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Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): EPIC Norfolk was supported by the Medical Research Council UK (programme grants numbers MRC G0401527, MRC G0701863, MRC G1000143) and Cancer Research UK (programme grant number CRUK 8257). Introduction The Systematic COronary Risk Evaluation 2 – Older Persons (SCORE2-OP) algorithm is developed to assess 10-year risk of fatal and non-fatal cardiovascular disease (CVD) in apparently healthy individuals aged ≥70 years. We evaluated the performance of SCORE2-OP in the European Prospective Investigation of Cancer Norfolk (EPIC-Norfolk) prospective population cohort. Purpose To validate the SCORE2-OP model in men and women aged 70-80 years without prior myocardial infarction or stroke. Methods We included individuals aged 70-80 without prior myocardial infarction or stroke. We compared SCORE2-OP (low-risk algorithm) calculated 10-year risk with 10-year observed event rates in the EPIC-Norfolk cohort. SCORE2-OP was calculated using baseline EPIC-Norfolk data (1993-1997). Cardiovascular events were defined as a composite outcome of (i) death due to ischemic heart disease, cardiac failure, cerebrovascular disease or peripheral-artery disease, (ii) non-fatal myocardial infarction or (iii) non-fatal stroke. Observed rates were adjusted for competing fatal events. We evaluated discriminative power using C-statistic and calibration by plotting predicted versus observed event rates and calculating the observed/predicted ratios. Results SCORE2-OP was evaluated in 3,712 individuals (54% women) with a median (IQR) age of 73 (72-75) years. Ten-year SCORE2-OP was 10.3% (95% confidence interval (CI) 10.2-10.4) versus observed CVD of 16.8% (95% CI 15.6-18.0), yielding a ratio of 1.6 (95% CI 1.5-1.7). Observed events consisted of 9.4% (95% CI 8.4-10.3) fatal CVD events, 10.6% (95% CI 9.6-11.5) non-fatal myocardial infarctions, 10.5% (95% CI 9.5-11.5) non-fatal strokes, adjusted for 68.9% (95% CI 67.4-70.4) competing mortality events. C-statistic was 0.60 (95% CI 0.58-0.63), with a calibration plot demonstrating underestimation of risk across sex and risk groups.(Figure). Conclusion SCORE2-OP underestimates risk in individuals aged 70-80 years, and demonstrates suboptimal discriminative ability. However some underestimation of risk is to be expected given the EPIC-Norfolk baseline between 1993-1997, a low SCORE2-OP calculated risk should not be used as a standalone argument to withhold preventive efforts in older individuals.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): EPIC-Norfolk is supported by programme grants from the Medical Research Council UK (MRC G0401527, MRC G0701863, MRC G1000143) and Cancer Research UK (CRUK 8257). Introduction The latest European guidelines recommend the use of the Systematic COronary Risk Evaluation 2 (SCORE2) to assess 10-year risk of fatal and non-fatal cardiovascular disease (CVD) in individuals aged 40-70 years. Therefore, validation of the SCORE2 algorithm in a large population is needed. Purpose To assess the predictive performance of SCORE2 in individuals without prior myocardial infarction, stroke or diabetes mellitus. Methods Individuals aged 40-70 without prior myocardial infarction, stroke or diabetes mellitus were included from the European Prospective Investigation of Cancer Norfolk (EPIC-Norfolk) prospective population cohort. We assessed discriminative power using the C-statistic; calibration was assessed by plotting calculated SCORE2 (low-risk algorithm) 10-year risks against observed CVD event rates. We defined the composite cardiovascular outcome as death due to ischemic heart disease, cardiac failure, cerebrovascular disease or peripheral-artery disease, or non-fatal myocardial infarction or non-fatal stroke. Observed probabilities were adjusted for competing mortality events. Results We included 20,318 individuals (56% women) with a median (IQR) age of 56 (50-63) years, with baseline measures between 1993-1997. Mean predicted 10-year risk was 3.7% (95% confidence interval (CI) 3.7-3.8) versus adjusted observed 4.2% (95% CI 3.9-4.5) 10-year CVD incidence, yielding a ratio of 1.1 (95% CI 1.1-1.2).(Figure) Observed events consisted of 1.5% (95% CI 1.3-1.7) fatal CVD events, 1.8% (95% CI 1.6-2.0) non-fatal myocardial infarctions, 1.5% (95% CI 1.3-1.6) non-fatal strokes and 23.4% (95% CI 22.1-23.2) competing mortality events. Overall C-statistic was 0.75 (95% CI 0.73-0.77). Conclusion SCORE2 demonstrates reasonable discriminative ability and accurate risk estimations in low-risk individuals in a large, prospective population cohort. However, as actual CVD incidence is expected to be lower given the baseline between 1993-1997, these findings do not indicate that SCORE2 is suitable for current use for risk assessment in individuals from the United Kingdom.

Aims: To identify the most effective dietary pattern for improving cardiovascular risk factors in people with type 2 diabetes. Methods: PubMed, Embase, the Cochrane library, SCOPUS and Web of Science were systematically searched for randomized controlled trials comparing the effects of dietary patterns on body weight, blood pressure, HbA1c and lipids after 6 and 12 months. Treatment effects were synthesized using Bayesian network meta-analysis. Six-month changes in HbA1c, SBP and LDL-C were used to estimate relative risk reductions (RRR) for cardiovascular events. Results: Seventy-three RCTs on eight different dietary patterns were included. All reduced body weight and HbA1c after 6 months, with the largest effects from the low carbohydrate (body weight −4.8 kg, 95 %credibility interval (95 %CrI) −6.5;−3.2 kg) and Mediterranean diet (HbA1c −1.0 %, 95 %CrI -15;−0.4 % vs usual diet). There were no significant 6-month blood pressure or lipid effects. Dietary patterns had non-statistically significant 12-months effects. The Mediterranean diet resulted in the largest expected RRR for cardiovascular events: −16 % (95 %CI -31;3.0) vs usual diet. Conclusions: In patients with type 2 diabetes, all dietary patterns outperformed usual diet in improving body weight and HbA1c after 6 months and clinically relevant cardiovascular risk reduction could be achieved. There was insufficient evidence to select one optimal dietary pattern.

Background Type 2 diabetes is a condition associated with a state of low-grade inflammation caused by adipose tissue dysfunction and insulin resistance. High sensitive-CRP (hs-CRP) is a marker for systemic low-grade inflammation and higher plasma levels have been associated with cardiovascular events in various populations. The aim of the current study is to evaluate the relation between hs-CRP and incident cardiovascular events and all-cause mortality in high-risk type 2 diabetes patients. Methods Prospective cohort study of 1679 type 2 diabetes patients included in the Second Manifestations of ARTerial disease (SMART). Cox proportional hazard models were used to evaluate the risk of hs-CRP on cardiovascular events (composite of myocardial infarction, stroke and vascular mortality) and all-cause mortality. Hs-CRP was log-transformed for continuous analyses. Findings were adjusted for age, sex, BMI, current smoking and alcohol use, non-HDL-cholesterol and micro-albuminuria. Results 307 new cardiovascular events and 343 deaths occurred during a median follow-up of 7.8 years (IQR 4.2–11.1). A one unit increase in log(hs-CRP) was related to an increased vascular- and all-cause mortality risk (HR 1.21, 95% CI 1.01–1.46 and HR 1.26, 95% CI 1.10–1.45 respectively). No relation was found between log(hs-CRP) and myocardial infarction or stroke. The relations were similar in patients with and without previous vascular disease. Conclusion Low grade inflammation, as measured by hs-CRP, is an independent risk factor for vascular- and all-cause mortality but not for cardiovascular events in high-risk type 2 diabetes patients. Chronic low-grade inflammation may be a treatment target to lower residual cardiovascular risk in type 2 diabetes patients.

Background Individuals with cardiovascular disease (CVD) are at increased risk of cancer compared to the general population. Adipose tissue dysfunction, as a consequence of excess adipose tissue, contributes to this risk via production of several hormones and cytokines. Whether the high risk of cancer in people with type 2 diabetes (T2D) is mainly attributable to the quantity of adipose tissue or the degree of adipose tissue dysfunction, is unknown. Purpose To assess the relation between the quantity of adipose tissue and adipose tissue dysfunction and the risk of cancer in a cohort of patients at high risk of CVD, with and without T2D. Methods 10792 participants from the UCC-SMART study were included for this prospective cohort study, including 7026 individuals with a history of CVD and 1769 individuals with pre-existent T2D. The effect of quantitative measures of adiposity [BMI, waist circumference and ultrasonographically determined visceral adipose tissue (VAT)] and of the degree of adipose tissue dysfunction on the risk of cancer was assessed using Cox proportional hazards models adjusted for confounders. Adipose tissue dysfunction was quantified by metabolic dysfunction (modified metabolic syndrome criteria with waist circumference replaced by hsCRP), the estimated glucose disposal rate (eGDR, a measure of insulin resistance), and HOMA-IR (only in people without T2D). Potential effect modification by T2D was tested by adding an interaction term to the models. Results During a median of 8.6 (IQR 5.0–12.8) years of follow-up, 1164 individuals were diagnosed with cancer, of which 219 individuals had pre-existent T2D. Incidence rates were 14.0 and 11.6 per 1000 person-years for people with and without T2D, respectively. Increases per SD in BMI [HR 0.98 (95% CI 0.92–1.05)], waist circumference [HR 1.01 (95% CI 0.95–1.09)] and VAT [HR 1.03 (95% CI 0.97–1.10)] were not significantly associated with an increased risk of cancer. These relations were not different for people with and without T2D (p>0.05). Metabolic dysfunction was associated with a higher risk of cancer [4–5 vs. 0–1 components: HR 1.14 (95% CI 1.03–1.25)]. The relation between eGDR and incident malignancy was different for people without T2D [HR 0.97 (95% CI 0.93–1.01)] than for people with T2D [HR 1.06 (95% CI 0.97–1.16)] (p=0.04), with this last relation being more pronounced in people with a higher amount of VAT. No significant relation was observed between HOMA-IR and the risk of cancer in people without T2D [HR 0.99 (95% CI 0.96–1.02)]. Conclusion Adipose tissue dysfunction, assessed by the degree of metabolic dysfunction, is associated with a higher risk of cancer in people at high risk of CVD. No significant associations were observed for quantitative measures of adiposity. The higher risk of cancer among individuals with adipose tissue dysfunction warrants awareness among clinicians and emphasizes the importance of obesity prevention. Funding Acknowledgement Type of funding sources: None.

