Thin-fat insulin-resistant phenotype also present in South Asian neonates born in the Netherlands.

Several studies have shown that South Asian neonates have a characteristic thin-fat insulin-resistant phenotype. The aim of our study was to determine whether this phenotype is also present in South Asians who have migrated to a Western country (the Netherlands). South Asian and white Dutch pregnant women were included in our study. After delivery, cord blood was collected and neonatal anthropometry was measured within 72 h. Compared with white Dutch mothers, South Asian mothers were younger (28.5 v. 32.2 years, P<0.001) and had a higher prepregnancy body mass index (25.1 v. 23.0, P=0.001). Gestational age at delivery was on average 4 days shorter in South Asians (274.9 v. 278.8, P=0.001). To compare the two groups of neonates, we calculated sex- and gestation-specific s.d. scores using the values for mean and s.d. obtained from the white Dutch subjects as a reference. All measurements were smaller in South Asian neonates, except for those of the skinfolds. The largest difference was found in abdominal circumference (s.d. score 1.39, 95% CI -1.76 to -1.01). Triceps and subscapular skinfolds were similar in both groups (triceps s.d. score -0.34, 95% CI -0.88 to +0.20 and subscapular s.d. score -0.03, 95% CI -0.31 to +0.25). South Asian neonates had higher cord plasma levels of triglycerides (0.40 v. 0.36, P=0.614), glucose (5.4 v. 4.8, P=0.079) and insulin (6.3 v. 4.0, P=0.051). However, these differences were not statistically significant. After adjustment for birth weight, the difference in insulin became statistically significant (P=0.001). We therefore conclude that the thin-fat insulin-resistant phenotype is also present in South Asian neonates in the Netherlands.

The effect of hypertension on aortic pulse wave velocity in type-1 diabetes mellitus patients: assessment with MRI.

To investigate in type-1 diabetes mellitus (DM1) patients the role of hypertension and of DM1 itself on aortic stiffness by using magnetic resonance imaging (MRI). Consecutive patients from the diabetes and hypertension outpatient clinic and healthy volunteers were included in our study. Subjects were divided into four groups: 32 healthy volunteers (mean age: 54.5 ± 6.8 years), 20 DM1 patients (mean age: 48.3 ± 5.9 years), 31 hypertensive patients (mean age: 59.9 ± 7.2 years) and 28 patients with both DM1 and hypertension (mean age: 50.1 ± 6.2 years). Aortic stiffness was measured by means of pulse wave velocity (PWV) using velocity-encoded MRI. Analysis of variance (ANOVA), uni- and multivariable regression models and the Bonferroni-test for multiple testing, were used for statistical analyses. Mean aortic PWV was 5.7 ± 1.2 m/s in healthy volunteers, 5.9 ± 1.2 m/s in DM1 patients without hypertension, 7.3 ± 1.2 m/s in hypertensive patients and 7.3 ± 1.3 m/s in patients with both DM1 and hypertension. Compared to healthy control subjects, aortic PWV was significantly higher in patients with hypertension (P < 0.001) and in patients with both DM1 and hypertension (P < 0.001), whereas aortic PWV was not increased in patients having DM1 alone. Furthermore, aortic PWV was significantly higher in DM1 patients with hypertension than in patients with DM1 alone (P = 0.002). These findings remained after adjustment for confounding factors. Hypertension has a predominant contributive effect on aortic stiffness in DM1 patients whereas the direct diabetic effect on aortic stiffness is small.

Human CD34+/KDR+ cells are generated from circulating CD34+ cells after immobilization on activated platelets.

