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Background: Lately, high dose of biotin is often given orally to patients with a primary progressive multiple sclerosis (PPMS). However, the molecule biotin is also a principle compound in various analytic immunoassays., Clinical Case: An asymptomatic 60-year-old woman with PPMS on high dose of biotin therapy (3 × 100 mg/d) displayed abnormal thyroid function tests (TSH 0.02 mU/l, fT4 > 103 pmol/l, and fT3 > 46 pmol/l). TSH was determined by a homogeneous sandwich chemiluminescent immunoassay and fT4 and fT3 were both determined by a homogeneous, sequential, chemiluminescent immunoassay. TSH receptor antibodies were found to be markedly elevated (>40 IU/l) using a electrochemiluminescence immunoassay, suggestive for Graves' hyperthyroidism. Due to inconsistency between clinical presentation and laboratory results, thyroid function tests have been repeated with two other immunoassays. A direct, labeled antibody, competitive immunoassay to determine TSH and a luminescent immunometric immunoassay to determine fT4 and fT3 showed a subclinical hyperthyroidism (TSH < 0.02 mU/l, fT4 15.9 pmol/l, and fT3 4.7 pmol/l). Normal thyroid function tests (TSH 1.66 mU/l, fT4 15.3 pmol/l, and fT3 4.7 pmol/l) were obtained by a chemiluminescent microparticle immunoassay. All abnormal levels of TSH, fT4, fT3, and TSH-R-Ab were observed in immunoassays using biotin as a reagent., Conclusion: Abnormal thyroid function tests in this euthyroid patient were found to be false due to significant interference of supraphysiological levels of plasma biotin. Laboratory tests applying immunoassays using a biotin-containing reagent should be interpreted with caution in patients on biotin substitution.

Objective: To explore the association between health literacy and the risk of cardiovascular disease (CVD), and to assess the differential effects by health literacy level of a nurse-coordinated secondary prevention program (NCPP) in patients with coronary artery disease (CAD)., Methods: Data were collected in two medical centres participating in the RESPONSE trial (Randomised Evaluation of Secondary Prevention by Outpatient Nurse SpEcialists). CVD risk profiles were assessed at baseline and 12-month follow-up using the Systematic Coronary Risk Evaluation (SCORE). Health literacy was assessed by the short Rapid Estimate of Adult Literacy in Medicine (REALM-D) and the Newest Vital Sign (NVS-D); self-reported health literacy was evaluated by the Set of Brief Screening Questions (SBSQ-D)., Results: Among 201 CAD patients, 18% exhibited reading difficulties, 52% had difficulty understanding and applying written information, and 5% scored low on self-reported health literacy. Patients with low NVS-D scores had a higher CVD risk [mean SCORE 5.2 (SD 4.8) versus 3.3 (SD 4.1), p < 0.01]. Nurse-coordinated care seemed to reduce CVD risk irrespective of health literacy levels without significant differences., Conclusion: Inadequate health literacy is prevalent in CAD patients in the Netherlands, and is associated with less favourable CVD risk profiles. Where many other forms of CVD prevention fail, nurse-coordinated care seems to be effective among patients with inadequate health literacy.

Animal studies have shown that central dopamine signaling influences glucose metabolism. As a first step to show this association in an experimental setting in humans, we studied whether deep brain stimulation (DBS) of the subthalamic nucleus (STN), which modulates the basal ganglia circuitry, alters basal endogenous glucose production (EGP) or insulin sensitivity in patients with Parkinson's disease (PD). We studied 8 patients with PD treated with DBS STN, in the basal state and during a hyperinsulinemic euglycemic clamp using a stable glucose isotope, in the stimulated and non-stimulated condition. We measured EGP, hepatic insulin sensitivity, peripheral insulin sensitivity (Rd), resting energy expenditure (REE), glucoregulatory hormones, and Parkinson symptoms, using the Unified Parkinson's Disease Rating Scale (UPDRS). Basal plasma glucose and EGP did not differ between the stimulated and non-stimulated condition. Hepatic insulin sensitivity was similar in both conditions and there were no significant differences in Rd and plasma glucoregulatory hormones between DBS on and DBS off. UPDRS was significantly higher in the non-stimulated condition. DBS of the STN in patients with PD does not influence basal EGP or insulin sensitivity. These results suggest that acute modulation of the motor basal ganglia circuitry does not affect glucose metabolism in humans.