Background The 2021 ESC guideline on cardiovascular disease (CVD) prevention qualitatively categorizes moderate and severe chronic kidney disease (CKD) as high and very-high CVD risk status regardless of other factors like age and does not include estimated glomerular filtration rate (eGFR) and albuminuria in its algorithms, SCORE2 and SCORE2-OP, to predict CVD risk. Purpose To develop and validate an “Add-on” to incorporate CKD measures into these algorithms, using a validated approach. Methods In 3,054,840 participants from 34 datasets, we developed three Add-ons (eGFR only, eGFR + urinary albumin-to-creatinine ratio [ACR] [the primary Add-on], and eGFR + dipstick proteinuria) for SCORE2 and SCORE2-OP. We validated c-statistics and net reclassification improvement (NRI), accounting for competing risk of non-CVD death, in 5,995,067 participants from 33 different datasets. Results In the target population of SCORE2 and SCORE2-OP without diabetes, the CKD Add-on (eGFR only) and CKD Add-on (eGFR + ACR) improved c-statistic by 0.006 (95% CI 0.005–0.008) and 0.018 (0.012–0.024), respectively, for SCORE2 and 0.012 (0.009–0.015) and 0.023 (0.013–0.032), respectively, for SCORE2-OP. Similar results were seen when we included individuals with diabetes and tested the CKD Add-on (eGFR + dipstick). In 57,485 European participants with CKD, SCORE2 or SCORE2-OP with a CKD Add-on showed a significant NRI (e.g., 0.100 [0.062–0.138] for SCORE2) compared to the qualitative approach in the ESC guideline. Conclusion Our Add-ons with CKD measures improved CVD risk prediction beyond SCORE2 and SCORE2-OP. This approach will help clinicians and patients with CKD refine risk prediction and further personalize preventive therapies for CVD. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): US National Kidney Foundation funding as well as US NIDDK

Introduction Current primary prevention strategies in cardiovascular (CV) disease focus on initiating preventive interventions in people at high 10-year risk of CV mortality. However, initiating such strategies should be beneficial not only in the first 10 years, but throughout life. Established risk algorithms estimate the risk of 10-year CV mortality, but limited evidence is available about the relationship between 10-year and longer-term CV mortality. Purpose To compare cumulative incidence of CV mortality in a population cohort at 10- and 20-years follow-up, stratified by sex. Methods We analysed CV mortality at 10-years and 20-years follow-up using Kaplan-Meier estimates among men and women aged 39–70 years without baseline CV disease or diabetes mellitus in the large, prospective population-based EPIC-Norfolk cohort. CV mortality included death with as underlying or contributing cause ischaemic heart disease, heart failure, cerebrovascular disease or peripheral artery disease. Results We analysed data from 20,453 participants (56% women), with a mean age of 56±8 years, and median (IQR) follow-up of 22 (21–23) years. At baseline, there were no clinically relevant differences in CV risk factors between men and women. Overall cumulative CV mortality rate was 1.9% (384 deaths) in the first 10 years, and 7.3% (995 deaths) at 20 years follow-up (ratio 3.8). Among men, 10-year CV mortality was 2.9% (249 deaths), and 9.6% (785 deaths) at 20 years follow-up (ratio 3.3). Among women, CV mortality was 1.2% (135 deaths) at 10 year and 5.5% (594 deaths) at 20 years follow-up (ratio 4.6). Conclusion We observed an incremental increase in CV mortality beyond the 10-year scope of current established CV risk algorithms. At 20 years follow-up, CV mortality rates were 3–5 times higher compared with the first decade, indicating that 20-year CV mortality risk for both men and women cannot simply be estimated based on extrapolation of 10-year risk. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): EPIC-Norfolk is supported by programme grants from the Medical Research Council UK (MRC G0401527, MRC G0701863, MRC G1000143) and Cancer Research UK (CRUK 8257).

Introduction The associations between measures of body adiposity body mass index (BMI) and waist circumference (WC) and cardiovascular disease (CVD) mortality have been frequently studied and usually follow a J-shaped curve or show a positive relationship. However, less is known about the influence of diet and physical activity on these associations. Purpose We aimed to gain insight in potential lifestyle-related effect modifiers of the association of BMI and WC with CVD mortality in myocardial infarction (MI) patients. Methods We included 4,837 Dutch patients from the Alpha Omega Cohort with a MI Results Of the study population (69.0±5.6 y), 17% smoked, 21% had diabetes, 22% were female and >85% used any type of cardiovascular medication. During a median follow-up of 12.4 years [8.5–13.8], 1,010 deaths occurred due to CVD. A J-shaped continuous association was observed between BMI and CVD mortality with inverse associations for a BMI between 25–30 kg/m2, compared to 25 kg/m2. The nadir (HR, 95% CI) was 27.4 kg/m2 (HR: 0.94, 95% CI: 0.88, 1.00) (A). For WC, a non-linear association was observed with CVD mortality with higher mortality risks for a WC above 100 cm (A). Results were similar in patients with low versus high diet quality and in patients with low versus high physical activity (B), interaction terms were not significant (all p>0.55). Conclusion In MI patients, a BMI between 25–30 kg/m2 was associated with the lowest risk of CVD mortality. A WC above 100 cm was associated with a higher CVD mortality risk. The observed associations manifested independently of diet quality and physical activity level. Therefore, body adiposity seems to determine CVD mortality risk independently of underlying lifestyle factors. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Regio Deal Foodvalley

Background The life expectancy free of cardiovascular disease (CVD) in individuals without previous CVD can be estimated with the LIFEtime-perspective CardioVascular Disease (LIFE-CVD) model, as recommended by the 2021 ESC CVD prevention guidelines. Our aim was to systematically recalibrate the LIFE-CVD model to four European risk regions using contemporary and representative registry data. Methods and results The LIFE-CVD model was systematically recalibrated to four distinct risk regions within Europe, using representative aggregate data on age- and sex-specific expected CVD and non-CVD mortality incidences and risk factor distributions. For external validation, 1,451,077 individuals without previous CVD were included from seven European cohorts, with 53,721 CVD events and 62,902 non-CVD deaths during follow up. After applying the recalibrated risk prediction models to external validation cohorts, C-indices (figure 1) ranged from 0.670 (95% CI 0.650–0.690) to 0.787 (95% CI 0.785–0.789). Predicted risks matched the observed risks in the CPRD data. With the recalibrated LIFE-CVD model, the estimated gain in CVD-free life expectancy from preventive therapy differed per region, for example a 50-year-old smoking women with a systolic blood pressure of 140mm Hg was estimated to gain 0.4 years of CVD-free life from 10 mm Hg SBP reduction in the low risk region, whereas this would be 1.5 years in the very high risk region (figure 2). Interpretation By taking into account geographical differences in CVD incidence, the recalibrated LIFE-CVD model provides a more accurate tool for the prediction of lifetime risk and CVD-free life expectancy for individuals without previous CVD, facilitating shared decision-making in cardiovascular prevention options as recommended by the 2021 European Prevention Guidelines. Funding Acknowledgement Type of funding sources: None.

Background In clinical practice, factors known to be associated with cardiovascular disease (CVD) like albuminuria, education level, or coronary calcium score are not directly incorporated in cardiovascular risk prediction models. The aim of the current study was to quantify the added value of potential risk modifying characteristics when added to the SCORE2 algorithm for individuals without diabetes mellitus (DM) or prior CVD. Methods and results Individuals without previous CVD or DM were included from the ARIC, MESA, EPIC-NL and HNR studies (n=46,285) in whom 2,177 CVD events and 2,062 non-cardiovascular deaths were observed over exactly 10.0 years of follow-up. The effect of each possible risk modifying characteristic was derived using Fine and Gray models that included an offset term for the SCORE2 linear predictor. The risk modifying characteristics were applied to individual predictions using the “naïve approach”, which modifies predicted risks based on the population prevalence and the SHR of the relevant predictor. Subdistribution hazard ratios are presented in the table. External validation was performed in the CPRD cohort (UK, n=518,015, 12,675 CVD events). In the external validation, adjustment of SCORE2 predicted risks with both single and with all available risk modifiers did not negatively affect calibration (see figure) and led to a modest increase in discrimination (C-index 0.742 [95% CI 0.737–0.746] versus unimproved SCORE2 risk C-index 0.737 [95% CI 0.732–0.741]). The net reclassification index or adding all these predictors was +0.032 (95% CI 0.025; 0.028) for future events and −0.008 (95% CI −0.009; −0.007) for future non-events. The coronary calcium score was found to the single strongest added predictor. Interpretation The current analysis presents a method on how to integrate possible risk modifying characteristics that are not included in existing CVD risk models for the prediction of CVD event risk in apparently healthy people. This flexible methodology improves the accuracy of predicted risks and increases applicability of prediction models for individuals with additional risk known modifiers Funding Acknowledgement Type of funding sources: None.

