Despite criticism regarding its clinical relevance, the concept of the metabolic syndrome improves our understanding of both the pathophysiology of insulin resistance and its associated metabolic ...changes and vascular consequences. Free fatty acids (FFA) and tumour necrosis factor‐alpha (TNF‐α) play prominent roles in the development of insulin resistance by impairing the intracellular insulin signalling transduction pathway. Obesity is an independent risk factor for cardiovascular disease and strongly related to insulin resistance. In case of obesity, FFAs and TNF‐α are produced in abundance by adipocytes, whereas the production of adiponectin, an anti‐inflammatory adipokine, is reduced. This imbalanced production of pro‐ and anti‐inflammatory adipokines, as observed in adipocyte dysfunction, is thought to be the driving force behind insulin resistance. The role of several recently discovered adipokines such as resistin, visfatin and retinol‐binding protein (RBP)‐4 in the pathogenesis of insulin resistance is increasingly understood. Insulin resistance induces several metabolic changes, including hyperglycaemia, dyslipidaemia and hypertension, all leading to increased cardiovascular risk. In addition, the dysfunctional adipocyte, reflected largely by low adiponectin levels and a high TNF‐α concentration, directly influences the vascular endothelium, causing endothelial dysfunction and atherosclerosis. Adipocyte dysfunction could therefore be regarded as the common antecedent of both insulin resistance and atherosclerosis and functions as the link between obesity and cardiovascular disease. Targeting the dysfunctional adipocyte may reduce the risk for both cardiovascular disease and the development of type 2 diabetes. Although lifestyle intervention remains the cornerstone of therapy in improving insulin sensitivity and its associated metabolic changes, medical treatment might prove to be important as well.
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.
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).
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.
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.
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.
Diabet. Med. 28, 932–940 (2011)
Aims 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.
Methods 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.
Results 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 and < 3 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 and < 3 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).
Conclusions 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.
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.
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.
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 β = 0.24; 95% CI, 0.05 to 0.43 vs 0.71 cm β = 0.71; 95% CI, 0.29 to 1.12). There were no differences in SAT (β = -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 β = -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 β = 0.24; 95% CI, 0.05 to 0.43 vs -0.01 cm per decade β = -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 β = -0.36; 95% CI, -0.47 to -0.26 vs -0.22 cm β = -0.22; 95% CI, -0.27 to -0.18).
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.
Overall outcomes post hematopoietic stem cell transplant (HSCT) for children and young adults with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) continue to improve over the ...years. However, HSCT is often the last resort for high risk relapsed/refractory (r/r) leukemias and when these patients relapse post-HSCT the outcomes are dismal. Our current pilot study aims to evaluate the clinical utility of sequential testing of CD4+CD25+FOXP3+CD127dim regulatory T cells (CD127dim Tregs), CD4+CD25+FOXP3+CD127hi regulatory T cells (CD127hi Tregs), cytotoxic T cells (Tcons), natural killer (NK) cells, and relevant cytokines to predict potential relapse.
Investigate the correlation between Treg:Tcon:NKcell proportions sequentially monitored starting prior to HSCT therapy and one year relapse free survival in HSCT patients.
Investigate the correlation between Treg:Tcon:NKcell proportions sequentially monitored starting prior to HSCT therapy up to one year post and presence and severity of graft vs versus host disease (GVHD).
We designed and implemented a pilot prospective observational study at a single institution with target enrollment of 30 children and young adults with acute leukemias undergoing allo-HSCT. Peripheral blood samples are collected at sequential timepoints (7-14 days prior to HSCT; Day 0 HSCT (on donated product, not recipient); after HSCT at Day 30, Day 60, Day 100, Day 180 and Day 365). Each sample is characterized with flow cytometry-based measurements for host immune profiling using peripheral blood testing CD127dim Tregs (CD4+CD25+FOXP3+CD127dim), CD127hi Tregs (CD4+CD25+FOXP3+CD127hi), Tcons (CD3+CD8+), NK cells (CD56+) with relevant cytokines (GM-CSF, Granzyme B, IFN-γ, IL-2, IL-4, IL-6, IL-10, IL-17A, IL-21, MCP-1 (CCL2), Perforin, and TNF-α) using flowcytometry at sequential timepoints.
Preliminary analysis of the first 12 samples showed 5 patients with no GVHD, 5 with Grade 1 or 2 GVHD, and 2 with Grade 3 or 4 GVHD. Age ranged from 13 months to 19 years, 6 females and 6 males, 5 AML and 7 high risk ALL.
It is feasible to perform serial exploratory Treg and immune function assays on blood specimens collected from study participants undergoing HSCT during their regularly scheduled standard of care procedures. Preliminary analysis suggests that Day 30 CD127dim to CD127hi Tregs may be predictive of GVHD.
