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Angiopoietin-like 3 is an inhibitor of lipoprotein lipase. Evinacumab is a monoclonal antibody that inhibits angiopoietin-like 3, activating lipoprotein lipase. In patients with hypercholesterolemia that is refractory to statin and PCSK9 inhibitor therapy, the use of evinacumab reduced plasma lipid levels by more than 50% at the maximum dose.

Loss of Endothelial Glycocalyx During Acute Hyperglycemia Coincides With Endothelial Dysfunction and Coagulation Activation In Vivo Max Nieuwdorp 1 , Timon W. van Haeften 2 , Mirella C.L.G. Gouverneur 3 , Hans L. Mooij 1 , Miriam H.P. van Lieshout 1 , Marcel Levi 4 , Joost C.M. Meijers 1 , Frits Holleman 4 , Joost B.L. Hoekstra 4 , Hans Vink 3 , John J.P. Kastelein 1 and Erik S.G. Stroes 1 1 Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands 2 Department of Internal Medicine, University Medical Center Utrecht, Utrecht, the Netherlands 3 Department of Medical Physics, Academic Medical Center, Amsterdam, the Netherlands 4 Department of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands Address correspondence and reprint requests to Erik S.G. Stroes, MD, PhD, Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Rm. F4-159.2, 1105 AZ, Amsterdam, Netherlands. E-mail: e.s.stroes{at}amc.uva.nl Abstract Hyperglycemia is associated with increased susceptibility to atherothrombotic stimuli. The glycocalyx, a layer of proteoglycans covering the endothelium, is involved in the protective capacity of the vessel wall. We therefore evaluated whether hyperglycemia affects the glycocalyx, thereby increasing vascular vulnerability. The systemic glycocalyx volume was estimated by comparing the distribution volume of a glycocalyx permeable tracer (dextran 40) with that of a glycocalyx impermeable tracer (labeled erythrocytes) in 10 healthy male subjects. Measurements were performed in random order on five occasions: two control measurements, two measurements during normoinsulinemic hyperglycemia with or without N -acetylcysteine (NAC) infusion, and one during mannitol infusion. Glycocalyx measurements were reproducible (1.7 ± 0.2 vs. 1.7 ± 0.3 l). Hyperglycemia reduced glycocalyx volume (to 0.8 ± 0.2 l; P < 0.05), and NAC was able to prevent the reduction (1.4 ± 0.2 l). Mannitol infusion had no effect on glycocalyx volume (1.6 ± 0.1 l). Hyperglycemia resulted in endothelial dysfunction, increased plasma hyaluronan levels (from 70 ± 6 to 112 ± 16 ng/ml; P < 0.05) and coagulation activation (prothrombin activation fragment 1 + 2: from 0.4 ± 0.1 to 1.1 ± 0.2 nmol/l; d -dimer: from 0.27 ± 0.1 to 0.55 ± 0.2 g/l; P < 0.05). Taken together, these data indicate a potential role for glycocalyx perturbation in mediating vascular dysfunction during hyperglycemia. FMD, flow-mediated dilation NAC, N-acetylcysteine Footnotes Accepted October 25, 2005. Received August 24, 2005. DIABETES

This phase 3 trial showed that treatment with volanesorsen, an antisense oligonucleotide drug complementary to mRNA encoding apolipoprotein C-III, resulted in a mean reduction in triglyceride levels of 77% over the course of 3 months.

Bhatt et al. report in the Journal the results of the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT), in which 8179 high-risk patients who had elevated triglyceride levels and had been receiving statin therapy were randomly assigned to receive 2 g of icosapent ethyl twice daily or placebo containing mineral oil. 1 The patients were enrolled mostly on the basis of secondary prevention (71%), and almost 60% had diabetes. At baseline, low-density lipoprotein (LDL) cholesterol levels were well controlled among the patients (median value, 75.0 mg per deciliter [1.94 mmol per liter]), and triglyceride levels were slightly elevated (median . . .

In a 2-year clinical trial, the addition of ezetimibe to simvastatin had no effect on the progression of atherosclerosis, as measured by carotid-artery intima–media thickness, despite the additional lowering of levels of low-density lipoprotein cholesterol and C-reactive protein by ezetimibe when added to simvastatin. However, the study was not powered to assess clinical end points. The addition of ezetimibe to simvastatin had no effect on the progression of atherosclerosis, as measured by carotid-artery intima–media thickness, despite the additional lowering of levels of low-density lipoprotein cholesterol and C-reactive protein. A reduction in levels of low-density lipoprotein (LDL) cholesterol constitutes one of the cornerstones in the prevention of cardiovascular disease. In recent trials comparing various statins or the same statin at various doses, aggressive therapy to lower LDL cholesterol levels was associated with a reduction in rates of cardiovascular events. 1 – 4 However, administration of the highest approved statin dose offers only limited additional lowering of LDL cholesterol at the expense of an increased incidence of side effects. 5 Therefore, novel compounds that further reduce LDL cholesterol levels when added to statin therapy are of interest. A recently introduced compound, ezetimibe, selectively . . .

