to 37.5% [1,700/4,532], absolute change 1.1%), but did not increase in sites using a uniform threshold (from 34.3% [1,676/4,882] to 32.4% [5,314/16,394], absolute change −1.9%). In patients with a diagnosis of myocardial infarction, one-year mortality was 15.6% (485/3,111) and 11.6% (814/7,014) in women, and was 11.8% (673/5,712) and 9.4% (1,303/13,912) in men, before and after implementation of hs-cTn. Conclusions In patients presenting with anginal symptoms, the diagnosis of acute myocardial infarction doubled after implementation of hs-cTn testing in both women and men. Use of sex-specific thresholds increased the proportion of patients with myocardial infarction who were women compared to use of a uniform threshold. Implementation was associated with a reduction in one-year mortality, but further research is needed to understand whether this is due to differences in the risk profile of patients with myocardial infarction or improvements in treatment. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This study was supported by a grant from Abbott Laboratories to S.J.R.M.

Background To assess the trend in age- and sex-stratified mortality after hospitalization for heart failure (HF) in the Netherlands. Methods Two nationwide cohorts of patients, hospitalized for new onset heart failure between 01.01.2000–31.12.2002 and between 01.01.2008–31.12.2010, were constructed by linkage of the Dutch Hospital Discharge Registry and the National Cause of Death registry. 30-day, 1-year and 5 -year overall and cause-specific mortality rates stratified by age and sex were assessed and compared over time. Results We identified 40,230 men and 41,582 women. In both cohorts, men were on average younger than women (74–75 and 78–79 years, respectively) and more often had comorbid conditions (37 and 30%, respectively). In the 2008–10 cohort, mortality rates for men were 13, 32 and 64% for respectively 30-day, 1-year and 5-year mortality and 14, 33 and 66% for women. Mortality rates increased considerably with age similarly in men and women (e.g. from 10.5% in women aged 25–54 to 46.1% in those aged 85 and older after 1 year). Between the two time periods, mortality rates dropped across all ages, equally strong in women as in men. The 1-year absolute risk of death declined by 4.0% (from 36.1 to 32.1%) in men and 3.2% (from 36.2 to 33.0%) in women. Conclusions Mortality after hospitalization for new onset HF remains high, however, both short-term and long-term survival is improving over time. This improvement was similar across all ages and equally strong in women as in men.

Introduction Knowledge on factors that influence atherosclerotic plaque composition may allow improved risk stratification and treatment selection in iliofemoral and carotid atherosclerotic disease, since outcomes of different treatment strategies are influenced by the type of underlying lesions. The sex- and age-related differences in iliofemoral atherosclerotic plaque composition is largely unknown. Unravelling the intertwined relation between sex, age and plaque composition might provide important implications for the treatment of peripheral artery disease. Purpose We aimed to elucidate the associations between sex, age and plaque composition in a histopathological analysis of plaque specimens of patients undergoing iliofemoral endarterectomy. Given the systemic nature of atherosclerosis, analyses are replicated in atherosclerotic plaque specimens obtained from patients undergoing carotid surgery. Methods Peripheral atherosclerotic plaques of 790 patients who underwent iliofemoral endarterectomy were harvested between 2002 and 2014. A cohort of patients (n=2006) who underwent carotid endarterectomy was used to replicate analyses on sex-specific aging effects in plaques from a different vascular bed. The atherosclerotic plaques were semi-quantitatively analyzed for the presence of lipid cores, plaque calcifications, plaque hemorrhages and collagen, macrophage and smooth muscle cell content, and quantitatively for microvessel density. Patients were stratified by age tertiles and by sex. Results Men had a higher prevalence of lipid cores (25.7% versus 20.5%, odds ratio [OR] 1.62 and 95% confidence interval [CI] 1.06–2.45, P=0.025) and plaque hemorrhage (54.3% versus 42.9%, OR 1.62 and 95% CI 1.16–2.54, P=0.004) when compared to women. Women showed an increase in plaque calcifications, plaque hemorrhage and a decrease in macrophages with increasing age (figure panel B, D, E), whereas men only showed a decrease in collagen content (figure panel C). These sex-specific aging effects were replicated in plaques obtained from the carotid arteries. s Conclusion Atherosclerotic iliofemoral plaques derived from men display more rupture-prone characteristics compared to women. However, advanced age was more often associated with an increase in the presence of vulnerable plaque characteristics in women as compared to men in both the iliofemoral and carotid atherosclerotic plaque.

