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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.

Purpose To assess the potential role of computed tomography (CT) texture analysis (CTTA) in identifying vulnerable patients with carotid artery atherosclerosis. Methods In this case-control pilot study, 12 patients with carotid atherosclerosis and a subsequent history of transient ischemic attack or stroke were age and sex matched with 12 control cases with asymptomatic carotid atherosclerosis (follow-up time 103.58 ± 9.2 months). CTTA was performed using a commercially available research software package (TexRAD) by an operator blinded to clinical data. CTTA comprised a filtration-histogram technique to extract features at different scales corresponding to spatial scale filter (fine = 2 mm, medium = 3 mm, coarse = 4 mm), followed by quantification using histogram-based statistical parameters: mean, kurtosis, skewness, entropy, standard deviation, and mean value of positive pixels. A single axial slice was selected to best represent the largest cross-section of the carotid bifurcation or the greatest degree of stenosis, in presence of an atherosclerotic plaque, on each side. Results CTTA revealed a statistically significant difference in skewness between symptomatic and asymptomatic patients at the medium (0.22 ± 0.35 vs − 0.18 ± 0.39, p < 0.001) and coarse (0.23 ± 0.22 vs 0.03 ± 0.29, p = 0.003) texture scales. At the fine-texture scale, skewness (0.20 ± 0.59 vs − 0.18 ± 0.58, p = 0.009) and standard deviation (366.11 ± 117.19 vs 300.37 ± 82.51, p = 0.03) were significant before correction. Conclusion Our pilot study highlights the potential of CTTA to identify vulnerable patients in stroke and TIA. CT texture may have the potential to act as a novel risk stratification tool in patients with carotid atherosclerosis.

ObjectivesTo comprehensively explore metabolic and genetic contributors to liver fat accumulation in overweight/obese children.MethodsTwo hundred thirty Italian children with obesity were investigated for metabolic parameters and genotyped for PNPLA3, TM6SF2, GCKR, and MBOAT7 gene variants. Percentage hepatic fat content (HFF%) was measured by nuclear magnetic resonance.ResultsHFF% was positively related with BMI, HOMAIR, metabolic syndrome, ALT, AST, γGT, and albumin. Carriers of [G] allele in PNPLA3, [T] allele in GCKR and [T] allele in TM6SF2 genes had significantly higher hepatic fat content than wild-type carriers. HFF% was explained for 8.7% by metabolic and for 16.1% by genetic factors and, a model including age, gender, BMI, HOMAIR, PNPLA3, GCKR, and TM6SF2 variants was the best predictor of HFF%, explaining 24.8% of its variation (P < 0.001). A weighted-genetic risk score combining PNPLA3, GCKR, and TM6SF2 risk alleles was associated with almost eightfold higher risk of NAFLD.ConclusionsOur data highlighted the predominant role of genetic factors in determining the amount of liver fat content in children with obesity.

Background: Proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) lower LDL-cholesterol and slow atherosclerosis preventing cardiovascular events. While it is known that circulating PCSK9 enhances platelet activation (PA) and that PCSK9i reduce it, the underlying mechanism is not still clarified. Methods: In a multicenter before–after study in 80 heterozygous familial hypercholesterolemia (HeFH) patients on treatment with maximum tolerated statin dose ± ezetimibe, PA, soluble-NOX2-derived peptide (sNOX2-dp), and oxidized-LDL (ox-LDL) were measured before and after six months of PCSK9i treatment. In vitro study investigates the effects of plasma from HeFH patients before and after PCK9i on PA in washed platelets (wPLTs) from healthy subjects. Results: Compared to baseline, PCSK9i reduced the serum levels of LDL-c, ox-LDL, Thromboxane (Tx) B2, sNOX2-dp, and PCSK9 (p < 0.001). The decrease of TxB2 correlates with that of ox-LDL, while ox-LDL reduction correlated with PCSK9 and sNOX2-dp delta. In vitro study demonstrated that wPLTs resuspended in plasma from HeFH after PCSK9i treatment induced lower PA and sNOX2-dp release than those obtained using plasma before PCSK9i treatment. This reduction was vanished by adding ox-LDL. ox-LDL-induced PA was blunted by CD36, LOX1, and NOX2 inhibition. Conclusions: PCSK9i treatment reduces PA modulating NOX2 activity and in turn ox-LDL formation in HeFH patients.

