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Probiotics, gut microbiome, and cardiovascular diseases: An update.
Dosh, L, Ghazi, M, Haddad, K, El Masri, J, Hawi, J, Leone, A, Basset, C, Geagea, AG, Jurjus, R, Jurjus, A
Transplant immunology. 2024;:102000
Abstract
Cardiovascular diseases (CVD) are one of the most challenging diseases and many factors have been demonstrated to affect their pathogenesis. One of the major factors that affect CVDs, especially atherosclerosis, is the gut microbiota (GM). Genetics play a key role in linking CVDs with GM, in addition to some environmental factors which can be either beneficial or harmful. The interplay between GM and CVDs is complex due to the numerous mechanisms through which microbial components and their metabolites can influence CVDs. Within this interplay, the immune system plays a major role, mainly based on the immunomodulatory effects of microbial dysbiosis and its resulting metabolites. The resulting modulation of chronic inflammatory processes was found to reduce the severity of CVDs and to maintain cardiovascular health. To better understand the specific roles of GM-related metabolites in this interplay, this review presents an updated perspective on gut metabolites related effects on the cardiovascular system, highlighting the possible benefits of probiotics in therapeutic strategies.
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Lipid-lowering therapy and risk-based LDL-C goal attainment in Belgium: DA VINCI observational study.
van de Borne, P, Peeters, A, Janssens, L, Leone, A, Lemmens, R, Verhaegen, A, De Meulemeester, M, Balthazar, Y, Heijmans, S, Calozet, Y, et al
Acta cardiologica. 2024;(1):20-29
Abstract
BACKGROUND Cardiovascular disease (CVD) is one of the leading causes of death in Belgium. Current strategies for the prevention and management of CVD focus on reducing low-density lipoprotein cholesterol (LDL-C) levels. This analysis assessed whether LDL-C goals, recommended by the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines, were being achieved in a Belgian study population. METHODS The cross-sectional, observational, DA VINCI study enrolled patients prescribed lipid-lowering therapy (LLT) between 21 June 2017 and 20 November 2018. Data for patients from Belgium were extracted for this country-specific analysis. Primary endpoint was the proportion of patients who achieved 2016 ESC/EAS risk-based LDL-C goals; attainment of 2019 risk-based LDL-C goals was evaluated post hoc. RESULTS Of 497 enrolled patients, 41% were female and mean age was 68 years. Among subjects with an LDL-C measurement on stabilised LLT, moderate-intensity statin monotherapy was the most prescribed LLT regimen (59%). Overall, 63% of patients achieved their risk-based LDL-C goals according to the 2016 ESC/EAS guidelines. Among patients with established ASCVD, risk-based LDL-C goal attainment was higher in patients with peripheral arterial disease (53%) than patients with coronary (37%) and cerebrovascular disease (42%). According to the updated 2019 ESC/EAS guidelines, less than half (41%) of patients achieved their risk-based LDL-C goal. The proportion of primary and secondary prevention patients who achieved 2019 risk-based LDL-C goals was 59% and 18%, respectively. CONCLUSION These findings reveal a large gap between the LDL-C goals advocated by the ESC/EAS and the levels achieved in routine clinical practice in Belgium.
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Acute Insulin Secretory Effects of a Classic Ketogenic Meal in Healthy Subjects: A Randomized Cross-Over Study.
Battezzati, A, Foppiani, A, Leone, A, De Amicis, R, Spadafranca, A, Mari, A, Bertoli, S
Nutrients. 2023;15(5)
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The ketogenic diet is a dietary regimen providing very low carbohydrate, high fat, and modest protein. Low carbohydrate and ketogenic diets have become increasingly popular in the treatment of metabolic syndrome, obesity, and type 2 diabetes. The main aim of this study was to measure the insulin secretory response to a typical ketogenic meal providing ~40% of individual energy needs and to compare it to the response to an isocaloric Mediterranean meal in healthy subjects. This study is a randomised cross-over study which enrolled twelve healthy subjects (50/50 female/male), adults with an age range of 19–31 years, and with a normal weight. The participants received mixed standardised meals of different compositions on two different days spaced apart by a washout period of 7 days. Each subject consumed two meals of identical energy content but differing in macronutrient composition. Results show that a Mediterranean meal accounting for 40% of daily dietary intake, requires, for its metabolism, the production of 7.8 ± 0.8 times the amount of insulin compared to fasting values, temporarily spiking the insulin secretory rate to 8.9 ± 1.2-fold the basal values. Authors conclude that a ketogenic meal is disposed of with only a minimal insulin secretory response compared to a Mediterranean meal.