OBJECTIVE: The presence of kinase-insert domain-containing receptor (KDR) on circulating CD34+ cells is assumed to be indicative for the potential of these cells to support vascular maintenance and repair. However, in bone marrow and in granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood, less than 0.5% of CD34+ cells co-express KDR. Therefore, we studied whether CD34+/KDR+ cells are generated in the peripheral circulation. METHODS AND RESULTS: Using an ex vivo flow model, we show that activated platelets enable CD34+ cells to home to sites of vascular injury and that upon immobilization, KDR is translocated from an endosomal compartment to the cell-surface within 15 minutes. In patients with diabetes mellitus type 2, the percentage of circulating CD34+ co-expressing KDR was significantly elevated compared to age-matched controls. When treated with aspirin, the patients showed a 49% reduction in the generation of CD34+/KDR+ cells, indicating that the level of circulating CD34+/KDR+ cells also relates to in vivo platelet activation. CONCLUSIONS: Circulating CD34+/KDR+ are not mobilized from bone marrow as a predestined endothelial progenitor cell population but are mostly generated from circulating multipotent CD34+ cells at sites of vascular injury. Therefore, the number of circulating CD34+/KDR+ cells may serve as a marker for vascular injury.

The tolerability and efficacy of low-dose simvastatin in statin-intolerant patients.

BACKGROUND/AIM: Statin intolerance is increasingly recognized as a therapy limiting factor in the primary and secondary prevention of cardiovascular disease. Since vulnerability to dose related adverse events differ between subjects treated with statins we hypothesized low-dose simvastatin would be tolerated and effective in statin-intolerant patients. METHOD: A single center open label prospective observational study was performed assessing tolerability and efficacy of low-dose simvastatin treatment in 35 statin-intolerant patients. Statin intolerance was defined as not being able to tolerate a registered dose statin due to myalgia-myopathy, myositis, or elevation of serum liver enzyme levels. These statin-intolerant patients were treated with simvastatin with an initial dose of 2.5mg every other day. The dose was titrated upwards if possible. Tolerability was defined as remaining on treatment. Efficacy was defined as change of LDL-cholesterol compared to baseline. RESULTS: The reached simvastatin dose ranged from 0.825 to 8.75mg/day with a mean dose of 4mg/day. Fifty-seven percent of the patients tolerated low-dose therapy and remained on treatment. Of these patients, 30% noted recurrent myalgia. Low-dose simvastatin significantly decreased mean(SD) LDL-cholesterol levels with 25.9(12.1)% (p<0.001). Eleven percent of the patients reached LDL-cholesterol target levels (<2.6mmol/l) in an intention to treat analysis and in 20% of patients that tolerated low-dose simvastatin. CONCLUSION: Low-dose simvastatin therapy is tolerated in a considerable proportion of statin-intolerant patients with significant lipid lowering efficacy. Low-dose statin therapy can be considered in multidrug regimens in statin-intolerant patients.

Accuracy of carotid plaque detection and intima-media thickness measurement with ultrasonography in routine clinical practice.

BACKGROUND: Current guidelines in cardiovascular disease prevention advocate the use of carotid ultrasound measurements for risk stratification. Carotid abnormalities (plaques or increased intima-media thickness (IMT)) are associated with high risk of coronary and peripheral artery disease. An office-based measurement by clinicians would considerably broaden the clinical applicability of carotid ultrasound. In the present study we have assessed the accuracy of ultrasound detection of carotid plaques and intima-media thickness by trained internists in a routine outpatient setting. METHODS AND RESULTS: Carotid ultrasound was performed in 112 vascular outpatients by internists, after a six-week training period. The internists' results were independently compared to the reference standard, consisting of carotid ultrasound performed in a specialized vascular laboratory. Sensitivity and specificity were calculated for plaque detection and IMT determination. The mean time required to perform the scans on the outpatient department was 7.3 min (range 4.5 to 16.7 min). A high level of accuracy for detecting plaques (sensitivity 78.5%; specificity 93.6%) was achieved. Identifying abnormal IMT had lower sensitivity but adequate specificity of 46.7% and 87.6%, respectively. CONCLUSIONS: In conclusion, our findings demonstrate that clinicians can be trained well enough in six weeks to accurately and efficiently detect carotid plaques in an outpatient setting. IMT abnormalities were less accurately detected in the office-based approach and may require a specialized vascular laboratory.

Aortic stiffness is associated with cardiac function and cerebral small vessel disease in patients with type 1 diabetes mellitus: assessment by magnetic resonance imaging.