Two patients with severe bradykinin-mediated angioedema received weekly subcutaneous injections of antisense oligonucleotides targeting prekallikrein messenger RNA. Subsequent to drug administration, they had reduced attack rates.

An altered intestinal microbiota composition has been implicated in the pathogenesis of metabolic disease including obesity and type 2 diabetes mellitus (T2DM). Low grade inflammation, potentially initiated by the intestinal microbiota, has been suggested to be a driving force in the development of insulin resistance in obesity. Here, we report that bacterial DNA is present in mesenteric adipose tissue of obese but otherwise healthy human subjects. Pyrosequencing of bacterial 16S rRNA genes revealed that DNA from the Gram-negative species Ralstonia was most prevalent. Interestingly, fecal abundance of Ralstonia pickettii was increased in obese subjects with pre-diabetes and T2DM. To assess if R. pickettii was causally involved in development of obesity and T2DM, we performed a proof-of-concept study in diet-induced obese (DIO) mice. Compared to vehicle-treated control mice, R. pickettii-treated DIO mice had reduced glucose tolerance. In addition, circulating levels of endotoxin were increased in R. pickettii-treated mice. In conclusion, this study suggests that intestinal Ralstonia is increased in obese human subjects with T2DM and reciprocally worsens glucose tolerance in DIO mice.

Background: Danazol is a synthetic androgen derivative frequently used as prophylaxis in patients with hereditary angioedema (HAE) due to complement-1 esterase inhibitor deficiency. However, danazol has been reported to decrease high-density lipoprotein cholesterol (HDL-C) levels and to adversely affect coagulation parameters, which are considered to be proatherothrombotic. Objective: The short- and long-term effects of danazol were evaluated on proatherogenic intermediate end points in healthy volunteers and patients with HAE. Methods: Short-term effects were evaluated in healthy men randomly assigned to 200 mg/d of danazol or placebo for 4 weeks in a crossover trial with no washout period. Long-term effects of danazol on lipoproteins, coagulation, and carotid intima-media thickness (CIMT) were evaluated in a cross-sectional study in which patients with HAE treated with danazol, a mean dose of 170 mg/d for ≥2 years, were compared with healthy controls matched for age, sex, and body mass index (BMI). Drug tolerability was assessed by questionnaires and adherence was measured by pill count whendrug bottles were returned after every study visit. Results: Patients in the short-term study were 15 men with a mean (SD) age of 32.6 (6.9) years and BMI of 24.3 (4.1) kg/m2. In the long-term study, patients with HAE were 10 women and 7 men with a mean (SD) age of 41.1 (12.9) years and BMI of 25.4 (2.6) kg/m2; the 17 matched controls had a mean (SD) age of 39.8 (11.8) years and BMI of 25.4 (2.6) kg/m2. Short-term danazol treatment was associated with a decrease from baseline in apolipoprotein A-I of 21% and in HDL-C of 23%. Flow-mediated dilation and coagulation parameters were unaffected after 4 weeks. Longterm danazol treatment did not adversely affect HDL-C concentration (1.1 [0.5] vs baseline, 1.2 [0.5] pmol/L), HDL-related transfer proteins such as paraoxonase-1 activity (92 [62] vs 80 [40] U/mM), cholesteryl-ester transfer protein mass (1.5 [0.4] vs 2.2 [0.6] µg/mL), lecithin cholesterol acyltransferase activity (21.2 [4.5] vs 32.1 [7.2] nmol CE · mL-1 · h-1), plasma phospholipid transfer protein activity (15.4 [1.5] vs 14.9 [1.2] AU), and apolipoproteins between patients with HAE and controls. The mean (SD) CIMT was similar between patients with HAE and controls (0.62 [0.09] vs 0.59 [0.08] mm; P = NS). However, HAE patients using danazol had increased coagulation activation when compared with controls (prothrombin fragments, 286 [119] vs 164 [57] pmol/L, P = 0.002; thrombinantithrombin complex, 3.9 [1.4] vs 2.6 [1.1] µg/L, P = 0.01). Conclusions: Short-term danazol treatment in healthy volunteers was associated with a reduction in HDL-C levels without a significant effect on endothelial function or coagulation parameters. In contrast, patients with HAE treated for >2 years with danazol had increased activation of coagulation, but there were no significant differences in HDL-C or CIMT compared with matched healthy controls.