Background Recent observations have suggested a decline in vulnerable carotid artery and iliofemoral atherosclerotic plaque characteristics over the past decade. The aim of this study was to determine whether, in the presence of clinically manifest carotid or peripheral artery disease, secondary adverse cardiovascular events decreased over this period. Methods Patients included in the Athero-Express biobank between 2003 and 2012 were analysed. During 3-year follow-up, composite cardiovascular endpoints were documented yearly, including: myocardial infarction, coronary interventions, stroke, peripheral interventions and cardiovascular death. The major cardiovascular endpoint consisted of myocardial infarction, stroke and cardiovascular death. Results Some 1684 patients who underwent carotid endarterectomy (CEA) and another 530 who had iliofemoral endarterectomy (IFE) were analysed. In total, 405 (25·2 per cent) and 236 (45·9 per cent) patients had a composite cardiovascular endpoint within 3 years after CEA and IFE respectively. Corrected for possible confounders, the percentage of patients with a secondary cardiovascular event after CEA did not change over time (hazard ratio (HR) 0·91, 95 per cent c.i. 0·65 to 1·28; P = 0·590, for 2011–2012 versus 2003–2004). In patients who had IFE, the incidence of secondary cardiovascular events significantly decreased only in the last 2 years (HR 0·62, 0·41 to 0·94; P = 0·024), owing to a decrease in peripheral (re)interventions in 2011–2012 (HR 0·59, 0·37 to 0·94; P = 0·028). No decrease in major cardiovascular events was observed in either group. Conclusion In patients who had undergone either CEA or IFE there was no evidence of a decrease in all secondary cardiovascular events. There were no differences in major cardiovascular events.

Introduction Dual antiplatelet therapy (DAPT) has mainly replaced mono antiplatelet therapy (MAPT) and is recommended after arterial endovascular revascularization. The aim of this meta-analysis was to summarize the available evidence for DAPT after endovascular revascularization throughout the arterial system. Methods A systematic search was performed in Medline, Embase, and the Cochrane Register. Two reviewers independently performed data extraction and quality assessment using the Cochrane Collaboration risk of bias assessment tool. Included in the search were randomized controlled trials (RCTs) comparing DAPT with MAPT after endovascular procedures for the treatment of coronary, carotid, or peripheral artery disease, reporting at least one clinical outcome. Articles were excluded if patients received anticoagulation in addition to antiplatelet therapy in the post-procedural phase. The primary outcome was restenosis or stent thrombosis, and secondary outcomes were major adverse cardiac events (MACE), target lesion revascularization, cerebrovascular accident or transient ischemic attack, bleeding, and death. Meta-analyses of binary outcomes were performed using the random effects model and described as risk ratios (RRs) and 95% confidence intervals (95% CIs). Chi-square tests were used to test for heterogeneity. Results Nine articles were included in this study, involving lower limb peripheral arteries (1), carotid arteries (2), and coronary arteries (6). The pooled results of coronary trials showed a RR for restenosis with DAPT of 0.60 (95% CI 0.28–1.31) and for myocardial infarction 0.49 (95% CI 0.12–2.03). In the carotid artery trials the RR for restenosis was 0.22 (95% CI 0.04–1.20) and for peripheral arteries 1.02 (95% CI 0.56–1.82). A meta-analysis of bleeding risk of all the included trials showed a RR of 1.06 (95% CI 0.32–3.52) with DAPT. Conclusion The available evidence comparing DAPT with MAPT after endovascular arterial revascularization is limited and the majority of trials were conducted in the cardiology field. No significant evidence for superiority of DAPT compared with MAPT was found, but there was also no evidence of an increased bleeding risk with DAPT over MAPT.

Background: Medical guidelines increasingly use risk stratification and implicitly assume that individuals classified in the same risk category forma homogeneous group, while individuals with similar, or even identical, predicted risks can still be very different. We evaluate a strategy to identify homogeneous subgroups typically comprising predicted risk categories to allow further tailoring of treatment allocation and illustrate this strategy empirically for cardiac surgery patients with high postoperative mortality risk. Methods: Using a dataset of cardiac surgery patients (n=6517) we applied cluster analysis to identify homogenous subgroups of patients comprising the high postoperative mortality risk group ( EuroSCORE >= 15%). Cluster analyses were performed separately within younger (= 75 years) patients. Validity measures were calculated to evaluate quality and robustness of the identified subgroups. Results: Within younger patients two distinct and robust subgroups were identified, differing mainly in preoperative state and indication of recent myocardial infarction or unstable angina. In older patients, two distinct and robust subgroups were identified as well, differing mainly in preoperative state, presence of chronic pulmonary disease, previous cardiac surgery, neurological dysfunction disease and pulmonary hypertension. Conclusions: We illustrated a feasible method to identify homogeneous subgroups of individuals typically comprising risk categories. This allows a single treatment strategy - optimal only on average, across all individuals in a risk category - to be replaced by subgroup-specific treatment strategies, bringing us another step closer to individualized care. Discussions on allocation of cardiac surgery patients to different interventions may benefit from focusing on such specific subgroups. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Objective Quality of life (QoL) is an important outcome in evaluating treatment effect in severe limb ischemia. The randomized, double blind, placebo controlled JUVENTAS trial, investigating the effect of bone marrow derived mononuclear cell (BMMNC) administration in no option severe limb ischemia, showed an improved QoL at 6 months compared with baseline in both the treatment and placebo groups. The aim of the present study was to evaluate whether the improved QoL persisted beyond 6 months' follow up, whether this differed in both trial arms, and if major amputation influenced QoL. Methods Short form 36 (SF-36) and EuroQol 5D (EQ5D), including the EQ Visual Analogue Scale (EQ-VAS), questionnaires were sent to JUVENTAS trial participants. In the JUVENTAS trial, a norm based scoring method was applied to report the results of the SF-36. The results of the long-term follow up were compared with baseline and 6 month follow up and the results of both trial arms were compared, as were the results of patients with and without amputation. Results One hundred and nine patients (86.5% of surviving patients) responded to the questionnaires. Median follow up after inclusion was 33 months (interquartile range [IQR] 21.2–50.6) for the BMMNC and 36 months (IQR 21.4–50.9) for the placebo group. The improvement in QoL at 6 months persisted in both arms at a median follow up of 35 months. The long-term QoL did not differ between the BMMNC and placebo group in any of the SF-36 or EQ5D domains. Patients with and without a major amputation had similar QoL scores. Conclusions The increased QoL in patients with no option severe limb ischemia persisted until 3 years after inclusion, but did not differ between the BMMNC and placebo arms or between patients with and without a major amputation.