Familial Combined Hypolipidemia (FHBL2) is a genetic disorder caused by loss-of-function mutations in the Angiopoietin-like 3 ( ANGPTL3 ) gene. FHBL2 subjects exhibit hypolipidemia and protection from atherosclerotic cardiovascular diseases. Here, we explored the hypothesis that immunometabolic events contribute to this atheroprotective phenotype. To this aim, circulating monocytes from FHBL2 subjects and controls were profiled through gene expression and phenotypic analysis in vivo and ex vivo. In parallel, immune responses were analyzed in monocytes that were lipid-deprived in vitro. In FHBL2 subjects, leukocytes exhibited lower content of intracellular lipids, together with a spontaneous type I IFN signature in vivo and higher sensitivity to IFN stimulation ex vivo. Lipid restriction in vitro was sufficient to recapitulate the higher IFN sensitivity in monocytes, while activating the mevalonate and isoprenoid synthetic pathway. These two events were linked, since a prenylation inhibitor reverted the high IFN response under lipid deprivation. Finally, we found that lipid restriction repressed, in a prenylation- and IFN-dependent fashion, the production of the inflammatory and proatherogenic cytokine IL-1β, and suppressed mitochondrial metabolism, which is a known trigger for inflammasome activation. In summary, we uncovered a novel immunometabolic mechanism linking lipid deprivation in monocytes, isoprenoid synthesis, enhanced IFN response, and IL-1β control. This circuit may provide an immunometabolic basis for the protection from atherosclerotic diseases in hypolipidemic subjects.

Extracorporeal photopheresis (ECP) involves the reinfusion of autologous peripheral blood lymphocytes rendered apoptotic by in vitro exposure to psoralen and ultraviolet A light. Antigenic determinants presented by apoptotic lymphocytes, primarily T cells, elicit immunomodulatory responses that have shown therapeutic benefit in several conditions, including cutaneous T-cell lymphoma, graft-versus-host disease, and various inflammatory/autoimmune disorders. We treated with ECP a 41-year-old woman diagnosed with cutaneous lupus erythematosus and concomitant hypercholesterolemia, achieving a marked improvement of skin lesions. A study in hypercholesterolemic apolipoprotein E-deficient mice demonstrated that immunization with syngeneic apoptotic thymocytes, a process mimicking ECP, induced the production of IgM antibodies against oxidized low-density lipoproteins (OxLDL) that attenuated atherosclerosis. Thus, we explored whether ECP could similarly induce anti-OxLDL antibodies in our patient. Indeed, over the course of a 14-week ECP treatment we observed a steady increase in circulating IgM antibodies against malondialdehyde-modified LDL, a class of antibodies known to confer atheroprotection in preclinical models. Additionally, we documented an increase in circulating regulatory T cells, which are recognized as suppressing pro-atherogenic immune responses. These findings support the translational potential of a preclinical atheroprotection model and provide a proof of concept for clinical trials evaluating ECP in autoimmune diseases associated with accelerated atherosclerosis, where achieving dual benefits, clinical improvement and reduced cardiovascular risk, may be feasible.

Introduction: The literature and international Guidelines agree in identifying LDL cholesterol (LDL-C) control asthe primary goal for reducing cardiovascular (CV) risk, while hypertriglyceridemia management is a secondaryobjective. Nevertheless, experimental evidence indicates that elevated triglyceride levels represent a significantCV risk factor.Epidemiological data about patients with hypertriglyceridemia and residual CV risk in Italy are limited. This studyaims to estimate the prevalence of these patients that, despite treatment with high-intensity statins plus ezetimibeand LDL-C levels < 70 mg/dL, may be eligible for treatment with icosapent ethyl (IPE) in Italy.Methods: A literature review was performed to identify evidence on the reimbursed indication of IPE in Italy.Data from literature were used to estimate the number of patients eligible for IPE treatment by calculating aminimum, a maximum, and an average scenario.Results: A total of 94 articles were identified, which, after screening, were reduced to 7 articles included in theanalysis. The analysis estimated a range of 2,500 to 78,590 total patients with residual hypertriglyceridemia potentially eligible for IPE treatment in Italy, with an average scenario of 22,427 patients.The number of eligible patients will depend on the prescription and reimbursement criteria established by AIFAand the evolution of clinical practice concerning lipid-lowering therapies.Conclusions: The reported evidence may be useful for physicians and healthcare policymakers in managing residual CV risk in populations already treated for hypercholesterolemia, contributing to more effective preventionof CV events.