For decades, a fasting lipid profile was required to predict the cardiovascular risk of patients. This was due to the assumption that if low-density lipoprotein cholesterol (LDL-C) is calculated with the Friedewald Formula, LDL-C is dependent on the triglycerides concentration, which can vary after fat consumption. However, several prospective studies show minimal differences of lipid values in fasting and non-fasting lipid profiles. There is also evidence that a non-fasting lipid profile is equally accurate in the prediction of cardiovascular risk. Only in select cases, such as non-fasting triglycerides8 mmol/l (708 mg/dl), it is advised to obtain a fasting lipid profile. In conclusion, it is not a necessity to obtain a fasting lipid profile for determining cardiovascular risk. This has many advantages for patients, laboratories and physicians.

Background The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial has demonstrated that adding low-dose rivaroxaban to aspirin in patients with stable atherosclerotic disease on average reduces recurrence of cardiovascular disease (CVD) events, but increases the risk of major bleeding. For clinical practice, it is important to be able to weigh the absolute benefit from the intervention in terms of lower cardiovascular risk against the absolute increase in risk for major bleeding. Purpose The aim of this study was to estimate the individual lifetime benefit and harm of adding low-dose rivaroxaban to aspirin in patients with stable cardiovascular disease by predicting individual months free from CVD events gained and individual months free from major bleeding lost. Methods Analyses were based on data of patients with established CVD in the COMPASS trial (n=27,390) and SMART prospective cohort study (n=8,139). The externally validated lifetime SMART-REACH model for recurrent CVD was used to predict life expectancy free of stroke and myocardial infarction, based on the following predictors: sex, current smoking, diabetes mellitus, systolic blood pressure, total cholesterol, creatinine, number of locations of CVD, history of atrial fibrillation, and history of congestive heart failure. A new Fine & Gray competing-risk adjusted Cox proportional hazard model was derived in the COMPASS study population for prediction of life expectancy free from major bleeding, including the same predictors as the SMART-REACH model and additionally ethnicity, geographical region, and history of bleeding requiring transfusion. These lifetime estimates were then combined with hazard ratios from the COMPASS trial to estimate lifetime treatment effects from adding low-dose rivaroxaban to aspirin, expressed in terms of 1) months free from stroke or myocardial infarction gained, and 2) months free from major bleeding lost. Results External goodness-of-fit of the SMART-REACH model in the COMPASS study was sufficient. The newly developed major bleeding risk model also showed sufficient external goodness-of-fit in the SMART cohort. The median predicted individual gain in life-expectancy free of stroke or MI from added low-dose rivaroxaban was 16 months (range 1–48 months), while the median predicted individualized lifetime lost in terms of major bleeding was 2 months (range 0–20 months) (Figure 1A). Predicted benefit was higher than predicted harm in more than 90% of the study population. An interactive calculator for use in clinical practice will be made available (example in figure 1B). Figure 1 Conclusions There is a wide distribution in lifetime gain and harm from adding low-dose rivaroxaban to aspirin in individual patients with stable CVD. Using these lifetime models, benefits and bleeding risk can be weighed for and with each individual patient, to support treatment decision making in clinical practice.

Background Chronic systemic low-grade inflammation, measured by elevated plasma concentrations of high sensitive C-reactive Protein (CRP), is a risk factor for cardiovascular disease (CVD). There is evidence that systemic low-grade inflammation is also related to a higher risk of cancer. Purpose In the present prospective cohort study the relation between systemic low-grade inflammation and risk of cancer was evaluated in patients with clinically manifest vascular disease. Methods In total 7178 patients from the SMART cohort with manifest cardiovascular disease and plasma CRP levels ≤10 mg/L were included. Data of the cohort were linked to the Dutch national cancer registry. Cox regression models were fitted to study the relation between CRP and incident cardiovascular disease as well as incident cancer. Cancer types were classified according to anatomical location of origin, as well as histopathological subtype, irrespective of their anatomical location of origin. To adjust for potential confounding, age, sex, smoking status, packyears of smoking, and body mass index were added to the models, and additional cardiovascular risk factors, including diabetes mellitus, and systolic blood pressure. Results After a median follow-up time of 8.3 years (interquartile range 4.6–12.3) 1289 recurrent cardiovascular events (myocardial infarction, stroke, or vascular mortality) and 1072 incident cancer diagnoses were observed. CRP level was related to recurrent cardiovascular disease risk (HR 1.57; 95% CI 1.35–1.82) (Figure 1A), as well as risk of CVD and/or cancer (HR 1.45; 95% CI 1.29–1.62) (Figure 1B) comparing the third tertile of CRP to the first tertile. CRP concentration was related to total cancer risk (HR 1.33; 95% CI 1.13–1.55 for the third tertile of CRP compared to the first tertile) (Figure 1C). Especially incident lung cancer, independent of histopathological subtype, was related to CRP level (HR 2.64; 95% CI 1.77–3.93 for the third tertile of CRP compared to the first) (Figure 1D). No effect modification by smoking status or years of smoking cessation was observed of the relation between CRP and lung cancer (p-values for interaction >0.05). Incidence of epithelial neoplasms and especially squamous cell neoplasms were related to CRP concentration, irrespective of their anatomical location of origin (HR 1.17; 95% CI 1.08–1.27, and HR 1.11; 95% CI 1.02–1.20 for 1 mg/L higher CRP level respectively). Sensitivity analyses accounting for reverse causality by excluding patients with a cancer diagnosis within 1 and within 2 years of follow up showed similar results. Kaplan Meier curves per CRP tertile Conclusion Chronic systemic low-grade inflammation, measured by plasma CRP levels ≤10mg/L, is a risk factor for incident cancer, markedly lung cancer, independent of smoking status, in patients with stable cardiovascular disease.

Background Increased left ventricular mass (LVM) is known to predict cardiovascular morbidity and mortality. LVM is high in patients with advanced kidney disease. Our aim was to study the relationship between renal parameters and LVM in hypertensive subjects at high risk of cardiovascular disease. Design Cardiac MRI was performed in 527 patients participating in the single-centre SMART cohort study. Participants free from previous symptomatic coronary heart disease but with a history of hypertension were recruited. Subjects were screened for cardiovascular risk factors in a standardized way. Multivariable linear regression was used to study the relationship of both estimated glomerular filtration rate (eGFR) and presence of albuminuria with left ventricular mass. Results Mean LVM was 121 g for men (SD 26) and 87 g for women (SD 20). Mean eGFR was 82 mL/min/1·73 m² (SD 19). A total of 73 patients (14%) had albuminuria. After adjusting for known determinants of LVM (height, weight, sex and age) eGFR did not relate to LVM while presence of albuminuria did (mean change in LVM per 10 mL/min/1·73 m2 change in eGFR 0·79 g, 95% CI −0·33 to 1·91, P = 0·17, mean change in LVM in presence vs. absence of albuminuria 9·9 g, 95% CI 4·33 to 15·45, P = 0·001). Additional adjustment for systolic blood pressure did not change results (B for eGFR 0·54, 95% CI −0·58 to 1·66, P = 0·35, B for albuminuria 9·09, 95% CI 3·57 to 14·60, P = 0·001). Conclusions In this study in hypertensive patients with high vascular risk, albuminuria was related to increased LVM and eGFR was not.

Syncope can be caused by a pulmonary embolism. This applies in particular to elderly patients admitted with syncope; in the general population, however, syncope is far more frequently caused by a vasovagal response or orthostatic hypotension. Syncope can be the symptom of a pulmonary embolism, even in the absence of any clinical manifestations of this diagnosis; it is, therefore, important to exclude pulmonary embolism in any syncope patient in the accident and emergency department by applying the Wells clinical decision rule. GPs should also be alert to syncope as a possible symptom of pulmonary embolism, and be alert to breathing rate and signs of venous thrombosis.

Background Previous studies suggest that elevated resting heart rate (RHR) is related to an increased risk of cancer mortality. The aim of this study was to evaluate the relation between RHR and cancer incidence and mortality in patients with vascular disease. Methods Patients with manifest vascular disease ( n =6007) were prospectively followed-up for cancer incidence and mortality. At baseline, RHR was obtained from an electrocardiogram. The relation between RHR and cancer incidence, cancer mortality and total mortality was assessed using competing risks models. Results During a median follow-up of 6.0 years (interquartile range: 3.1–9.3) 491 patients (8%) were diagnosed with cancer and 907 (15%) patients died, 248 (27%) died from cancer. After adjustment for potential confounders, the hazard ratio (HR) for incident cancer per 10beats/min increase in RHR was 1.00 (95% confidence interval [CI]: 0.93–1.07). There was a trend toward an increased risk of colorectal cancer in patients with higher RHR (HR 1.15, 95% CI 0.97–1.36). The risk of all-cause mortality was increased in patients in the highest quartile of RHR compared to the lowest quartile (HR 1.86, 95% CI 1.53–2.27), but no effect of RHR on cancer mortality was observed (HR 1.01, 95% CI 0.70–1.46). Conclusions In patients with manifest vascular disease, elevated RHR was related to a higher risk of premature all-cause mortality, but this was not due to increased cancer mortality. RHR was not related to risk of overall cancer incidence, although a relation between elevated RHR and incident colorectal cancer risk could not be ruled out.