Objective: Exogenous insulin use in patients with type 2 diabetes (DM2) has been associated with an increased risk of cardiovascular events. Through which mechanisms insulin may increase atherosclerotic plaque vulnerability is currently unclear. Because insulin has been suggested to promote angiogenesis in diabetic retinopathy and tumors, we hypothesized that insulin enhances intra-plaque angiogenesis., Methods: An in vitro model of pathological angiogenesis was used to assess the potential of insulin to enhance capillary-like tube formation of human microvascular endothelial cells (hMVEC) into a three dimensional fibrin matrix. In addition, insulin receptor expression within atherosclerotic plaques was visualized in carotid endarterectomy specimens of 20 patients with carotid artery stenosis, using immunohistochemical techniques. Furthermore, microvessel density within atherosclerotic plaques was compared between 68 DM2 patients who received insulin therapy and 97 DM2 patients who had been treated with oral glucose lowering agents only., Results: Insulin, at a concentration of 10(-8)M, increased capillary-like tube formation of hMVEC 1.7-fold (p<0.01). Within human atherosclerotic plaques, we observed a specific distribution pattern for the insulin receptor: insulin receptor expression was consistently higher on the endothelial lining of small nascent microvessels compared to more mature microvessels. There was a trend towards an increased microvessel density by 20% in atherosclerotic plaques derived from patients using insulin compared to plaques derived from patients using oral glucose lowering agents only (p=0.05)., Conclusion: Exogenous insulin use in DM2 patients may contribute to increased plaque vulnerability by stimulating local angiogenesis within atherosclerotic plaques., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Despite improvement of microvascular outcomes as a consequence of optimal glucose control in patients with type 2 diabetes, prevention of macrovascular complications is still a major challenge. Of interest, large-scale intervention studies (Action to Control Cardiovascular Risk in Diabetes, Action in Diabetes and Vascular Disease-Preterax and Diamicron Modified Release Controlled Evaluation and Veterans Affairs Diabetes Trial) comparing standard therapy versus more intensive glucose-lowering therapy failed to report beneficial impacts on macrovascular outcomes. Consequently, it is currently under debate whether the high doses of exogenous insulin that were administered in these trials to achieve strict target glucose levels could be responsible for these unexpected outcomes. Additionally, a potential role for plasma insulin levels in predicting macrovascular outcomes has emerged in patients with or without type 2 diabetes. These observations, combined with evidence from in vitro and animal experiments, suggest that insulin might have intrinsic atherogenic effects. In this review, we summarize clinical trials, population-based studies as well as data emerging from basic science experiments that point towards the hypothesis that the administration of high insulin doses might not be beneficial in patients with type 2 diabetes and established macrovascular disease., (© 2011 Blackwell Publishing Ltd.)

Introduction: In North-West Europe, cardiovascular disease is still a major cause of death and despite several efforts (e.g. European guidelines and conferences) cardiovascular risk factors are still inconsistently diagnosed and treated., Methods: We evaluated the first consultations of patients in two cardiovascular referral clinics in France and the Netherlands, while evaluating the differences in national guidelines and between the profiles of patients at their first consultation., Results: Notable differences exist between the two locally used guidelines in their programmes of cardiovascular risk assessment and their definition of LDL-cholesterol target levels. With regard to the LDL-cholesterol levels, more patients are 'on target' when using the French guideline than when using the Dutch guideline. Evaluation of the patient's profile at first presentation showed that the LDL-cholesterol levels were significantly lower in the Dutch patients (n = 77) compared with the French patients (n = 119). Dutch patients used significantly more statins than French patients., Conclusion: Despite the small study population included in this study, we found that comparison of daily care (as part of a primary prevention programme) is rather difficult due to several national differences in the approach to patients. All these factors combined should be taken into account, when discussing and extrapolating results obtained from analysis of cardiovascular prevention programmes.

Objective: Decreased insulin-like growth factor-I (IGF-I) levels in adults have been associated with an increased risk of ischemic heart disease and heart failure. It is currently unknown whether patients with low circulating IGF-I levels due to a homozygous acid-labile subunit (IGFALS) gene mutation also have increased risk of cardiovascular disease. Therefore, we evaluated atherosclerotic burden in a 27 year old male patient who was diagnosed with a homozygous IGFALS mutation and consequently had extremely low circulating IGF-I levels., Methods: Ten year's cardiovascular risk was calculated using the Framingham risk score. Presence of (subclinical) atherosclerosis was assessed using a 64-slice CT scan of the coronary arteries. Cardiac performance was measured by conventional echocardiographic measurements, three dimensional (3D)-echocardiography, and tissue deformation imaging., Results: Despite his extremely low circulating IGF-I levels due to Acid-Labile Subunit (ALS) deficiency, our patient had a low Framingham risk score and no signs of coronary atherosclerosis. Adjusted for physical height, cardiac performance was not impaired compared with healthy subjects., Conclusion: The present case report does not lend support to routine cardiovascular screening in patients with extremely low circulating IGF-I levels due to a homozygous IGFALS mutation, when cardiovascular risk is low., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Health literacy measures for use in clinical-epidemiological research have all been developed outside Europe. In the absence of validated Dutch measures, we evaluated the cross-cultural applicability of the Rapid Estimate of Adult Literacy in Medicine (REALM), the Newest Vital Sign (NVS), the Set of Brief Screening Questions (SBSQ), and the measure of Functional Communicative and Critical Health Literacy (FCCHL). Each measure was translated into Dutch following standardized procedures. We assessed feasibility, internal consistency, and construct validity among patients with coronary artery disease (n = 201) and patients with diabetes type 2 (n = 88). Patients expressed most problems in responding to the NVS-D. They were not familiar with the type of food label and had difficulties calculating in portions instead of grams. The FCCHL-D items seemed too theoretical for many patients. Cronbach's alpha was acceptable for all measures. Correlation patterns between the measures were moderately coherent with a priori hypotheses. All translated measures were able to distinguish between high- and low-educated groups of patients, with the NVS-D performing best. Despite reasonable psychometric properties as demonstrated so far, these measures need to be further developed in order to increase applicability for assessing health literacy in clinical-epidemiological research in the Netherlands.