OBJECTIVE: To evaluate, with the use of magnetic resonance imaging (MRI), whether aortic pulse wave velocity (PWV) is associated with cardiac left ventricular (LV) function and mass as well as with cerebral small vessel disease in patients with type 1 diabetes mellitus (DM). MATERIALS AND METHODS: We included 86 consecutive type 1 DM patients (49 male, mean age 46.9 +/- 11.7 years) in a prospective, cross-sectional study. Exclusion criteria included aortic/heart disease and general MRI contra-indications. MRI of the aorta, heart and brain was performed for assessment of aortic PWV, as a marker of aortic stiffness, systolic LV function and mass, as well as for the presence of cerebral white matter hyperintensities (WMHs), microbleeds and lacunar infarcts. Multivariate linear or logistic regression was performed to analyse the association between aortic PWV and outcome parameters, with covariates defined as age, gender, mean arterial pressure, heart rate, BMI, smoking, DM duration and hypertension. RESULTS: Mean aortic PWV was 7.1 +/- 2.5 m/s. Aortic PWV was independently associated with LV ejection fraction (ss = -0.406, P = 0.006), LV stroke volume (ss = -0.407, P = 0.001), LV cardiac output (ss = -0.458, P = 0.001), and with cerebral WMHs (P < 0.05). There were no independent associations between aortic stiffness and LV mass, cerebral microbleeds or lacunar infarcts. CONCLUSION: Aortic stiffness is independently associated with systolic LV function and cerebral WMHs in patients with type 1 DM.

A systematic review of implementation of established recommended secondary prevention measures in patients with PAOD.

OBJECTIVE: Since patients with peripheral arterial occlusive disease (PAOD) are at high-risk for cardiovascular morbidity and mortality, preventive measures aimed to reduce cardiovascular adverse events are advocated in the current guidelines. We conducted a systematic review to assess the implementation of secondary prevention (SP) measures in PAOD patients. METHODS: PubMed, Cochrane Library, EMBASE and Web of Science databases were searched to perform a systematic review of the literature from 1999 till June 2008 on SP for PAOD patients. Assessment of study quality was done following the Cochrane Library review system. The record outcomes were antiplatelet agents, heart rate lowering agents, blood pressure lowering agents, lipid lowering agents, glucose lowering agents, smoking cessation and walking exercise. RESULTS: From a total of 2137 identified studies, 83 observational studies met the inclusion criteria, of which 24 were included in the systematic review comprising 34 157 patients. These patients suffered from coronary artery disease (n=3516, 41%), myocardial infraction (n=2647, 38%), angina pectoris (n=1790, 31%), congestive heart failure (n=2052, 14%), diabetes mellitus (n=10 690, 31%),hypertension (n=20 823, 73%) and hyperlipidaemia (n=15 067, 64%). Contrary to what the guidelines prescribe, antiplatelet agents, heart rate lowering agents, blood pressure lowering agents and lipid lowering agents were prescribed in 63%, 34%, 46% and 45% of the patients, respectively. Glucose lowering agents were prescribed in 81% and smoking cessation in 39% of the patients. CONCLUSION: The majority of patients suffering from PAOD do not receive the entire approach of SP measures as suggested by the current guidelines. To our knowledge, the cause of this undertreatment is multifactorial: patient, physician or health-care-related.

Neonatal anthropometry: thin-fat phenotype in fourth to fifth generation South Asian neonates in Surinam.

