Reinold Gans

Microvascular function relates to insulin sensitivity and blood pressure in normal subjects.

BACKGROUND A strong but presently unexplained inverse association between blood pressure and insulin sensitivity has been reported. Microvascular vasodilator capacity may be a common antecedent linking insulin sensitivity to blood pressure. To test this hypothesis, we studied 18 normotensive and glucose-tolerant subjects showing a wide range in insulin sensitivity as assessed with the hyperinsulinemic, euglycemic clamp technique. METHODS AND RESULTS Blood pressure was measured by 24-hour ambulatory blood pressure monitoring. Videomicroscopy was used to measure skin capillary density and capillary recruitment after arterial occlusion. Skin blood flow responses after iontophoresis of acetylcholine and sodium nitroprusside were evaluated by laser Doppler flowmetry. Insulin sensitivity correlated with 24-hour systolic blood pressure (24-hour SBP; r=-0.50, P<0.05). Capillary recruitment and acetylcholine-mediated vasodilatation were strongly and positively related to insulin sensitivity (r=0.84, P<0.001; r=0.78, P<0.001, respectively), and capillary recruitment was inversely related to 24-hour SBP (r=-0.53, P<0.05). Waist-to-hip ratio showed strong associations with insulin sensitivity, blood pressure, and the measures of microvascular function but did not confound the associations between these variables. Subsequent regression analysis showed that the association between insulin sensitivity and blood pressure was not independent of the estimates of microvascular function, and part of the variation in both blood pressure (R2=38%) and insulin sensitivity (R2=71%) could be explained by microvascular function. CONCLUSIONS Insulin sensitivity and blood pressure are associated well within the physiological range. Microvascular function strongly relates to both, consistent with a central role in linking these variables.

Impaired skin capillary recruitment in essential hypertension is caused by both functional and structural capillary rarefaction

Capillary rarefaction occurs in many tissues in patients with essential hypertension and may contribute to an increased vascular resistance and impaired muscle metabolism. Rarefaction may be caused by a structural (anatomic) absence of capillaries, functional nonperfusion, or both. The aim of this study was to assess the extent of structural versus functional capillary rarefaction in the skin of subjects with essential hypertension. We examined skin capillary density with video microscopy before and during maximization of the number of perfused capillaries by venous congestion (structural capillary number) and before and during postocclusive reactive hyperemia (capillary recruitment, which may have a structural and/or functional basis). The study group was composed of 26 patients with never-treated essential hypertension and 26 normotensive control subjects. In both groups, intermittently perfused capillaries in the resting state were an important functional reserve for recruitment during postocclusive hyperemia. Recruitment of perfused capillaries during postocclusive reactive hyperemia was decreased in the hypertensive subjects compared with normotensive control subjects (47.9±6.8 versus 55.3±8.2 capillaries/mm2, respectively;P <0.01). During venous occlusion, maximal capillary density was significantly lower in the hypertensive subjects than in the control subjects (52.5±6.6 versus 57.2±8.6 capillaries/mm2, respectively;P <0.05), suggesting structural rarefaction. However, in the hypertensive subjects compared with the normotensive subjects, a smaller proportion of the maximal number of capillaries was perfused during postocclusive hyperemia (91.6±7.5% versus 97.2±2.7%, respectively;P <0.05), suggesting an additional functional impairment of capillary recruitment. If the difference in capillary numbers during venous congestion (≈4.6 capillaries/mm2) truly reflects the structural difference between the normotensive and hypertensive subjects, then, at most, 62% (4.6/7.4×100%) of the difference in capillary numbers during postocclusive hyperemia (≈7.4 capillaries/mm2) can be explained by structural defects, and at least 38% can be explained by functional defects. In conclusion, in patients with essential hypertension, recruitment of perfused capillaries is impaired, which can be explained by both functional and structural rarefaction.

Cytosolic triglycerides and oxidative stress in central obesity: the missing link between excessive atherosclerosis, endothelial dysfunction, and β-cell failure?