Abstract
The classic ketogenic diet (KD) is a high-fat, low-carbohydrate diet that mimics a starvation state with sufficient caloric intake to sustain growth and development. KD is an established treatment for several diseases, and it is currently evaluated in the management of insulin-resistant states, although insulin secretion after a classic ketogenic meal has never been investigated. We measured the insulin secretion to a ketogenic meal in 12 healthy subjects (50% females, age range 19-31 years, BMI range 19.7-24.7 kg/m2) after cross-over administrations of a Mediterranean meal and a ketogenic meal both satisfying ~40% of an individual's total energy requirement, in random order and separated by a 7-day washout period. Venous blood was sampled at baseline and at 10, 20, 30, 45, 60, 90, 120, and 180 min to measure glucose, insulin, and C-peptide concentrations. Insulin secretion was calculated from C-peptide deconvolution and normalized to the estimated body surface area. Glucose, insulin concentrations, and insulin secretory rate were markedly reduced after the ketogenic meal with respect to the Mediterranean meal: glucose AUC in the first OGTT hour -643 mg × dL-1 × min-1, 95% CI -1134, -152, p = 0.015; total insulin concentration -44,943 pmol/L, 95% CI -59,181, -3706, p < 0.001; peak rate of insulin secretion -535 pmol × min-1 × m-2, 95% CI -763, -308, p < 0.001. We have shown that a ketogenic meal is disposed of with only a minimal insulin secretory response compared to a Mediterranean meal. This finding may be of interest to patients with insulin resistance and or insulin secretory defects.
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Safety and efficacy of bempedoic acid: a systematic review and meta-analysis of randomised controlled trials.
De Filippo, O, D'Ascenzo, F, Iannaccone, M, Bertaina, M, Leone, A, Borzillo, I, Ravetti, E, Solano, A, Pagliassotto, I, Nebiolo, M, et al
Cardiovascular diabetology. 2023;(1):324
Abstract
BACKGROUND AND AIMS Bempedoic Acid (BA) is a novel Lipid-Lowering Therapy (LLT). We performed a systematic review and meta-analysis to assess the efficacy and safety of BA in patients with hypercholesterolemia. METHODS PubMed, Scopus, and Cochrane library databases were searched for randomised controlled trials evaluating the efficacy and/or safety of BA compared with placebo. Trials investigating dosages other than 180 mg/die were excluded. Major adverse cardiovascular events (MACE) were the primary efficacy endpoint. LDL-cholesterol reduction was the primary laboratory endpoint. Pre-specified safety endpoints included muscle-related adverse events, new-onset diabetes, and gout. The protocol was registered on PROSPERO (temporary ID:399,867). RESULTS Study search identified 275 deduplicated results. 11 studies, encompassing 18,315 patients (9854 on BA vs 8461 on placebo/no treatment) were included. BA was associated with a reduced risk of MACE (OR 0.86, 95% CI 0.79-0.95), myocardial infarction (OR 0.76, 95% CI 0.64-0.88) and unstable angina (OR 0.69, 95% CI 0.54-0.88) compared to control, over a median follow up of 87 (15-162) weeks. BA was associated with a reduction of LDL-Cholesterol (mean difference [MD]-22.42,95% CI - 24.02% to - 20.82%), total cholesterol (- 16.50%,95% - 19.21% to - 13.79%), Apo-B lipoprotein (- 19.55%, - 22.68% to - 16.42%) and high-sensitivity CRP (- 27.83%, - 31.71% to - 23.96%) at 12 weeks. BA was associated with a higher risk of gout (OR 1.55, 95% CI 1.27-1.90) as compared with placebo. Efficacy on laboratory endpoints was confirmed, with a variable extent, across patients on statin or ezetimibe background therapy. CONCLUSIONS The improved cholesterol control achieved with BA translates into a reduced risk of MACE, including myocardial infarction and coronary revascularisation. The drug has a satisfactory safety profile except for an increased risk of gout.
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Innovative Device-Based Strategies for Managing Acute Decompensated Heart Failure.
Bertolone, DT, Paolisso, P, Gallinoro, E, Belmonte, M, Bermpeis, K, De Colle, C, Esposito, G, Caglioni, S, Fabbricatore, D, Leone, A, et al
Current problems in cardiology. 2023;(12):102023
Abstract
Acute decompensated heart failure (ADHF) is a major cause of hospitalizations in older adults, leading to high mortality, morbidity, and healthcare costs. To address the persistent poor outcomes in ADHF, novel device-based approaches targeting specific pathophysiological mechanisms are urgently needed. The recently introduced DRI2P2S classification categorizes these innovative therapies based on their mechanisms. Devices include dilators (increasing venous capacitance), removers (directly removing sodium and water), inotropes (enhancing left ventricular contractility), interstitials (accelerating lymph removal), pushers (increasing renal arterial pressure), pullers (decreasing renal venous pressure), and selective drippers (selective intrarenal drug infusion). Some are tailored for chronic HF, while others focus on the acute setting. Most devices are in early development, necessitating further research to understand mechanisms, assess clinical effectiveness, and ensure safety before routine use in ADHF management. Exploring these innovative device-based strategies may lead to improved outcomes and revolutionize HF treatment in the future.
