Epicardial fat and liver stiffness by ARFI elastography in people living with Human Immunodeficiency Virus type 1 (HIV-1) infection without liver disease.

OBJECTIVE: To evaluate the association between increased epicardial fat thickness (EFT) and liver stiffness measurement (LSM), as assessed by elastography in people living with Human Immunodeficiency Virus type 1 (HIV-1) infection (PWH). METHODS: 91 PWH on effective antiretroviral treatment (ART) were enrolled. EFT was measured by transthoracic echocardiography. Liver steatosis was evaluated by ultrasound Hamaguchi criteria and LSM by elastography with Acoustic Radiation Force Impulse (ARFI) Tecnique. LSM ≥8 Kpa was suggestive of clinically relevant fibrosis. RESULTS: Mean age was 54.3 years and 27.5% were women. EFT correlated with HIV-1 infection duration (rS 0.252, p = 0.016), age at study entry (rS 0.527, p < 0.001), BMI (rS 0.363, p < 0.001), waist circumference (rS 0.549, p < 0.001), HDL (rS -0.391, p < 0.001), triglycerides (rS 0.375, p < 0.001), Hamaguchi score (rS 0.279, p = 0.007), right lobe of the liver (rS 0.259, p = 0.014), Left ventricular mass/Body surface area (rS 0.220, p = 0.036).A LSM ≥8 Kpa was found in 20.9% of PWH, more commonly in those with EFT above the median >5.6 mm (30.4% vs 11.1%, p = 0.038). LSM significantly correlated with EFT (rS 0.274, p = 0.009), CD4+ cells (rS -0.320, p = 0.003) and nadir of CD4+ cells (rS -0.292, p = 0.007).In a subgroup (n = 53), an HOMA-IR index >2.33 identified increased EFT, (AUC 0.73, 95%CI 0.59-0.84, p = 0.001) while an HOMA-IR >3.27 predicted increased LSM (AUC 0.76, 95%CI 0.62-0.87, p = 0.005). CONCLUSIONS: PWH with increased EFT have worse metabolic profile and a high proportion of clinically relevant fibrosis at ARFI elastography, despite normal liver function tests. The HOMA-IR index might be used to identify PWH with increased EFT and liver fibrosis.

Impact of Sodium Glucose Cotransporter 2 Inhibitors (SGLT2i) Therapy on Dementia and Cognitive Decline.

Dementia is an age-related syndrome characterized by the progressive deterioration of cognition and capacity for independent living. Diabetes is often associated with cognitive decline and shares similar pathophysiological mechanisms with dementia, such as systemic inflammation, oxidative stress, insulin resistance, and advanced glycation end-products formation. Therefore, adequate diabetes management may reduce the risk of cognitive decline, especially in patients with other comorbidities and risk factors. The sodium glucose cotransporter inhibitors (SGLT2i) regulate renal glucose reabsorption by blocking the SGLT2 cotransporters located in the proximal tubules, causing glycosuria and intraglomerular pressure reduction. Their use helps to lower blood pressure by modifying sodium and water homeostasis; these drugs are also commonly used in the treatment of heart failure and chronic kidney disease, while recently, a potential neuroprotective role in the central nervous system has been suggested. The aim of our scoping review is to analyze current evidence about the potential neuroprotective effects of SGLT2i in adult patients. We performed a scoping literature review to evaluate the effect of SGLT2i on dementia, mild cognitive impairment (MCI) and Alzheimer's disease incidence and progression. The screening process was performed through different searches on PubMed and EMBASE, evaluating original works published up to January 2024. In conclusion, the use of SGLT2i could be associated with a neuroprotective effect in patients with diabetes, reducing the incidence or the progression of MCI and dementia. Further prospective studies are needed to validate this hypothesis and to evaluate the effectiveness of this class of drugs in normal glycemic profile patients.

Lipid-based insulin-resistance markers predict cardiovascular events in metabolic dysfunction associated steatotic liver disease.