In the multidisciplinary practice guideline 'Heart failure 2010', the diagnosis of heart failure relies on a combination of signs and symptoms and on supplementary investigation with natriuretic peptides and echocardiography. Once diagnosed, it is important to detect the potentially treatable cause of the heart failure. The non-medical treatment consists of lifestyle advice, of which regular body exercise is the most important component. The medical treatment of patients with systolic heart failure consists of a diuretic, ACE inhibitor, and beta-blocker, optionally extended by an aldosterone antagonist, an angiotensin receptor blocker and/or digoxin. A restricted group of patients may require an internal cardiac defibrillator (ICD) and/or cardiac resynchronisation therapy. There is limited scientific evidence concerning treatment of patients with diastolic heart failure. It is important to coordinate the care of the patient with heart failure within a multidisciplinary team to provide optimal treatment and information for the patient.

Aims/hypothesis: Negative effects on the progression of adenocarcinomas by hyperinsulinaemia and the insulin analogue glargine (A21Gly,B31Arg,B32Arg human insulin) have recently been suggested. Most actions of this insulin analogue have hitherto been explained by direct stimulation of growth potential of neoplastic cells and by its IGF-1 related properties. However, insulin-stimulated angiogenesis could be an additional factor involved in tumour progression and clinical outcomes associated with cancer., Methods: Five types of human adenocarcinoma (breast, colon, pancreas, lung and kidney) were evaluated for the presence of insulin receptors (IRs) on angiogenic structures. In an in vitro angiogenesis assay, various commercially available insulin compounds were evaluated for their potential to increase capillary-like tube formation of human microvascular endothelial cells (hMVEC). Insulin compounds used were: human insulin, insulin lispro (B28Lys,B29Pro human insulin), insulin glargine and insulin detemir (B29Lys[e-tetradecanoyl],desB30 human insulin)., Results: Insulin receptors were found to be strongly expressed on the endothelium of microvessels in all evaluated adenocarcinomas, in addition to variable expression on tumour cells. Low or no detectable expression of IRs was seen on microvessels in extratumoral stroma. Incubation with commercially available insulin compounds increased capillary-like tube formation of hMVEC in vitro., Conclusions/interpretation: Our results suggest that all tested insulin compounds may stimulate tumour growth by enhancing local angiogenesis. Future studies need to confirm the association between insulin therapy in type 2 diabetes and tumour progression.

Fabry disease is an X-linked lysosomal storage disorder due to deficiency of the enzyme alpha-galactosidase A. The principal clinical manifestations of Fabry disease consist of cardiovascular complications including cerebrovascular, renal and cardiac disease but the pathophysiology of this specific vasculopathy is unclear. With the development of targeted treatment for Fabry disease, i.e. enzyme replacement therapy, it has become apparent that the removal of stored glycosphingolipid from the endothelial cells does not prevent progression of vascular disease in many patients. The aim of this study is to review the current available literature on vascular function tests, imaging and pathology studies and propose a hypothesis on the evolution of arterial complications in Fabry disease. Clearly, although premature atherosclerosis is suggested to occur, most studies describe absence of characteristic plaque formation. Smooth muscle cell hypertrophy, is probably the earliest feature of a complex vasculopathy, as in females and atypical cardiac variants, who have residual enzyme activity, no endothelial storage of significance is found. Subsequently, processes occur as observed in neo intima formation however with formation of more fibrotic structures. In the presence of a hyperdynamic circulation in combination with a less compliant vascular wall, it is hypothesized that upregulation of local renin angiotensine systems may occur. Angiotensin II is known to increase adhesion molecules, cytokines and chemokines and exerts a pro-inflammatory effect on leucocytes, endothelial cells and vascular smooth muscle cells. This enhances release of pro-thrombotic factors and opposes actions mediated through angiotensin 2 (AT2) receptor, including the release of nitric oxide (NO). A combination of reduced vascular compliance and activation of pro-thrombotic factors can lead to vascular complications in Fabry disease., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

A strong epidemiological association has been revealed between air pollution and the occurrence of cardiovascular disease (CVD). Deleterious consequences of such pollution, including myocardial infarction and coronary ischaemia, have occurred after both acute as well as chronic exposure to air pollution. The causal pathophysiological mechanisms through which these effects occur have not been identified but potential pathways include endothelial dysfunction and systemic reactions such as inflammation and oxidative stress. Because of increasing urbanisation and associated anthropogenic activities, air pollution is considered an important topic in public health and it remains challenging to translate these epidemiological observations into clinical consequences and guidelines. Nevertheless, for the high cardiovascular risk population, air pollution might have direct clinical relevance. In the future, more knowledge is required about the absolute risk of air pollution in specific high-risk populations and the pathophysiological mechanisms behind this relationship.

Health literacy is the combination of cognitive and social skills that is necessary for adequate response to information about health, illness and health care. Subjects with limited health literacy often experience difficulty in understanding the information provided by health care professionals and finding their way in the health care system, with consequent increased morbidity and mortality. Health literacy is a wider concept than literacy. Approximately 1.5 million people in the Netherlands, of which two thirds are of ethnic Dutch origin, have low literacy skills or are illiterate. The group with low health literacy is even larger. Health care professionals, including physicians, must be able to recognise limited health literacy in order to react appropriately, for example by adapting information provision, checking understanding, supporting communication with visual aids, and making longer appointments.Such measures may be expected to improve results, but investigation of their effectiveness is necessary.

