Microvascular endothelial dysfunction in skin is associated with higher risk of heart failure with preserved ejection fraction in women with type 2 diabetes: the Hoorn Diabetes Care System Cohort.

BACKGROUND: Microvascular dysfunction plays a crucial role in complications of type 2 diabetes and might contribute to heart failure with preserved ejection fraction (HFpEF), a disease that disproportionally affects women. We aimed to investigate if presence and degree of microvascular dysfunction (MVD) in skin relates to markers of left ventricular diastolic dysfunction (LVDD) and HFpEF risk in adults with type 2 diabetes, and whether sex modifies this association. METHODS: We recruited 154 participants (50% women) from the Hoorn Diabetes Care System Cohort, a prospective cohort study, for in vivo evaluation of skin MVD, echocardiography and blood sampling. MVD was assessed by laser speckle contrast analysis combined with iontophoresis of insulin, acetylcholine and sodium nitroprusside (SNP). We performed a cross-sectional analysis of the association between perfusion responses and echocardiographic and clinical markers of LVDD and the H2FPEF score by multivariable linear regression analysis adjusted for confounders. Sex was evaluated as a potential effect modifier and the analysis was stratified. RESULTS: Mean age was 67 ± 6y, mean HbA1c 7.6 ± 1.3%. Women were more frequently obese (54.5 vs. 35.1%), had higher NT-proBNP plasma levels (80, IQR:34-165 vs. 46, 27-117 pg/ml) and E/E'(13.3 ± 4.3 vs. 11.4 ± 3.0) than men. Eleven women and three men were diagnosed with HFpEF, and showed lower perfusion response to insulin than those without HFpEF. A lower perfusion response to insulin and acetylcholine was associated with higher HFpEF risk in women, but not men (10% decreased perfusion response was associated with 5.8% [95%CI: 2.3;9.4%] and 5.9% [1.7;10.1%] increase of the H2FPEF score, respectively). A lower perfusion response to SNP was associated with higher pulmonary arterial systolic pressure in men while a lower perfusion response to acetylcholine associated with higher LV mass index in women and with worse LV longitudinal strain in the total population. No significant associations were found between perfusion responses and conventional LVDD markers. CONCLUSIONS: Impaired microvascular responses to insulin and acetylcholine in skin confers a higher risk of HFpEF in women with type 2 diabetes. In vivo measures of systemic MVD could represent novel risk markers for HFpEF, opening new avenues for the prevention of HFpEF in type 2 diabetes.

Real-world characteristics and outcomes of patients with intermediate high risk acute pulmonary embolism.

BACKGROUND: Exact benefits of currently recommended close monitoring in intermediate high risk acute pulmonary embolism (PE) patients are unknown. METHODS: This prospective observational cohort study determined clinical characteristics, and disease course of intermediate high risk acute PE patients in an academic hospital setting . Frequency of hemodynamic deterioration, use of rescue reperfusion therapy and PE related mortality, were outcomes of interest. RESULTS: Of 98 intermediate high risk PE patients included for analysis, 81 patients (83%) were closely monitored. Two deteriorated hemodynamically and were treated with rescue reperfusion therapy. One patient survived after this. CONCLUSIONS: In these 98 intermediate high risk PE patients, hemodynamic deterioration occurred in three patients and rescue reperfusion therapy of two closely monitored patients led to survival of one. Underlining the need for better recognition of patients benefitting from and research in the optimal way of close monitoring.

