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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 . . .

Patients with aneurysmal subarachnoid hemorrhage (SAH) who experience delayed cerebral ischemia (DCI) have an increased risk of poor outcome. Delayed cerebral ischemia is considered to be caused by vasospasm. However, not all patients with DCI have vasospasm. Inversely, not all patients with vasospasm develop clinical symptoms and signs of DCI. In the past, treatments aiming at vasospasm were not successful in preventing ischemia. The purpose of this review is to give an overview of clinical data showing that DCI cannot always be attributed to vasospasm, and to present an in-depth analysis of clinical and autopsy studies on the role of microthrombosis in the pathogenesis of DCI. Clinical studies show that DCI is associated with an activation of the coagulation cascade within a few days after SAH, preceding the time window during which vasospasm occurs. Furthermore, impaired fibrinolytic activity, and inflammatory and endothelium-related processes, lead to the formation of microthrombi, which ultimately result in DCI. The presence of microthrombi is confirmed by autopsy studies. Insight in the pathophysiology of DCI is crucial for the development of effective therapies against this complication. Because multiple pathways are involved, future research should focus on drugs with pleiotropic effects.

Therapeutic and diagnostic nanomaterials are being intensely studied for several diseases, including cancer and atherosclerosis. However, the exact mechanism by which nanomedicines accumulate at targeted sites remains a topic of investigation, especially in the context of atherosclerotic disease. Models to accurately predict transvascular permeation of nanomedicines are needed to aid in design optimization. Here we show that an endothelialized microchip with controllable permeability can be used to probe nanoparticle translocation across an endothelial cell layer. To validate our in vitro model, we studied nanoparticle translocation in an in vivo rabbit model of atherosclerosis using a variety of preclinical and clinical imaging methods. Our results reveal that the translocation of lipid–polymer hybrid nanoparticles across the atherosclerotic endothelium is dependent on microvascular permeability. These results were mimicked with our microfluidic chip, demonstrating the potential utility of the model system.

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.

Background Using serial coronary CT angiography (CCTA) imaging, we aimed to characterize baseline coronary plaque characteristics and quantify 10-year coronary plaque progression, including high-risk and low-density plaque presence, in patients with and without type 2 diabetes. Methods A total of 299 patients underwent CCTA with a median scan interval of 10.2 [IQR 8.7–11.2] years. Patients who underwent coronary artery bypass grafting and vessels revascularized by percutaneous coronary intervention were excluded (n = 32). Scans were analyzed using atherosclerosis imaging-quantitative CCTA analysis (AI-QCT; Cleerly Inc.). Associations between diabetic status, baseline and follow-up plaque burden and characteristics were evaluated using multivariable regression adjusted for cardiovascular risk factors, statin use, baseline plaque volumes, and scanner settings. Results In total, 267 patients were included (mean age 57 ± 7 years; 43% were women), 44 (16.5%) had type 2 diabetes (HbA1c 56 ± 14 mmol/mol). At baseline, patients with diabetes had a higher percent atheroma volume (PAV) compared to non-diabetic individuals (5.1% [1.7, 10.9] versus 2.2% [0.5, 5.8]). Adjusted for cardiovascular risk factors, patients with diabetes had a higher plaque burden at both baseline and follow-up. After adjustment for cardiovascular risk factors and baseline plaque volumes, individuals with diabetes had a more than threefold higher rate of plaque progression. After 10 years of follow-up, patients with diabetes had a higher prevalence of both high-risk plaque (OR 2.75; 95% CI 1.38–5.48; p  = 0.004) and low-density plaque (OR 2.88; 95% CI 1.45–5.70; p  = 0.002). Conclusions Patients with diabetes had a more than threefold higher rate of coronary plaque progression and an increased development of high-risk plaque. Graphical abstract

The results of this phase 3 trial of the effect of olezarsen, a drug that targets APOC3 mRNA, on plasma triglyceride levels and acute pancreatitis in familial chylomicronemia syndrome support further clinical research.

Individuals with chronic kidney disease are at an increased risk for cardiovascular disease. This risk may partially be explained by a chronic inflammatory state in these patients, reflected by increased arterial wall and cellular inflammation. Statin treatment decreases cardiovascular risk and arterial inflammation in non-CKD subjects. In patients with declining kidney function, cardiovascular benefit resulting from statin therapy is attenuated, possibly due to persisting inflammation. In the current study, we assessed the effect of statin treatment on arterial wall and cellular inflammation. Fourteen patients with chronic kidney disease stage 3 or 4, defined by an estimated Glomerular Filtration Rate between 15 and 60 mL/min/1.73 m 2 , without cardiovascular disease were included in a single center, open label study to assess the effect of atorvastatin 40 mg once daily for 12 weeks (NTR6896). At baseline and at 12 weeks of treatment, we assessed arterial wall inflammation by 18 F-fluoro-deoxyglucose positron-emission tomography computed tomography ( 18 F-FDG PET/CT) and the phenotype of circulating monocytes were assessed. Treatment with atorvastatin resulted in a 46% reduction in LDL-cholesterol, but this was not accompanied by an attenuation in arterial wall inflammation in the aorta or carotid arteries, nor with changes in chemokine receptor expression of circulating monocytes. Statin treatment does not abolish arterial wall or cellular inflammation in subjects with mild to moderate chronic kidney disease. These results imply that CKD-associated inflammatory activity is mediated by factors beyond LDL-cholesterol and specific anti-inflammatory interventions might be necessary to further dampen the inflammatory driven CV risk in these subjects.

Hypertriglyceridemia and Risk of PancreatitisThis meta-analysis of three clinical trials assessed the effect of triglyceride-lowering pharmacologic therapy on the risk of acute pancreatitis in patients with severe hypertriglyceridemia.

Background Epidemiological studies substantiated that subjects with elevated lipoprotein(a) [Lp(a)] have a markedly increased cardiovascular risk. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) lowers both LDL cholesterol (LDL-C) as well as Lp(a), albeit modestly. Effects of PCSK9 inhibition on circulating metabolites such as lipoprotein subclasses, amino acids and fatty acids remain to be characterized. Methods We performed nuclear magnetic resonance (NMR) metabolomics on plasma samples derived from 30 individuals with elevated Lp(a) (> 150 mg/dL). The 30 participants were randomly assigned into two groups, placebo ( N  = 14) and evolocumab ( N  = 16). We assessed the effect of 16 weeks of evolocumab 420 mg Q4W treatment on circulating metabolites by running lognormal regression analyses, and compared this to placebo. Subsequently, we assessed the interrelationship between Lp(a) and 14 lipoprotein subclasses in response to treatment with evolocumab, by running multilevel multivariate regression analyses. Results On average, evolocumab treatment for 16 weeks resulted in a 17% (95% credible interval: 8 to 26%, P  < 0.001) reduction of circulating Lp(a), coupled with substantial reduction of VLDL, IDL and LDL particles as well as their lipid contents. Interestingly, increasing concentrations of baseline Lp(a) were associated with larger reduction in triglyceride-rich VLDL particles after evolocumab treatment. Conclusions Inhibition of PCSK9 with evolocumab markedly reduced VLDL particle concentrations in addition to lowering LDL-C. The extent of reduction in VLDL particles depended on the baseline level of Lp(a). Our findings suggest a marked effect of evolocumab on VLDL metabolism in subjects with elevated Lp(a). Trial registration Clinical trial registration information is registered at ClinicalTrials.gov on April 14, 2016 with the registration number NCT02729025 .

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 . . .