Objectives A remarkable variation exists in the cardiometabolic consequences of obesity. We evaluated the separate and combined effects of adiposity and cardiometabolic dysfunction on the occurrence of cardiovascular events and mortality in patients with vascular disease. Methods We prospectively followed 5231 patients with a history of clinical cardiovascular disease without diabetes from the Second Manifestations of ARTerial disease (SMART) study. Patients were classified according to body mass index and cardiometabolic function. The presence of cardiometabolic dysfunction was defined as ≥3 of the modified National Cholesterol Education Program (NCEP) metabolic syndrome criteria (waist circumference replaced by elevated C-reactive protein). Cox proportional-hazards analysis was used to estimate HRs for cardiovascular events and mortality. Results The prevalence of cardiometabolic dysfunction was 40% in normal weight, 58% in overweight and 75% in obese patients. During a median follow-up of 6.1 years, 769 patients died and 705 patients experienced a major cardiovascular event. In the absence of cardiometabolic dysfunction, overweight (HR 1.18, 95% CI 0.90 to 1.55) and obese patients (HR 0.93, 95% CI 0.53 to 1.64) were not at increased risk of recurrent major cardiovascular events compared with normal weight patients without cardiometabolic dysfunction. An increased cardiovascular risk was observed in patients with cardiometabolic dysfunction and normal weight (HR 1.58, 95% CI 1.23 to 2.04), overweight (HR 1.35, 95% CI 1.07 to 1.70) and obesity (HR 1.50, 95% CI 1.12 to 2.00) compared with normal weight patients without cardiometabolic dysfunction. A similar pattern was observed for vascular and all-cause mortality. Conclusions In patients with vascular disease, the cardiometabolic consequences of adiposity rather than adiposity per se increase the risk of recurrent cardiovascular events and mortality.

BackgroundPlasma triglyceride (TG) levels are known to confer an increased risk of vascular disease in healthy populations, but data in high-risk patients are scarce. In this study we evaluated the risk on recurrent vascular events conferred by increased plasma TG levels in patients with various clinical manifestations of vascular disease.MethodsProspective cohort study of 5731 patients with clinically manifest vascular disease.ResultsFirst new vascular events (myocardial infarction, ischemic stroke, vascular death) occurred in 782 subjects during a median follow-up of 4.9years (interquartile range 2.5–8.1years). Patients in the highest plasma TG quintile (>2.24mmol/L) had a higher risk for recurrent vascular events (HR 1.45; 95%CI 1.13–1.86) compared with the lowest plasma TG quintile (0.05). Plasma TG still contributed to vascular risk when other lipid levels were at target level.ConclusionsHigher plasma TG levels are associated with increased risk for recurrent vascular events, in particular in CAD patients. This increased risk is independent of the presence of T2DM and the use of lipid-lowering medication and is not modified by other lipid levels.

BACKGROUND: Patients with cardiovascular disease might be at increased risk of non-vascular mortality due to shared risk factors. Our aim was to evaluate causes of death and years of life lost (YLL) in patients with different manifestations of vascular disease. DESIGN: The design was a prospective cohort study. METHODS: A total of 5911 patients with stable coronary artery disease, cerebrovascular disease, peripheral artery disease (PAD), abdominal aortic aneurysm or polyvascular disease were followed-up for mortality. Cause-specific standardised mortality ratios (SMRs) and YLL, compared to the Dutch population, were estimated. Determinants for cause-specific mortality were evaluated using competing risks models. RESULTS: During a median follow-up of 6.0 years (interquartile range (IQR): 3.1-9.2), 958 (16.2%) patients died. All-cause mortality was increased compared to the general population (SMR: 1.26, 95% confidence interval (CI): 1.18-1.34). Patients with PAD and polyvascular disease were at highest risk, especially for ischaemic heart disease (SMR: 2.52, 95% CI: 1.70-3.60 and SMR: 3.97, 95% CI: 3.18-4.90, respectively). Patients with PAD were at increased risk of dying from cancer (SMR: 1.67, 95% CI: 1.25-2.17). On average, patients with vascular disease of ≥50 years died 7.8 years younger than the general population, with 80% of the excess YLL attributable to cardiovascular disease. In middle-aged patients the excess YLL were about 10 years, of which 24% were lost due to cancer. Important determinants for mortality were male gender, smoking, physical inactivity, renal insufficiency and polyvascular disease. CONCLUSIONS: Patients with manifest vascular disease are at increased risk of both cardiovascular and cancer mortality, particularly patients with PAD or polyvascular disease. On average, patients with vascular disease of ≥50 years die 7.8 years younger than the general population.

Obesity is related to left ventricular hypertrophy (LVH). Whether LVH on electrocardiography (ECG-LVH) is a result of increased cardiac electrical activity or due to increased left ventricular mass (LVM) remains to be determined. The aims of the present study were to investigate the relation between obesity and ECG-LVH and LVM by magnetic resonance imaging (MRI-LVM) in patients with hypertension and to investigate the relation of insulin resistance (IR) and LVH. Patients with hypertension (n = 421) were evaluated using Sokolow-Lyon voltage, Cornell voltage, and cardiac magnetic resonance imaging. Waist circumference was used as a measure of abdominal obesity. Linear regression analysis revealed an inverse relation (adjusted β = -0.02, 95% confidence interval -0.02 to -0.01) between waist circumference and Sokolow-Lyon voltage, indicating a decrease of 0.02 mV per 1-cm increase in waist circumference. There was a positive relation between waist circumference and MRI-LVM (β = 0.49, 95% confidence interval 0.32 to 0.67). Patients in the highest quartile of LVM had a worse metabolic profile than patients with the Sokolow-Lyon voltage criterion. The relations of IR with ECG-LVH and MRI-LVM were similar to those of waist circumference in relation to ECG-LVH and MRI-LVM. In conclusion, there is an inverse relation between waist circumference and ECG-LVH and a positive relation between waist circumference and MRI-LVM. This study indicates that obesity has a different relation to voltage criteria for LVH compared to anatomic criteria for LVH, supporting the hypothesis that IR decreases electrocardiographic voltages, despite an increase in MRI-LVM. The clinical implication is that especially in patients with IR, Sokolow-Lyon voltage is low in contrast to high MRI-LVM.

AIM: Based on guidelines, patients with established cardiovascular disease are likely to already receive a combination of aspirin, a statin, and blood pressure (BP)-lowering agents. Combining these pharmacological agents into a cardiovascular polypill could be considered in these patients to reduce prescription gaps and non-adherence. We aimed to assess the prevalence of the combined use of aspirin, statin, and BP-lowering agents in patients with established cardiovascular diseases or type 2 diabetes mellitus (DM2) in the period 1996-2009.METHODS: In total, 5702 patients with coronary artery disease (CAD), cerebrovascular disease (CVD), peripheral arterial occlusive disease (PAOD), abdominal aortic aneurysm (AAA) or, DM2 were included in the period 1996-2009.RESULTS: The overall use of combination therapy with aspirin, statin, and ≥ 1 BP-lowering agent increased substantially from 9% in 1996 to 66% in 2009 and ≥ 2 BP-lowering agents increased from 1% to 47%. In 2009, combination therapy with ≥ 1 BP-lowering agent was used by 83% of those with CAD, 48% of those with CVD, 43% of those with PAOD, 36% of the patients with AAA, and 19% of the patients with DM2. In most patient groups, obesity, metabolic syndrome, hypertension concomitant CAD, CVD, or DM2 were related to the use of combination therapy in models adjusted for age and gender.CONCLUSION: A high proportion of patients with established cardiovascular diseases already uses a combination of pharmacological agents. Introduction of a polypill in high-risk patients might be feasible to reduce prescription gaps and increase adherence to indicated therapy.

A relationship between depression and mortality has been well established, but underlying mechanisms remain unclear. We investigated the influence of cerebral small vessel disease (CSVD), characterized by white matter lesions (WMLs) and lacunar infarcts, on the relationship between mood mortality during 6 years follow-up.Mood problems were assessed with the mental component summary of the 36-item Short-Form Medical Outcomes Study in 1110 patients with symptomatic atherosclerotic disease (mean age 59 years). Volumetric WML estimates were obtained with 1.5-T magnetic resonance imaging; lacunar infarcts were scored visually. Cox regression models were adjusted for age, sex, vascular risk, physical functioning, antidepressants and infarcts. We adjusted for CSVD to examine whether it may be an intermediate or confounding factor. Second, we added interaction terms to investigate whether associations differed between patients with CSVD (absent/present).Patients in the lowest quartile of mental functioning, representing most severe mood problems, were at higher, although not significant, risk of death (hazard ratio [HR] = 1.47, 95% confidence interval [CI] = 0.94-2.30) compared with patients in higher quartiles. Adjustment for CSVD did not change this association. Lacunar infarcts, not WML, modified the association of mood problems with mortality (p value for interaction = .01); mood problems strongly increased the risk of mortality in patients with lacunar infarcts (HR = 2.75, 95% CI = 1.41-5.38) but not in those without it (HR = 0.78, 95% CI = 0.39-1.57).Patients with lacunar infarcts may be especially vulnerable for the effect of mood problems on mortality.

Summary. Aims: Atherosclerosis is the most frequent cause of coronary artery disease (CAD), cerebrovascular disease (CVD), and peripheral arterial obstructive disease (PAD). We previously found that patients with CVD or PAD had a two-fold higher risk of major hemorrhagic complications than patients with CAD. We investigated whether this difference was attributable to baseline risk factors or genetic variants involved in hemostasis. Methods and results: We included 2622 consecutive patients from a single university hospital who presented with non-disabling CAD, CVD, or PAD. All patients were followed for the occurrence of major hemorrhagic complications for a mean of 6.6 years. Major hemorrhagic events included intracranial hemorrhagic events, fatal hemorrhagic events, and any hemorrhagic complications requiring hospitalization, irrespective of interventions. Major hemorrhagic complications occurred in 122 patients (annual event rate of 0.77%). Patients with CVD or PAD had more hemorrhagic complications than patients with CAD (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.39–3.01). Hypertension, diabetes, renal failure and use of oral anticoagulants or antiplatelet therapy did not explain the difference (HR adjusted for all characteristics 1.74; 95% CI 1.14–2.61). Additional adjustment for genetic variants did not further change the HR. Conclusion: Patients with CVD or PAD are at higher risk for major hemorrhagic events than patients with CAD. This difference could not be explained by known risk factors, use of antithrombotic agents, or genetic variants involved in hemostasis. Further research to find the reason for this difference and possible differences in pathogenesis is warranted.