Sodium-glucose cotransporter 2 inhibitors: a practical guide for the Dutch cardiologist based on real-world experience.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors include a relatively new class of glucose-lowering drugs that reduce plasma glucose concentrations by inhibiting proximal tubular reabsorption of glucose in the kidney, while increasing its excretion in urine. Recent large randomised controlled trials have demonstrated that many of these agents reduce the occurrence of major adverse cardiovascular events, hospitalisation for heart failure, cardiovascular death and/or chronic kidney disease progression in patients with and without type 2 diabetes mellitus (DM2). Given their unique insulin-independent mode of action and favourable efficacy and adverse-event profile, SGLT2 inhibitors are promising and they offer an interesting therapeutic approach for the cardiologist to incorporate into routine practice. However, despite accumulating data supporting this class of therapy, cardiologists infrequently prescribe SGLT2 inhibitors, potentially due to a lack of familiarity with their use and the reticence to change DM medication. Here, we provide an up-to-date practical guide highlighting important elements of treatment initiation based on real-world evidence and expert opinion. We describe how to change DM medication, including insulin dosing when appropriate, and how to anticipate any adverse events based on real-world experience in patients with DM2 in the Meander Medical Centre in Amersfoort, the Netherlands. This includes a simple algorithm showing how to initiate SGLT2 inhibitor treatment safely, while considering the consequence of the glucosuric effects of these inhibitors for the individual patient.

Keeping safe. Continuous glucose monitoring (CGM) in persons with Type 1 diabetes and impaired awareness of hypoglycaemia: a qualitative study.

AIM: To further our understanding of individual use and experience of continuous glucose monitoring (CGM) in adults with Type 1 diabetes and impaired awareness of hypoglycaemia, we conducted a qualitative study supplementary to a randomized controlled trial, using semi-structured interviews. METHODS: Twenty-three participants of the IN CONTROL trial were interviewed within 4 weeks after the last study visit. The interview centred around experiences of CGM, taking into account the person's expectations prior to the trial. The interview was semi-structured, using open-ended questions and, if needed, prompts were offered to elicit further responses. Using thematic analysis, the interview transcripts were coded independently by three members of the research team. The consolidated criteria for reporting qualitative research (COREQ) were followed. RESULTS: Overall, CGM was experienced as helpful in gaining more insight into glucose variability, and temporarily improved sense of control, reduced distress and made participants less dependent on others. However, some participants experienced confrontation with CGM output as intrusive, while some reported frustration due to failing technique and difficulty trusting the device. Participants reported active and passive self-management behaviours mirroring individual differences in attitudes and coping styles. CONCLUSIONS: In adults with Type 1 diabetes at risk of recurrent hypoglycaemia due to impaired awareness of hypoglycaemia, CGM use enhances a sense of control and safety for most, but not all. Future studies should further explore differential use of CGM in this population in the context of active and passive self-management styles.

Postprandial microvascular function deteriorates in parallel with gradual worsening of insulin sensitivity and glucose tolerance in men with the metabolic syndrome or type 2 diabetes.

AIMS/HYPOTHESIS: Hyperinsulinaemia-induced whole-body glucose uptake during a euglycaemic-hyperinsulinaemic clamp is partly mediated by increased capillary density. We hypothesised that physiological insulinaemia in response to a mixed meal may also enhance microvascular function, and that this may be impaired in insulin-resistant individuals and patients with type 2 diabetes. METHODS: Twelve men with uncomplicated type 2 diabetes, 13 with metabolic syndrome and 12 age-matched healthy normoglycaemic controls, mean age 57 ± 6 years, underwent skin capillary video microscopy before and 60 and 120 min following a standardised mixed meal to measure baseline capillary density (BCD) and capillary density during post-occlusive peak reactive hyperaemia (PRH), also termed capillary recruitment. Oral glucose insulin sensitivity (Matsuda index) and postprandial hyperglycaemia (2 h AUC(glucose)) were calculated. RESULTS: Fasting BCD was similar among groups, but fasting PRH was lowest in diabetes (p < 0.05). Postprandially, both BCD and PRH increased in all groups (p < 0.001); however, the meal-related increase in BCD was significantly lower in diabetes and metabolic syndrome vs controls (both p < 0.05). At all time points, postprandial PRH was lower in both diabetes and metabolic syndrome vs controls (both p < 0.05). In pooled analysis, postprandial mean PRH correlated with Matsuda index (r = 0.386, p = 0.018) and inversely with 2 h AUC(glucose) (r = -0.336, p = 0.042). CONCLUSIONS/INTERPRETATION: Gradual deterioration in meal-related capillary recruitment was paralleled by decreasing insulin sensitivity and postprandial hyperglycaemia, as assessed in healthy normoglycaemic men, men with the metabolic syndrome and those with type 2 diabetes. These findings suggest that in both impaired glucose tolerance and in overt diabetes microvascular dysfunction might contribute to postprandial dysglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT00721552.