Central obesity is increasingly recognized as a risk factor for atherosclerosis and type 2 diabetes mellitus. Here we present a hypothesis that may explain the excess atherosclerosis, endothelial dysfunction and progressive beta-cell failure. Central obesity is associated with increased cytosolic triglyceride stores in non-adipose tissues such as muscles, liver and pancreatic beta-cells. A high cytosolic triglyceride content is accompanied by elevated concentrations of cytosolic long-chain acyl-CoA esters, the metabolically active form of fatty acids. These esters inhibit mitochondrial adenine nucleotide translocators, resulting in an intramitochondrial ADP deficiency. In vitro, such ADP deficiency is a potent stimulator of mitochondrial oxygen free radical production, and we assume that this mechanism is also active in vivo. The decline of organ function with normal ageing is thought to be due, at least partly, to a continuous low-grade mitochondrial oxygen free radical production. In tissues containing increased cytosolic triglyceride stores this process will be accelerated. Tissues with a high-energy demand or poor free radical scavenging capacity, such as pancreatic beta-cells, are likely to be more susceptible to this process. This is how we explain their gradual dysfunctioning in central obesity. Likewise we propose that the enhanced production of oxygen free radicals in endothelial cells, or vascular smooth muscle cells, leads to the increased subendothelial oxidation of LDL and atherosclerosis, as well as to the endothelial dysfunction and microalbuminuria.

Metabolic syndrome is associated with impaired long-term renal allograft function; not all component criteria contribute equally.

Chronic renal transplant dysfunction (CRTD) remains a leading cause of renal allograft loss. Evidence suggests that immunological and ischemic insults are mainly associated with CRTD occurring within the first year after transplantation, whereas nonimmunological insults are predominantly associated with CRTD beyond the first year. Several cardiovascular risk factors, such as obesity, dyslipidemia, hypertension, and diabetes mellitus have been identified as important nonimmunological risk factors for CRTD. These risk factors constitute the metabolic syndrome (MS). As renal allograft function is a surrogate marker of renal allograft loss, we investigated the association of MS with impairment of renal allograft function beyond the first year after transplantation in a cross‐sectional study of 606 renal transplant outpatients. Metabolic syndrome was defined using the definition of the National Cholesterol Education Program. Renal allograft function was assessed as the 24‐h urinary creatinine clearance. A total of 383 out of 606 patients (63%) suffered from MS at a median time of 6 years (2.6–11.4) post‐transplant. Presence of MS was associated with impaired renal allograft function beyond 1 year post‐transplant [−4.1 mL/min, 95%CI (−7.1, −1.1)]. The impact of MS did not change appreciably after adjustment for established risk factors for CRTD [−3.1 mL/min, 95%CI (−6.0, −0.2)]. However, not all component criteria of MS contributed equally. Only systolic blood pressure and hypertriglyceridemia were independently associated with impaired renal allograft function beyond 1 year post‐transplant in multivariate analyses.

High urinary excretion of kidney injury molecule-1 is an independent predictor of graft loss in renal transplant recipients

Background. Chronic transplant dysfunction is characterized by renal function decline and proteinuria. Kidney injury molecule (KIM)-1, a transmembrane tubular protein with unknown function, is undetectable in normal kidneys, but markedly induced after injury. Urinary KIM-1 excretion has been quantified as biomarker of renal damage. We prospectively studied whether urinary KIM-1 predicts graft loss, independent of renal function and proteinuria. Methods. Renal transplant recipients (n=145) visiting our outpatient clinic between August 2001 and July 2003 collected 24-hour urine samples for assessment of baseline urinary KIM-1 excretion (microsphere-based Luminex technology), and were followed for graft loss. Results. Recipients participated at a median (interquartile range) of 6.0 (2.5–12.0) years posttransplant in baseline measurements. Follow-up beyond baseline was 4.0 (3.2–4.5) years. Urinary KIM-1 excretion was 0.72 (0.42–1.37) ng per 24 hours. Occurrence of graft loss increased over tertiles of KIM-1 excretion: 3 (6.3%), 11 (22.4%), and 17 cases (35.4%; P=0.001), respectively. High KIM-1 excretion was associated with proteinuria, low creatinine clearance, and high donor age (all P<0.01). In multivariate Cox regression analyses, prediction of graft loss by KIM-1 appeared independent of creatinine clearance, proteinuria, and donor age. Hazard ratios (95% CI) for the second and third tertile of KIM-1 excretion were 3.6 (0.9–13.5) and 5.1 (1.5–17.8) in the final model. Conclusions. Urinary excretion of KIM-1 is an independent predictor of long-term graft loss and therefore a promising new biomarker in early prediction of graft loss.