BACKGROUND: Insulin resistance (IR) is the cornerstone of Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD), pathophysiologically being the key link between MASLD, metabolic disorders, and cardiovascular (CV) diseases. There are no prospective studies comparing the predictive values of different markers of insulin resistance (IR) in identifying the presence of MASLD and the associated risk of cardiovascular events (CVEs). METHODS: Post hoc analysis of the prospective Plinio Study, involving dysmetabolic patients evaluated for the presence of MASLD. The IR markers considered were Homeostatic Model Assessment for IR (HOMA-IR), Triglycerides-Glycemia (TyG) index, Triglycerides to High-Density Lipoprotein Cholesterol ratio (TG/HDL-C), Lipid Accumulation Product (LAP) and Visceral Adiposity Index (VAI). Receiver operative characteristic (ROC) analyses were performed to find the optimal cut-offs of each IR marker for detecting MASLD and predicting CVEs in MASLD patients. Logistic and Cox multivariable regression analyses were performed, after dichotomizing the IR markers based on the optimal cut-offs, to assess the factors independently associated with MASLD and the risk of CVEs. RESULTS: The study included 772 patients (age 55.6 ± 12.1 years, 39.4% women), of whom 82.8% had MASLD. VAI (Area Under the Curve [AUC] 0.731), TyG Index (AUC 0.723), and TG/HDL-C ratio (AUC: 0.721) predicted MASLD but was greater with HOMA-IR (AUC: 0.792) and LAP (AUC: 0.787). After a median follow-up of 48.7 (25.4-75.8) months, 53 MASLD patients experienced CVEs (1.8%/year). TyG index (AUC: 0.630), LAP (AUC: 0.626), TG/HDL-C (AUC: 0.614), and VAI (AUC: 0.590) demonstrated comparable, modest predictive values in assessing the CVEs risk in MASLD patients. CONCLUSION: In dysmetabolic patients HOMA-IR and LAP showed the best accuracy in detecting MASLD. The possible use of lipid-based IR markers in stratifying the CV risk in patients with MASLD needs further validation in larger cohorts.

Clinical Approach in the Management of Paediatric Patients with Familial Hypercholesterolemia: A National Survey Conducted by the LIPIGEN Paediatric Group.

Detection and treatment of patients with familial hypercholesterolemia (FH) starting from childhood is fundamental to reduce morbidity and mortality. The activity of National realities such as the LIPIGEN (LIpid transPort disorders Italian GEnetic Network) Paediatric Group, founded in 2018, is a milestone in this context. The aim of this exploratory survey, conducted in October 2021 among Italian lipid clinics included in the LIPIGEN Paediatric Group, was to investigate the current clinical approach in the management and treatment of paediatric patients with suspected FH. A digital questionnaire composed of 20 questions investigating nutritional treatment and nutraceutical and pharmacological therapy for children and adolescents with FH was proposed to the principal investigators of 30 LIPIGEN centres. Twenty-four centres responded to the section referring to children aged < 10 years and 30 to that referring to adolescents. Overall, 66.7% of children and 73.3% of adolescents were given lipid-lowering nutritional treatment as the first intervention level for at least 3-4 months (29.2% and 23.3%) or 6-12 months (58.3% and 53.3%). Nutraceuticals were considered in 41.7% (regarding children) and 50.0% (regarding adolescents) of the centres as a supplementary approach to diet. Lipid-lowering drug therapy initiation was mainly recommended (91.7% and 80.0%). In 83.3% of children and 96.7% of adolescents, statins were the most frequently prescribed drug. We highlighted several differences in the treatment of paediatric patients with suspected FH among Italian centres; however, the overall approach is in line with the European Atherosclerosis Society (EAS) recommendations for FH children and adolescents. We consider this survey as a starting point to reinforce collaboration between LIPIGEN centres and to elaborate in the near future a consensus document on the management of paediatric patients with suspected FH so as to improve and uniform detection, management, and treatment of these patients in our country.

Challenges in Improving Adherence to Diet and Drug Treatment in Hypercholesterolemia Patients.

Poor adherence to chronic disease treatment may seriously compromise the effectiveness of therapy, characterizing itself as a critical element for the population's health, both from the point of view of quality of life and health economics. The causes of low adherence are many and can depend on the patient, the physician and the healthcare system. Low adherence to dietary recommendations and lipid-lowering drug therapy for hypercholesterolemia is a widespread phenomenon that may strongly limit the great advantages of serum lipid reduction strategies in primary and secondary cardiovascular prevention. Many patients discontinue treatment, and adherence decreases with time. Increasing therapeutic adherence can have a much greater impact on the health of the population than any other therapeutic advance. There are numerous strategies to increase therapy adherence according to behavior change theories. They concern the doctor and the patient. Some must be implemented at the time of prescription, others later during the follow-up. The active role of the patient in the therapeutic decision and the shared definition of LDL cholesterol targets are of paramount importance. The aim of this narrative review is to summarize evidence on current levels of adherence to lipid-lowering strategies, the causes of the lack of adequate adherence and possible physician-applicable strategies to improve it.

Diet and metabolic syndrome: a narrative review.