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Longitudinal Anthropometry and Body Composition in Children With SARS-CoV-2-Associated Multisystem Inflammatory Syndrome.
Di Profio, E, Leone, A, Vizzuso, S, Fiore, G, Pascuzzi, MC, Agostinelli, M, Dilillo, D, Mannarino, S, Fiori, L, D'Auria, E, et al
Journal of pediatric gastroenterology and nutrition. 2023;(4):505-511
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Abstract
OBJECTIVES Acute coronavirus disease 2019 infection has been shown to negatively affect body composition among adult and malnourished or obesity children. Our aim is to longitudinally evaluate body composition in children affected by the Multisystem Inflammatory Syndrome (MIS-C). METHODS In this cohort study, we recruited 40 patients affected by MIS-C, aged 2-18 years old, who were admitted in our clinic between December 2020 and February 2021. Physical examination for each participant included weight, height, body mass index (BMI) z score, circumferences, and skinfolds assessment. The same measurements were repeated during outpatient follow-up at 10 (T2), 30 (T3), 90 (T4), and 180 (T5) days after hospital discharge. Fat mass and fat free mass were calculated according to skinfolds predictive equations for children and adolescents. A control group was randomly selected among patients attending a pediatric nutritional outpatient clinic. RESULTS BMI z score significantly decrease between preadmission and hospital discharge. Similarly, arm circumference z score, arm muscular area z score, and arm fat area z score significantly decreased, during hospital stay. Fat mass index (FMI) significantly increased over time, peaking at T3. Fat free mass index decreased during hospitalization. CONCLUSIONS To the best of our knowledge, this is the first study to assess body composition in a numerically large pediatric MIS-C population from acute infection to 6 months after triggering event. FMI and anthropometric parameters linked to fat deposits were significantly higher 6 months after acute event. Thus, limiting physical activity and having sedentary lifestyle may lead to an accumulation of adipose tissue even in healthy children who experienced MIS-C and long hospitalization.
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Browning of Adipocytes: A Potential Therapeutic Approach to Obesity.
Schirinzi, V, Poli, C, Berteotti, C, Leone, A
Nutrients. 2023;(9)
Abstract
The increasing prevalence of overweight and obesity suggests that current strategies based on diet, exercise, and pharmacological knowledge are not sufficient to tackle this epidemic. Obesity results from a high caloric intake and energy storage, the latter by white adipose tissue (WAT), and when neither are counterbalanced by an equally high energy expenditure. As a matter of fact, current research is focused on developing new strategies to increase energy expenditure. Against this background, brown adipose tissue (BAT), whose importance has recently been re-evaluated via the use of modern positron emission techniques (PET), is receiving a great deal of attention from research institutions worldwide, as its main function is to dissipate energy in the form of heat via a process called thermogenesis. A substantial reduction in BAT occurs during normal growth in humans and hence it is not easily exploitable. In recent years, scientific research has made great strides and investigated strategies that focus on expanding BAT and activating the existing BAT. The present review summarizes current knowledge about the various molecules that can be used to promote white-to-brown adipose tissue conversion and energy expenditure in order to assess the potential role of thermogenic nutraceuticals. This includes tools that could represent, in the future, a valid weapon against the obesity epidemic.
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Altered H3K4me3 profile at the TFAM promoter causes mitochondrial alterations in preadipocytes from first-degree relatives of type 2 diabetics.