Background Vascular age is an alternate means of representing an individual's cardiovascular risk. Little consensus exists on what vascular age represents and its clinical utility has not been determined. We systematically reviewed the literature to provide a comprehensive overview of different methods that have been used to define vascular age, and to examine its potential clinical value in patient communication and risk prediction. Design This was a systematic review with data sources of PubMed and Embase. Results We identified 39 articles on vascular age, 20 proposed to use vascular age as a communication tool and 19 proposed to use vascular age as a means to improve cardiovascular risk prediction. Eight papers were methodological and 31 papers reported on vascular age in study populations. Of these 31 papers, vascular age was a direct translation of the absolute risk estimated by existing cardiovascular risk prediction models in 15 papers, 12 derived vascular age from the reference values of an additional test, and in three papers vascular age was defined as the age at which the estimated cardiovascular risk equals the risk from non-invasive imaging observed degree of atherosclerosis. One trial found a small effect on risk factor levels when vascular age was communicated instead of cardiovascular risk. Conclusion Despite sharing a common name, various studies have proposed distinct ways to define and measure vascular age. Studies into the effects of vascular age as a tool to improve cardiovascular risk prediction or patient communication are scarce but will be required before its clinical use can be justified.

Background The aim of this study was to evaluate absolute mortality risks and to determine whether changes in mortality risk occurred in patients with intermittent claudication (IC) or critical limb ischaemia (CLI) in the Netherlands between 1998 and 2010. Methods Data for patients treated between 1998 and 2010 were obtained from Dutch nationwide registers: the Hospital Discharge Register, Population Register and Cause of Death Register. The registers were used to obtain information regarding IC and CLI hospitalizations, co-morbidities, demographic factors, and date and cause of death. The cohort was split into two time intervals for comparison: 1998–2004 (period 1) and 2005–2010 (period 2). Thirty-day mortality was excluded to eliminate per-admission complications. One- and 5-year cardiovascular and all-cause mortality rates were compared with those of a representative sample of the general Dutch population (28 494 persons) by Cox proportional hazards models. Results Some 47 548 patients were included, 34 078 with IC and 13 470 with CLI. In patients with IC, the age-adjusted 5-year mortality risk for cardiovascular disease decreased significantly in period 2 (14·1 per cent) compared with that in period 1 (16·1 per cent) in men only (5-year adjusted hazard ratio (HR) 0·76, 95 per cent c.i. 0·69 to 0·83; P < 0·001). In patients with CLI, the cardiovascular mortality risk decreased significantly only in women, with the 5-year risk reducing from 31·2 per cent in period 1 to 29·2 per cent in period 2 (adjusted HR 0·84, 0·74 to 0·94; P = 0·004). Compared with the general population, the mortality risk in patients with IC was increased between 1·70 (1·58 to 1·83) and 3·20 (2·69 to 3·81) times, and in those with CLI the risk was increased between 2·24 (2·09 to 2·40) and 5·19 (4·30 to 6·26) times. Conclusion The risk of premature death in patients with IC and CLI declined significantly in the Netherlands, in a sex-specific manner, over the period from 1998 to 2010. The absolute risk of cardiovascular mortality remains high in these patients.