Metabolic syndrome (MetS) is a highly prevalent condition defined by the presence of at least three out of five risk factors including central obesity, increased fasting glucose, high blood pressure, and dyslipidaemia. Metabolic syndrome is associated with a 2-fold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality. Excess energy intake and Western dietary pattern may influence the development of metabolic syndrome. By contrast, both Mediterranean diet (Med-diet) and Dietary Approaches to Stop Hypertension (DASH) diet, with or without calorie restriction, have positive effects. For the prevention and management of MetS, it is recommended to increase the daily intake of fiber-rich and low-glycaemic-index foods and the consumption of fish and dairy products, especially yogurt and nuts. Moreover, it is advisable to consume a large variety of unprocessed cereals, legumes, and fruit. Finally, it is suggested to replace saturated fatty acids with monounsaturated and polyunsaturated fatty acids and to limit the consumption of free sugars to less than 10% of the total energy intake. The aim of this narrative review is to analyze current evidence on the different dietary patterns and nutrients that may affect prevention and treatment of MetS and to discuss the underlying pathophysiological mechanisms.

The Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors Reduce Platelet Activation and Thrombus Formation by Lowering NOX2-Related Oxidative Stress: A Pilot Study.

Sodium−glucose co-transporter-2 inhibitors or gliflozins, the newest anti-hyperglycemic class, induce cardioprotective benefits in patients with type 2 diabetes (T2D). As platelet activation and oxidative stress play a key role in atherothrombotic-related complications, we hypothesized that gliflozins might modulate oxidative stress, platelet activation and thrombus formation. We performed an interventional open-label single-arm before-after study in 32 T2D patients on top of their ongoing metformin therapy. The population was divided into two groups: treatment with GLP-1 receptor agonists (GLP-1RA, Group A) and gliflozins (Group B). Oxidative stress, platelet activation and thrombus growth were assessed before and after 15 days of treatment. Compared to the baseline, gliflozins treatment significantly decreased sNOX2-dp (−45.2%, p < 0.001), H2O2 production (−53.4%, p < 0.001), TxB2 (−33.1%, p < 0.001), sP-selectin (−49.3%, p < 0.001) and sCD40L levels (−62.3%, p < 0.001) as well as thrombus formation (−32%, p < 0.001), whereas it potentiated anti-oxidant power (HBA, +30.8%, p < 0.001). Moreover, a significant difference in oxidative stress, platelet activation and thrombus formation across groups A and B was found. In addition, an in vitro study on stimulated platelets treated with gliflozins (10−30 µM) showed a reduction in oxidative stress, platelet activation and thrombus growth. Our results showed that gliflozins have antiplatelet and antithrombic activity related to an NOX2 down-regulation, suggesting a new mechanism responsible for cardiovascular protection.

Heterogeneity of non-alcoholic fatty liver disease (NAFLD): Implication for cardiovascular risk stratification.

NAFLD is currently considered the most common liver disease worldwide and mounting data support its strong link with atherosclerotic cardiovascular disease (ASCVD). This association is important as cardiovascular disease (CVD) is generally recognized as the leading cause of death in individuals with NAFLD. However, NAFLD represents a heterogeneous condition showing a wide spectrum of clinical and pathophysiological sub-phenotypes with different adverse outcomes ranging from ASCVD to liver damage progression. The contribution to NAFLD pathogenesis of different environmental, metabolic, and genetic factors underlies this heterogeneity. The more frequent phenotype of NAFLD patients is associated with metabolic dysfunctions such as obesity and insulin-resistant syndrome and this has been recently named as Metabolic Associated Fatty Liver disease (MAFLD). However, NAFLD is encountered also in subjects without insulin resistance and metabolic alterations and in whom genetic factors play a major role. It has been suggested that these individuals are at risk of liver disease progression but not of cardiovascular complications. Separating metabolic from genetic factors could be useful in disentangling the intricate relationship between NAFLD and atherosclerosis. In the present review, we aim to address the epidemic of NAFLD, its epidemiologically association with ASCVD complications and the overall mechanisms involved in the pathophysiology of atherosclerotic vascular damage in NAFLD patients. Finally, we will revise the potential role of genetics in identifying disease subtyping and predicting individualised CVD risk.

Extra Virgin Olive Oil Reduces Gut Permeability and Metabolic Endotoxemia in Diabetic Patients.