Context: Acid-labile subunit (ALS) deficiency due to homozygous inactivation of the ALS gene (IGFALS) is associated with moderate short stature, and in few cases pubertal delay. The clinical expression of heterozygosity is unknown., Objective: To investigate the clinical, laboratory, and radiological features of homozygous and heterozygous carriers of a novel mutation in the ALS gene in comparison with non-carriers., Subjects: Three short Kurdish brothers and their relatives., Results: The index cases presented with short stature, microcephaly, and low circulating IGF-I and IGF-binding protein-3 (IGFBP-3), and undetectable ALS levels. Two were known with a low bone mineral density and one of them had suffered from two fractures. We found a novel homozygous ALS gene mutation resulting in a premature stop codon (c.1490dupT, p.Leu497PhefsX40). The IGF-I, IGFBP-3, and ALS 150 kDa ternary complex was absent, and ALS proteins in serum were not detected with western blot. IGFPB-1 and IGFPB-2 were low and there was a mild insulin resistance. Five heterozygous carriers tended to have a lower height and head circumference than five non-carriers, and had low plasma ALS and IGFBP-3 levels. Bone mineral (apparent) density was low in two out of three homozygous carriers, and also in four out of nine relatives., Conclusions: The clinical presentation of homozygous ALS mutations may, besides short stature, include microcephaly. Heterozygous carriers may have less statural and head growth, suggestive for a gene dosage effect.

The objective of this study was to investigate whether patients with the metabolic syndrome (MetS) and an imbalance in cortisol metabolism express increased urinary albumin excretion compared to those patients with metabolic syndrome alone. Seventy-four patients with MetS were evaluated using a low-dose dexamethasone suppression test (LDDST) to identify disturbed cortisol balance (cortisol levels > 50 nmol/L after LDDST). The level of albumin in the urine was also evaluated. Disturbed cortisol balance was found in 8% of all evaluated patients with MetS. Microalbuminuria was present significantly more often (p<0.01) in those patients with MetS and an imbalance in cortisol metabolism compared with patients suffering MetS alone (urine albumin: 210 mg/L vs. 26 mg/L, respectively, p<0.01). A substantial percentage of patients with MetS had inappropriate cortisol homeostasis. Of importance, excretion of urinary albumin was increased in these patients. This observation may indicate that this subgroup within the MetS population has a higher cardiovascular risk and possible increased endothelial dysfunction, with a subsequent need for stricter control to prevent cardiovascular morbidity and mortality.

Cardiovascular disease is the principal cause of morbidity and mortality in the Netherlands. In this background, various initiatives have been launched to reduce the frequency of cardiovascular disease. One of those is the creation of clinical units with a special focus on prevention of cardiovascular disease. Hitherto, the prevention programmes of these clinics have been heterogeneous and therefore difficult to compare with respect to results. Similar developments in creating clinical initiatives concerning prevention of cardiovascular disease are found across Europe. With this in mind, lessons could be learned from each other's experiences. In our contribution, we would like to present the Cardiovascular Prevention Clinic in the Pitié- Salpêtrière Hospital in Paris, France, as an interesting example of a well-acknowledged cardiovascular prevention clinic that combines both daily clinical care and cardiovascular science. (Neth Heart J 2007;15:22-6.).

We report a 42-year-old female who presented with retrosternal pain, dyspnoea and nausea. Electrocardiography suggested a recent anterior myocardial infarction. However, emergency coronary angiography showed normal blood flow through all the coronary arteries. Paroxysmal hypertension raised the suspicion of a pheochromocytoma. Indeed, abdominal ultrasonography and computed tomography revealed a mass in the left adrenal gland. Elevated levels of plasma and urine catecholamines supported the diagnosis of pheochromocytoma. Left adrenalectomy was performed without complications and pathological examination revealed a 5.5 cm pheochromocytoma. After surgery, all antihypertensive medication was discontinued and the blood pressure returned to normal within several days. Currently, the patient is asymptomatic, has normal catecholamine levels and the electrocardiographic signs of ischaemia have resolved entirely. This case illustrates that a rare clinical entity such as pheochromocytoma should be considered in the differential diagnosis of acute coronary syndrome. (Neth Heart J 2007;15:248-51.).