Objectives Peri-procedural ischaemic brain lesions on diffusion weighted imaging (DWI) after carotid endarterectomy (CEA) and carotid artery stenting (CAS) have been related to a higher chance of recurrent cerebrovascular events. This systematic review provides an overview of patient characteristics associated with increased risk of new DWI lesions. Methods MEDLINE, EMBASE, and Cochrane library databases were systematically searched (update November 2018) for studies reporting post-procedural DWI lesions after CEA or CAS. Data derived from both procedures were analysed separately. Studies reporting predictive features that were present prior to intervention were assigned to 10 categories: age, gender, cardiovascular risk factors, symptomatology, plaque vulnerability, atherosclerotic burden, cerebrovascular haemodynamics, carotid/arch anatomy, inflammatory markers, and markers of coagulation. A semi-quantitative analysis was performed by plotting studies that found an association between the investigated features and DWI lesions against those that did not find an association. Results Forty-six studies (5018 patients) were included: 10 reported only CEA, 33 CAS, and three both interventions. 68.0% of 1873 CEA patients and 55.9% of 3145 CAS patients were symptomatic. The weighted prevalence of DWI lesions was 18.1% (95% CI 14.0–22.7%) in CEA patients compared with 40.5% (95% CI 35.4–45.7%) in CAS patients. Studies reporting on CEA patients predominantly found an increased risk in symptomatic patients (two of seven studies, including 848/1661 patients), those with impaired haemodynamics (five of five studies), and increased inflammatory markers (two of three studies). Studies reporting on CAS patients often found a positive association with age (10/26 studies), high plaque vulnerability (25/34 studies), or complex carotid/arch anatomy (three out of five studies). Conclusions For patients undergoing CEA, symptomatic status, impeded cerebral haemodynamics, and increased inflammatory markers are associated with increased susceptibility to peri-operative DWI lesions. In CAS patients, higher age, plaque vulnerability and complex carotid/aortic arch anatomy were identified as risk factors. These clinical predictors may assist with decision making on patient selection for medical treatment, CEA or CAS.

Objectives: The occurrence of cerebral ischemia during carotid endarterectomy (CEA) can be prevented by (selective) placement of an intraluminal shunt during cross-clamping. We set out to develop a rule to predict the likelihood for shunting during CEA based on preoperative assessment of collateral cerebral circulation and patient characteristics.Methods: Patients who underwent CEA between 2004 and 2010 were included. Patients without preoperative magnetic resonance (MRA) or computed tomography angiography (CTA) were excluded. The primary endpoint was intraluminal shunt placement based on electroencephalography changes. Age, sex, cardiovascular risk factors peripheral artery disease, symptomatic status, degree of ipsilateral and contralateral carotid, status of the vertebral arteries, and morphology of the CoW were studied as potential predictors for shunt use. A prediction model was derived from a multivariable regression model using discrimination, calibration, and bootstrapping approaches and transformed into a clinical prediction model.Results: A total of 431 patients were included, of which 65 patients (15%) received an intraluminal shunt. In the MRA group (n = 285) factors related to shunt use in multivariate analysis were ipsilateral carotid stenosis 90 99% (odds ratio [OR] 0.15, 95% Cl 0.04-0.53), contralateral carotid occlusion (OR 4.29, 95% CI 1.68-10.95) and any not-visible anterior (OR 4.96, 95% Cl 1.95-12.58) or ipsilateral posterior segment of the CoW (OR 5.08, 95% Cl 2.10-12.32). In the CT group none of the factors were independently related to shunt use; therefore, only predictors describing morphology of CoW derived from MRA findings were included in our model. The c-statistic of this model was 0.79 (95% Cl 0.72-0.86). Among patients with an estimated chance of needing a shunt of under 10% (49% of the population), the likelihood of shunting was 5%. In those in whom this chance was estimated higher than 30% (13%. of the population) the likelihood was 51%.Conclusions: Among patients scheduled for CEA, assessment of cerebral arteries and of the configuration of the CoW based on MRA-derived images can help to identify patients with low and high likelihood of the need of shunt use during surgery. (C) 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Objective Restenosis and stent thrombosis after endovascular intervention in patients with peripheral arterial disease (PAD) can potentially be tackled by more intensive antiplatelet therapy, such as dual antiplatelet therapy (DAPT) consisting of aspirin and P2Y 12 inhibitor. Despite clopidogrel treatment, some patients still display high platelet reactivity (HCPR). Tailored antiplatelet therapy, based on platelet reactivity testing, might overcome HCPR. However, more data are warranted regarding the proportion of patients with HCPR in the PAD population, different platelet reactivity tests, their correlation, and the optimal timing for these tests as a stepping stone for a future trial investigating the potential benefit of tailored antiplatelet therapy in PAD patients. Methods Thirty patients on DAPT after percutaneous transluminal angioplasty underwent platelet reactivity testing by VerifyNow, vasodilator-stimulated phosphoprotein (VASP) and platelet activation assay, and CYP2C19-polymorphism testing. Results The proportion of patients with HCPR measured by VerifyNow varied between 43.3% and 83.3%, depending on the cut off values used. Testing within 24 hours of initiation of DAPT gave a higher proportion of HCPR than testing after more than 24 hours. According to DNA testing, 14.8% were CYP2C19*2 homozygote, 22.2% heterozygote, and 63% CYP2C19*2 negative. VASP assay revealed 24% HCPR. The highest HCPR rate was found with a VerifyNow cut off of less than 40% inhibition, whereas the lowest HCPR rate was found with the VASP assay. There was a low correlation between the tests. Conclusion HCPR is present in PAD patients and research on HCPR is needed in this population; timing of tests is relevant and standardisation of tests is needed. The optimal conditions for platelet function testing should be determined.