Simple Noninvasive Measurement of Skin Autofluorescence

Abstract: Accumulation of advanced glycation end products (AGEs) is thought to play a role in the pathogenesis of chronic complications of diabetes mellitus and renal failure. Several studies indicate that AGE accumulation in tissue may reflect the cumulative effect of hyperglycemia and oxidative stress over many years. Simple quantitation of AGE accumulation in tissue could provide a tool for assessing the risk of long‐term complications. Because several AGEs exhibit autofluorescence, we developed a noninvasive autofluorescence reader (AFR). Skin autofluorescence measured with the AFR correlates with collagen‐linked fluorescence and specific skin AGE levels from skin biopsy samples. Furthermore, skin autofluorescence correlates with long‐term glycemic control and renal function, and preliminary results show correlations with the presence of long‐term complications in diabetes. The AFR may be useful as a clinical tool for rapid assessment of risk for AGE‐related long‐term complications in diabetes and in other conditions associated with AGE accumulation.

Increased accumulation of skin advanced glycation end-products precedes and correlates with clinical manifestation of diabetic neuropathy

Aims/hypothesisThe accumulation of AGE is related to the progression of the renal, retinal and vascular complications of diabetes. However, the relationship with diabetic neuropathy remains unclear. We recently showed that skin autofluorescence, measured non-invasively with an AutoFluorescence Reader (AFR), could be used to assess skin AGE accumulation. We evaluated the relationship between skin autofluorescence and the severity of diabetic neuropathy.Materials and methodsSkin autofluorescence in arbitrary units (AU) was assessed in 24 diabetic patients with a history of neuropathic foot ulceration (NP+), 23 diabetic patients without clinical neuropathy (NP−) and 21 control subjects, using the AFR. Arterial occlusive disease was excluded in all. The severity of foot ulceration was assessed by the Wagner score. Peripheral nerve function was assessed by neurography, measuring motor and sensory nerve conduction velocity and amplitude of the median, peroneal and sural nerves. Heart rate variability (HRV) and baroreflex sensitivity (BRS) were measured by Finapres to assess autonomic nervous function.ResultsAutofluorescence was increased in NP− compared with control subjects. In NP+ patients, autofluorescence was further increased and correlated with the Wagner score. Autofluorescence correlated negatively with nerve conduction velocity and amplitude, HRV and BRS in both NP+ and NP− groups. Autofluorescence correlated with age, diabetes duration, mean HbA1c of the previous year, serum creatinine level, presence of microalbuminuria and severity of diabetic retinopathy.Conclusions/interpretationSkin autofluorescence correlates with the severity of peripheral and autonomic nerve abnormalities in diabetes, even before being clinically manifest. The AFR may be a convenient and rapid clinical tool for assessing risk of progression of long-term diabetic complications.

Disease spectrum of patients with antineutrophil cytoplasmic autoantibodies of defined specificity : distinct differences between patients with anti-proteinase 3 and anti-myeloperoxidase autoantibodies

Franssen C, Gans R, Kallenberg C, Hageluken C, Hoorntje S (University Hospital, Groningen; Free University Hospital, Amsterdam; and Catharina Hospital, Eindhoven; the Netherlands). Disease spectrum of patients with antineutrophil cytoplasmic autoantibodies of defined specificity: distinct differences between patients with antiproteinase 3 and antimyeloperoxidase autoantibodies. J Intern Med 1998; 244: 209–16.