Background A small number of patients affected by Neutral Lipid Storage Diseases (NLSDs: NLSD type M with Myopathy and NLSD type I with Ichthyosis) have been described in various ethnic groups worldwide. However, relatively little is known about the progression and phenotypic variability of the disease in large specific populations. The aim of our study was to assess the natural history, disability and genotype-phenotype correlations in Italian patients with NLSDs. Twenty-one patients who satisfied the criteria for NLSDs were enrolled in a retrospective cross-sectional study to evaluate the genetic aspects, clinical signs at onset, disability progression and comorbidities associated with this group of diseases. Results During the clinical follow-up (range: 2–44 years, median: 17.8 years), two patients (9.5%, both with NLSD-I) died of hepatic failure, and a further five (24%) lost their ability to walk or needed help when walking after a mean period of 30.6 years of disease. None of the patients required mechanical ventilation. No patient required a heart transplant, one patient with NLSD-M was implanted with a cardioverter defibrillator for severe arrhythmias. Conclusion The genotype/phenotype correlation analysis in our population showed that the same gene mutations were associated with a varying clinical onset and course. This study highlights peculiar aspects of Italian NLSD patients that differ from those observed in Japanese patients, who were found to be affected by a marked hypertrophic cardiopathy. Owing to the varying phenotypic expression of the same mutations, it is conceivable that some additional genetic or epigenetic factors affect the symptoms and progression in this group of diseases.

ContextDifferentiation between familial chylomicronemia syndrome (FCS, type 1 hyperlipoproteinemia), a rare metabolic disorder, and the more common multifactorial severe hypertriglyceridemia (sHTG, type 5 hyperlipoproteinemia) is challenging because of their overlapping symptoms but important in patient management.ObjectiveTo assess whether readily obtainable clinical information beyond triglycerides can effectively diagnose and differentiate patients with FCS from those with sHTG, based on well-curated data from two intervention studies of these conditions.MethodsThe analysis included 154 patients from two phase 3 clinical trials of patients with sHTG, one cohort with genetically confirmed FCS (n = 49) and one with multifactorial sHTG (n = 105). Logistic regression analyses were performed to determine the ability of variables (patient demographics, medical history, and baseline lipids, individually or in sets) to differentiate the patient populations. Receiver operating characteristics were used to determine the variable sets with the highest accuracy (percentage of times actual values matched predicted) and optimal sensitivity and specificity.ResultsThe primary model diagnosed 45 of 49 patients with FCS and 99 of 105 patients with sHTG correctly. Optimal sensitivity for all available parameters (n = 17) was 91.8%, optimal specificity was 94.3%, and accuracy was 93.5%. Fasting low-density lipoprotein cholesterol (LDL-C) provided the highest individual predictability. However, a three-variable set of ultracentrifugally measured LDL-C, body mass index, and pancreatitis history differentiated the diseases with a near similar accuracy of 91.0%, and adding high-density lipoprotein cholesterol and very low-density lipoprotein cholesterol for a five-variable set provided a small incremental increase in accuracy (92.2%).ConclusionsIn the absence of genetic testing, hypertriglyceridemic patients with FCS and sHTG can be differentiated with a high degree of accuracy by analyzing readily obtainable clinical information.

Statins are effective in reducing cardiovascular events and are safe for almost all patients. Nevertheless, intolerance to statins is frequently faced in clinical practice. This is mostly due to muscular symptoms (myalgia with or without increase of plasma creatinine kinase) and/or elevation of hepatic aminotransferases, which overall constitutes approximately two-thirds of reported adverse events during statin therapy. These side effects raise concerns in patients as well as in doctors and are likely to reduce patients' adherence and, as a consequence, the cardiovascular benefit. Therefore, it is mandatory that clinicians improve their knowledge on the clinical aspects of muscular and hepatic side effects of statin therapy as well as their ability to manage patients with statin intolerance. Besides briefly examining the clinical aspects and the mechanisms that are proposed to be responsible for the most common statin-associated side effects, the main purpose of this article is to review the available approaches to manage statin-intolerant patients. The first step is to determine whether the adverse events are indeed related to statin therapy. If so, lowering the dosage or changing statin, alternate dosing options, or the use of nonstatin compounds may be practical strategies. The cholesterol-lowering potency as well as the usefulness of these different approaches in treating statin-intolerant patients will be examined based on currently available data. However, the cardiovascular benefit of these strategies has not been well established, so their use has to be guided by a careful clinical assessment of each patient.