Insulin-induced capillary recruitment is impaired in both lean and obese women with PCOS.

BACKGROUND: Insulin resistance, i.e. impaired insulin-mediated glucose uptake (IMGU), is a major risk factor for type 2 diabetes in women with polycystic ovary syndrome (PCOS). Insulin-induced capillary recruitment (IICR) is considered a significant determinant of IMGU. We investigated whether IICR is a determinant IMGU in obese and lean women with and without PCOS. METHODS: The study included 36 women with PCOS (20 lean, BMI 21.9 ± 2.3 kg/m(2) and 16 obese, BMI 35.9 ± 6.0 kg/m(2)) and 27 age-matched healthy controls (14 lean, BMI 22.2 ± 1.8 kg/m(2) and 13 obese, BMI 40.5 ± 7.0 kg/m(2)). IICR was evaluated by capillary microscopy during an isoglycemic-hyperinsulinemic clamp. IMGU was expressed as M/I value. RESULTS: The M/I value was significantly lower in obese PCOS women compared with obese controls [0.5 (0.2-1.1) versus 0.8 (0.3-1.4) (mg kg(-1) min(-1) pmol l(-1)) × 100, P < 0.01], whereas the small difference between lean PCOS and lean control women was non-significant [1.5 (0.5-2.6) versus 1.7 (1.0-3.7) (mg kg(-1) min(-1) pmol l(-1)) × 100, P = 0.17]. Hyperinsulinemia increased capillary recruitment in lean controls (53.5 ± 20.3 versus 64.9 ± 27.4 n/mm(2), P < 0.05), but not in either PCOS group nor in obese controls. IICR and androgens were a determinant of M/I value only in lean women with or without PCOS. CONCLUSIONS: PCOS per se is associated with impaired IICR. Obese women with PCOS, in part independent of obesity, demonstrated a profound insulin resistance, whereas the difference between lean PCOS women and healthy controls was small and statistically non-significant. IICR was a determinant of IMGU in lean, but not in obese, women regardless of the presence of PCOS.

Microvascular changes of the retina in ankylosing spondylitis, and the association with cardiovascular disease - the eye for a heart study.

OBJECTIVE: Ankylosing spondylitis (AS) is associated with an increased risk of cardiovascular disease (CVD). Microvasculature changes can precede overt CVD, but have been studied poorly in AS. The retinal vasculature is easily accessible and changes are associated with CVD (e.g. arteriolar narrowing, venular widening, loss of tortuosity). This proof of concept study compared the retinal microvasculature of AS patients with healthy controls, and the influence of gender. METHODS: Cross-sectional case-control study comparing AS patients with healthy controls. Main inclusion criteria were: age 50-75 years, no diabetes mellitus and, for AS, fulfillment of the modified New York criteria. All subjects underwent fundus photography, analyzed with Singapore I Vessel Assessment software, and Optical Coherence Tomography Angiography (OCTA). Subjects were compared with generalized estimating equations (GEE). Multivariable analyses were adjusted for demographics and cardiovascular risk, and stratified for gender. RESULTS: Fifty-nine AS patients and 105 controls were included (50% women). Controls were significantly older than patients (68 versus 60, p<0.01), but did not differ in cardiovascular profile. Patients had a lower retinal arteriolar tortuosity (ß Ì¶-0.1, 95%CI [-0.2; -0.01], p = 0.02), and higher vessel density (ß 0.5, 95% CI [0.1; 0.9], p = 0.02). In addition, male AS patients showed a lower arteriovenular ratio compared to male controls (ß -0.03, p = 0.04, 95%CI [-0.05; -0.001]). There were no differences found between women with and without AS. CONCLUSION: This study detected several retinal microvascular changes, in AS patients compared to controls, which have been associated with CVD. Retinal imaging might be an interesting tool for future CVD screening.

