C-reactive protein and incident diabetes in patients with arterial disease.

INTRODUCTION: Systemic low-grade inflammation, as measured by high-sensitive C-reactive protein (hsCRP), may contribute to the risk of type 2 diabetes in patients with manifest arterial disease. METHODS: Cohort study in 4072 patients with manifest arterial disease without diabetes. The relation between quartiles of hsCRP and type 2 diabetes was assessed with Cox regression analyses, taking age, smoking and blood pressure-lowering medication and lipid-lowering medication into account. Insulin resistance was estimated with homeostasis model of insulin resistance (HOMA-IR). In exploratory models, adjustments were performed for body mass index (BMI) and visceral and subcutaneous adipose tissue thickness. RESULTS: During a median follow-up of 5·0 (IQR 2·5-8·2) years, 288 subjects developed diabetes. High hsCRP was independently associated with incident diabetes (Q4 vs. Q1 males: HR 1·62; 95% CI 1·06-2·48; females: HR 3·12; 95% CI 1·57-6·21). HOMA-IR at baseline is related to hsCRP plasma levels (Q4 vs. Q1: males: ß 0·27; 95% CI 0·19-0·36; females: ß 0·35; 95% CI 0·22-0·48). The risk of diabetes associated with hsCRP was abolished in males (Q4 vs. 1 HR 1·23; 95% CI 0·80-1·88) and attenuated in females (Q4 vs. 1 HR 2·32; 95% CI 1·14-4·75) after adding BMI to the model, but not modified by statin use (P for interaction: 0·61). CONCLUSIONS: Patients with manifest arterial disease with high hsCRP plasma levels are at increased risk to develop type 2 diabetes and are more insulin resistant as compared to those with low hsCRP levels. This increase in risk is more pronounced in females than in males and is not modified by statin use.

Aspirin for primary prevention of vascular events in women: individualized prediction of treatment effects.

AIMS To identify women who benefit from aspirin 100 mg on alternate days for primary prevention of vascular events by using treatment effect prediction based on individual patient characteristics. METHODS AND RESULTS Randomized controlled trial data from the Women's Health Study were used to predict treatment effects for individual women in terms of absolute risk reduction for major cardiovascular events (i.e. myocardial infarction, stroke, or cardiovascular death). Predictions were based on existing risk scores, i.e. Framingham (FRS), and Reynolds (RRS), and on a newly developed prediction model. The net benefit of different aspirin treatment-strategies was compared: (i) treat no one, (ii) treat everyone, (iii) treatment according to the current guidelines (i.e. selective treatment of women >65 years of age or having >10% FRS), and (iv) prediction-based treatment (i.e. selective treatment of patients whose predicted treatment effect exceeds a given decision threshold). The predicted reduction in 10-year absolute risk for major cardiovascular events was <1% in 97.8% of 27 939 study subjects when based on the refitted FRS, in 97.0% when based on the refitted RRS, and in 90.0% when based on the newly developed model. Of the treatment strategies considered, only prediction-based treatment using the newly developed model and selective treatment of women >65 years of age yielded more net benefit than treating no one, provided that the 10-year number-willing-to-treat (NWT) to prevent one cardiovascular event was above 50. CONCLUSION Aspirin was ineffective or even harmful in the majority of patients. Age was positively related to treatment effect, whereas current smoking and baseline risk for cardiovascular events were not. When the NWT is 50 or lower, the aspirin treatment strategy that is associated with optimal net benefit in primary prevention of vascular events in women is to treat none.

Insulin resistance increases the occurrence of new cardiovascular events in patients with manifest arterial disease without known diabetes. the SMART study.

