Background: Altered lipid metabolism has been described in some types of cancer. To analyse in depth the metabolic modifications in breast cancer patients, advanced 1H-nuclear magnetic resonance was ...performed in these patients. The main objective of this paper was to define a specific lipidomic signature for these cancer patients. Materials and methods: Serum from 240 women (171 breast cancer patients and 69 control women) were studied and analysed by nuclear magnetic resonance. Results: Triglyceride-enriched particles, specifically very low-density lipoprotein triglycerides, intermediate-density lipoprotein triglycerides, low-density lipoprotein triglycerides, and high-density lipoprotein triglycerides, were positively associated with breast cancer. Moreover, alanine, tyrosine, and branched amino acids were also associated with increased risk of breast cancer. Conclusions: Breast cancer patients showed a modified metabolome, giving a very interesting tool to draw different radar charts between control women and breast cancer patients. To our knowledge, this is the first time that advanced nuclear magnetic resonance profiling has been used to identify relevant and specifically altered lipid or amino acid metabolites in BC serum samples. The altered metabolic signature could be analysed for early and reliable BC patient diagnosis and prognosis.
Abstract HDL-increasing drugs such as fenofibrate and niacin have failed to decrease the cardiovascular risk in patients with type 2 diabetes. Drug-mediated quantitative and qualitative HDL ...modifications could be involved in these negative results. To evaluate the quantitative and qualitative effects of niacin and fenofibrate on HDL in patients with type 2 diabetes, a prospective, randomised controlled intervention trial was conducted. Thirty type 2 diabetic patients with low HDL were randomised to receive either fenofibrate (FFB) or niacin + laropiprant (ERN/LPR) as an add-on to simvastatin treatment for 12 weeks according to a crossover design. At the basal point and after each intervention period, physical examinations and comprehensive standard biochemical determinations and HDL metabolomics were performed. Thirty nondiabetic patients with normal HDL were used as a basal control group. ERN/LRP, but not FFB, significantly increased HDL cholesterol. Neither ERN/LRP nor FFB reversed the HDL particle size or particle number to normal. ERN/LRP increased apoA-I but not apoA-II, whereas FFB produced the opposite effect. FFB significantly increased Preβ1-HDL, whereas ERN/LRP tended to lower Preβ1-HDL. CETP and LCAT activities were significantly decreased only by ERN/LRP. PAF-AH activity in HDL and plasma decreased with the use of both agents. Despite their different actions on antioxidant parameters, none of the treatments induced detectable antioxidant improvements. ERN/LRP and FFB had strikingly different effects on HDL quantity and quality, as well as on HDL cholesterol concentrations. When prescribing HDL cholesterol increasing drugs, this differential action should be considered.
Abstract Aim Our objective was to assess the number of patients with an indication for lipid-lowering therapy according to their non-HDL cholesterol (N-HDL-C) (>130 mg/dL) concentrations despite ...on-target LDL (≤100 mg/dL) values determined using ultracentrifugation (UC) or direct enzymatic methods (DM). Methods In 1590 patients we studied the lipid profile using standard biochemical methods and sequential UC ( N = 637) or triglyceride (TG) independent DM ( N = 953). The indications for lipid-lowering therapy were compared by evaluating the real LDL concentration or N-HDL-C concentration. Results The LDL/N-HDL-C correlation significantly decreased with increasing triglyceride concentrations: normal ( r = 0.924, p < 0.001), 150–400 mg/dL ( r = 0.825, p < 0.001) and higher than 400 mg/dL ( r = 0.460, p < 0.001) ( p < 0.001). The percentage of patients with an N-HDL-C concentration above the recommended level, despite having an LDL concentration that was on target, also increased significantly across the TG tertiles (3.1%, 15.6% and 57.%, respectively; p < 0.001). Of the patients with a TG level above 400 mg/dL and an LDL concentration that was on target, 86% had an N-HDL-C concentration above 130 mg/dL. Of the patients with a TG level above 400 and an N-HDL-C concentration qualifying for therapy, 40% had an LDL concentration that was on target. The ApoB concentration had a stronger concordance with the LDL concentration than N-HDL-C. Conclusions Using the N-HDL-C concentration as a therapeutic target in hypertriglyceridemic patients almost doubled the number of patients requiring treatment. The ApoB concentration had a better association with LDL when determining the need for lipid-lowering therapy.