Nailfold capillary density is associated with the presence and severity of pulmonary arterial hypertension in systemic sclerosis.

OBJECTIVE: The aim of this study was to investigate whether there are differences in capillary nailfold changes in patients with systemic sclerosis (SSc) with and without pulmonary arterial hypertension (PAH), and whether these changes are associated with PAH severity and disease specificity. METHODS: Capillary density and loop dimensions were studied in 21 healthy controls, 20 patients with idiopathic PAH (IPAH) and 40 patients with SSc. Of the 40 patients with SSc, 19 had no PAH (SSc-nonPAH) and 21 had PAH (SSc-PAH), of whom eight had PAH during exercise. RESULTS: Capillary density was lower in SSc-PAH compared with patients who had SSc-nonPAH (4.33/mm vs 6.56/mm respectively, p = 0.001), but loop dimensions were equal. In comparison with IPAH, patients with SSc-PAH had reduced capillary density (4.33/mm vs 7.86/mm, p<0.001) and larger loop dimensions (total width 101.05 microm vs 44.43 microm, p<0.001). Capillary density in healthy controls (9.87/mm) was significantly higher when compared with SSc-nonPAH (6.56/mm), SSc-PAH (4.33/mm) and with IPAH (7.86/mm). No differences in capillary dimensions were present between healthy controls and IPAH. Capillary density correlated with mean pulmonary arterial pressure (PAP) at rest in SSc-PAH at rest (r = -0.58, p = 0.039) and IPAH (r = -0.67, p = 0.001). CONCLUSIONS: Reduction of nailfold capillary density, but not capillary loop dimensions is associated with PAH, and correlates with the severity of PAH in both SSc and IPAH. This suggests that either systemic microvascular changes play a part in the development of PAH, or that PAH itself contributes to systemic microvascular changes.

Microvascular function is impaired in ankylosing spondylitis and improves after tumour necrosis factor alpha blockade.

OBJECTIVES: Ankylosing spondylitis (AS) is associated with increased cardiovascular morbidity and mortality. Microvascular function has been linked to several risk factors for cardiovascular disease. Inflammation in AS may cause microvascular dysfunction. To test this, we assessed microvascular function in (a) patients with AS compared to healthy controls and (b) patients with AS before and after 1 month of anti-tumour necrosis factor (TNF)alpha treatment with etanercept. METHODS: A total of 15 consecutive patients with AS, who were scheduled for etanercept treatment according to the Assessment in Ankylosing Spondylitis (ASAS) group guidelines, and 12 healthy controls matched for age and sex, were recruited. Endothelium-dependent and independent vasodilatation in skin were evaluated with laser Doppler fluxmetry after iontophoresis of acetylcholine and sodium nitroprusside, respectively. Videomicroscopy was used to measure recruitment of skin capillaries after arterial occlusion. RESULTS: Compared to healthy controls, patients with AS had impaired endothelium-dependent vasodilatation and capillary recruitment. Following anti-TNFalpha treatment, microvascular function improved significantly for endothelium-dependent vasodilatation (p = 0.03) and capillary recruitment (p = 0.006). A significant correlation was observed between changes in endothelium-dependent vasodilatation and changes in erythrocyte sedimentation rate (ESR) (r = -0.56; p = 0.03). CONCLUSION: Microvascular dysfunction is present in patients with AS with active disease, but improves as inflammation regresses after TNFalpha blockade.