Objective Myocardial infarction (MI) is a frequent complication of carotid endarterectomy (CEA), yet most events are silent. Routine post-operative monitoring of cardiac troponin was implemented to facilitate timely recognition of MI and stratify high risk patients. The aim was to evaluate the incidence of troponin elevation after CEA and its association with adverse cardiovascular events. Methods This analysis included patients ≥60 years old who underwent CEA, whose troponin-I levels were routinely monitored post-operatively and were included in a cohort study that assessed clinical outcomes. A clinical troponin cutoff of 60 ng/L was used. The primary endpoint was the composite of MI, stroke, and cardiovascular death. Secondary endpoints were MI, stroke, coronary intervention, cardiovascular death, and all cause death. Results 225 consecutive patients were included in the analysis. Troponin elevation occurred in 34 patients (15%) and a post-operative MI was diagnosed in eight patients. After a median follow up of 1.8 years (IQR 1.0–2.6), the primary endpoint occurred in 29% of patients with troponin elevation versus 6.3% without (HR 5.6, 95% CI 2.4–13), MI in 24% versus 1.6% (HR 18.0, 95% CI 4.7–68), stroke in 5.9% versus 4.2% (HR 1.4, 95% CI 0.3–6.7), coronary intervention in 5.9% versus 2.6% (HR 2.7, 95% CI 0.5–14), cardiovascular death in 5.9% versus 0.5% (HR 11.8, 95% CI 1.1–131), and all cause death in 15% versus 5.8% (HR 3.0, 95% CI 1.0–8.7), respectively. Incidences of the primary endpoint and all cause mortality in patients with a post-operative MI versus “troponin only” were 25% versus 7.7% and 25% versus 12%, respectively. Conclusion Troponin elevation after CEA occurred in 15% of patients. The incidence of adverse cardiovascular events was significantly higher in patients with troponin elevation, which was mainly attributable to silent non-ST segment elevation MIs that occurred in the early post-operative phase.

BACKGROUND: Risk factor burden and clinical characteristics of patients with coronary artery disease (CAD) differ among ethnic groups. We related biomarkers to CAD severity in Caucasians, Chinese, Indians and Malays. METHODS: In the Dutch-Singaporean UNICORN coronary angiography cohort (n = 2033) we compared levels of five cardiovascular biomarkers: N-terminal pro-brain natriuretic peptide (NTproBNP), high-sensitivity C-reactive protein (hsCRP), cystatin C (CysC), myeloperoxidase (MPO) and high-sensitivity troponin I (hsTnI). We assessed ethnicity-specific associations of biomarkers with CAD severity, quantified by the SYNTAX score. RESULTS: Adjusted for baseline differences, NTproBNP levels were significantly higher in Malays than in Chinese and Caucasians (72.1 vs. 34.4 and 41.1 pmol/l, p