Objective: Untreated GH-deficient adults are predisposed to insulin resistance and excess cardiovascular mortality. We showed previously that short-term treatment with a very low GH dose (LGH) enhanced insulin sensitivity in young healthy adults. The present study was therefore designed to explore the hypothesis that LGH, in contrast to the standard GH dose titrated to normalize serum IGF-I levels (SGH), may have differing effects on insulin sensitivity, body composition, and cardiovascular risk markers [lipid profile, C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) and adiponectin] in adults with severe GH deficiency., Patients and Methods: In this 12-month open, prospective study, 25 GH-deficient adults were randomized to receive either a fixed LGH (0.10 mg/day, n = 13) or SGH (mean dose 0.48 mg/day, n = 12), and eight age- and body mass index (BMI)-matched GH-deficient adults acted as untreated controls. Fasting blood samples were collected at baseline and at months 1, 3, 6, 9 and 12. Assessments of insulin sensitivity, using the hyperinsulinaemic euglycaemic clamp technique, and body composition, using dual-energy X-ray absorptiometry, were performed at baseline and at month 12., Results: The LGH decreased fasting glucose levels (P < 0.01) and enhanced insulin sensitivity (P < 0.02), but body composition, nonesterified fatty acid (NEFA) levels and cardiovascular risk markers were unchanged. The SGH did not modify insulin sensitivity, decreased truncal fat mass (P < 0.05), CRP (P < 0.05) and IL-6 (P < 0.05) levels, and increased NEFA levels (P < 0.05). No changes were observed with the untreated controls., Conclusion: Our data indicate that, in contrast to the SGH, fixed administration of the LGH enhances insulin sensitivity with no apparent effects on body composition, lipolysis and other surrogate cardiovascular risk markers in adults with severe GH deficiency. Thus, the LGH may potentially be a beneficial replacement dose in reducing type 2 diabetes risk in adults with severe GH deficiency.

Cardiomyopathy is a major cause of death in overt acromegaly. Recent progress in research has increasingly revealed the molecular mechanisms concerning growth hormone and insulin-like growth factor in the development of heart failure. In this article, we propose mechanisms according to which heart failure occurs, and we aim to extrapolate this knowledge to more general processes involved in heart failure.

In addition to cholecystokinin, other hormones have been suggested to be involved in regulation of postprandial gallbladder contraction. We aimed to evaluate effects of growth hormone (GH) on gallbladder contractility and cholecystokinin release. Gallbladder and gastric emptying (by ultrasound) and cholecystokinin release were determined before and after 6 months of recombinant human GH (rhGH) therapy in 12 patients with GH deficiency, after either a mixed (n = 5) or a liquid (n = 7) meal. Basal postprandial gallbladder contraction was severely impaired (19 +/- 2 and 26 +/- 3% of fasting volume after mixed and liquid meal, respectively). Histology and cholecystokinin sulfation patterns in duodenal biopsies from two patients were normal. After 6 months of rhGH therapy, fasting gallbladder volumes increased (from 20.8 +/- 0.9 to 25.9 +/- 1.1 mL, P < 0.05) and postprandial gallbladder emptying was restored (70 +/- 6 and 70 +/- 7% of fasting volume after mixed and liquid meal, respectively), without change of gastric emptying. Cholecystokinin secretion after a mixed meal and gallbladder sensitivity to cholecystokinin were significantly enhanced during rhGH replacement compared to the basal state. Postprandial cholecystokinin release, gallbladder responsiveness to cholecystokinin, and gallbladder emptying are severely impaired in the absence of GH. Reversibility during GH suppletion suggests its involvement in regulation of gallbladder contractility.

Unlabelled: GROWTH HORMONE AND ATHEROSCLEROSIS: Adult-onset growth hormone (GH) deficiency is associated with an increase in cardiovascular morbidity and mortality., Mechanisms: Other than classical risk factors, such as dyslipidemia, a direct interaction between the activity of the GH/IGF-1 axis and the endothelium also plays a part. It is possible that the modulating effect of IGF-1 on nitric oxide (NO) synthesis is also important, together with the anabolic effect on the myocardiocytes. Substitution of recombinant GH induces rapid reduction in the atherosclerotic plaques, suggesting a direct effect of the GH/IGF axis on the atherosclerotic process. In addition to the acquired GH deficiency, as in non-substituted patients following hypophysectomy, attention has recently been focused on the relative GH deficiency as is seen in obesity and in the course of ageing. PERSPECTIVES FOR CARDIOVASCULAR ENDOCRINOLOGY: Therapeutic intervention in the GH/IGF axis might influence the atherosclerotic process. Study of the GH/IGF axis activity and of its correlation with atherosclerosis opens new perspectives in the understanding of the role of this axis in cardiovascular diseases.

Increased cardiovascular mortality due to premature atherosclerosis is a clinical feature in the adult-onset GH deficiency (AGHD) syndrome. Inflammation is a key feature in atherogenesis and may be triggered by postprandial lipoprotein remnants. We hypothesized that increased postprandial lipoprotein remnant levels in AGHD may be associated with an inflammatory response. In this case-control study, 10 AGHD patients [6 males and 4 females; age, 48 +/- 9 yr; body mass index (BMI), 26.9 +/- 2.6 kg/m(2)] and 10 healthy control subjects (matched for age, BMI, gender, baseline lipid levels, and apolipoprotein E genotype) were included. They all ingested an oral fat load. Fasting and postprandial levels of plasma remnant-like particle-cholesterol (RLP-C; 0.31 +/- 0.13 mmol/liter and 4.14 +/- 1.37 mmol/liter.h in GHD; 0.18 +/- 0.06 mmol/liter and 2.56 +/- 1.02 mmol/liter.h in controls, respectively) were significantly increased in AGHD patients compared with control subjects. The median inflammatory cytokines, IL-6 and TNF-alpha, were higher in the fasting [3.9 (range, 3.1-11.9) pg/ml and 6.8 (range, 2.5-27.6) pg/ml, respectively] and postprandial [151.7 (range, 87.0-294.3) pg/ml.24 h and 289.9 (range, 87.5-617.6) pg/ml.24 h, respectively] states in AGHD than in controls [fasting, 0.9 (range, 0.2-5.2) pg/ml and 2.8 (range, 2.5-5.7) pg/ml; and postprandial, 54.5 (range, 11.50-126.5) pg/ml.24 h and 118.3 (range, 81.2-243.1) pg/ml.24 h, respectively]. In addition, postprandial profile of RLP-C and IL-6 in AGHD and in the total group were significantly associated (r(2) = 0.44, P < 0.05; and r(2) = 0.38, P < 0.01, respectively). In conclusion, the increased postprandial RLP-C level in GHD is associated with an inflammatory response that may result in increased susceptibility for premature atherosclerosis.

