Jan Westerink

Increased visceral adipose tissue mass is associated with increased C-reactive protein in patients with manifest vascular diseases.

BACKGROUND Obesity is related to the development of vascular diseases and metabolic complications. Low grade inflammation is a key feature of central obesity, characterized by elevated plasma levels of C-reactive protein (CRP). We hypothesize that visceral adipose tissue contributes to systemic concentrations of CRP. METHODS In 2410 patients (1729 men and 681 women) with vascular diseases, subcutaneous and visceral fat masses were analyzed with ultrasonography. Metabolic parameters and CRP were measured in a fasting state. The association between fat measurements and plasma CRP was quantified using linear regression analysis. CRP levels were logarithmically transformed. Adjustments were made for age, smoking, type 2 diabetes mellitus, insulin resistance (HOMA-IR) and medication use. RESULTS Visceral fat was categorized into quartiles (Q) ranging from 3.2 to 7.8 cm in Q1 (reference) to 11.0-19.8 cm in Q4 in men and 2.7-6.0 cm in Q1 (reference) to 9.0-17.4 cm in Q4 in women. beta-coefficients gradually increased across the quartiles from 0.07 (0.01-0.13) in Q2 to 0.25 (0.19-0.31) in Q4 in men and 0.17 (0.07-0.26) in Q2 to 0.42 (0.32-0.52) in Q4 in women, indicating 0.25 and 0.42 mg/l higher logarithmically transformed (log)CRP levels in Q4 compared to Q1 in respectively men and women. Per standard deviation increase of visceral fat, logCRP levels increased with 0.10 mg/l (0.07-0.12) in men and with 0.11 (0.15-0.19) in women. Likewise, in separate analyses waist circumference and body mass index showed a positive, but weaker association with logCRP levels across quartiles (in men: beta 0.21 (0.15-0.27) in Q4 for waist circumference and beta 0.23 (0.17-0.30) in Q4 for body mass index; in women: beta 0.32 (0.22-0.42) in Q4 for waist circumference and beta 0.32 (0.22-0.42) in Q4 for body mass index). In men subcutaneous fat was not associated with logCRP (beta-coefficients relative to Q1: -0.01 (-0.07 to -0.05), -0.01 (-0.07 to -0.05) and 0.05 (-0.01 to -0.11) in Q2 to Q4 respectively). CONCLUSIONS In conclusion, visceral fat thickness is the strongest contributor to the systemic CRP concentrations in patients with vascular diseases.

Pharmacological and non-pharmacological interventions to influence adipose tissue function

Obesity is associated with metabolic derangements such as insulin resistance, inflammation and hypercoagulobility which can all be understood as consequences of adipose tissue dysfunction. The potential role for adipose tissue derived cytokines and adipokines in the development of vascular disease and diabetes may produce a clinical need to influence adipose tissue function. Various pharmacological and non-pharmacological interventions affect plasma cytokine and adipokine levels. The effects of these interventions depend on weight loss per se, changes in fat distribution without weight loss and/or direct effects on adipose tissue inflammation.Weight loss, as a result of diet, pharmacology and surgery, positively influences plasma adipokines and systemic inflammation. Several classes of drugs influence systemic inflammation directly through their anti-inflammatory actions. PPAR-γ agonism positively influences adipose tissue inflammation in several classes of intervention such as the thiazolidinediones and perhaps salicylates, CB1-antagonists and angiotensin II receptor blockers. Furthermore, within drug classes there are differential effects of individual pharmacologic agents on adipose tissue function.It can be concluded that several commonly used pharmacological and non-pharmacological interventions have unintended influences on adipose tissue function. Improving adipose tissue function may contribute to reducing the risk of vascular diseases and the development of type 2 diabetes.

Low high-density lipoprotein cholesterol is not a risk factor for recurrent vascular events in patients with vascular disease on intensive lipid-lowering medication.