[Blood pressure control in patients with a symptomatic carotid artery stenosis]. / Bloeddrukregulatie bij patiënten met een symptomatische carotisstenose.

Carotid artery stenosis is an important cause of transient ischaemic attacks (TIAs) and ischaemic strokes, and is associated with a particularly high risk of recurrent stroke both in the acute phase and the long-term. Early secondary preventive measures would therefore seem warranted. Carotid endarterectomy (CEA) is an effectively therapy in patients with a severe symptomatic stenosis. Hypertension is an important risk factor for recurrent stroke both in the acute phase and the long-term. Moreover, hypertension is an important risk factor for complications of CEA. In patients on the waiting list for CEA, following a TIA or a non-disabling ischaemic stroke, it would seem worthwhile to attempt to start antihypertensive treatment after approximately 24 h, and to at least strive after a preoperative systolic blood pressure of < 180 mmHg and a diastolic blood pressure of < 90 mmHg. In patients who cannot undergo surgery in the desirable short run, hypotensive treatment must be considered in the context of secondary prevention. The blood pressure target level depends on the presence or absence of a severe unilateral or bilateral stenosis (> 70% lumen diameter). In postoperative hypertension one must strive after a blood pressure < 140/90 mmHg, thereby avoiding an excessively rapid hypotensive response (> 25% daily). Patients with a TIA or an ischaemic stroke and a carotid artery stenosis must also be treated with antiplatelet agents and a statin, while other vascular risk factors must be controlled.

Clinical and economic impact of compression in the acute phase of deep vein thrombosis.

Essentials The value of compression therapy in acute phase of deep vein thrombosis is still unclear. Patients with deep vein thrombosis received acute compression hosiery, bandaging, or none. Acute compression reduces irreversible skin signs related to post thrombotic syndrome. Compression hosiery may be the preferred choice for the acute phase SUMMARY: Background The effectiveness of compression therapy in the acute phase of deep vein thrombosis (DVT) is not yet determined. Objectives To investigate the impact of compression therapy in the acute phase of DVT on determinants of the Villalta score, health-related quality of life (HRQOL), and costs. Patients/Methods Eight hundred and sixty-five patients with proximal DVT (substudy of the IDEAL DVT study) received, immediately after DVT diagnosis, either no compression, multilayer bandaging, or hosiery. In the acute phase and 3 months after diagnosis, HRQOL was determined by use of the EQ-5D, SF6D, and VEINES-QoL intrinsic method (VEINES-QoLint ). At 3 months, signs and symptoms were assessed for the total and separate items of the Villalta score, and healthcare costs were calculated. Results The compression groups had lower overall objective Villalta scores than the no-compression group (1.47 [standard deviation (SD) 1.570] and 1.59 [SD 1.64] versus 2.21 [SD 2.15]). The differences were mainly attributable to irreversible skin signs (induration, hyperpigmentation, and venectasia) and pain on calf compression. Subjective and total Villalta scores were similar across groups. Differences in HRQOL were only observed at 1 month; HRQOL was better for hosiery (EQ-5D 0.86 [SD 0.18]; VEINES-QoLint  0.66 [SD 0.18]) than for multilayer compression bandaging (EQ-5D 0.81 [SD 0.23; VEINES-QoLint  0.62 [SD 0.19]). Mean healthcare costs per patient were €417.08 (€354.10 to €489.30) for bandaging, €114.25 (€92.50 to €198.43) for hosiery, and €105.86 (€34.63 to €199.30) for no compression. Conclusions Initial compression reduces irreversible skin signs, edema, and pain on calf compression. Multilayer bandaging is slightly more effective than hosiery, but has substantially higher costs, without a gain in HRQOL. From a patient and economic perspective, compression hosiery would be preferred when initial compression is applied. TRIAL REGISTRATION: IDEAL DVT study ClinicalTrials.gov number, NCT01429714.