Peters SAE, Lind L, Palmer MK, Grobbee DE,Crouse JR III, O’Leary DH, Evans GW, Raichlen J,Bots ML, den Ruijter HM, on behalf of the METEORstudygroup(UniversityMedicalCenterUtrecht,Utr-echt, The Netherlands; Uppsala University Hospital,Uppsala, Sweden;KeeleUniversity,Keele, UK; WakeForest University School of Medicine, Winston-Salem, NC, USA; Caritas Carney Hospital, Boston,MA, USA; and AstraZeneca, Wilmington, DE, USA).Increasedage,highbodymassindexandlowHDL-Clevels are related to an echolucent carotid intima–media: the METEOR study. J Intern Med 2012;272:257–266.Introduction. Echolucentplaquesarerelatedtoahighercardiovascular risk. Studies to investigate the rela-tionship between echolucency and cardiovascularriskintheearlystages ofatherosclerosisare limited.We studied the relationship between cardiovascularrisk factors and echolucency of the carotid intima–mediainlow-riskindividuals.Methods. Data were analysed from the Measuring Ef-fects on Intima-Media Thickness: an Evaluation ofRosuvastatin (METEOR) study, a randomized pla-cebo-controlledtrialincluding984individualswhichshowed that rosuvastatin attenuated the rate ofchange of carotid intima–media thickness (CIMT). Inthisposthocanalysis,duplicatebaselineultrasoundimagesfromthefarwalloftheleftandrightcommoncarotid arteries were used for the evaluation of theecholucency of the carotid intima–media, measuredbygrey-scalemedian(GSM)onascaleof0–256.LowGSM values reflect echolucent, whereas high valuesreflect echogenic structures. The relationship be-tween baseline GSM and cardiovascular risk factorswasevaluatedusinglinearregressionmodels.Results. MeanbaselineGSM(± SD)was84 ± 29.LowerGSMofthecarotidintima–mediawasassociatedwitholder age, highbodymass index (BMI) andlow levelsof high-density lipoprotein cholesterol (HDL-C) [beta)4.49, 95% confidence interval (CI) )6.50 to )2.49;beta)4.51,95%CI)6.43to)2.60;beta2.45,95%CI0.47to4.42,respectively].CommonCIMTwasinver-selyrelatedtoGSMofthecarotidintima–media(beta)3.94,95%CI)1.98to)5.89).Conclusion. Olderage,highBMIandlowlevelsofHDL-Carerelatedtoecholucencyofthecarotidintima–med-ia. Hence, echolucency of the carotid intima–mediamaybeusedasamarkerofcardiovascularriskprofiletoprovidemoreinformationthanthicknessalone.Keywords: atherosclerosis, carotid intima–mediathickness, carotid ultrasound, echolucency, riskfactors.IntroductionAtherosclerosis is a chronic and progressive diseaseofthe arterial wallandis theunderlyingcause ofthemajority of cardiovascular events worldwide [1, 2].B-modeultrasoundmeasurements of thecarotidar-teryhavecommonlybeenusedtoassessthepresenceand severity of atherosclerotic disease in a safe, reli-able and reproducible way [3]. Histological studieshave shown that plaques that appear echolucent onB-mode ultrasound are rich in lipids, whereas echo-genic plaqueshavea higher contentoffibrous tissue*

Background: Cerebral hyperperfusion syndrome (CHS) after carotid endarterectomy (CEA) is a potential life-threatening complication. Therefore, early identification and treatment of patients at risk is essential. CHS can be predicted by a doubling of postoperative transcranial Doppler (TCD)-derived mean middle cerebral artery blood velocity (Vmean) compared to preoperative values. However, in approximately 15% of CEA patients, an adequate TCD signal cannot be obtained due to an insufficient temporal bone window. Moreover, the use of TCD requires specifically skilled personnel. An alternative and promising technique of noninvasive cerebral monitoring is relative frontal lobe oxygenation (rSO2) measured by near-infrared spectroscopy (NIRS), which offers on-line information about cerebral oxygenation without the need for specialized personnel. In this study, we assess whether NIRS and perioperative TCD are related to the onset CHS following CEA. Methods: Patients who underwent CEA under general anesthesia and had a sufficient TCD window were prospectively included. The Vmean and rSO2 measured before induction of anesthesia were compared to measurements performed in the first postoperative hour (ΔVmean, ΔrSO2, respectively). Logistic regression analysis was performed to determine the relationship between ΔV and ΔrSO2 and the occurrence of CHS. Subsequently, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff values. Diagnostic values were shown as positive and negative predictive values (PPV and NPV). Results: In total, 151 patients were included, of which 7 patients developed CHS. The ΔVmean and ΔrSO2 differed between CHS and non-CHS patients (median, interquartile range), i.e. 74% (67–103) versus 16% (–2 to 41), p = 0.001, and 7% (4–15) versus 1% (–6 to 7), p = 0.009, respectively. The mean arterial blood pressure did not change. Postoperative ΔVmean and ΔrSO2 were significantly related to the occurrence of CHS [odds ratio (OR) 1.40 (95% CI 1.02–1.93) per 30% increase in Vmean and OR 1.82 (95% CI 1.11–2.99) per 5% increase in rSO2]. ROC curve analysis showed an area under the curve of 0.88 (p = 0.001) for ΔVmean and an optimal cutoff value of 67% increase (PPV 38% and NPV 99%), and an area under the curve of 0.79 (p = 0.009) for ΔrSO2 and an optimal cutoff value of 3% rSO2 increase (PPV 11% and NPV 100%). The combination of both monitoring techniques provided a PPV of 58% and an NPV of 99%. Conclusions: Both TCD and NIRS measurements can be used to safely identify patients not at risk of developing CHS. It appears that NIRS is a good alternative when a TCD signal cannot be obtained.