OBJECTIVES This study sought to evaluate the vascular risk of low high-density lipoprotein-cholesterol (HDL-C) in relation to the use and intensity of lipid-lowering medication in patients with clinically manifest vascular diseases. BACKGROUND Low levels of HDL-C are associated with an increased risk for vascular diseases and may contribute to residual vascular risk in patients already treated for other risk factors. However, post-hoc analyses from statin trials indicate that the vascular risk associated with low HDL-C may be low or even absent in patients using intensive statin therapy. METHODS We performed a prospective cohort study of 6,111 patients with manifest vascular disease. Cox proportional hazards models were used to evaluate the risk of HDL-C on vascular events in patients using no, usual dose, or intensive lipid-lowering therapy. RESULTS New vascular events (myocardial infarction, stroke, or vascular death) occurred in 874 subjects during a median follow-up of 5.4 years (interquartile range: 2.9 to 8.6 years). In patients not using lipid-lowering medication at baseline (n = 2,153), a 0.1 mmol/l increase in HDL-C was associated with a 5% reduced risk for all vascular events (hazard ratio [HR]: 0.95; 95% confidence interval [CI]: 0.92 to 0.99). In patients on usual dose lipid-lowering medication (n = 1,910) there was a 6% reduced risk (HR: 0.94; 95% CI: 0.90 to 0.98). However, in patients using intensive lipid-lowering treatment (n = 2,046), HDL-C was not associated with recurrent vascular events (HR: 1.02; 95% CI: 0.98 to 1.07) irrespective of low-density lipoprotein cholesterol level. CONCLUSIONS In patients with clinically manifest vascular disease using no or usual dose lipid-lowering medication, low plasma HDL-C levels are related to increased vascular risk, whereas in patients using intensive lipid-lowering medication, HDL-C levels are not related to vascular risk.

Angiotensin II type 1 receptor blockade improves hyperglycemia-induced endothelial dysfunction and reduces proinflammatory cytokine release from leukocytes.

Angiotensin II and glucose share components of their intracellular redox signaling pathways in endothelial and inflammatory cells. We hypothesized that valsartan, an angiotensin II blocker, attenuates hyperglycemia-induced endothelial dysfunction and downregulates release of proinflammatory cytokines from leukocytes. A sustained hyperglycemic clamp (12 mmol/L) to induce endothelial dysfunction was performed in healthy volunteers before and after 4 weeks of treatment with 160 mg of valsartan. Brachial artery flow-mediated vasodilation (FMD), lipopolysaccharide-induced release of interleukin-6 and TNF-α from peripheral blood leukocytes ex vivo, and circulating proinflammatory cytokines were determined before and during the clamp. The hyperglycemic clamp induced a decrease in FMD from 9.2 ± 0.8 (t = 0 hr) to 4.4± 0.5 (t = 2 hr), 3.8 ± 0.5 (t = 4 hr), and 4.8 ± 0.5% (t = 22 hr) during the clamp. Valsartan attenuated endothelial dysfunction [FMD 7.0 ± 0.7 (t = 2 hr), 6.1 ± 0.7 (t = 4 hr), 6.2 ± 0.6% (t = 22 hr); P < 0.005] and decreased the release of interleukin-6 and TNF-α from leukocytes both before and during the clamp (P < 0.05). Valsartan improves hyperglycemia-induced endothelial dysfunction and reduces the cytokine response to an inflammatory stimulus. A pathophysiological link between the effects of hyperglycemia and the renin-angiotensin system on endothelium and peripheral blood leukocytes may underlie the beneficial effects of inhibitors of the renin-angiotensin system on cardiovascular outcome in patients with diabetes mellitus.

Distribution of Estimated 10-Year Risk of Recurrent Vascular Events and Residual Risk in a Secondary Prevention Population

Background: Among patients with clinically manifest vascular disease, the risk of recurrent vascular events is likely to vary. We assessed the distribution of estimated 10-year risk of recurrent vascular events in a secondary prevention population. We also estimated the potential risk reduction and residual risk that can be achieved if patients reach guideline-recommended risk factor targets. Methods: The SMART score (Second Manifestations of Arterial Disease) for 10-year risk of myocardial infarction, stroke, or vascular death was applied to 6904 patients with vascular disease. The risk score was externally validated in 18 436 patients with various manifestations of vascular disease from the TNT (Treating to New Targets), IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering), SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), and CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trials. The residual risk at guideline-recommended targets was estimated by applying relative risk reductions from meta-analyses to the estimated risk for targets for systolic blood pressure, low-density lipoprotein cholesterol, smoking, physical activity, and use of antithrombotic agents. Results: The external performance of the SMART risk score was reasonable, apart from overestimation of risk in patients with 10-year risk >40%. In patients with various manifestations of vascular disease, median 10-year risk of a recurrent major vascular event was 17% (interquartile range, 11%–28%), varying from <10% in 18% to >30% in 22% of the patients. If risk factors were at guideline-recommended targets, the residual 10-year risk would be <10% in 47% and >30% in 9% of the patients (median, 11%; interquartile range, 7%–17%). Conclusions: Among patients with vascular disease, there is very substantial variation in estimated 10-year risk of recurrent vascular events. If all modifiable risk factors were at guideline-recommended targets, half of the patients would have a 10-year risk <10%. These data suggest that even with optimal treatment, many patients with vascular disease will remain at >20% and even >30% 10-year risk, clearly delineating an area of substantial unmet medical need.