BACKGROUND: Insulin resistance is accompanied by a cluster of metabolic changes, often referred to as metabolic syndrome. Metabolic syndrome is associated with an increased cardiovascular risk in patients with manifest arterial disease. We investigated whether insulin resistance is associated with an increased risk for cardiovascular events in patients with manifest arterial disease without known diabetes and whether this can be explained by the components of the metabolic syndrome or by inflammation. METHODS: Prospective cohort study in 2611 patients with manifest arterial disease without known diabetes. Homeostasis model of insulin resistance (HOMA-IR) was used to quantify insulin resistance. The relation of HOMA-IR with cardiovascular events (vascular death, myocardial infarction or stroke) and all cause mortality was assessed with Cox regression analysis. In additional models adjustments were performed for the single components constituting the metabolic syndrome and for inflammation. RESULTS: HOMA-IR increases with the number of metabolic syndrome components (mean HOMA-IR ± SD in groups with 0, 1, 2, 3, 4 and 5 metabolic syndrome components: 1.4 ± 0.7; 1.8 ± 1.2; 2.4 ± 1.5; 3.1 ± 1.8; 4.0 ± 2.6; and 5.6 ± 3.6 respectively). High HOMA-IR was independently associated with an increased risk of cardiovascular events (tertile 2 vs. 1 HR 1.92; 95%CI 1.20-3.08) (tertile 3 vs.1 HR 1.78; 95%CI 1.10-2.89) and with all cause mortality (tertile 2 vs. 1 HR 1.80; 95%CI 1.04-3.10) (tertile 3 vs.1 HR 1.56; 95%CI 0.88-2.75). These relations were not influenced by the individual components of metabolic syndrome or by inflammation. CONCLUSIONS: In patients with manifest arterial disease without known diabetes, insulin resistance increases with the number of metabolic syndrome components, and elevated insulin resistance increases the risk of new cardiovascular events.

Age-related differences in abdominal fat distribution in premenopausal and postmenopausal women with cardiovascular disease.

OBJECTIVE: The aim of this study was to determine the effect of sex and the menopausal transition on age-related differences in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) among patients with cardiovascular disease. METHODS: A cross-sectional study of 997 women and 3,409 men with cardiovascular disease was performed. VAT and SAT were measured by ultrasonography. Differences in abdominal fat per decade in premenopausal and postmenopausal women were analyzed with linear regression and compared with men younger and older than the mean menopause age of women. RESULTS: VAT increased gradually across advancing age groups. For postmenopausal women, the 10-year differences in VAT were smaller than those for premenopausal women (0.24 cm [ß = 0.24; 95% CI, 0.05 to 0.43] vs 0.71 cm [ß = 0.71; 95% CI, 0.29 to 1.12]). There were no differences in SAT (ß = -0.12; 95% CI, -0.37 to 0.13) in premenopausal women, and SAT decreased across the age groups of postmenopausal women (-0.36 cm per decade [ß = -0.36; 95% CI, -0.47 to -0.26]). Postmenopausal women showed 10-year differences in VAT that were larger than those for men 48 years or older (0.24 cm per decade [ß = 0.24; 95% CI, 0.05 to 0.43] vs -0.01 cm per decade [ß = -0.01; 95% CI, -0.12 to 0.10]). In addition, 10-year differences in SAT were larger in postmenopausal women than in men 48 years or older (-0.36 cm [ß = -0.36; 95% CI, -0.47 to -0.26] vs -0.22 cm [ß = -0.22; 95% CI, -0.27 to -0.18]). CONCLUSIONS: Menopause is not associated with accelerated fat gain in women with cardiovascular disease. Compared with similar-aged men, postmenopausal women show a steeper increase in VAT and a steeper decrease in SAT. These ongoing changes might add to an unfavorable metabolic profile associated with an increased risk of recurrent cardiovascular events.

Plasma triglyceride levels increase the risk for recurrent vascular events independent of LDL-cholesterol or nonHDL-cholesterol.

BACKGROUND: Plasma 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. METHODS: Prospective cohort study of 5731 patients with clinically manifest vascular disease. RESULTS: First new vascular events (myocardial infarction, ischemic stroke, vascular death) occurred in 782 subjects during a median follow-up of 4.9 years (interquartile range 2.5-8.1 years). Patients in the highest plasma TG quintile (>2.24 mmol/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 (<0.97 mmol/L) after adjustments for age, gender, body mass index, smoking, lipid-lowering medication and low-density lipoprotein-cholesterol. The increased risk associated with increasing plasma TG levels was irrespective of the presence of type 2 diabetes (T2DM), but only present in patients without the metabolic syndrome. Furthermore, the increased risk was particularly present in patients with coronary artery disease (CAD) (HR 1.45; 95%CI 1.02-2.08) and was not modified by other lipid levels (p-value for interaction >0.05). Plasma TG still contributed to vascular risk when other lipid levels were at target level. CONCLUSIONS: Higher 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.

The risk of resting heart rate on vascular events and mortality in vascular patients.