Background: Premature atherosclerosis is a clinical feature in untreated acromegaly. Increased postprandial lipoprotein remnant levels are associated with premature atherosclerosis. In most studies, remnants have been measured indirectly using retinyl esters (RE) as a chylomicron core label. Remnants can also be directly quantified by immunoseparation using monoclonal antibodies to apolipoprotein (apo) AI and apo B100 to remove nonremnant lipoproteins. Cholesterol is quantified in the remaining apo E-rich remnant fraction (RLP-C)., Objective: The aim of the present study was to investigate the role of postprandial lipaemia in patients with acromegaly to further define abnormalities leading to increased susceptibility for atherosclerosis., Patients: In a case-control study, the plasma postprandial lipoprotein remnant fraction (RLP-C and RE) were analysed in six patients with active acromegaly [two females, four males; aged 53 +/- 9 years; body mass index (BMI), 29 +/- 4 kg/m2] and in six normolipidaemic control subjects (matched for age, gender, BMI and apo E genotype). They underwent an oral vitamin A fat loading test., Results: Baseline plasma triglycerides (TG) were not significantly different in patients (1.75 +/- 0.71 mM) and controls (1.15 +/- 0.46 mM). Lipoprotein lipase activity was significantly lower in patients than in controls (108 +/- 21 vs. 141 +/- 19 U/l, respectively; P < 0.05). Baseline plasma apo E levels were higher in patients (60.8 +/- 7.9 mg/l) than in controls (48.3 +/- 5.9 mg/l; P < 0.05). No differences were found in the area under the postprandial TG curve (AUC-TG), the incremental AUC-TG (DeltaAUC-TG) and AUC-RE in the Sf < 1000 remnant fraction. However, fasting plasma RLP-C concentrations, isolated by immunoseparation, were increased in patients with active acromegaly (0.41 +/- 0.13 mM) compared to control subjects (0.20 +/- 0.07 mM; P < 0.05). Incremental postprandial RLP-C response (corrected for fasting values) was also significantly elevated in patients (2.14 +/- 1.19 mM/h/l) compared to controls (0.86 +/- 0.34 mM/h/l; P < 0.05). In both groups, the maximal RLP-C concentration was reached between 2 and 4 h., Conclusions: In conclusion, the atherogenic postprandial remnants, represented by RLP-C, were significantly elevated at baseline and in the postprandial period, whereas the larger-sized remnants, represented by retinyl esters (Sf < 1000), were not different from controls. The disturbances in the postprandial RLP-C response increased the susceptibility for premature atherosclerosis as observed in patients with acromegaly.

Abnormal postprandial lipoproteins are associated with an increased risk for cardiovascular disease. Postprandial remnant lipoproteins were usually analyzed indirectly using retinyl esters (RE) as a chylomicron core label during an oral fat loading test. Apo B-100 containing VLDL remnants in addition to apo B-48 containing chylomicron remnants can also be directly quantified using the RLP-Cholesterol Immunoseparation Assay. This recently available method uses monoclonal antibodies to apo A-I and apo B-100 to remove non-remnant lipoproteins and quantifies cholesterol in the remaining apo E-rich remnant fraction. In the present study we compared the analysis of retinyl ester with the immuno-based RLP-Cholesterol (RLP-C) analysis in measuring postprandial remnant lipoproteins in healthy normolipidemic subjects. Sixteen healthy normolipidemic subjects were selected for this study. Postprandial plasma retinyl esters peaked at 5.0+/-1.2 h, whereas plasma RLP-C showed a peak significantly earlier (P<0.001) at 3.5+/-0.6 h. In comparison, postprandial plasma TG and FFA peaked at 3.3+/-1.1 h (P<0.005 compared to retinyl esters). In conclusion, levels of RLP-C changed, during the postprandial phase, in parallel with plasma TG and FFA concentrations and peaked significantly earlier than retinyl esters. Postprandial measurements of RLP-C can be considered as a fast alternative method for the more laborious retinyl-ester analysis in clinical studies.