Abstract Introduction and objectives PCSK9 inhibitors (PCSK9i) are safe and effective lipid-lowering drugs. Their main limitation is their high cost. The aim of this study was to estimate the number ...of patients eligible for treatment with PCSK9i according to distinct published criteria. Methods Data were obtained from the Information System for the Development of Research in Primary Care. Included patients were equal to or older than 18 years and had at least 1 low-density lipoprotein cholesterol measurement recorded between 2006 and 2014 (n = 2 500 907). An indication for treatment with PCSK9i was assigned according to the following guidelines: National Health System, Spanish Society of Arteriosclerosis, Spanish Society of Cardiology, National Institute for Health and Care Excellence, and the European Society of Cardiology/European Atherosclerosis Society Task Force. Lipid-lowering treatment was defined as optimized if it reduced low-density lipoprotein levels by ≥ 50% and adherence was > 80%. Results Among the Spanish population aged 18 years or older, the number of possible candidates to receive PCSK9i in an optimal lipid-lowering treatment scenario ranged from 0.1% to 1.7%, depending on the guideline considered. The subgroup of patients with the highest proportion of potential candidates consisted of patients with familial hypercholesterolemia, and the subgroup with the highest absolute number consisted of patients in secondary cardiovascular prevention. Conclusions The number of candidates to receive PCSK9i in conditions of real-world clinical practice is high and varies widely depending on the recommendations of distinct scientific societies.
Abstract Objective Reactive hyperaemia after shear stress is a surrogate marker of endothelial function. However, the mechanisms controlling the dilation capacity of small peripheral resistance ...arteries are not well characterised. We evaluated reactive hyperaemia by peripheral artery tonometry (PAT) in the acral arteries and studied their clinical and biochemical determinants. Methods Eight hundred sixteen subjects at intermediate to high cardiovascular risk were recruited. The reactive hyperaemia index (RHI) of small digital arteries was measured by PAT. Clinical history data, anthropometry and biochemical parameters were also analysed. We studied the associations between clinical and biochemical factors and small artery RHI. Results HDL cholesterol and apolipoprotein A1 levels were strongly and directly correlated with an increased dilation response. Metabolic syndrome components, such as increased waist circumference, hypertriglyceridaemia and smoking, were inversely associated with RHI as were serum markers of inflammation. The predictors of small peripheral artery RHI were HDL cholesterol, which had a protective effect, and smoking, which had a negative impact. Conclusion HDL cholesterol and apolipoprotein A1 levels had a strong, positive correlation with small artery reactive hyperaemia, whereas smoking, waist circumference and triglyceride levels were inversely associated. HDL cholesterol was the main determinant of RHI in small peripheral resistance arteries.
Here we studied the impact of 5-aminoimidazole-4-carboxamide riboside (AICAR), a well-known AMPK activator, on cardiac metabolic adaptation. AMPK activation by AICAR was confirmed by increased ...phospho-Thr172-AMPK and phospho-Ser79-ACC protein levels in HL-1 cardiomyocytes. Then, cells were exposed to AICAR stimulation for 24 h in the presence or absence of the AMPK inhibitor Compound C, and the mRNA levels of the three PPARs were analyzed by real-time RT-PCR. Treatment with AICAR induced gene expression of all three PPARs, but only the Ppara and Pparg regulation were dependent on AMPK. Next, we exposed HL-1 cells to high palmitate/high insulin (HP/HI) conditions either in presence or in absence of AICAR, and we evaluated the expression of selected PPAR-targets genes. HP/HI induced insulin resistance and lipid storage was accompanied by increased Cd36, Acot1, and Ucp3 mRNA levels. AICAR treatment induced the expression of Acadvl and Glut4, which correlated to prevention of the HP/HI-induced intramyocellular lipid build-up, and attenuation of the HP/HI-induced impairment of glucose uptake. These data support the hypothesis that AICAR contributes to cardiac metabolic adaptation via regulation of transcriptional mechanisms.