Relation between thyroid-stimulating hormone and the occurrence of cardiovascular events and mortality in patients with manifest vascular diseases.

Aims: To investigate whether levels of thyroid-stimulating hormone (TSH) within the normal range are associated with an increased risk of new vascular events and mortality in patients with clinical manifest vascular diseases and whether this relation is influenced by adiposity. Methods and results: Prospective cohort study in 2443 patients (1790 men and 653 women) with clinical manifest vascular disease and TSH levels in the normal range. Median follow up was 2.7 (interquartile range 1.4–3.9) years. Clinical endpoints of interest were: myocardial infarction, stroke, vascular death, and all-cause mortality. In patients with manifest vascular disease, the prevalence of (subclinical) hypothyroidism was 5.7%, while 3.6% had (subclinical) hyperthyroidism. An increase in 1 unit of TSH was associated with a 33% higher risk (HR 1.33; 95% CI 1.03–1.73) for the occurrence of myocardial infarction, adjusted for age, gender, renal function, and smoking. In patients with a body mass index (BMI) below the median of 26.7 kg/m2 the HR per unit TSH for myocardial infarction was 1.55 (95% CI 1.08–2.21) compared to 1.18 (95% CI 0.81–1.71) in patients with a BMI ≥26.7 kg/m2. Visceral adipose tissue thickness below the median (≤8.8 cm) was associated with higher HR per unit TSH for myocardial infarction (HR 1.69; 95% CI 1.21–2.35) compared to visceral adipose tissue thickness >8.9 cm (HR 1.00; 95% CI 0.66–1.49). There was no relation between TSH and risk of stroke, vascular death, the combined endpoint, or all-cause mortality. Conclusion: Higher TSH levels within the normal range are associated with an increased risk of myocardial infarction, in patients with clinical manifest vascular disease. This relation is most prominent in patients without visceral obesity.

The relation between thyroid-stimulating hormone and measures of adiposity in patients with manifest vascular disease

Eur J Clin Invest 2011; 41 (2): 159–166

Association of High Ankle Brachial Index With Incident Cardiovascular Disease and Mortality in a High-Risk Population.

Objective— The objective of this present study is to determine whether high ankle brachial index (ABI) as compared with ABIs within reference limits is associated with an increased incidence of cardiovascular disease (CVD) events and all-cause mortality in a high-risk population and whether this association is the same for patients with and without diabetes mellitus or prevalent CVD. Approach and Results— Seven thousand five hundred and thirty-eight patients with ABI>0.9 and either prevalent CVD or a high risk for CVD were selected from the Second Manifestations of Arterial Disease (SMART) study. Three hundred and thirty-six participants (4.5%) had high ABI (≥1.4 or incompressible). Higher age, male sex, higher body mass index, and diabetes mellitus were associated with higher prevalences of high ABI; smoking and higher non–high-density lipoprotein levels were associated with lower prevalences of high ABI. Cox proportional hazards models were fitted assessing the association of high ABI (as compared with ABI 0.9–1.4) with the risk of myocardial infarction, stroke, cardiovascular death, the combined outcome of these 3, and total mortality (median follow-up 6.9 years). After multivariable adjustment, high ABI was associated with an increased risk of myocardial infarction (hazard ratio 1.83 [95% confidence interval 1.22–2.76]), but not with stroke (hazard ratio 0.86 [95% confidence interval 0.44–1.69]), cardiovascular (hazard ratio 1.14 [95% confidence interval 0.70–1.84]), or all-cause mortality (hazard ratio 0.95 [95% confidence interval 0.67–1.34]). Associations of high ABI with CVD outcomes tended to be stronger in patients with diabetes mellitus but without statistically significant interactions. Conclusions— In a high-risk population, the presence of an ABI≥1.4 was associated with an increased risk for myocardial infarction, but not with stroke, all-cause, or vascular mortality.