Adiposity is associated with an increased but also with a decreased risk for successive vascular events or mortality in patients with different manifestations of vascular disease. In this study we directly compare the risk of general adiposity or abdominal obesity on the occurrence of new vascular events or mortality in these patients.Patients with cerebrovascular disease (CVD; n=973), coronary artery disease (CAD; n=2339) or peripheral arterial disease (PAD; n=894) were prospectively followed for the occurrence of a vascular event or death. The median follow-up was 4.5 years. Adiposity was assessed with body mass index (BMI), waist circumference (WC) and determination of intra-abdominal fat through ultrasound. Cox proportional hazards models were used to evaluate the risk for new vascular events, vascular mortality and all-cause mortality.CAD patients had a 12% increased risk for vascular mortality with 1 BMI unit increase (hazard ratio (HR) 1.12; 95% confidence interval (CI) 1.05-1.20) and a 25% increased risk with 1cm increase in intra-abdominal adipose tissue (HR 1.25; 95% CI 1.12-1.39). The risk for all-cause mortality was increased by 3% (HR 1.03; 95% CI 1.01-1.05) with 1 cm increase in WC and was increased by 15% (HR 1.15; 95% CI 1.06-1.25) with 1 cm increase in intra-abdominal adipose tissue. In PAD patients there was an inverse relationship between BMI and vascular mortality (HR 0.93; 95% CI 0.87-0.98) and all-cause mortality (HR 0.90; 95% CI 0.86-0.94). In CVD patients there was no relation between obesity and vascular events or mortality.General adiposity is associated with an increased risk for vascular mortality in CAD patients and a decreased risk for (vascular) mortality in PAD patients.

Aims: To investigate time trends in vascular risk factors and medication use for patients referred to a vascular specialist with manifest vascular disease or type 2 diabetes mellitus (DM2). Methods and results: Change in risk factor profile and medication use at referral over a 12-year period was evaluated and compared between patients with coronary heart disease, cerebrovascular disease, peripheral arterial disease, abdominal aortic aneurysm, and DM2, who participated in the Second Manifestations of ARTerial disease study in the period of 1996-2007. A total of 4731 patients were included (mean age 59+/-11 years, 75% male) in the period 1996-2007. Obesity (body mass index >=30 kg/m2) prevalence increased from 14 to 24%, and no change in smoking behavior was observed. The prevalence of hyperlipidemia (total cholesterol >=4.5 mmol/l or low-density lipoprotein cholesterol >=2.5 mmol/l) at referral declined from 92% in 1996-1997 to 45% in 2006-2007. The proportion of patients with blood pressure above 140/90 mmHg decreased from 66 to 51%. The use of lipid-lowering, blood pressure-lowering, and antithrombotic medication at referral increased over the observation period. Conclusion: An improvement in risk factor profile was seen in patients referred with manifest vascular disease or DM2 over a 12-year period. Nevertheless, the prevalence of modifiable risk factors is still high leaving patients at elevated vascular risk

Low blood pressure (BP) has been related to increased risk of brain atrophy. As brain hypoperfusion might be a marker for impaired cerebral autoregulation, the risk of brain atrophy may be especially increased if BP is low in combination with brain hypoperfusion. We examined whether low BP was associated with brain atrophy and whether this association was stronger in patients with lower parenchymal cerebral blood flow (CBF), as an indicator of brain perfusion.Within the Second Manifestations of ARTerial disease-Magnetic Resonance study, a cohort study among 1309 patients with atherosclerotic disease, cross-sectional analyses were performed in 965 patients (mean age 58 +/- 10 years) with available BP and CBF measures. Parenchymal CBF was measured with magnetic resonance angiography and was expressed per 100 ml brain volume. Brain segmentation was used to quantify cortical gray matter volume and ventricular volume (% of intracranial volume).Linear regression analyses, adjusted for age, sex, and vascular risk factors showed that the association of systolic BP and pulse pressure, but not diastolic BP, with cortical gray matter volume was modified by parenchymal CBF (P interaction0.05). In patients with lower parenchymal CBF, but not in those with high parenchymal CBF, lower systolic BP and pulse pressure (per SD decrease) were associated with reduced cortical gray matter volume: beta (95% confidence interval) -0.29% (-0.63; 0.00) and -0.34% (-0.69; -0.01).Our findings suggest that lower BP by itself is not sufficient to induce brain atrophy; however, lower SBP and lower pulse pressure in combination with lower parenchymal CBF increased the risk for cortical atrophy.

Objective: This study investigated the relation between alcohol consumption and specific vascular events and mortality in a high risk population of patients with clinical manifestations of vascular disease and diabetes. Methods: Patients with clinically manifest vascular disease or diabetes (n= 5447) from the SMART study were followed for cardiovascular events and mortality. Alcohol consumption was assessed with a baseline questionnaire and analysed in relation with coronary heart disease (CHD), amputations, stroke, and all-cause and vascular death. Results: After a follow up of 4.7 years, we documented 363 cases of CHD, 187 cases of stroke, 79 amputations and 641 cases of all-cause death, of which 382 were vascular. In multivariate-adjusted models, alcohol consumption was inversely associated with CHD (plinear trend=0.007) and stroke (plinear trend=0.051) with respective hazard ratios of 0.39 (95%CI: 0.20-0.76) and 0.67 (0.31-1.46) for consuming 10-20 drinks/week compared with abstainers. We observed significant U-shaped associations between alcohol consumption and amputations (pquadratic trend=0.001), all-cause death (pquadratic trend=0.001) and vascular death (pquadratic trend=0.013). Hazard ratios for consuming 10-20 drinks/week were 0.29 (0.07-1.30) for amputations, 0.40 (0.24-0.69) for all-cause death and 0.34 (0.16-0.71) for vascular death compared with abstainers. Similar associations were observed for red wine consumption only. Conclusion: Moderate alcohol consumption (1-2 drinks/day) is not only associated with a reduced risk of vascular and all-cause death in a high risk patients with clinical manifestations of vascular disease, but also with reduced risks of non-fatal events like CHD, stroke and possibly amputations.

Background and aims Both vascular disease and diabetes type 2 (DM2) decrease cognitive functioning in elderly people. It is uncertain if DM2 affects cognition independent of vascular disease. In patients with symptomatic arterial disease, we studied the effect of DM2 on cognition and identified clinical and radiological determinants for impaired cognition in patients with DM2. Methods 766 patients (mean age 58.8 ± 9.5 years; 108 DM2) with symptomatic arterial disease underwent neuropsychological testing. In 542 patients (77 DM2), volumes of brain tissue, ventricles and white matter lesions were obtained by segmentation of brain MR images. Infarcts were distinguished into small (lacunar) or large (cortical or subcortical). Results Patients with arterial disease and DM2 performed worse on neuropsychological tests compared to similar patients without DM2 (adjusted composite z-score: β − 0.14 [− 0.25 to − 0.02]). Insulin treatment, systolic and diastolic blood pressures were significantly associated with cognition in patients with DM2. Large infarcts, global and cortical atrophy on MRI were independently associated with cognition in patients with DM2. Conclusion The presence of DM2 in patients with symptomatic arterial disease is associated with decreased cognitive functioning. Insulin treatment, high blood pressure, brain atrophy and large infarcts were determinants for cognitive dysfunction in patients with DM2 and arterial disease.

We investigated whether total cerebral blood flow (CBF) was associated with brain atrophy, and whether this relation was modified by white matter lesions (WML). Within the Second Manifestations of ARTerial disease-magnetic resonance (SMART-MR) study, a prospective cohort study among patients with arterial disease, cross-sectional analyses were performed in 828 patients (mean age 58±10 years, 81% male) with quantitative flow, atrophy, and WML measurements on magnetic resonance imaging (MRI). Total CBF was measured with MR angiography and was expressed per 100 mL brain volume. Total brain volume and ventricular volume were divided by intracranial volume to obtain brain parenchymal fraction (BPF) and ventricular fraction (VF). Lower BPF indicates more global brain atrophy, whereas higher VF indicates more subcortical brain atrophy. Mean CBF was 52.0±10.2 mL/min per 100 mL, mean BPF was 79.2±2.9%, and mean VF was 2.03±0.96%. Linear regression analyses showed that lower CBF was associated with more subcortical brain atrophy, after adjusting for age, sex, vascular risk factors, intima-media thickness, and lacunar infarcts, but only in patients with moderate to severe WML (upper quartile of WML): Change in VF per s.d. decrease in CBF 0.18%, 95% CI: 0.02 to 0.34%. Our findings suggest that cerebral hypoperfusion in the presence of WML may be associated with subcortical brain atrophy.