BACKGROUND: Resting heart rate (RHR) reflects sympathetic nerve activity and is independently related to the occurrence of cardiovascular events and death in healthy subjects, patients with coronary artery disease (CAD) and patients with cardiovascular risk factors. We investigated and compared the risk of RHR on the occurrence of cardiovascular events and death in patients with CAD, cerebrovascular disease (CVD), peripheral arterial disease (PAD) or abdominal aortic aneurysm (AAA). METHODS: Data were used from a prospective cohort study of 4272 patients with manifest vascular disease: CAD (n=2244), CVD (n=930), PAD (n=823) or AAA (n=275). RHR was obtained at baseline from an electrocardiogram. The median follow-up time was 4.4 (interquartile range 2.1-7.4) years. The relation between RHR and the occurrence of cardiovascular events and death was estimated by Cox proportional hazard analyses. RESULTS: Each increase in RHR of 10 beats/min was related to an increased risk for all-cause mortality (hazard ratio (HR) 1.14; 95% confidence interval (CI) 1.07-1.21) and vascular mortality (HR 1.15; 95% CI 1.06-1.25), but not for myocardial infarction (HR 1.03; 95% CI 0.94-1.14) or ischemic stroke (HR 1.05; 95% CI 0.92-1.20). The relation between an increased RHR and increased risk for all-cause mortality was present irrespective of beta-blocker use and irrespective of the location of vascular disease: CAD (HR 1.23; 95% CI 1.05-1.44), CVD (HR 1.18; 95% CI 1.05-1.33) and PAD/AAA (HR 1.10; 95% CI 1.01-1.20). CONCLUSIONS: Elevated RHR is associated with increased risk for mortality but not for myocardial infarction or stroke in patients with manifest vascular diseases irrespective of location of vascular disease.

Development and validation of a prediction rule for recurrent vascular events based on a cohort study of patients with arterial disease: the SMART risk score.

OBJECTIVES: To enable risk stratification of patients with various types of arterial disease by the development and validation of models for prediction of recurrent vascular event risk based on vascular risk factors, imaging or both. DESIGN: Prospective cohort study. SETTING: University Medical Centre. PATIENTS: 5788 patients referred with various clinical manifestations of arterial disease between January 1996 and February 2010. MAIN OUTCOME MEASURES: 788 recurrent vascular events (ie, myocardial infarction, stroke or vascular death) that were observed during 4.7 (IQR 2.3 to 7.7) years' follow-up. RESULTS: Three Cox proportional hazards models for prediction of 10-year recurrent vascular event risk were developed based on age and sex in addition to clinical parameters (model A), carotid ultrasound findings (model B) or both (model C). Clinical parameters were medical history, current smoking, systolic blood pressure and laboratory biomarkers. In a separate part of the dataset, the concordance statistic of model A was 0.68 (95% CI 0.64 to 0.71), compared to 0.64 (0.61 to 0.68) for model B and 0.68 (0.65 to 0.72) for model C. Goodness-of-fit and calibration of model A were adequate, also in separate subgroups of patients having coronary, cerebrovascular, peripheral artery or aneurysmal disease. Model A predicted < 20% risk in 59% of patients, 20-30% risk in 19% and > 30% risk in 23%. CONCLUSIONS: Patients at high risk for recurrent vascular events can be identified based on readily available clinical characteristics.

Risk of elevated resting heart rate on the development of type 2 diabetes in patients with clinically manifest vascular diseases.

OBJECTIVE: Sympathetic nerve activation is causally related to insulin resistance as both a cause and a consequence. Resting heart rate (RHR) reflects sympathetic nerve activity. We investigated the effect of RHR on the incidence of type 2 diabetes mellitus (T2DM) in patients with clinically manifest vascular diseases. DESIGN: Data were used from the second manifestations of arterial disease (SMART) study: a prospective cohort study of patients with clinically manifest vascular diseases (n=3646). METHODS: RHR was obtained using an electrocardiogram. Patients were followed up for incident type 2 diabetes (n=289) during a median period of 5.5 (interquartile range 3.2-8.4) years. The relation between RHR and incident T2DM was estimated by Cox proportional hazard analysis. As age was an effect modifier (P=0.048), analyses were stratified for age. RESULTS: Patients in quartile 4 (Q4) of RHR had a 65% increased risk of T2DM compared with those in Q1 (reference; hazard ratios (HR), 1.65; 95% confidence interval (95% CI), 1.15-2.36) adjusted for age, gender, smoking, estimated glomerular filtration rate, systolic blood pressure, location of vascular disease, and antihypertensive medication. Every 10 beats per minute (bpm) increase in RHR increased the risk for T2DM with 10% (HR, 1.10; 95% CI, 1.00-1.21) in the total population. This risk was particularly high in subjects aged 55-63 years (per 10 bpm: HR, 1.22; 95% CI, 1.04-1.43) and was independent of the location of vascular disease and beta-blocker use. CONCLUSIONS: Increased RHR, an indicator of sympathetic nerve activity, is associated with an increased risk for T2DM in patients with manifest vascular diseases, particularly in middle-aged patients.