In this study, a detailed characterization of a rabbit model of atherosclerosis was performed to assess the optimal time frame for evaluating plaque vulnerability using superparamagnetic iron oxide nanoparticle (SPION)-enhanced magnetic resonance imaging (MRI). The progression of atherosclerosis induced by ballooning and a high-cholesterol diet was monitored using angiography, and the resulting plaques were characterized using immunohistochemistry and histology. Morphometric analyses were performed to evaluate plaque size and vulnerability features. The accumulation of SPIONs (novel dextran-coated SPION and ferumoxytol) in atherosclerotic plaques was investigated by histology and MRI and correlated with plaque age and vulnerability. Toxicity of SPION was evaluated in rats. Weak positive correlations were detected between plaque age and intima thickness, and total macrophage load. A strong negative correlation was observed between the minimum fibrous cap thickness and plaque age as well as the mean macrophage load. The accumulation of SPION in the atherosclerotic plaques was detected by MRI 24 h after administration and was subsequently confirmed by Prussian blue staining of histological specimens. Positive correlations between Prussian blue signal in atherosclerotic plaques, plaque age, and macrophage load were detected. Very little iron was observed in the histological sections of the heart and kidney, whereas strong staining of SPION and ferumoxytol was detected in the spleen and liver. In contrast to ferumoxytol, SPION administration in rabbits was well tolerated without inducing hypersensitivity. The maximum tolerated dose in rat model was higher than 100 mg Fe/kg. Older atherosclerotic plaques with vulnerable features in rabbits are a useful tool for investigating iron oxide-based contrast agents for MRI. Based on the experimental data, SPION particles constitute a promising candidate for further clinical translation as a safe formulation that offers the possibility of repeated administration free from the risks associated with other types of magnetic contrast agents.

Endothelial Glycocalyx Damage Coincides With Microalbuminuria in Type 1 Diabetes Max Nieuwdorp 1 , Hans L. Mooij 1 , Jojanneke Kroon 1 , Bektas Atasever 2 , Jos A.E. Spaan 3 , Can Ince 2 , Frits Holleman 4 , Michaela Diamant 5 , Robert J. Heine 5 , Joost B.L. Hoekstra 4 , John J.P. Kastelein 1 , Erik S.G. Stroes 1 and Hans Vink 3 1 Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands 2 Department of Clinical Physiology, Academic Medical Center, Amsterdam, the Netherlands 3 Department of Medical Physics, Academic Medical Center, Amsterdam, the Netherlands 4 Department of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands 5 Department of Endocrinology, Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands Address correspondence and reprint requests to Erik Stroes, MD, PhD, Department of Vascular Medicine, Room F4.275, Academic Medical Center University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands. E-mail: e.s.stroes{at}amc.uva.nl Abstract Chronic hyperglycemia underlies microvascular complications in patients with type 1 diabetes. The mechanisms leading to these vascular complications are not fully understood. Recently, we observed that acute hyperglycemia results in endothelial glycocalyx damage. To establish whether glycocalyx is associated with microvascular damage, we performed glycocalyx perturbation volume measurements in type 1 diabetic patients with microalbuminuria (DM1-MA group; n = 7), without microalbuminuria (DM1-NA group; n = 7), and in age-matched control subjects (CON; n = 7). Systemic glycocalyx volume was determined comparing intravascular distribution volume of a glycocalyx-permeable tracer (dextran 40) to that of a glycocalyx-impermeable tracer (labeled erythrocytes). Sublingual capillaries were visualized using orthogonal polarization spectral microscopy to estimate microvascular glycocalyx. Patients and control subjects were matched according to age and BMI. Glycocalyx volume decreased in a stepwise fashion from CON, DM1-NA, and finally DM1-MA subjects (1.5 ± 0.1, 0.8 ± 0.4, and 0.2 ± 0.1 l, respectively, P < 0.05). Microvascular glycocalyx in sublingual capillaries was also decreased in type 1 diabetes versus the control group (0.5 ± 0.1 vs. 0.9 ± 0.1 μm, P < 0.05). Plasma hyaluronan, a principal glycocalyx constituent, and hyaluronidase were increased in type 1 diabetes. In conclusion, type 1 diabetic patients are characterized by endothelial glycocalyx damage, the severity of which is increased in presence of microalbuminuria. OPS, orthogonal polarization spectral Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted January 9, 2006. Received December 14, 2005. DIABETES