Premature atherosclerosis is a clinical feature in adult-onset GH deficiency. Evidence is accumulating that disturbances in triglyceride metabolism, reflected by abnormalities in circulating remnant lipoproteins, are associated with increased atherogenic potential. In a case-controlled intervention study, we investigated postprandial lipoprotein metabolism using a new remnant lipoprotein method based on immunoseparation principle [RLP-cholesterol (RLP-C)]. In addition, we analyzed retinyl ester (RE) analysis in plasma and in Sf < 1000 fraction. Endothelial function was assessed as flow-mediated dilatation (FMD). Eight patients diagnosed with acquired adult-onset GH deficiency and eight controls matched for gender, age, body mass index, and apolipoprotein (apo) E genotype were enrolled in the study. Oral vitamin A fat loading tests were performed at baseline in both groups and after 6 months of treatment with recombinant human GH (rh-GH) in the adult-onset GH-deficient patients. Adult-onset GH-deficient patients had significantly higher fasting RLP-C, postprandial RLP-C concentrations (plasma RLP-C, 0.29 +/- 0.14 mmol/L; and incremental area under the curve-RLP-C, 2.13 +/- 1.60 mmol*h/L, respectively) than controls (0.19 +/- 0.06 mmol/L and 1.05 +/- 0.72 mmol*h/L (P: < 0.05), respectively). They also had significantly higher postprandial RE in plasma and Sf < 1000 fraction. Treatment with rh-GH significantly reduced postprandial RLP-C concentrations (incremental area under the curve-RPL-C 0.73 +/- 0.34 mmol*h/L; P: < 0.05) but had no effects on the fasting RLP-C concentrations (0.317 +/- 0.09 mmol/L, P: < 0.05), or on the postprandial RE in plasma and in Sf < 1000 fraction. Endothelial function measured as FMD was improved from 5.9 +/- 3.3% to 10.2 +/- 4.0% (P: < 0.05) in patients treated with rh-GH. It is concluded that patients with adult-onset GH deficiency have increased levels of fasting and postprandial RLP-C and an impaired endothelial function as measured as FMD. Treatment with rh-GH resulted in a decrease of postprandial RLP-C concentration, thereby improving the postprandial atherogenic lipoprotein profile and improvement of endothelial function, however, the clearance of large chylomicron particles as reflected by RE remained disturbed.

Background: Elevated fasting and postprandial triglycerides (TG) are established risk factors for Coronary Heart Disease (CHD). Usually, fasting plasma TG are measured, although TG are mainly produced in a postprandial state. Our objective was to investigate diurnal TG profiles using serial capillary TG measurements, in normolipidemic healthy males., Materials and Methods: Forty-eight, non-obese, non-smoking males (range: 20-55 years, mean age: 32 +/- 12 years), measured diurnal capillary TG, at six fixed timepoints during the day on three different days and recorded their food intake. Insulin sensitivity was estimated by HOMA. Diurnal capillary TG profiles were calculated as integrated area under the mean capillary TG curve (TGc-AUC)., Results: All subjects had normal fasting plasma TG and cholesterol. The average TGc-AUC was 23.6 +/- 6.7 mmol h L-1. Significant correlations with TGc-AUC were: fasting insulin (r = 0. 40, P < 0.005), HOMA (r = 0.32, P < 0.05), relative fat mass (r = 0. 31, P < 0.05), dietary protein-(r = 0.31, P < 0.05) and saturated fat intake (r = 0.30, P < 0.05). Age was not associated to diurnal triglyceridemia. After subdividing the group into quartiles on the base of TGc-AUC, differences were found between the highest (n = 12) and lowest quartile (n = 12) for: fasting capillary TG, fasting insulin, HOMA and systolic blood pressure. Fasting plasma TG and dietary intake were not different., Conclusion: Diurnal TG profiles in healthy normolipidemic males are not age-dependent, but are associated to insulin sensitivity, fat mass and diet. Diurnal capillary TG profiles may be a valuable additional tool in estimating a risk profile for CHD since significant differences in diurnal TG are not always reflected by elevated fasting plasma TG.

Familial hypercholesterolemia (FH) and disturbances in postprandial lipoprotein metabolism are both associated with premature atherosclerosis. The effect of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors on plasma cholesterol levels in patients with FH is well established; however, it is not known whether postprandial lipoproteins are also influenced. In this case-controlled intervention study, we investigated the effects of high-dose simvastatin on postprandial lipoproteins. We used a new method to analyze remnant lipoproteins based on the immunoseparation principle (remnant-like particle cholesterol [RLP-C] assay) and the well-established measurement of retinyl ester (RE) analysis in plasma and in the Svedberg flotation unit (Sf)<1000 fraction. Seven heterozygous FH patients and 7 control subjects matched for sex, age, body mass index, triglycerides, and apolipoprotein E genotype were enrolled in the study. An oral vitamin A (RE) fat-loading test was performed at baseline in both groups and after 3 months of high-dose simvastatin (80 mg/d) treatment in the FH patients. Before treatment, FH patients had significantly higher fasting and postprandial concentrations of lipoprotein remnants (plasma RLP-C 42+/-19 mg/dL and area under the RLP-C curve 415+/-82 mg. L(-1). h(-1), respectively) than did control subjects (7+/-3 mg/dL and 101+/-35 mg. L( -1). h(-1), respectively; P<0.05), suggesting a delayed clearance of chylomicron remnant particles in the FH patients. Treatment with simvastatin significantly reduced fasting and postprandial remnant lipoprotein cholesterol concentrations (13+/-3 mg/dL and 136+/-53 mg. L(-1). h(-1), respectively; P<0.05 for both). Postprandial RE in the Sf<1000 fraction, not total RE in plasma, was also significantly higher in FH patients than in control subjects (24+/-10 versus 6.3+/-5.9 mg. L( -1). h(-1), P<0.05), but treatment with simvastatin did not result in improvement of the postprandial RE response, either in the Sf<1000 fraction or in plasma. It is concluded that heterozygous FH patients have increased fasting and postprandial remnant lipoprotein concentrations. Treatment with simvastatin significantly reduced the fasting and postprandial RLP-C concentrations but did not result in improved postprandial RE response.