Statins effectively lower low-density lipoprotein-cholesterol (LDL-C) and reduce cardiovascular risk in people with dyslipidemia and cardiometabolic diseases such as Metabolic syndrome (MetS) or type ...2 diabetes (T2D). In addition to elevated levels of LDL-C, people with these conditions often have other lipid-related risk factors, such as high levels of triglycerides, low levels of high-density lipoprotein-cholesterol (HDL-C), and a preponderance of highly atherogenic, small, dense low-density lipoprotein particles. The optimal management of dyslipidemia in people with MetS or T2D should therefore address each of these risk factors in addition to LDL-C. Although statins typically have similar effects on LDL-C levels, differences in chemical structure and pharmacokinetic profile can lead to variations in pleiotropic effects, adverse event profiles and drug-drug interactions. The choice of statin should therefore depend on the characteristics and needs of the individual patient. Compared with other statins, pitavastatin has distinct pharmacological features that translate into a broad range of actions on both apolipoprotein-B-containing and apolipoprotein-A-containing lipoproteins. Studies show that pitavastatin 1 to 4 mg is well tolerated and significantly improves LDL-C and triglyceride levels to a similar or greater degree than comparable doses of atorvastatin, simvastatin or pravastatin, irrespective of diabetic status. Moreover, whereas most statins show inconsistent effects on HDL-C levels, pitavastatin-treated patients routinely experience clinically significant elevations in HDL-C that are maintained and even increased over the long term. In addition to increasing high-density lipoprotein quantity, pitavastatin appears to improve high-density lipoprotein function and to slow the progression of atherosclerotic plaques by modifying high-density lipoprotein-related inflammation and oxidation, both of which are common in patients with MetS and T2D. When choosing a statin, it is important to note that patients with MetS have an increased risk of developing T2D and that some statins can exacerbate this risk via adverse effects on glucose regulation. Unlike many statins, pitavastatin appears to have a neutral and even beneficial effect on glucose regulation, making it a useful treatment option in this high-risk group of patients. Together with pitavastatin's beneficial effects on the cardiometabolic lipid profile and its low potential for drug-drug interactions, this suggests that pitavastatin might be a useful lipid-lowering option for people with cardiometabolic disease.
Autosomal dominant hypercholesterolemia (ADH) is associated with mutations in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 ...(PCSK9) genes, and it is estimated to be greatly underdiagnosed. The most cost-effective strategy for increasing ADH diagnosis is a cascade screening from mutation-positive probands.
The objective of this study was to evaluate the results from 2008 to 2016 of ADH genetic analysis performed in our clinical laboratory, serving most lipid units of Catalonia, a Spanish region with approximately 7.5 million inhabitants.
After the application of the Dutch Lipid Clinic Network (DLCN) clinical diagnostic score for ADH, this information and blood or saliva from 23 different lipid clinic units were investigated in our laboratory. DNA was screened for mutations in LDLR, APOB, and PCSK9, using the DNA-array LIPOchip, the next-generation sequencing SEQPRO LIPO RS platform, and multiplex ligation-dependent probe amplification (MLPA). The Simon Broome Register Group (SBRG) criteria was calculated and analyzed for comparative purposes.
A total of 967 unrelated samples were analyzed. From this, 158 pathogenic variants were detected in 356 patients. The main components of the DLCN criteria associated with the presence of mutation were plasma LDL cholesterol (LDLc), age, and the presence of tendinous xanthomata. The contribution of family history to the diagnosis was lower than in other studies. DLCN and SBRG were similarly useful for predicting the presence of mutation.
In a real clinical practice, multicenter setting in Catalonia, the percentage of positive genetic diagnosis in patients potentially affected by ADH was 38.6%. The DLCN showed a relatively low capacity to predict mutation detection but a higher one for ruling out mutation.
•Mutation detection (38.6%) was relatively low.•There was up to a 3-fold difference in mutation detection among centers.•Dutch Lipid Clinic Network (DLCN) scores relied more on personal history than on family history.•DLCN scores of >6 yielded a mutation detection of 41.1%; 48.5% in DLCN ≥ 8.•Up to 80% of DLCN scores < 6 yielded no mutation.
Treating dyslipidemia: something more than giving statins Masana, Luis
Clinica e investigacion en arteriosclerosis : publicacion oficial de la Sociedad Espanola de Arteriosclerosis,
2019 May - Jun, Volume:
31, Issue:
3
Journal Article
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