Introduction The apolipoprotein E gene ( APOE ) is associated with coronary heart disease and stroke, but the relation with peripheral artery disease (PAD) is unknown. We investigated the relation of APOE genotype with PAD and other types of vascular disease. Methods The cross-sectional association between APOE genotype and ankle-brachial index (ABI) and vascular disease prevalence; and the prospective relation with incident PAD and other types of vascular disease (coronary artery disease, stroke and vascular mortality) were evaluated in 7418 patients from the Secondary Manifestations of ARTerial disease (SMART) study. This is a prospective cohort study in patients with cardiovascular disease or a cardiovascular risk factor. Analyses were adjusted for age and sex. Results Mean age was 56.7 ± 12.4 years and 68% of the patients was male. APOE genotype frequencies were e2e2 1.3%; e2e3 9.9%; e2e4 2.4%; e3e3 56.9%; e3e4 26.7% and e4e4 2.8%. Median follow-up time was 8.1 years (IQR 5.4–11.4) in which 452 new PAD events occurred. The e2e2 genotype was significantly associated with a lower ABI (regression coefficient −0.04, 95%CI −0.07 to −0.01), increased PAD prevalence (prevalence ratio 1.54, 95%CI 1.01–2.17) and a higher risk of incident PAD (HR 2.31, 95%CI 1.29–4.12) compared with e3e3. No relations between APOE genotypes and other vascular disease were observed. Conclusion Of the six APOE genotypes, the e2e2 variant is associated with an increased risk for PAD in patients at high risk for cardiovascular disease. No association was observed between APOE genotype and coronary artery disease, stroke or vascular mortality in this population.

Hypertension has been related to structural and functional brain changes. In high-risk populations, hypertensive target organ damage might better represent exposure to high blood pressure than the blood pressure measurement itself. We examined the association of hypertensive target organ damage with longitudinal changes in brain structure and function within the Second Manifestations of Arterial Disease–Magnetic Resonance (SMART-MR) study. Renal function, albuminuria, and left ventricular hypertrophy on electrocardiography were measured in 663 patients with manifest arterial disease (mean age, 57±9 years; 81% men). Automated brain segmentation was used to quantify progression of global brain atrophy (change in brain parenchymal fraction) and progression of cerebral small vessel disease on 1.5T magnetic resonance imaging, and memory and executive functioning were assessed at baseline and after on average 3.9 years of follow-up. Regression analyses showed that an increasing number of signs of target organ damage was associated with more progression of global brain atrophy and more rapid decline in memory performance. Compared with no target organ damage, mean differences in change in brain parenchymal fraction (95% confidence interval) for 1 and ≥2 signs of organ damage were −0.12 (−0.30; 0.06) and −0.41 (−0.77; −0.05) % intracranial volume, and mean (95% confidence interval) differences in change in memory performance ( z score) were −0.15 (−0.29; −0.00) and −0.27 (−0.54; −0.01). Results were independent of blood pressure, antihypertensive treatment, and other confounders. Hypertension target organ damage was not associated with progression of cerebral small vessel disease or change in executive functioning. Routinely assessed signs of hypertensive target organ damage, and in particular impaired renal function, could be used to identify patients at the highest risk of cognitive decline.

BackgroundDepressive symptoms and cognitive impairment often co-occur, but their interactive relationship is complex and the direction of causation is still a topic of research. We examined the influence of cognitive performance on the course of depressive symptoms during 7 years of follow-up in patients with vascular disease.MethodWithin the SMART-MR study, 736 patients (mean age 62 ± 10 years) had neuropsychological assessment on four cognitive domains at baseline [memory (MEM), working memory (WMEM), executive functioning (EXEC), and information processing speed (SPEED)]. Depressive symptoms were assessed with the Patient Health Questionnaire-9 (PHQ-9) at baseline and every 6 months during 7 years of follow-up. Generalized Estimating Equation (GEE) models were used to assess the association between cognitive performance with depressive symptoms at multiple time points during follow-up. Interaction terms between the respective cognitive domains and time was included to examine if the course of depressive symptoms differed according to baseline cognitive performance.ResultsThe GEE analyses showed no significant interactions between the respective cognitive domains and time indicating no different course of depressive symptoms according to baseline cognitive performance. Lower MEM, EXEC or SPEED, but not WMEM performance, was significantly associated with more depressive symptoms during follow-up per z score decrease: MEM [B = 0.70, 95% confidence interval (CI) 0.35–1.05]; EXEC (B = 0.88, 95% CI 0.41–1.36), and SPEED (B = 0.57, 95% CI 0.21–0.92).ConclusionsPoorer cognitive performance on the domains MEM, EXEC and SPEED, but not WMEM, was associated with higher levels of depressive symptoms over 7 years of follow-up, but not with a different course of depressive symptoms over time.

BACKGROUND: Women with a complication of pregnancy are at increased risk of cardiovascular morbidity and mortality later in life. Yet, information on risk of recurrent events in women with a previous cardiovascular event is lacking. We aimed to assess the relationship between early preterm delivery, (recurrent) miscarriage and the risk for recurrent cardiovascular events in women with manifest vascular disease. METHODS: We included 1014 women with a mean age of 60 years from the SMART study, a prospective ongoing cohort study among subjects with clinically manifest vascular disease. The included women had a history of ≥1 pregnancy and were followed for the occurrence of subsequent vascular events. The relationship between the pregnancy complications ((miscarriage (gestational age

Objective Various cardiovascular prediction models have been developed for patients with type 2 diabetes. Their predictive performance in new patients is mostly not investigated. This study aims to quantify the predictive performance of all cardiovascular prediction models developed specifically for diabetes patients. Design and methods Follow-up data of 453, 1174 and 584 type 2 diabetes patients without pre-existing cardiovascular disease (CVD) in the EPIC-NL, EPIC-Potsdam and Secondary Manifestations of ARTerial disease cohorts, respectively, were used to validate 10 prediction models to estimate risk of CVD or coronary heart disease (CHD). Discrimination was assessed by the c-statistic for time-to-event data. Calibration was assessed by calibration plots, the Hosmer-Lemeshow goodness-of-fit statistic and expected to observed ratios. Results There was a large variation in performance of CVD and CHD scores between different cohorts. Discrimination was moderate for all 10 prediction models, with c-statistics ranging from 0.54 (95% CI 0.46 to 0.63) to 0.76 (95% CI 0.67 to 0.84). Calibration of the original models was poor. After simple recalibration to the disease incidence of the target populations, predicted and observed risks were close. Expected to observed ratios of the recalibrated models ranged from 1.06 (95% CI 0.81 to 1.40) to 1.55 (95% CI 0.95 to 2.54), mainly driven by an overestimation of risk in high-risk patients. Conclusions All 10 evaluated models had a comparable and moderate discriminative ability. The recalibrated, but not the original, prediction models provided accurate risk estimates. These models can assist clinicians in identifying type 2 diabetes patients who are at low or high risk of developing CVD.

Objective : The objective was to explore the interdependence between cardiovascular risk factors and cardiovascular calcifications on the cardiac valves and in multiple vascular beds in the chest and abdomen in a high-risk population. Methods : 276 participants of the SMART study who received a CT scan of the chest and abdominal region within one year were evaluated for the presence of cardiovascular calcifications throughout the body. Cardiovascular calcifications were manually scored in the coronary arteries, the aorta, the supra aortic vessels, the infra aortic vessels, the aortic valve, the renal arteries and the splenic artery. The following clinical risk factors of cardiovascular disease were included in principal component analysis, body mass index, systolic blood pressure, glucose, total cholesterol and carotid intima media thickness (cIMT) as a marker of atherosclerosis. Results : Principal component analysis yielded three uncorrelated components. The first consisted of cardiovascular calcifications and cIMT (variance = 35.4%), the second contained BMI and glucose (variance = 11.1%), and the third component consisted of systolic blood pressure and cholesterol (variance = 9.0%). Combined these three components explained 56% of the total variance within the dataset. Strong associations were observed among vascular calcifications and cIMT, whereas the association between clinical risk factors and cardiovascular calcifications was weak. Conclusion : The results suggest a single systemic nature of cardiovascular calcifications throughout the body that do not cluster with traditional cardiovascular risk factors.

Background: Single nucleotide polymorphisms in the APOA5-A4-C3-A1 gene complex are associated with elevated plasma triglycerides and elevated vascular risk in healthy populations. In patients with clinically manifest vascular disease, hypertriglyceridemia and metabolic syndrome are frequently present, but the contribution of these single nucleotide polymorphisms to plasma triglycerides, effect modification by obesity and risk of recurrent vascular events is unknown in these patients. Methods: Prospective cohort study of 5547 patients with vascular disease. Rs964184 (APOA5-A4-C3-A1 gene complex) was genotyped, and we evaluated the relation with plasma lipid levels, presence of metabolic syndrome and the risk for new vascular events. Results: The minor allele of rs964184 was strongly associated with log plasma triglycerides (b 0.12; 95%CI 0.10-0.15, p=1.1*10 219 ), and was also associated with 0.03 mmol/L lower high-density lipoprotein-cholesterol (95%CI 0.01–0.04), and 0.14 mmol/L higher non-high-density lipoprotein-cholesterol (95%CI 0.09–0.20). The minor allele frequency increased from 10.9% in patients with plasma triglycerides ,1 mmol/L to 24.6% in patients with plasma triglycerides between 4 and 10 mmol/L. The relation between rs964184 and plasma triglycerides was modified by body mass index in patients with one minor allele (b 0.02; (95%CI 20.04–0.09) if body mass index ,24 kg/m2, b 0.17 (95%CI 0.12–0.22) if body mass index .27 kg/m2, p for interaction=0.02). The prevalence of the metabolic syndrome increased from 52% for patients with two copies of the major allele to 62% for patients with two copies of the minor allele (p=0.01). Rs964184 was not related with recurrent vascular events (HR 0.99; 95%CI 0.86–1.13). Conclusion: The single nucleotide polymorphism rs964184 (APOA5-A4-C3-A1) is associated with elevated plasma triglycerides concentrations in patients with clinically manifest vascular disease. In carriers of one minor allele, the effect on plasma triglycerides was modified by body mass index. There is no relation between rs964184 and recurrent vascular events in these patients.