Do grape polyphenols improve metabolic syndrome components? A systematic review.

BACKGROUND/OBJECTIVES: Epidemiological, in vitro and animal studies suggest that grape polyphenols, such as those present in wine, have favorable effects on the metabolic syndrome. However, controversy remains whether treatment with grape polyphenols is effective in humans. Here, we aimed to systemically review the effects of grape polyphenols on metabolic syndrome components in humans. SUBJECTS/METHODS: We systematically searched Medline, EMBASE and the Cochrane database for all clinical trials assessing the effects of grape polyphenols on insulin sensitivity, glycemia, blood pressure or lipid levels. We screened all titles and reviewed abstracts of potentially relevant studies. Full papers were assessed for eligibility and quality-rated according to the Jadad scale by two independent assessors. RESULTS: Thirty-nine studies met the eligibility criteria. In individuals without component criteria of the metabolic syndrome, only low- and medium-quality studies were found with primarily neutral results. In individuals with the metabolic syndrome or related conditions, one of two high-quality studies suggested improvement in insulin sensitivity. Glycemia was improved in 2 of 11 lower-quality studies and 2 of 4 high-quality studies. Seven of 22 studies demonstrated a significant decrease in blood pressure, but only one was of high quality. Two of four high-quality studies pointed towards effects on total cholesterol while other lipidemic parameters were not affected. CONCLUSIONS: No compelling data exist that grape polyphenols can positively influence glycemia, blood pressure or lipid levels in individuals with or without the metabolic syndrome. Limited evidence suggests that grape polyphenols may improve insulin sensitivity.

Pre-awakening diastolic hypotension in treated hypertensive patients: prevalence and predictors.

In the pre-awakening hours, diastolic blood pressure (DBP) is normally at its lowest, and diastolic hypotension is a risk factor for cardiac ischemia. We investigated pre-awakening DBP values and its predictors in treated hypertensive patients who underwent ambulatory blood pressure monitoring. The pre-awakening period was defined as the 3-h period ending 1 h before awakening (most frequently 03:00-06:00). In 269 included subjects, office DBP was 86.4±12.0 mm Hg, 24-h DBP was 78.6±9.6 mm Hg, mean pre-awakening DBP was 70.3±10.9 mm Hg, and trough pre-awakening DBP was 62.5±11.2 mm Hg. Half of the patients (51%) had a mean pre-awakening DBP <70 mm Hg, and 14% had <60 mm Hg. Trough pre-awakening DBP <60 mm Hg was seen in 36% and <50 mm Hg in 12% of patients. Office DBP was the most important predictor of mean and trough pre-awakening DBP (both beta=0.4; P<0.001), and of pre-awakening DBP <70 mm Hg and <60 mm Hg (both P⩽0.001). Diabetes mellitus was associated with a lower trough pre-awakening DBP (beta=-3.2; P=0.02). Among variables that failed to independently predict low pre-awakening DBP were age, a history of vascular disease, and classes and number of antihypertensive drugs. We found that many hypertensive patients have low DBP in the pre-awakening period. Office DBP is the main predictor of low pre-awakening DBP. Further studies are needed to define the prognostic relevance and potential risks of low pre-awakening DBP.

[Microvascular dysfunction as an explanation for the metabolic syndrome]. / Microvasculaire disfunctie als verklaring van het metabool syndroom.

The metabolic syndrome is a cluster of mutually related risk factors that confers an increased risk for both type 2 diabetes mellitus and cardiovascular disease. Although the metabolic syndrome seems to have multiple aetiological factors, microvascular dysfunction is a potential explanation for the above-mentioned cluster of multiple metabolic risk factors such as hypertension, insulin resistance and glucose intolerance. Microvascular dysfunction leads not only to increased peripheral vascular resistance and blood pressure, but may also decrease the insulin-mediated glucose uptake in muscles. The different effect on the microcirculation may explain why some antihypertensive drugs (beta-blockers) lead to an increased incidence of type 2 diabetes, whereas others (angiotensin-converting enzyme (ACE) inhibitors) are associated with a decrease of that risk.

