No abstract

Toll-like receptors (TLRs) can orchestrate an inflammatory response upon activation by pathogenassociated motifs and release of endogenous stress ligands during tissue injury. The kidney constitutively expresses most TLRs, including TLR4. The function of TLR4 during the inflammation, tubular atrophy, and fibrosis that accompany progressive renal injury is unknown. Here, we subjected wild-type (WT) and TLR4-deficient mice to unilateral ureteral obstruction and observed elevated levels of TLR4 mRNA in the kidney after obstruction. One day after unilateral ureteral obstruction, TLR4-deficient mice had fewer proliferating tubular epithelial cells and more tubular damage than WT mice; however, TLR4-deficient mice developed considerably less renal fibrosis despite decreased matrix metalloproteinase activity and without significant differences in myofibroblast accumulation. In vitro, TLR4-deficient primary tubular epithelial cells and myofibroblasts produced significantly less type I collagen mRNA after TGF-␤ stimulation than WT cells. The reduced fibrosis in TLR4-deficient mice associated with an upregulation of Bambi, a negative regulator of TGF-␤ signaling. In conclusion, TLR4 attenuates tubular damage but promotes renal fibrosis by modulating the susceptibility of renal cells to TGF-␤. These data suggest that TLR4 signaling may be a therapeutic target for the prevention of renal fibrosis.

BACKGROUNDEvolocumab, a fully human monoclonal antibody directed against proprotein convertase subtilisin-kexin type 9, is widely used in adult patients to lower low-density lipoprotein (LDL) cholesterol levels. Its effects in pediatric patients with heterozygous familial hypercholesterolemia are not known. METHODSWe conducted a 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of evolocumab in pediatric patients with heterozygous familial hypercholesterolemia. Patients 10 to 17 years of age who had received stable lipid-lowering treatment for at least 4 weeks before screening and who had an LDL cholesterol level of 130 mg per deciliter (3.4 mmol per liter) or more and a triglyceride level of 400 mg per deciliter (4.5 mmol per liter) or less were randomly assigned in a 2:1 ratio to receive monthly subcutaneous injections of evolocumab (420 mg) or placebo. The primary end point was the percent change in LDL cholesterol level from baseline to week 24; key secondary end points were the mean percent change in LDL cholesterol level from baseline to weeks 22 and 24 and the absolute change in LDL cholesterol level from baseline to week 24. RESULTSA total of 157 patients underwent randomization and received evolocumab (104 patients) or placebo (53 patients). At week 24, the mean percent change from baseline in LDL cholesterol level was −44.5% in the evolocumab group and −6.2% in the placebo group, for a difference of −38.3 percentage points (P<0.001). The absolute change in the LDL cholesterol level was −77.5 mg per deciliter (−2.0 mmol per liter) in the evolocumab group and −9.0 mg per deciliter (−0.2 mmol per liter) in the placebo group, for a difference of −68.6 mg per deciliter (−1.8 mmol per liter) (P<0.001). Results for all secondary lipid variables were significantly better with evolocumab than with placebo. The incidence of adverse events that occurred during the treatment period was similar in the evolocumab and placebo groups. CONCLUSIONSIn this trial involving pediatric patients with familial hypercholesterolemia, evolocumab reduced the LDL cholesterol level and other lipid variables. (Funded by Amgen; HAUSER-RCT ClinicalTrials.gov number, NCT02392559.

BackgroundCardiovascular magnetic resonance (CMR) allows for non-invasive assessment of arterial stiffness by means of measuring pulse wave velocity (PWV). PWV can be calculated from the time shift between two time-resolved flow curves acquired at two locations within an arterial segment. These flow curves can be derived from two-dimensional CINE phase contrast CMR (2D CINE PC CMR). While CMR-derived PWV measurements have proven to be accurate for the aorta, this is more challenging for smaller arteries such as the carotids due to the need for both high spatial and temporal resolution. In this work, we present a novel method that combines retrospectively gated 2D CINE PC CMR, high temporal binning of data and compressed sensing (CS) reconstruction to accomplish a temporal resolution of 4 ms. This enables accurate flow measurements and assessment of PWV in regional carotid artery segments.MethodsRetrospectively gated 2D CINE PC CMR data acquired in the carotid artery was binned into cardiac frames of 4 ms length, resulting in an incoherently undersampled ky-t-space with a mean undersampling factor of 5. The images were reconstructed by a non-linear CS reconstruction using total variation over time as a sparsifying transform. PWV values were calculated from flow curves by using foot-to-foot and cross-correlation methods. Our method was validated against ultrasound measurements in a flow phantom setup representing the carotid artery. Additionally, PWV values of two groups of 23 young (30 ± 3 years, 12 [52%] women) and 10 elderly (62 ± 10 years, 5 [50%] women) healthy subjects were compared using the Wilcoxon rank-sum test.ResultsOur proposed method produced very similar flow curves as those measured using ultrasound at 1 ms temporal resolution. Reliable PWV estimation proved possible for transit times down to 7.5 ms. Furthermore, significant differences in PWV values between healthy young and elderly subjects were found (4.7 ± 1.0 m/s and 7.9 ± 2.4 m/s, respectively; p < 0.001) in accordance with literature.ConclusionsRetrospectively gated 2D CINE PC CMR with CS allows for high spatiotemporal resolution flow measurements and accurate regional carotid artery PWV calculations. We foresee this technique will be valuable in protocols investigating early development of carotid atherosclerosis.Electronic supplementary materialThe online version of this article (10.1186/s12968-018-0499-y) contains supplementary material, which is available to authorized users.