We assessed whether the earlier described 'thin-fat phenotype' is present in Surinam South Asian babies of the fourth to fifth generation after migration from India. In this observational study we collected data from 39 South Asian term neonates and their mothers in Paramaribo, Surinam. We compared the following data with data from an earlier study in Southampton, UK (338 neonates) and in Pune, India (631 neonates): maternal body mass index, neonatal weight, length, head, mid-upper arm and abdominal circumferences and subscapular skinfold thickness. The mothers in Paramaribo were older than the Southampton mothers; their body mass index was comparable. Mean birth weight was 3159 g (Southampton: 3494 g; Pune: 2666 g). Compared with Southampton babies, the Paramaribo babies were smaller in nearly all body measurements, the smallest being abdominal circumference at the umbilicus level (s.d. score: -1.62; 95% confidence interval (CI): -2.07 to -1.16) and mid-upper arm circumference (s.d. score: -1.08; 95% CI: -1.46 to -0.69). In contrast, subscapular skinfold thickness was similar (s.d. score: +0.08; 95% CI: -0.24 to +0.55). Except for subscapular skinfold thickness and length, all neonatal measurements were intermediate between those from Southampton and Pune. The thin-fat phenotype is preserved in Surinam South Asian neonates of the fourth to fifth generation after migration from India.

The role of inflammation on atherosclerosis, intermediate and clinical cardiovascular endpoints in type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with increased cardiovascular morbidity and mortality. Sub-clinical systemic inflammation is often present in T2DM patients. Systemic inflammation has also been implicated in the pathophysiology of atherosclerosis. This review investigates the direct evidence present in literature for the effect of inflammation on atherosclerosis, specifically in the setting of T2DM. Special emphasis is given to the pathogenesis of atherosclerosis as well as intermediate and clinical cardiovascular endpoints. The important role of deteriorated endothelial function in T2DM was excluded from the analysis. METHODS: Extensive literature searches were performed using the PubMed and Web of Science databases. Articles were identified, retrieved and accepted or excluded based on predefined criteria. RESULTS: Substantial evidence was found for an important inflammatory component in the pathogenesis of atherosclerosis in T2DM, demonstrated by inflammatory changes in plaque characteristics and macrophage infiltration. Most epidemiologic studies found a correlation between inflammation markers and intermediate cardiovascular endpoints, especially intima-media thickness. Several, but not all clinical trials in T2DM found that reducing sub-clinical inflammation had a beneficial effect on intermediate endpoints. When regarding cardiovascular events however, current literature consistently indicates a strong relationship between inflammation and clinical endpoints in subjects with T2DM. CONCLUSION: Current literature provides direct evidence for a contribution of inflammatory responses to the pathogenesis of atherosclerosis in T2DM. The most consistent relation was observed between inflammation and clinical endpoints.

Four weeks high fat feeding induces insulin resistance without affecting dopamine release or gene expression patterns in the hypothalamus of C57Bl6 mice.

Obesity is associated with diminished dopaminergic neurotransmission. It remains unclear whether this is a cause or a consequence of the obese state. We hypothesized that high fat feeding, a well known trigger of obesity in diet sensitive mice, would blunt dopaminergic neurotransmission prior to the development of insulin resistance. We monitored in vivo dopamine release in the dorsomedial region of the hypothalamus, and determined hypothalamic gene expression patterns of dopamine receptors 1 and 2 (DRD1 and 2), tyrosine hydroxylase (TH) and the dopamine transporter (DAT) in C57Bl6 mice maintained on a high fat diet for 4 weeks. Also, a hyperinsulinemic euglycemic clamp was performed to evaluate the metabolic status of the mice. Mice maintained on a low fat diet served as controls. The high fat diet did not alter dopamine release in the dorsomedial hypothalamus of fed or fasted mice or the dopaminergic response to refeeding. Furthermore, gene expression levels of DRD1, DRD2, TH and DAT were not affected by high fat feeding. However, the high fat diet did hamper insulin action as evidenced by diminished glucose disposal during hyperinsulinemia (p<0.05). We show here that short term high fat feeding does not affect dopaminergic neurotransmission in the hypothalamus, whereas it does impair insulin action. This suggests that reduced dopaminergic neurotransmission in the hypothalamus of obese animal models is due to mechanism(s) that are not directly triggered by diet composition.

Non-invasive cardiac imaging techniques and vascular tools for the assessment of cardiovascular disease in type 2 diabetes mellitus.