Capillary recruitment is impaired in essential hypertension and relates to insulin's metabolic and vascular actions.

OBJECTIVE: In patients with essential hypertension, defects in both the metabolic and vascular actions of insulin have been described. Impaired microvascular function, a well-established abnormality in essential hypertension, may explain part of these defects. In the present study we investigated whether microvascular function is impaired in essential hypertension and relates to insulin's metabolic and vasodilatatory actions. METHODS: We measured 24-h ambulatory blood pressure, capillary recruitment after arterial occlusion, and skin blood flow responses to iontophoresis of acetylcholine and sodium nitroprusside in 18 subjects with untreated essential hypertension and in 18 control subjects. Whole body insulin sensitivity and leg insulin-mediated vasodilatation were assessed with the hyperinsulinaemic clamp technique and plethysmography. RESULTS: Hypertensive, as compared to normotensive, subjects had a decreased insulin sensitivity (0.8+/-0.3 vs. 1.7+/-0. 6 mgkg(-1)min(-1) per pmoll(-1); P<0.001), capillary recruitment after arterial occlusion (21.5+/-5.8 vs. 45.9+/-10.4%; P<0.001), acetylcholine-mediated vasodilatation (331+/-84 vs. 688+/-192%; P<0. 001), and insulin-mediated vasodilatation (median 29.3 vs. 47.2%; P<0.05). Correlation analyses with adjustment for sex, age, body mass index and waist-to-hip ratio showed significant relationships of capillary recruitment after arterial occlusion with blood pressure (r=-0.68; P<0.01), insulin sensitivity (r=+0.55; P<0.01) and insulin-mediated vasodilatation (r=+0.51; P<0.05), which extended from the normotensive to the hypertensive range. CONCLUSION: Skin microvascular function is associated with blood pressure and insulin's metabolic and vasodilatatory actions, both in normotensive and hypertensive subjects. These findings offer a potential mechanistic explanation of the links among insulin resistance, impaired insulin-mediated vasodilatation and hypertension.

Renal sodium handling and haemodynamics are equally affected by hyperinsulinaemia in salt-sensitive and salt-resistant hypertensives.

OBJECTIVE: It is well-known that insulin induces renal sodium retention. It is not yet known whether insulin's renal effects are involved in the development of salt-sensitive hypertension. We assessed the effects of insulin on renal sodium handling and haemodynamics in 10 salt-sensitive (SS) and 10 salt-resistant (SR) essential hypertensives. DESIGN: After a baseline period of 90 min, all subjects underwent a euglycaemic clamp with sequential infusion of a physiological and supraphysiological dose of insulin (50 and 150 mU/kg per h) during 90 min periods each. Time-control studies were performed in the same subjects. Clearances of 131I-hippuran, 125I-iothalamate, sodium and lithium were used to evaluate renal plasma flow (RPF), CNa/glomerular filtration rate (GFR) and fractional proximal and distal sodium reabsorption. RESULTS: Plasma insulin levels and insulin-mediated glucose uptake did not differ between both groups. RPF and GFR showed similar increases during both insulin infusions in both groups. During physiological hyperinsulinaemia, fractional sodium excretion decreased 38% (P = 0.009) in the SS group and 36% (P = 0.002) in the SR group. During supraphysiological hyperinsulinaemia, fractional sodium excretion decreased 49% (P = 0.01) in the SS group and 19% (P = 0.2) in the SR group, not statistically different between both groups. Fractional proximal sodium reabsorption was unaffected and fractional distal sodium reabsorption increased to a similar magnitude in both groups. CONCLUSION: The comparable renal effects of acute exogenous hyperinsulinaemia in SS and SR hypertensives do not support a role for insulin in the development of salt-sensitive hypertension. However, the results do not yet exclude a role for chronic hyperinsulinaemia.