Influence of APOE-2 genotype on the relation between adiposity and plasma lipid levels in patients with vascular disease

Background:Apolipoprotein E (APOE) genotypes are associated with different plasma lipid levels. People with the APO ɛ2 genotype can develop a disorder called dysbetalipoproteinemia (DBL). A possible predisposing factor for DBL is adiposity. We evaluated whether and to what extent the APOE genotype modifies the relation between adiposity and lipids in patients with manifest arterial disease and we looked at possible determinants of DBL in ɛ2 homo- and heterozygote patients.Methods:This prospective cohort study was performed in 5450 patients with manifest arterial disease from the Secondary Manifestations of ARTerial disease (SMART) study. The APOE genotype was measured in all patients and revealed 58 ɛ2 homozygotes, 663 ɛ2 heterozygotes, 3181 ɛ3 homozygotes and 1548 ɛ4 carriers. The main dependent variable was non-high-density lipoprotein cholesterol (non-HDL-c). The relation between adiposity (including body mass index (BMI), waist circumference (waist), visceral adipose tissue (VAT) and metabolic syndrome (MetS)) and lipids was evaluated with linear regression analyses. Determinants of DBL were evaluated using logistic regression.Results:There was significant effect modification by the APOE genotype on the relation between non-HDL-c and BMI, waist, VAT and MetS. There was an association between BMI and non-HDL-c in ɛ2 homozygotes (β 0.173, 95% confidence interval (CI) 0.031–0.314, P=0.018) and ɛ4 carriers (β 0.033, 95% CI 0.020–0.046, P<0.001). In all genotypes, there was an effect of waist, VAT and MetS on non-HDL-c, but these effects were most distinct in ɛ2 homozygotes (waist β 0.063, 95% CI 0.015–0.110, P=0.011; VAT β 0.580, 95% CI 0.270–0.889, P=0.001; MetS β 1.760, 95% CI 0.668–2.852, P=0.002). Determinants of DBL in ɛ2 homo- and heterozygotes were VAT and MetS.Conclusion:The APOE genotype modifies the relation between adiposity and plasma lipid levels in patients with vascular disease. The relation between adiposity and lipids is present in all patients, but it is most distinct in ɛ2 homozygote patients. Abdominal fat and MetS are determinants of DBL.

Body Weight, Metabolic Dysfunction, and Risk of Type 2 Diabetes in Patients at High Risk for Cardiovascular Events or With Manifest Cardiovascular Disease: A Cohort Study

OBJECTIVE To quantify the role of BMI and metabolic dysfunction in the risk of development of type 2 diabetes in patients at high risk or with manifest vascular disease. RESEARCH DESIGN AND METHODS A total of 6,997 patients participating in the prospective Secondary Manifestations of ARTerial disease (SMART) cohort study were classified according to BMI and metabolic dysfunction, defined as three or more of the modified National Cholesterol Education Program (NCEP) metabolic syndrome criteria (waist circumference replaced by hs-CRP ≥2 mg/L). Risk of type 2 diabetes (assessed with biannually questionnaires) was estimated with Cox proportional hazards analysis. RESULTS During a median follow-up of 6.0 years (interquartile range 3.1–9.1 years), 519 patients developed type 2 diabetes (incidence rate 12/1,000 person-years). In the absence of metabolic dysfunction (≤2 NCEP criteria), adiposity increased the risk of type 2 diabetes compared with normal-weight patients (HR 2.5 [95% CI 1.5–4.2] for overweight and HR 4.3 [95% CI 2.2–8.6] for obese patients). In the presence of metabolic dysfunction (≥3 NCEP criteria), an increased risk of type 2 diabetes was observed in patients with normal weight (HR 4.7 [95% CI 2.8–7.8]), overweight (HR 8.5 [95% CI 5.5–13.4]), and obesity (HR 16.3 [95% CI 10.4–25.6]) compared with normal-weight patients without metabolic dysfunction. CONCLUSIONS Adiposity, even in the absence of metabolic dysfunction, is a risk factor for type 2 diabetes. Moreover, presence of metabolic dysfunction increases the risk of type 2 diabetes in all BMI categories. This supports the assessment of adiposity and metabolic dysfunction in patients with vascular disease or at high risk for cardiovascular events.