Increased visceral adipose tissue is associated with increased resting heart rate in patients with manifest vascular disease.

Abdominal obesity is characterized by sympathetic nerve activation (SNA), probably mediated by elevated insulin and leptin levels. Resting heart rate (RHR) is a marker of sympathetic tone, and independently associated with cardiovascular events and death in various populations. We investigated and quantified the relation between visceral adipose tissue (VAT) and RHR in patients with vascular disease. In 3,723 patients with manifest vascular disease, visceral and subcutaneous fat tissue was measured with ultrasonography. RHR was obtained from an electrocardiogram (ECG). The association between quartiles of VAT and RHR was quantified using linear regression analysis with adjustments for potential confounding factors. Separate analyses were performed for men and women and for location of vascular disease. Visceral fat was categorized into sex-pooled quartiles (Q) ranging from 2.7-8.0 cm in Q1 (reference) to 9.4-20.6 cm in Q4. High visceral fat thickness was associated with increased RHR, in men (Q4 vs. Q1, ß = 4.36; 95% confidence interval (CI) = 3.11-5.61) and women (ß = 1.48; 95% CI = -0.70 to 3.66), after full adjustment. Waist circumference and BMI had a significant relation with RHR in men (ß = 3.51; 95% CI = 2.21-4.81 and ß = 2.80; 95% CI = 1.51-4.08, respectively) but these relations were smaller and not significant in women (ß = 0.71; 95% CI = -1.44 to 2.85 and ß = 0.24; 95% CI = -1.90 to 2.37, respectively). There was no relation between subcutaneous fat and RHR in men and women. The relation between visceral fat and RHR was similar in patients with different locations of vascular diseases. Increased visceral fat is associated with increased RHR in male and female patients with vascular disease, independent of the location.

The relationship between walking speed and changes in cardiovascular risk factors during a 12-day walking tour to Santiago de Compostela: a cohort study.

OBJECTIVES: Physical exercise has beneficial effects on cardiovascular risk factors. Knowledge about the effect of exercise intensity, specifically walking speed, on cardiovascular risk factors is limited. We report the relationship between walking speed and changes in cardiovascular risk factors in participants of a 12-day walking tour to Santiago de Compostela. DESIGN: Prospective cohort study. SETTING: Single-centre study with healthy middle-aged volunteers. PARTICIPANTS: Healthy middle-aged men (n=15) and women (n=14). Subjects using lipid-lowering medication were excluded. INTERVENTION: Participants walked 281±10 km of the classical route to Santiago de Compostela in 12 days in 2009. PRIMARY AND SECONDARY OUTCOME MEASURES: Walking speed was recorded and blood pressure, weight, waist circumference, lipids and glucose were measured every other day. Changes in risk factors were compared between gender-pooled groups with faster and slower walking speed. Second, the relationship between walking speed and changes in risk factors was quantified using a linear mixed effects model. RESULTS: In the faster walking speed (4.6±0.2 km/h) group, high-density lipoprotein cholesterol (HDL-c) increased more than in the slower walking speed (4.1±0.2 km/h) group (difference in change between groups: 0.20; 95% CI -0.02 to 0.42 mmol/l), while low-density lipoprotein cholesterol (LDL-c) and total cholesterol decreased more in the slower walking speed group (differences in changes between groups: LDL-c: -0.50; 95% CI -0.88 to -0.12 mmol/l and total cholesterol: -0.75; 95% CI -1.19 to -0.31 mmol/l). A 1 km/h higher walking speed was related to an increase in HDL-c (0.24; 95% CI 0.12 to 0.30 mmol/l), LDL-c (0.18; 95% CI -0.16 to 0.42 mmol/l) and total cholesterol (0.36; 95% CI 0.12 to 0.60 mmol/l), adjusted for age, gender, smoking, body mass index and heart rate, during the whole walking tour. CONCLUSIONS: Walking the same distance faster improves HDL-c more, while LDL-c and total cholesterol decrease more with lower walking speed independent of changes in body weight in healthy middle-aged subjects.