Birth weight relates to blood pressure and microvascular function in normal subjects.

OBJECTIVE: The relationship between low birth weight and elevated blood pressure in adult life is well established but presently unexplained. Both microvascular dysfunction and insulin resistance have been proposed as a possible explanation. We have examined the relation between birth weight and blood pressure in 30 healthy subjects exhibiting a wide range of insulin sensitivity, and assessed whether microvascular function and/or insulin resistance may underlie this relationship. METHODS: Birth weight data were obtained from birth announcements. Blood pressure was measured with an ambulatory blood pressure monitor and insulin sensitivity was assessed by the hyperinsulinaemic, euglycaemic clamp technique. Microvascular function, i.e. capillary recruitment and endothelium-dependent and -independent vasodilatation in the skin, was evaluated by videomicroscopy and iontophoresis of acetylcholine and sodium nitroprusside. RESULTS: Birth weight was significantly associated with blood pressure (r= -0.50; P< 0.05), capillary recruitment (r= +0.52; P< 0.05), acetylcholine-mediated vasodilatation (r= +0.40; P< 0.05), insulin sensitivity (r= +0.62; P< 0.01) and waist-to-hip ratio (r= -0.42; P< 0.05). Regression analysis showed a significant association of birth weight with 24 h systolic blood pressure (regression coefficient: -7.6 mmHg/kg; 95% confidence interval: -13.0 to -1.0). Adjustment for capillary recruitment and waist-to-hip ratio decreased the regression coefficient by 39 and 41%, respectively. The results were similar after adjustment for age, sex or body mass index. CONCLUSION: These results suggest that capillary recruitment and body fat distribution may partly explain the relationship between birth weight and blood pressure.

Effects of insulin on glucose uptake and leg blood flow in patients with sickle cell disease and normal subjects.

The hemodynamic concept of insulin resistance assumes that vasodilatory effects of insulin determine glucose uptake. Sickle cell disease (SCD) is characterized by microangiopathy and microvascular occlusion. Therefore, we hypothesized that patients with SCD have a reduced insulin-mediated glucose uptake. In 8 patients with SCD and 8 matched normal controls, we studied the effects of a 4-hour insulin infusion (50 mU/kg/h) on glucose uptake and leg blood flow (LBF) using the euglycemic clamp technique and venous occlusion plethysmography. Time-control experiments were performed in the same subjects. Insulin-mediated glucose uptake (M value, mg/kg/min) did not differ between patients with SCD and control subjects during the second (6.3 +/- 4.6 and 7.6 +/- 2.6, P =.5), third (7.5 +/- 4.6 and 9.3 +/- 3.4, P =.4) and fourth hour (8.6 +/- 4.7 and 11.0 +/- 2.9, P =.2) of the clamp. At baseline, LBF was higher in the patients with SCD than in the controls (3.28 +/- 1.68 and 1.37 +/- 0.47 mL/min/dL, respectively; P =.005). Insulin-induced increases in LBF in patients with SCD and in normal subjects were not different (P =.9). Respectively, 56% and 24% of the changes in glucose uptake could be explained from changes in LBF in the course of the insulin infusion in the patients with SCD and controls. We suppose that the comparable insulin sensitivity between both groups is due to a compensatory hemodynamic state in SCD characterized by vasodilation and increased flow.

Amanita phalloides, a potentially lethal mushroom: its clinical presentation and therapeutic options.

Mushroom poisoning with Amanita phalloides, a rare phenomenon in everyday clinical practice in the Netherlands, must be recognized early in view of its potential morbidity and mortality. In this article 2 cases of amanita intoxication are presented and the pharmacological basis and clinical manifestations discussed. Furthermore, the rationale of various treatment modalities, including the role of liver transplantation, is outlined.