Cardiovascular disease is the major cause of mortality in type 2 diabetes mellitus. The criteria for the selection of those asymptomatic patients with type 2 diabetes who should undergo cardiac screening and the therapeutic consequences of screening remain controversial. Non-invasive techniques as markers of atherosclerosis and myocardial ischaemia may aid risk stratification and the implementation of tailored therapy for the patient with type 2 diabetes. In the present article we review the literature on the implementation of non-invasive vascular tools and cardiac imaging techniques in this patient group. The value of these techniques as endpoints in clinical trials and as risk estimators in asymptomatic diabetic patients is discussed. Carotid intima-media thickness, arterial stiffness and flow-mediated dilation are abnormal long before the onset of type 2 diabetes. These vascular tools are therefore most likely to be useful for the identification of 'at risk' patients during the early stages of atherosclerotic disease. The additional value of these tools in risk stratification and tailored therapy in type 2 diabetes remains to be proven. Cardiac imaging techniques are more justified in individuals with a strong clinical suspicion of advanced coronary heart disease (CHD). Asymptomatic myocardial ischaemia can be detected by stress echocardiography and myocardial perfusion imaging. The more recently developed non-invasive multi-slice computed tomography angiography is recommended for exclusion of CHD, and can therefore be used to screen asymptomatic patients with type 2 diabetes, but has the associated disadvantages of high radiation exposure and costs. Therefore, we propose an algorithm for the screening of asymptomatic diabetic patients, the first step of which consists of coronary artery calcium score assessment and exercise ECG.

Effects of aspirin on serum C-reactive protein and interleukin-6 levels in patients with type 2 diabetes without cardiovascular disease: a randomized placebo-controlled crossover trial.

AIM: Low-grade inflammation plays a pivotal role in atherogenesis in type 2 diabetes. Next to its antithrombotic effects, several lines of evidence demonstrate anti-inflammatory properties of aspirin. We determined the effects of aspirin on inflammation - represented by C-reactive protein (CRP) and interleukin-6 (IL-6) - in type 2 diabetic subjects without cardiovascular disease and assessed differential effects of aspirin 300 mg compared with 100 mg. METHODS: A randomized, placebo-controlled, double-blind, crossover trial was performed in 40 type 2 diabetic patients. In two periods of 6 weeks, patients used 100 or 300 mg aspirin and placebo. Plasma CRP and IL-6 levels were measured before and after both periods. RESULTS: Use of aspirin resulted in a CRP reduction of 1.23 +/- 1.02 mg/l (mean +/- s.e.m.), whereas use of placebo resulted in a mean increase of 0.04 +/- 1.32 mg/l (P = 0.366). Aspirin reduced IL-6 with 0.7 +/- 0.5 pg/ml, whereas use of placebo resulted in a mean increase of 0.2 +/- 0.8 pg/ml (P = 0.302). There were no significant differences in effects on CRP and IL-6 between 100 and 300 mg aspirin. CONCLUSIONS: Our results indicate that a 6-week course of aspirin does not improve low-grade inflammation in patients with type 2 diabetes without cardiovascular disease, although a modest effect could not be excluded. No significant differential effects between aspirin 100 and 300 mg were found.

The challenges of extrapulmonary presentations of sarcoidosis: A case report and review of diagnostic strategies.

A patient presenting with overweight, amenorrhea, diabetes insipidus, and oral, nasal, and pharyngeal inflammation was admitted to our hospital. Using a non-invasive approach, we were able to narrow the differential diagnosis down to a systemic lymphoproliferative or granulomatous disease, most likely sarcoidosis. This diagnosis was eventually confirmed by a biopsy of an enlarged tonsil. To our knowledge, tonsil biopsies have not been reported to be of help in the diagnostic strategy for systemic sarcoidosis. In this report, we review the possible diagnostic approaches and point out that the pharyngeal tonsils, if enlarged or inflamed, can be targeted to obtain tissue for histological confirmation.

Vascular phenotype and subclinical inflammation in diabetic Asian Indians without overt cardiovascular disease.