Autonomic Function in Hypertensive and Normotensive Subjects: The Importance of Gender

Abstract—Baroreceptor reflex sensitivity (BRS) has been found lower and heart rate variability (HRV) parasympathetic markers have been found higher in healthy women than in healthy men. Thus, in the present study we hypothesized gender differences in the autonomic function among hypertensive subjects. Forty-one hypertensive patients and 34 normotensive subjects, age 53±1 years, were examined. Four weeks after cessation of antihypertensive therapy, HRV was assessed in 24-hour Holter ECGs, and BRS was calculated with the transfer technique. A t test was performed after log transformation of spectral values. Resting blood pressure and heart rate in the hypertensive and the normotensive groups were 150±2/100±1 (mean±SEM) and 121±2/81±1 mm Hg, respectively, and 68±1 and 60±1 bpm, respectively (P <0.0005). Compared with normotensive controls, hypertensive patients had lower total power (1224±116 versus 1797±241 ms2;P =0.03), lower low frequency power (550±57 versus 813±115 ms2;P =0.04), lower high frequency power (141±23 versus 215±38 ms2;P =0.06), lower root mean square successive difference (28.7±2.7 versus 35.7±3.0 ms;P =0.03), and PNN50 (4.9±0.6% versus 9.8±1.5%;P =0.003). BRS was also lower in the hypertensive subjects (7.6±0.6 versus 10.4±0.8 ms/mm Hg;P =0.005). When comparing the same parameters between normotensive subjects and hypertensive subjects within the same gender group, we found significant reduction (P <0.05) only within the female group. The difference in BRS within the female group was twice that within the male group. Stepwise multiple regression analysis revealed gender, age, HDL cholesterol, and blood pressure as independent explanatory variables of BRS and HRV. Our results suggest that gender is an important determinant of BRS and HRV. Autonomic function parameters were especially impaired in hypertensive women compared with hypertensive men.

Urinary creatinine excretion, an indirect measure of muscle mass, is an independent predictor of cardiovascular disease and mortality in the general population

OBJECTIVE Low muscle mass often indicates poor health, but the relation with cardiovascular disease (CVD) is unknown. Skeletal muscles are responsible for approximately 75% of insulin stimulated whole body glucose disposal and therefore insulin resistance could underlie the relation between muscle mass and CVD. We aimed to determine whether muscle mass, as reflected by 24h urinary creatinine excretion, is associated with CVD and whether this depends on insulin resistance. METHODS The study was performed in the prospective, community-based, observational cohort of the PREVEND study in Groningen, the Netherlands. 24h creatinine excretion was assessed in 4044 women and 4048 men. Outcome events were incidence of major adverse cardiovascular events (MACE) and all-cause mortality, with a follow-up of 7.5 [7.3-7.9] years. Insulin resistance was estimated using fasting insulin and HOMA. RESULTS In women every doubling of creatinine excretion was associated with an approximate 60% decrease in risk for MACE (hazard ratio (HR) 0.41 [95%CI 0.26-0.64], P<0.001) and 50% decrease in risk for all-cause mortality (HR: 0.52 [0.31-0.90], P=0.02) independent of age, smoking, CVD history, race, fasting insulin concentrations and components of the metabolic syndrome. In men every doubling of creatinine excretion was borderline associated with an approximately 25% decrease in risk for MACE (HR: 0.74 [0.53-1.03], P=0.07) and independently associated with a 55% decreased risk for all-cause mortality (HR: 0.45 [0.32-0.62], P<0.001). CONCLUSIONS Low creatinine excretion, as indirect measure of low muscle mass, is associated with MACE and all-cause mortality in the general population, independent of insulin resistance. Perhaps protein-calorie malnutrition or physical activity could underlie the association between muscle mass and CVD.