Overproduction of very low density lipoprotein (VLDL) is the major characteristic of subjects with familial combined hyperlipidemia (FCHL). As enhanced free fatty acid (FFA) flux to the liver may be one of the determinants of VLDL overproduction, we studied FFA changes and products of hepatic FFA metabolism in response to a 24-h oral fat loading test (50 g/m(2)) in 7 FCHL subjects and 7 matched control subjects. The response to the meal was subdivided into a postprandial (up to 8 h after ingestion of the meal) and postabsorptive period (from 8 to 24 h). Although postheparin plasma lipolytic activities were not different between both groups, the postprandial FFA area under the curve (FFA-AUC) and FFA incremental area under the curve (FFA-dAUC) were higher in FCHL subjects than in control subjects (6.05 +/- 0.45 vs. 3.43 +/- 0.46 and 2.60 +/- 0.49 vs. 0.96 +/- 0.31 mmol. h/L, respectively; P < 0.01 for each). The postprandial increase in ketone bodies was almost four times higher in FCHL patients. As ketogenesis occurs predominantly in hepatocytes, these findings suggest that during the postprandial period in FCHL an increased flux of FFA to the liver occurs, possibly because of inadequate incorporation of FFA into triglycerides (TGs) in adipocytes. In the postabsorptive period, FFA and ketone bodies significantly decreased in FCHL subjects, in contrast to control subjects, in whom both increased. These results may represent a diminished release of FFA from adipocytes by hormone-sensitive lipase (HSL) in FCHL patients. The decrease in postabsorptive FFA and ketone bodies in FCHL patients could not be explained by insulin-mediated inhibition of HSL, as both FCHL subjects and control subjects had similar postabsorptive insulin concentrations, which were below fasting concentrations. This study provides in vivo evidence of impaired metabolism of postprandial FFA in FCHL, which may explain in part the hepatic VLDL overproduction characteristic of FCHL subjects.

Objective: To study predictors of diurnal capillary triglyceride (TG-c) profiles in healthy males., Design: Observational, cross-sectional., Setting: University Hospital Utrecht, Department of Internal Medicine, the Netherlands., Method: In 30 healthy males (20-34 years) TG-c was measured during three days, six times a day. Fasting blood was collected at inclusion. Body composition and HOMA ratio as insulin sensitivity index were determined. TG-c profiles were calculated as integrated area under the mean TG-c curve (TG-AUC)., Results: All subjects had normal fasting plasma and capillary TG and cholesterol concentrations. Diurnal TG-c values were higher than fasting values. The average TG-AUC was 24.6 +/- 6.7 mmol/l over 14 hrs. Variables associated with TG-AUC were: fasting TG-c, relative fat mass, total protein and saturated fat intake. After correction for fasting TG-c only diet and fat mass were correlated with TG-AUC. The relative fat mass was positively correlated with the HOMA ratio and fasting insulin concentrations, suggesting that decreased insulin sensitivity accompanied increased body fat., Conclusion: Triglyceride profiles provide information about the total diurnal TG load. The best determinant of diurnal triglyceride changes was fasting triglycerides. However, diet, body composition and insulin sensitivity are also important. Future investigations should address the question whether triglyceride profiles may be used to estimate more accurately the individual risk profile for coronary heart disease.

Induction and downregulation of cytokine production occurs after contact with various inflammatory stimuli. To elucidate the early events after a physical stressor, we studied these processes in 13 patients undergoing elective total hip replacement surgery. In these patients we followed the plasma concentrations of tumour necrosis factor alpha (TNF), interleukin 1beta (IL-1beta), IL-6 and IL-1 receptor antagonist (IL-1Ra), mRNA for these cytokines in peripheral blood cells (PBCs), and the lipopolysaccharide(LPS)-stimulated ex vivo production of these cytokines in whole blood cultures (WBCs). Plasma TNF and IL-1beta were not affected by the surgical procedure, although IL-1beta mRNA levels in PBCs increased significantly. Plasma IL-6 and IL-1Ra increased from 2 to 3 h post-incision onwards. The LPS-induced ex vivo production in WBCs of TNF, IL-1beta and IL-6 decreased from 2 h post-incision; that of IL-1Ra increased. Downregulation of TNF production was not associated with lower TNF-mRNA suggesting post-transcriptional regulatory processes. In contrast, downregulation of IL-1beta production was associated with significantly lower IL-1beta mRNA, suggesting both post-transcriptional and transcriptional mechanisms. Remarkably, the increase of plasma IL-6 occurred when the IL-6 production ex-vivo in WBCs was maximally downregulated. This suggests that other immunocompetent cells and not PBCs are the source for plasma IL-6 and that the IL-6 production in those other cells might be regulated differentially., (Copyright 1998 Academic Press)