Although Asian Indian (AI) patients with diabetes mellitus type 2 (DM2) are at high risk for cardiovascular disease (CVD), not all patients develop CVD. The vascular phenotype of AI-DM2 without CVD has not been elucidated and may point to protective features. Using baseline data from a clinical trial we provide an initial description of vascular parameters in AI-DM2 compared to Europid Caucasian controls (ECs) matched for age and gender. Endpoints of the study were endothelial function, low-grade systemic inflammation (CRP) and carotid intima-media thickness (cIMT). AIs had longer duration of diabetes, worse glycemic control and more microangiopathy. Both groups demonstrated marked endothelial dysfunction. CRP levels were similar: 1.7 (4.9) mg/L in AIs and 2.8 (3.6) mg/L in ECs. cIMT values were significantly lower in AI-DM2 than EC-DM2 (0.655mm (0.12) versus 0.711mm (0.15), p=0.03). Multiple regression analysis showed that variability in CRP was mainly determined by waist circumference, not by ethnicity. In contrast, ethnicity was a significantly explanatory variable for cIMT. Vascular phenotype of AI-DM2 without CVD was characterized by endothelial dysfunction and relatively low levels of CRP, comparable to EC-DM2 controls. In contrast, lower cIMT values were observed in AI-DM2 despite longer duration of diabetes and worse metabolic control. We propose that mechanisms slowing its progression may have atheroprotective potential in AI-DM2.

Macrophage low-density lipoprotein receptor-related protein deficiency enhances atherosclerosis in ApoE/LDLR double knockout mice.

OBJECTIVE: In vitro studies implicate that the low-density lipoprotein receptor (LDLR)-related protein (LRP) in macrophages has a pro-atherogenic potential. In the present study, we investigated the in vivo role of macrophage specific LRP in atherogenesis independent of its role in the uptake of lipoproteins. METHODS AND RESULTS: We generated macrophage-specific LRP-deficient mice on an apoE/LDLR double-deficient background. Macrophage LRP deletion did not affect plasma cholesterol and triglyceride levels, lipoprotein distribution, and blood monocyte counts. Nevertheless, macrophage LRP deficiency resulted in a 1.8-fold increase in total atherosclerotic lesion area in the aortic root of 18-week-old mice. Moreover, LRP deficiency also resulted in a relatively higher number of advanced lesions. Whereas macrophage and smooth muscle cell content did not differ between LRP-deficient mice and control littermates, a 1.7-fold increase in collagen content and 2.3-fold decrease in relative number of CD3+ T cells were observed in lesions from macrophage specific LRP-deficient mice. CONCLUSIONS: Our data demonstrate that independent of its role in lipoprotein uptake, absence of LRP in macrophages resulted in more advanced atherosclerosis and in lesions that contained more collagen and less CD3+ T cells. In contrast to previous in vitro studies, we conclude that macrophage LRP has an atheroprotective potential and may modulate the extracellular matrix in the atherosclerotic lesions.

Aspirin in the prevention and treatment of venous thromboembolism.

This review summarizes available evidence on effects of aspirin on incidence and outcomes of venous thromboembolism (VTE). From a pathophysiological point of view, inhibition of platelet aggregation is associated with an impaired thrombus formation both in an experimental model of venous thrombosis and in vivo. Epidemiological evidence in support of a beneficial effect of acetylsalicylic acid on VTE incidence is provided by the Antiplatelet Trialists' Collaboration meta-analysis of studies on the use of antiplatelet agents in cardiovascular risk reduction, showing a significant 25% risk reduction of pulmonary embolism. Moreover, a meta-analysis on older trials of antiplatelet agents in postsurgical VTE prevention and the large Pulmonary Embolism Prevention trial demonstrate a protective effect of the same magnitude: 25-30%. However, as low-molecular-weight heparins (LMWH) and vitamin K antagonists (VKA) have shown a superior efficacy and safety profile, and no direct comparisons have been made between aspirin, LMWH and VKA in prolonged use, the most recent guidelines advise against aspirin monotherapy for thromboprophylaxis in the surgical patient. Currently, there is no evidence to support a role for aspirin in air travel-related VTE. Regarding prevention of recurrent VTE, studies are ongoing to determine the potential role of aspirin after a first unprovoked VTE.