Estimating treatment effects for individual patients based on the results of randomised clinical trials.

OBJECTIVES: To predict treatment effects for individual patients based on data from randomised trials, taking rosuvastatin treatment in the primary prevention of cardiovascular disease as an example, and to evaluate the net benefit of making treatment decisions for individual patients based on a predicted absolute treatment effect. SETTING: As an example, data were used from the Justification for the Use of Statins in Prevention (JUPITER) trial, a randomised controlled trial evaluating the effect of rosuvastatin 20 mg daily versus placebo on the occurrence of cardiovascular events (myocardial infarction, stroke, arterial revascularisation, admission to hospital for unstable angina, or death from cardiovascular causes). Population 17,802 healthy men and women who had low density lipoprotein cholesterol levels of less than 3.4 mmol/L and high sensitivity C reactive protein levels of 2.0 mg/L or more. METHODS: Data from the Justification for the Use of Statins in Prevention trial were used to predict rosuvastatin treatment effect for individual patients based on existing risk scores (Framingham and Reynolds) and on a newly developed prediction model. We compared the net benefit of prediction based rosuvastatin treatment (selective treatment of patients whose predicted treatment effect exceeds a decision threshold) with the net benefit of treating either everyone or no one. RESULTS: The median predicted 10 year absolute risk reduction for cardiovascular events was 4.4% (interquartile range 2.6-7.0%) based on the Framingham risk score, 4.2% (2.5-7.1%) based on the Reynolds score, and 3.9% (2.5-6.1%) based on the newly developed model (optimal fit model). Prediction based treatment was associated with more net benefit than treating everyone or no one, provided that the decision threshold was between 2% and 7%, and thus that the number willing to treat (NWT) to prevent one cardiovascular event over 10 years was between 15 and 50. CONCLUSIONS: Data from randomised trials can be used to predict treatment effect in terms of absolute risk reduction for individual patients, based on a newly developed model or, if available, existing risk scores. The value of such prediction of treatment effect for medical decision making is conditional on the NWT to prevent one outcome event. Trial registration number Clinicaltrials.gov NCT00239681.

Metabolic syndrome and the risk of new vascular events and all-cause mortality in patients with coronary artery disease, cerebrovascular disease, peripheral arterial disease or abdominal aortic aneurysm.

AIMS: To investigate the vascular risk associated with Metabolic Syndrome (MetS) according to different clinical criteria with subsequent vascular events and all-cause mortality in patients with coronary artery disease, cerebrovascular disease, peripheral artery disease or abdominal aortic aneurysm and to examine whether patients with MetS at treatment goals for systolic blood pressure (SBP) or low density lipoprotein-cholesterol (LDL-c) level are still at elevated risk. METHODS AND RESULTS: Prospective study of 3196 patients with a history or recent diagnosis of clinically manifest vascular disease. During a median follow-up of 3.2 years (interquartile range 1.4-5.4 years), 331 patients died and 373 patients experienced a first vascular event. National Cholesterol Education Program (NCEP) and revised NCEP (NCEP-R)-defined MetS were related to increased risk of vascular events [HR - hazard ratio 1.50 (95% CI - confidence interval 1.22-1.84) and 1.50 (1.22-1.87)] and all-cause mortality [HR 1.49(1.20-1.84) and 1.43 (1.14-1.78)]. Results were similar in the 2472 patients without type 2 diabetes (DM2) and localization of vascular disease; SBP-category (<140 or > or =140 mmHg) or LDL-category (<2.5 or > or =2.5 mmol/L) did not affect this relation. CONCLUSION: In patients with various manifestations of atherosclerosis, presence of NCEP and NCEP-R-defined MetS is associated with increased risk of cardiovascular events and all-cause mortality, independently of the presence of DM2. This risk is significantly higher than the risk associated with International Diabetes Federation-defined MetS. Also in patients at treatment goals for SBP (<140 mmHg) or LDL-c (<2.5 mmol/L) according to current guidelines, presence of NCEP-R-defined MetS points to a higher vascular risk.