Item does not contain fulltext BACKGROUND: Homocysteine may be a modifiable risk factor for cognitive decline and brain atrophy, particularly in older persons. We examined whether homocysteine increased the risk for cognitive decline and brain atrophy, and evaluated the modifying effect of age. METHODS: Within the Second Manifestations of ARTerial disease-Magnetic Resonance study-a prospective cohort study among patients with atherosclerotic disease-longitudinal analyses were performed in 663 patients (mean age: 57 +/- 9 years; follow-up: 3.9 +/- 0.4 years). At baseline and follow-up, brain segmentation on magnetic resonance imaging was used to quantify relative (%) cortical, ventricular, and global brain volumes, and z-scores of memory and executive functioning were calculated. Linear regression analysis was used to estimate associations of homocysteine (per standard deviation increase) and hyperhomocysteinemia (HHCY) with brain volumes, memory, and executive functioning at follow-up, adjusted for baseline brain volume, memory, and executive functioning, respectively, and age, sex, and vascular risk factors. Furthermore, interaction terms between homocysteine and age (continuous) were added. RESULTS: Significant interactions were observed between total plasma homocysteine (tHcy) and age with cortical, ventricular, and global brain volume (for all three measures: P < .05), and between HHCY and age with executive functioning (P = .04), and results were stratified by age. In patients aged >/=65 years, increasing tHcy level and HHCY were significantly associated with progression of ventricular enlargement (B = 0.07%, 95% confidence interval [CI]: 0.01% to 0.13% and B = 0.16%, 95% CI: 0.01% to 0.31%, respectively) and with a decline in executive function (B = -0.29, 95% CI: -0.54 to -0.04 and B = -0.84, 95% CI: -1.37 to -0.32, respectively). CONCLUSION: Elevated tHcy was related to progression of ventricular enlargement and increased the risk for a decline in executive functioning in older persons.

STUDY QUESTION: Is vascular health associated with ovarian reserve status using type 1 diabetes mellitus (DM-1) as a model for vascular compromise? SUMMARY ANSWER: No conclusive evidence for an association between vascular health and ovarian ageing was found in women with DM-1. WHAT IS KNOWN ALREADY: The mechanism behind advanced ovarian ageing has not yet been elucidated. We hypothesize that vascular impairment precedes ovarian ageing. DM-1 is hallmarked by premature vascular complications that may consequently play a role in the rate of primordial follicle decline. STUDY DESIGN, SIZE, DURATION: A cross-sectional, patient-control study was performed in 150 premenopausal, regular cycling women with DM-1, as well as a reference population of 177 healthy, fertile women. PARTICIPANTS/MATERIALS, SETTING, METHODS: In a single-study visit, an inventory of both ovarian reserve and vascular status was carried out in the DM-1 group. A transvaginal ultrasound to calculate the antral follicle count (AFC) and blood sampling for anti-Müllerian hormone (AMH), lipids, C-reactive protein and HbA1c measurements were performed. Furthermore, vascular screening including measurements of blood pressure, flow-mediated dilation, peripheral arterial tonometry, pulse wave velocity, pulse wave analysis and intima-media thickness was carried out. The relative decrease in serum AMH levels in women with DM-1 compared with healthy references was investigated. MAIN RESULTS AND THE ROLE OF CHANCE: Systolic blood pressure was negatively correlated with both serum AMH (P= 0.006) and AFC (P= 0.004) in the DM-1 group. A non-linear relationship between HDL-cholesterol and serum AMH was found (P= 0.0001). No associations were detected between other vascular risk factors or vascular function tests and serum AMH or AFC in women with DM-1. With regard to the comparison of AMH levels between women with and without DM-1, mean AMH levels were 2.5 ± 1.9 ng/ml and 3.0 ± 2.8 ng/ml, respectively. After adjustment for confounders the difference in AMH levels between both groups appeared non-significant (fold change: 0.92, 95% confidence interval: 0.68-1.23). LIMITATIONS, REASON FOR CAUTION: The use of different AMH assays and the cross-sectional design may limit the interpretation of this study. WIDER IMPLICATIONS OF THE FINDINGS: The lack of evident association between vascular health and ovarian ageing may be the result of an insufficient vascular compromise in the relatively young, DM-1 group. STUDY FUNDING/COMPETING INTERESTS: No external funding was received for conducting or publishing this study. F.Y., W.S., A.F., F.L.J.V., M.J.C.E. and H.W.d.V. have nothing to disclose. F.J.M.B. has received fees and grant support from the following companies: Ferring, Gedeon Richter, Merck Serono, Medical Specialties Distributors and Roche. TRIAL REGISTRATION NUMBER: Not applicable.

Background and Objectives Microvesicles (MVs) are small membrane vesicles that are involved in atherotrombotic processes. In the present study, we evaluated the risk of MV protein levels on the occurrence of new vascular events in patients with clinically manifest vascular disease. Methods In this cohort study 1060 patients were prospectively followed for the occurrence of a new vascular event or death (median follow up 6.4years, interquartile range 5.2–7.3years). MVs were isolated from plasma and MV protein levels of Cystatin C, Serpin G1, Serpin F2 and CD14 were measured. Multivariable Cox proportional hazards models were used to estimate the risk for new vascular events, vascular mortality and all-cause mortality. During follow up 136 vascular events occurred, 65 vascular mortality and 114 all-cause mortality. Results An increase in 1 standard deviation (SD) of Cystatin C MV level was related to an increased risk for myocardial infarction (HR 1.49; 95%CI 1.20–1.86), vascular mortality (HR 1.48; 95%CI 1.17–1.86), vascular events (HR 1.27; 1.07–1.52) and all-cause mortality (HR 1.41; 95%CI 1.18–1.69). Serpin F2 MV levels were related to an increased risk for myocardial infarction (HR 1.22; 95%CI 1.00–1.51), vascular mortality (HR 1.25; 95%CI 1.00–1.56), and all-cause mortality (HR 1.22; 95% CI 1.03–1.45). CD14 MV levels were related to an increased risk for myocardial infarction (HR 1.55; 95%CI 1.27–1.91), vascular mortality (HR 1.37; 95%CI 1.10–1.70), vascular events (HR 1.32; 95%CI 1.12–1.55), all-cause mortality (HR 1.36; 95%CI 1.15–1.62) and occurrence of ischemic stroke (HR 1.32; 95%CI 1.00–1.74). Conclusions Cystatin C, Serpin F2 and CD14 MV levels are related to an elevated risk for future vascular events and mortality in patients with clinically manifest vascular disease.

Objective To investigate whether an internet based, nurse led vascular risk factor management programme promoting self management on top of usual care is more effective than usual care alone in reducing vascular risk factors in patients with clinically manifest vascular disease. Design Prospective randomised controlled trial. Setting Multicentre trial in secondary and tertiary healthcare setting. Participants 330 patients with a recent clinical manifestation of atherosclerosis in the coronary, cerebral, or peripheral arteries and with at least two treatable risk factors not at goal. Intervention Personalised website with an overview and actual status of patients’ risk factors and mail communication via the website with a nurse practitioner for 12 months; the intervention combined self management support, monitoring of disease control, and drug treatment. Main outcome measures The primary endpoint was the relative change in Framingham heart risk score after 1 year. Secondary endpoints were absolute changes in the levels of risk factors and the differences between groups in the change in proportion of patients reaching treatment goals for each risk factor. Results Participants’ mean age was 59.9 (SD 8.4) years, and most patients (n=246; 75%) were male. After 1 year, the relative change in Framingham heart risk score of the intervention group compared with the usual care group was −14% (95% confidence interval −25% to −2%). At baseline, the Framingham heart risk score was higher in the intervention group than in the usual care group (16.1 (SD 10.6) v 14.0 (10.5)), so the outcome was adjusted for the separate variables of the Framingham heart risk score and for the baseline Framingham heart risk score. This produced a relative change of −12% (−22% to −3%) in Framingham heart risk score for the intervention group compared with the usual care group adjusted for the separate variables of the score and −8% (−18% to 2%) adjusted for the baseline score. Of the individual risk factors, a difference between groups was observed in low density lipoprotein cholesterol (−0.3, −0.5 to −0.1, mmol/L) and smoking (−7.7%, −14.9% to −0.4%). Some other risk factors tended to improve (body mass index, triglycerides, systolic blood pressure, renal function) or tended to worsen (glucose concentration, albuminuria). Conclusion An internet based, nurse led treatment programme on top of usual care for vascular risk factors had a small effect on lowering vascular risk and on lowering of some vascular risk factors in patients with vascular disease. Trial registration Clinical trials NCT00785031.

Higher body weight is associated with an increased prevalence of vascular risk factors. Obesity leads to hypertension by various mechanisms, often referred to as obesity-related hypertension. Aim of the present study was to evaluate the prevalence and the vascular risk of the combination of obesity and hypertension in patients with vascular diseases. A cohort of patients with various clinical manifest vascular diseases (n = 4,868) was screened for vascular risk factors and followed (median follow-up 4.2 years) for the occurrence of vascular events (stroke, myocardial infarction, and vascular death). The prevalence of obesity was 18% (95% confidence interval (CI) 17–19%) and the prevalence of hypertension was 83% (95% CI 82–84%). The prevalence of the combination of obesity and hypertension was 16% (95% CI 15–17%). Patients with high blood pressure (BP) combined with a high weight (highest tertile systolic BP (SBP) in the highest tertile BMI) were not at higher risk for new vascular events (hazard ratios (HR) 1.29; 95% CI 0.89–1.88) or mortality (HR 1.18; 95% CI 0.81–1.73) compared to patients without high BP and high weight (patients in the lowest tertile of SBP in the lowest tertile of BMI). Patients with only high weight did not have an elevated risk either for vascular events (HR 1.34; 95% CI 0.91–1.98) or mortality (HR 1.22; 95% CI 0.81–1.83) compared to patients without high BP and high weight. The prevalence of the combination of hypertension and obesity is low in patients with vascular diseases and does not confer a higher risk for recurrent vascular diseases and mortality than each risk factor alone.