Peters SAE, den Ruijter HM, Palmer MK, Grobbee DE, Crouse JR, O’Leary DH, Evans GW, Raichlen JS, Lind L, Bots ML, on behalf of the METEOR Study Group (University Medical Center Utrecht, Utrecht, The Netherlands; Keele University, Keele, UK; Wake Forest University School of Medicine, Winston-Salem, NC, USA; Caritas Carney Hospital, Boston, MA, USA; Wake Forest University School of Medicine, Winston-Salem, NC, USA; AstraZeneca, Wilmington, DE, USA; and Uppsala University Hospital, Uppsala, Sweden). Manual or semi-automated edge detection of the maximal far wall common carotid intima–media thickness: a direct comparison. J Intern Med 2012; 271: 247–256. Background. Automated edge detection is thought to be superior to manual edge detection in quantification of the far wall common carotid intima–media thickness (CIMT), yet published evidence making a direct comparison is not available. Methods. Data were used from the METEOR study, a randomized placebo-controlled trial among 984 individuals showing that rosuvastatin attenuated the rate of change of 2 year change in CIMT among low-risk individuals with subclinical atherosclerosis. For this post hoc analysis, CIMT images of the far wall of the common carotid artery were evaluated using manual and semi-automated edge detection and reproducibility, relation to cardiovascular risk factors, rates of change over time and effects of lipid-lowering therapy were assessed. Results. Reproducibility was high for both reading methods. Direction, magnitude and statistical significance of risk factor relations were similar across methods. Rate of change in CIMT in participants assigned to placebo was 0.0066 mm per year (SE: 0.0027) for manually and 0.0072 mm per year (SE: 0.0029) for semi-automatically read images. The effect of lipid-lowering therapy on CIMT changes was −0.0103 mm per year (SE: 0.0032) for manual reading and −0.0111 mm per year (SE: 0.0034) for semi-automated reading. Conclusion. Manual and semi-automated readings of the maximal far wall of the common CIMT images both result in high reproducibility, show similar risk factor relations, rates of change and treatment effects. Hence, choices between semi-automated and manual reading software for CIMT studies likely should be based on logistical and cost considerations rather than differences in expected data quality when the choice is made to use far wall common CIMT measurements.

Introduction: Although plasma lipid levels are known to influence the risk of cardiovascular disease (CVD), little is known about their effect on atherosclerotic plaque composition. To date, large-scale genome-wide association studies have identified 157 common single-nucleotide polymorphisms (SNPs) that influence plasma lipid levels, providing a powerful tool to investigate the effect of plasma lipid levels on atherosclerotic plaque composition. Methods: In this study, we included 1443 carotid endarterectomy patients from the Athero-Express Biobank Study with genotype data. Plasma concentrations of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC) and triglycerides (TG) were determined at the time of endarterectomy. Atherosclerotic plaques, obtained during surgery, were histologically examined. For all patients, we calculated weighted genetic burden scores (GBS) for all lipid traits on the basis of the available genotype data. Plasma lipid levels and GBS were tested for association with 7 histological features using linear and logistic regression models. Results: All GBS were associated with their respective plasma lipid concentrations (pHDL-C = 2.4 × 10-14, pLDL-C = 0.003, pTC = 2.1 × 10-6, pTG = 3.4 × 10-8). Neither the measured plasma lipids, nor the GBS, were associated with histological features of atherosclerotic plaque composition. In addition, neither the plasma lipids nor the GBS were associated with clinical endpoints within 3 years of follow-up, with the notable exception of a negative association between HDL-C and composite cardiovascular endpoints. Conclusion: This study found no evidence that plasma lipid levels or their genetic determinants influence carotid plaque composition.

Heart failure (HF) poses a heavy burden on patients, their families and society. The syndrome of HF comes in two types: with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). The latter is on the increase and predominantly present in women, especially the older ones. There is an urgent need for mortality-reducing drugs in HFpEF, a disease affecting around 5 % of those aged 65 years and over. HFpEF develops in patients with risk factors and comorbidities such as obesity, hypertension, diabetes, COPD, but also preeclampsia. These conditions are likely to drive microvascular disease with involvement of the coronary microvasculature, which may eventually evolve into HFpEF. Currently, the diagnosis of HFPEF relies mainly on echocardiography. There are no biomarkers that can help diagnose female microvascular disease or facilitate the diagnosis of (early stages of) HFpEF. Recently a Dutch consortium was initiated, Queen of Hearts, with support from the Netherlands Heart Foundation, with the aim to discover and validate biomarkers for diastolic dysfunction and HFpEF in women. These biomarkers come from innovative blood-derived sources such as extracellular vesicles and circulating cells. Within the Queen of Hearts consortium, we will pursue female biomarkers that have the potential for further evolution in assays with point of care capabilities. As a spin-off, the consortium will gain knowledge on gender-specific pathology of HFpEF, possibly opening up novel treatment options.