Longo, M, Zatterale, F, Spinelli, R, Naderi, J, Parrillo, L, Florese, P, Nigro, C, Leone, A, Moccia, A, Desiderio, A, et al
Clinical epigenetics. 2023;(1):144
Abstract
BACKGROUND First-degree relatives of type 2 diabetics (FDR) exhibit a high risk of developing type 2 diabetes (T2D) and feature subcutaneous adipocyte hypertrophy, independent of obesity. In FDR, adipose cell abnormalities contribute to early insulin-resistance and are determined by adipocyte precursor cells (APCs) early senescence and impaired recruitment into the adipogenic pathway. Epigenetic mechanisms signal adipocyte differentiation, leading us to hypothesize that abnormal epigenetic modifications cause adipocyte dysfunction and enhance T2D risk. To test this hypothesis, we examined the genome-wide histone profile in APCs from the subcutaneous adipose tissue of healthy FDR. RESULTS Sequencing-data analysis revealed 2644 regions differentially enriched in lysine 4 tri-methylated H3-histone (H3K4me3) in FDR compared to controls (CTRL) with significant enrichment in mitochondrial-related genes. These included TFAM, which regulates mitochondrial DNA (mtDNA) content and stability. In FDR APCs, a significant reduction in H3K4me3 abundance at the TFAM promoter was accompanied by a reduction in TFAM mRNA and protein levels. FDR APCs also exhibited reduced mtDNA content and mitochondrial-genome transcription. In parallel, FDR APCs exhibited impaired differentiation and TFAM induction during adipogenesis. In CTRL APCs, TFAM-siRNA reduced mtDNA content, mitochondrial transcription and adipocyte differentiation in parallel with upregulation of the CDKN1A and ZMAT3 senescence genes. Furthermore, TFAM-siRNA significantly expanded hydrogen peroxide (H2O2)-induced senescence, while H2O2 did not affect TFAM expression. CONCLUSIONS Histone modifications regulate APCs ability to differentiate in mature cells, at least in part by modulating TFAM expression and affecting mitochondrial function. Reduced H3K4me3 enrichment at the TFAM promoter renders human APCs senescent and dysfunctional, increasing T2D risk.
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Ultra-Processed Food Consumption and Incidence of Obesity and Cardiometabolic Risk Factors in Adults: A Systematic Review of Prospective Studies.
Mambrini, SP, Menichetti, F, Ravella, S, Pellizzari, M, De Amicis, R, Foppiani, A, Battezzati, A, Bertoli, S, Leone, A
Nutrients. 2023;(11)
Abstract
Ultra-processed foods (UPF) are energy-dense, nutritionally unbalanced products, low in fiber but high in saturated fat, salt, and sugar. Recently, UPF consumption has increased likewise the incidence of obesity and cardiometabolic diseases. To highlight a possible relationship, we conducted a systematic review of prospective studies from PubMed and Web of Science investigating the association between UPF consumption and the incidence of obesity and cardiometabolic risk factors. Seventeen studies were selected. Eight evaluated the incidence of general and abdominal obesity, one the incidence of impaired fasting blood glucose, four the incidence of diabetes, two the incidence of dyslipidemia, and only one the incidence of metabolic syndrome. Studies' quality was assessed according to the Critical Appraisal Checklist for cohort studies proposed by the Joanna Briggs Institute. Substantial agreement emerged among the studies in defining UPF consumption as being associated with the incident risk of general and abdominal obesity. More limited was the evidence on cardiometabolic risk. Nevertheless, most studies reported that UPF consumption as being associated with an increased risk of hypertension, diabetes, and dyslipidemia. In conclusion, evidence supports the existence of a relationship between UPF consumption and the incidence of obesity and cardiometabolic risk. However, further longitudinal studies considering diet quality and changes over time are needed.
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Long-term follow-up of nutritional status in children with GLUT1 Deficiency Syndrome treated with classic ketogenic diet: a 5-year prospective study.
De Amicis, R, Leone, A, Pellizzari, M, Foppiani, A, Battezzati, A, Lessa, C, Tagliabue, A, Ferraris, C, De Giorgis, V, Olivotto, S, et al
Frontiers in nutrition. 2023;:1148960
Abstract
INTRODUCTION The classic ketogenic diet (cKD) is an isocaloric, high fat, low-carbohydrate diet that induces the production of ketone bodies. High consumption of dietary fatty acids, particularly long-chain saturated fatty acids, could impair nutritional status and increase cardiovascular risk. The purpose of this study was to evaluate the long-term effects of a 5-year cKD on body composition, resting energy expenditure, and biochemical parameters in children affected by Glucose Transporter 1 Deficiency Syndrome (GLUT1DS). METHODS This was a prospective, multicenter, 5-year longitudinal study of children with GLUT1DS treated with a cKD. The primary outcome was to assess the change in nutritional status compared with pre-intervention, considering anthropometric measurements, body composition, resting energy expenditure, and biochemical parameters such as glucose and lipid profiles, liver enzymes, uric acid, creatinine, and ketonemia. Assessments were conducted at pre-intervention and every 12 months of cKD interventions. RESULTS Ketone bodies increased significantly in children and adolescents, and remained stable at 5 years, depending on the diet. No significant differences were reported in anthropometric and body composition standards, as well as in resting energy expenditure and biochemical parameters. Bone mineral density increased significantly over time according to increasing age. Body fat percentage significantly and gradually decreased in line with the increase in body weight and the consequent growth in lean mass. As expected, we observed a negative trend in respiratory quotient, while fasting insulin and insulin resistance were found to decrease significantly after cKD initiation. CONCLUSION Long-term adherence to cKD showed a good safety profile on anthropometric measurements, body composition, resting energy expenditure, and biochemical parameters, and we found no evidence of potential adverse effects on the nutritional status of children and adolescents.