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, β = 4.36; 95% confidence interval (CI) = 3.11–5.61) and women (β = 1.48; 95% CI = −0.70 to 3.66), after full adjustment. Waist circumference and BMI had a significant relation with RHR in men (β = 3.51; 95% CI = 2.21–4.81 and β = 2.80; 95% CI = 1.51–4.08, respectively) but these relations were smaller and not significant in women (β = 0.71; 95% CI = −1.44 to 2.85 and β = 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.
Abstract Background and aims Plasma aldosterone has been associated with all-cause and cardiovascular mortality in high-risk cardiovascular populations, including patients with heart failure, ...myocardial infarction and high-risk coronary artery disease (CAD) patients. In the present study, we evaluated the association of plasma aldosterone levels with vascular events in a large prospective cohort of stable CAD patients recruited in an outpatient setting. Moreover, we investigated the relationship between aldosterone and atherosclerotic burden. Methods and results Baseline plasma aldosterone levels were measured in 2699 subjects with CAD (mean age 60 ± 10 years, 82% male). During a median follow-up of 4.7 years, 308 (11%) patients died, of which 203 were from a vascular cause. Vascular endpoints of myocardial infarction, ischemic stroke or vascular death occurred in 355 (13%) patients. Multivariable Cox regression analysis was performed, adjusting for multiple confounders. Aldosterone (median 96 pg/mL, interquartile range 70–138 pg/mL, normal range 58–362 pg/mL) was independently associated with major vascular events (hazard ratio (HR) 1.56, 95% confidence interval (CI) 1.13–2.15) and vascular mortality (HR 1.95, 95% CI 1.27–3.00). By multivariable regression analysis, aldosterone was also associated with the presence of atherosclerosis in additional vascular territories (cerebrovascular disease and/or peripheral artery disease) ( p = 0.026). Conclusions In patients with stable coronary artery disease, plasma aldosterone is independently associated with the risk of major vascular events and vascular mortality and with atherosclerotic burden.
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: β 0·27; 95% CI 0·19–0·36; females: β 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.
Aim To explore the quality of the content of communication skills training programmes, we analysed and assessed guidelines for doctor–patient communication used in communication programmes for ...general practitioner (GP) trainees.
Method Guidelines for doctor–patient communication were extracted from educational materials supplied by the 8 Dutch university centres for vocational training in general practice. Four themes guided the analysis of the guidelines: content, type of contact, format and structure and status. The quality of the guidelines was assessed with the Appraisal of Guidelines Research and Evaluation (AGREE) instrument, a validated measurement instrument for guideline quality.
Results We identified 18 guidelines. Guideline content covered 64–100% of the GP qualification requirements. General consultations and specific situations were the subject of 9 guidelines each. Format and structure differed between guidelines. Guideline use seemed not to be obligatory. AGREE scores were low.
Conclusions Guidelines for doctor–patient communication are difficult to identify in materials of GP training courses. Guideline quality is low; guidelines are little evidence‐based and little attention has been paid to applicability and involvement of users. GP qualification requirements are only partly covered. Guidelines differed substantially without clarity about the reasons behind different choices. Guideline status was low.
Recommendations When studying the factors that influence training effect, the quality of training content should be considered as well as teaching methods. Communication skills training programmes should be based on evidence‐based guidelines that have been developed according to similar standards as for medical technical guidelines.
In postmenopausal women, tibolone shows clear tissue differences in its stimulatory effects on the vagina and uterus. In rats, however, it has stimulatory effects on both tissues, with a different, ...more estrogenic, effect on the uterus than in humans. This may be due to differences in local metabolism. Therefore, in the present study, the metabolism of tibolone was analyzed in incubations of uterine and vaginal tissue from postmenopausal women and ovariectomized rats using radiolabeled tibolone in order to understand the tissue- and species-specific metabolism. In the rat, tibolone (50
nM) was mainly 3α-reduced to the estrogenic 3α-OH-tibolone in the uterus and vagina. The 3β-OH tibolone can be isomerized to 3α-OH-tibolone with tibolone as intermediate. In contrast, in the same tissues from postmenopausal women, the progestagenic Δ
4-isomer and estrogenic 3β-OH-tibolone were the major metabolites of tibolone. The formation of the Δ
4-isomer was higher in uterine tissue. The 3β-hydroxysteroid dehydrogenase (HSD) inhibitor epostane had no effect on tibolone metabolism in human uterine and vaginal tissue microsomes and HEK293 cells expressing the human 3β-HSD types 1 and 2 isoforms did not metabolize tibolone. Moreover, the 3β-reduction of tibolone to 3β-OH-tibolone was NADPH dependent, while the isomerization of tibolone to the Δ
4-isomer did not require a cofactor. It was therefore concluded that human 3β-HSD isoforms are not involved in the metabolism of tibolone, and that the 3β-reduction and the Δ
5–10 to Δ
4 isomerization may be catalyzed by different enzymes. In conclusion, we showed that, in hormone therapy target tissues of the rat as compared with the human, different metabolic pathways for tibolone exist and therefore result in metabolites with different pharmacological properties. The rat is therefore a poor model to predict the effects of tibolone on the uterus in postmenopausal women.
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