Background Carotid artery stenting (CAS) is currently associated with an increased risk of 30-day stroke compared with carotid endarterectomy (CEA), whereas both interventions seem equally durable beyond the periprocedural period. Although the clinical outcomes continue to be scrutinized, there are few data summarizing the costs of both techniques. Methods A systematic search was conducted in MEDLINE, Embase and Cochrane databases in August 2016 identifying articles comparing the costs or cost-effectiveness of CAS and CEA in patients with carotid artery stenosis. Combined overall effect sizes were calculated using random-effects models. The in-hospital costs were specified to gain insight into the main heads of expenditure associated with both procedures. Results The literature search identified 617 unique articles, of which five RCTs and 12 cohort studies were eligible for analysis. Costs of the index hospital admission were similar for CAS and CEA. Costs of the procedure itself were 51 per cent higher for CAS, mainly driven by the higher costs of devices and supplies, but were balanced by higher postprocedural costs of CEA. Long-term cost analysis revealed no difference in costs or quality of life after 1 year of follow-up. Conclusion Hospitalization and long-term costs of CAS and CEA appear similar. Economic considerations should not influence the choice of stenting or surgery in patients with carotid artery stenosis being considered for revascularization.

Item does not contain fulltext AIMS/HYPOTHESIS: The aim of this work was to investigate whether measurement of the mean common carotid intima-media thickness (CIMT) improves cardiovascular risk prediction in individuals with diabetes. METHODS: We performed a subanalysis among 4,220 individuals with diabetes in a large ongoing individual participant data meta-analysis involving 56,194 subjects from 17 population-based cohorts worldwide. We first refitted the risk factors of the Framingham heart risk score on the individuals without previous cardiovascular disease (baseline model) and then expanded this model with the mean common CIMT (CIMT model). The absolute 10 year risk for developing a myocardial infarction or stroke was estimated from both models. In individuals with diabetes we compared discrimination and calibration of the two models. Reclassification of individuals with diabetes was based on allocation to another cardiovascular risk category when mean common CIMT was added. RESULTS: During a median follow-up of 8.7 years, 684 first-time cardiovascular events occurred among the population with diabetes. The C statistic was 0.67 for the Framingham model and 0.68 for the CIMT model. The absolute 10 year risk for developing a myocardial infarction or stroke was 16% in both models. There was no net reclassification improvement with the addition of mean common CIMT (1.7%; 95% CI -1.8, 3.8). There were no differences in the results between men and women. CONCLUSIONS/INTERPRETATION: There is no improvement in risk prediction in individuals with diabetes when measurement of the mean common CIMT is added to the Framingham risk score. Therefore, this measurement is not recommended for improving individual cardiovascular risk stratification in individuals with diabetes.

ObjectivesThis study assessed the value of cerebral near-infrared spectroscopy (NIRS) and transcranial Doppler (TCD) in relation to electroencephalography (EEG) changes for the detection of cerebral hypoperfusion necessitating shunt placement during carotid endarterectomy (CEA).MethodsThis was a prospective cohort study. Patients with a sufficient TCD window undergoing CEA from February 2009 to June 2011 were included. All patients were continuously monitored with NIRS and EEG. An intraluminal shunt was placed, selectively determined by predefined EEG changes in alpha, beta, theta, or delta activity. Relative changes in regional cerebral oxygen saturation (rSO2) in the frontal lobe and mean blood flow velocity (Vmean) 30 seconds before carotid cross-clamping versus 2 minutes after carotid cross-clamping were related to shunt placement. Receiver operating characteristic curve analysis was performed to determine the optimal thresholds. Diagnostic values were reported as positive and negative predictive value (PPV and NPV).ResultsOf a cohort of 151 patients, 17(11%) showed EEG changes requiring shunt placement. The rSO2 and Vmean decreased more in the shunt group than in the non-shunt group (mean ± standard error of the mean) 21 ± 4% versus 7 ± 5% and 76 ± 6% versus 12 ± 3%, respectively (p

Introduction We assessed the added value of multiple imputation (MI) of missing values in longitudinal datasets with carotid intima-media thickness (CIMT) as primary endpoint subsequently analysed with linear mixed effects (LME) models. Methods Analyses were based on a subset of 300 participants from the METEOR (Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin) trial. CIMT measurements were performed at 12 carotid sites over seven examinations. The “true” difference in rate of change in CIMT between rosuvastatin and placebo was derived from a completed dataset. Scenarios with missing values were defined, both MCAR (Missing Completely At Random) and MAR (Missing at Random), with 10 to 60% missing values, related to, among others, age and treatment allocation. LME analyses were performed with and without preceding MI. The added value of MI was assessed by comparing the LME estimates with the true value in terms of bias and precision. Results Bias in point estimates for LME analysis with and without preceding MI was similar in scenarios with ≤40% missings. With 60% missing values, LME without MI was superior to LME with MI. Coverage of the 95% CIs was similar for LME with and without MI for all scenarios. Conclusion Applying MI prior to LME analyses on longitudinal CIMT measurements does not increase precision or reduce bias in the estimated differences in rates of change in CIMT. Hence, MI has no added value in this context, and direct application of LME remains the preferred method in trials using CIMT as primary endpoint.