Lower self-rated health status has been associated with worse prognosis in patients with coronary artery disease (CAD). We investigated the influence of self-rated physical and mental health status on the risk of future vascular events and mortality for various locations of symptomatic atherosclerotic disease and asymptomatic disease.Patients with CAD (n = 2547), cerebrovascular disease (n = 1061), peripheral arterial disease (PAD; n = 648), abdominal aortic aneurysm (AAA; n = 272) and asymptomatic atherosclerotic disease (n = 1933) were followed for a median of 4 years for the occurrence of a new vascular event or death. Self-rated health status was assessed with the Short Form-36 physical and mental component summary scales. Cox regression models were used to estimate associations between health status and vascular events and death, adjusted for age, sex, vascular risk factors and intima-media thickness.In the total population, lower self-rated physical health status (per 10-point decrease) increased the risk of vascular events [hazard ratio (HR) = 1.37, 95% confidence interval (CI) 1.24-1.52], and all-cause (HR = 1.45, 95% CI 1.29-1.63) and vascular mortality (HR = 1.40, 95% CI 1.20-1.64). A 10-point decrease in mental health status was associated with a modest increase in the risk of vascular events (HR = 1.19, 95% CI 1.08-1.32), and all-cause (HR = 1.19, 95% CI 1.05-1.34) and vascular mortality (HR = 1.28, 95% CI 1.09-1.49). Risk estimates of physical and mental health status were highest in patients with asymptomatic atherosclerotic disease and lowest in those with PAD.Poorer self-rated physical and mental health status increases the risk of vascular events and mortality in a broad population of patients with symptomatic and asymptomatic atherosclerotic disease.

Background and Purpose— Cerebral small vessel disease may be related to vascular and nonvascular pathology. We assessed whether lacunar infarcts and white matter lesions on MRI increased the risk of vascular and nonvascular death and future vascular events in patients with atherosclerotic disease. Methods— Brain MRI was performed in 1309 patients with atherosclerotic disease from the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study. Infarcts were scored visually and volumetric assessment of white matter lesion was performed. Patients were followed for a median of 4.5 years (range, 0.2 to 7.1 years) for death, ischemic stroke, and ischemic cardiac complications. Results— Cox regression models showed that presence of lacunar infarcts (n=229) increased the risk of vascular (hazard ratio, 2.6; 95% CI, 1.4 to 4.9) and nonvascular death (hazard ratio, 2.7; 95% CI, 1.3 to 5.3), adjusted for age, sex, vascular risk factors, nonlacunar infarcts, and white matter lesion. These risks were similar for patients with silent lacunar infarcts. White matter lesion volume (relative to total intracranial volume) increased the risk of vascular death (hazard ratio per milliliter increase, 1.03; 95% CI, 1.01 to 1.05) and white matter lesions in the upper quintile compared with lower quintiles increased risk of ischemic stroke (hazard ratio, 2.6; 95% CI, 1.3 to 4.9). Conclusions— Cerebral small vessel disease, with or without a history of cerebrovascular disease, is associated with increased risk of death and ischemic stroke in patients with atherosclerotic disease.

BackgroundThe ‘vascular depression’ hypothesis states that brain changes located in frontal-subcortical pathways increase vulnerability for specific depressive symptom profiles, but studies examining locations of small-vessel and degenerative changes with individual symptoms are scarce. We examined whether location and progression of white-matter lesions (WMLs), lacunar infarcts and atrophy were associated with motivational and mood symptoms in patients with symptomatic atherosclerotic disease.MethodIn 578 patients [63 (s.d.=8) years] of the Second Manifestations of ARTerial disease (SMART)-Medea study, volumes of WMLs and atrophy and visually rated infarcts were obtained with 1.5 T magnetic resonance imaging at baseline and after 3.9 (s.d.=0.4) years' follow-up. Depressive symptoms were assessed with Patient Health Questionnaire-9 at follow-up and categorized into motivational and mood symptoms.ResultsRegression analyses adjusted for age, gender, education, Mini-Mental State Examination, physical functioning, antidepressant use and vascular risk factors showed that location in mainly deep white-matter tracts and progression of WMLs were associated with symptoms of anhedonia, concentration problems, psychomotor retardation and appetite disturbance. Lacunar infarcts in deep white matter were associated with greater motivational [Incidence rate ratio (IRR) 1.7, 95% confidence interval (CI) 1.2–2.4] and mood (IRR 1.7, 95% CI 1.1–2.6) sumscores, and with symptoms of psychomotor retardation, energy loss and depressed mood; lacunar infarcts in the thalamus were associated with psychomotor retardation only. Cortical atrophy was associated with symptoms of anhedonia and appetite disturbance. Excluding patients with major depression did not materially change the results.ConclusionsOur findings suggest that disruption of frontal-subcortical pathways by small-vessel lesions leads to a symptom profile that is mainly characteristic of motivational problems, also in the absence of major depression.

Obesity-related hypertension is increasingly recognized as a distinct hypertensive phenotype requiring a modified approach to diagnosis and management. In this review rapidly evolving insights into the complex and interdependent mechanisms linking obesity to hypertension are discussed. Overweight and obesity are associated with adipose tissue dysfunction, characterized by enlarged hypertrophied adipocytes, increased infiltration by macrophages and marked changes in secretion of adipokines and free fatty acids. This results in chronic vascular inflammation, oxidative stress, activation of the renin-angiotensin-aldosterone system and sympathetic overdrive, eventually leading to hypertension. These mechanisms may provide novel targets for anti-hypertensive drug treatment. Recognition of obesity-related hypertension as a distinct diagnosis enables tailored therapy in clinical practice. This includes lifestyle modification and accommodated choice of blood pressure-lowering drugs.

To assess the effect of various measures of adiposity and of metabolic risk factors, both separately and in combination, on the risk of future Type 2 diabetes in patients with manifest vascular diseases.This was a prospective cohort study in 2924 patients (mean age 59 ± 12 years) with manifest atherosclerosis. Metabolic risk factors were defined according to National Cholesterol Education Program criteria for the metabolic syndrome. Incidence of Type 2 diabetes was assessed by questionnaire and subsequent verification.During a median follow-up of 4.9 years (range 3.0-7.6 years) there were 178 cases (6.1%) of incident Type 2 diabetes. An increase with 1 sd waist circumference showed a strong association with incident Type 2 diabetes in both men (hazard ratio 2.45, 95% CI 1.97-3.04) and women (hazard ratio 1.77, 95% CI 1.38-2.26). Compared with patients with normal (i.e. below the National Cholesterol Education Program criteria for abdominal adiposity) waist circumference and3 metabolic risk factors, both patients with normal waist circumference and ≥ 3 metabolic risk factors and patients with high (i.e. above the National Cholesterol Education Program criteria for abdominal adiposity) waist circumference and3 metabolic risk factors had an increased risk of Type 2 diabetes (hazard ratio 2.44, 95% CI 1.37-4.36 and hazard ratio 3.61, 95% CI 2.23-5.85, respectively). Patients with both high waist circumference and ≥ 3 metabolic risk factors had the highest risk of developing Type 2 diabetes (hazard ratio 10.76, 95% CI 6.95-16.64).In patients with manifest atherosclerosis, both presence of ≥ 3 metabolic risk factors and presence of a high waist circumference alone are associated with increased risk for developing Type 2 diabetes. The combined presence of ≥ 3 metabolic risk factors and high waist circumference, which is present in 15% of patients, is associated with a 10-fold increased risk of future Type 2 diabetes. To identify patients with manifest atherosclerosis at the highest risk of developing Type 2 diabetes, fat distribution in combination with metabolic risk factors should be considered.

Elevated plasma triglyceride levels, as often seen in obese subjects, are independently associated with an increased risk of cardiovascular diseases. By secreting adipokines (such as adiponectin and leptin) and other proteins (such as lipoprotein lipase and cholesteryl ester transferase protein), adipose tissue affects triglyceride metabolism. In obesity, adipocyte hypertrophy leads to many changes in adipocyte function and production of anti- and pro-inflammatory cytokines. Furthermore, free fatty acids are released into the circulation contributing to insulin resistance. Adipose tissue dysfunction will eventually lead to abnormalities in lipid metabolism, such as hypertriglyceridemia (due to increased hepatic very-low-density lipoprotein production and decreased triglyceride hydrolysis), small dense low-density lipoprotein particles, remnant lipoproteins and low high-density lipoprotein cholesterol levels, all associated with a higher risk for the development of cardiovascular diseases. The clinical implications of elevated plasma triglycerides are still a matter of debate. Understanding the pathophysiology of adipose tissue dysfunction in obesity, which is becoming a pandemic condition, is essential for designing appropriate therapeutic interventions. Lifestyle changes are important to improve adipose tissue function in obese patients. Pharmacological interventions to improve adipose tissue function need further evaluation. Although statins are not very potent in reducing plasma triglycerides, they remain the mainstay of therapy for cardiovascular risk reduction in high-risk patients.