BACKGROUND: Extra virgin olive oil (EVOO) improves post-prandial glycemia, but the underlying mechanism has not been fully elucidated. We tested the hypothesis that EVOO improves post-prandial glycemia by reducing gut permeability-derived low-grade endotoxemia. METHODS: Serum levels of lipopolysaccharides (LPS), zonulin, a marker of gut permeability, glucose, insulin and glucagon-like peptide 1 (GLP1) were measured in 20 patients with impaired fasting glucose (IFG) and 20 healthy subjects (HS) matched for sex and age. The same variables were measured in IFG patients (n = 20) and HS (n = 20) before and after a Mediterranean diet with 10 g EVOO added or not (n = 20) or in IFG patients (n = 20) before and after intake of 40 g chocolate with EVOO added or not. RESULTS: Compared to HS, IFG had higher levels of LPS and zonulin. In HS, meal intake was associated with a significant increase of blood glucose, insulin, and GLP1 with no changes of blood LPS and zonulin. Two hours after a meal intake containing EVOO, IFG patients showed a less significant increase of blood glucose, a more marked increase of blood insulin and GLP1 and a significant reduction of LPS and zonulin compared to IFG patients not given EVOO. Correlation analysis showed that LPS directly correlated with blood glucose and zonulin and inversely with blood insulin. Similar findings were detected in IFG patients given a chocolate added or without EVOO. CONCLUSION: Addition of EVOO to a Mediterranean diet or chocolate improves gut permeability and low-grade endotoxemia.

Added Fructose in Non-Alcoholic Fatty Liver Disease and in Metabolic Syndrome: A Narrative Review.

Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease and it is considered the hepatic manifestation of metabolic syndrome (MetS). Diet represents the key element in NAFLD and MetS treatment, but some nutrients could play a role in their pathophysiology. Among these, fructose added to foods via high fructose corn syrup (HFCS) and sucrose might participate in NAFLD and MetS onset and progression. Fructose induces de novo lipogenesis (DNL), endoplasmic reticulum stress and liver inflammation, promoting insulin resistance and dyslipidemia. Fructose also reduces fatty acids oxidation through the overproduction of malonyl CoA, favoring steatosis. Furthermore, recent studies suggest changes in intestinal permeability associated with fructose consumption that contribute to the risk of NAFLD and MetS. Finally, alterations in the hunger-satiety mechanism and in the synthesis of uric acid link the fructose intake to weight gain and hypertension, respectively. However, further studies are needed to better evaluate the causal relationship between fructose and metabolic diseases and to develop new therapeutic and preventive strategies against NAFLD and MetS.

High Compliance to Mediterranean Diet Associates with Lower Platelet Activation and Liver Collagen Deposition in Patients with Nonalcoholic Fatty Liver Disease.

The Mediterranean diet (Med-Diet) is considered the most effective dietary patterns to obtain weight loss in NAFLD patients. Previous evidence suggested that Med-Diet adherence could reduce cardiovascular risk and have a beneficial effect on NAFLD severity. Aim of the study was to investigate the relationship between Med-Diet adherence, platelet activation (PA), and liver collagen deposition. The study was performed in 655 consecutive NAFLD outpatients from the PLINIO study, a prospective observational cohort study aimed to identify non-conventional predictors of liver fibrosis progression in NAFLD. PA was measured by the serum thromboxane B2 (TxB2), and liver collagen deposition by N-terminal propeptide of type III collagen (Pro-C3). Adherence to the Med-diet was investigated by a short nine-item validated dietary questionnaire. Patients with high Med-Diet adherence were older and had less metabolic syndrome and lower serum triglycerides, GGT, TxB2, and Pro-C3. At multivariate regression analyses, in the linear model, the Med-Diet score negatively correlated with both TxB2 (Beta = −0.106; p = 0.009) and Pro-C3 (Beta = −0.121; p = 0.002) and in the logistic model high adherence inversely correlated with higher TxB2 tertiles (II tertile: OR = 0.576, p = 0.044; III tertile: OR = 0.556, p = 0.026) and Pro-C3 tertile (III tertile: OR = 0.488, p = 0.013). Low consumption of red meat inversely correlated with higher TxB2 tertile (II tertile: OR = 0.448, p < 0.001, III tertile: OR = 0.567, p = 0.004). In conclusion, NAFLD patients with high adherence to the Med-Diet show lower PA and liver collagen deposition, suggesting a protective role of the Med-Diet against NAFLD progression and cardiovascular risk. In addition, the correlation between TxB2 and Pro-C3 suggests a link between NAFLD severity and cardiovascular risk.

Metabolic Syndrome but Not Fatty Liver-Associated Genetic Variants Correlates with Glomerular Renal Function Decline in Patients with Non-Alcoholic Fatty Liver Disease.

The association between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) has been extensively demonstrated. Recent studies have focused attention on the role of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism in the association between NAFLD and CKD in non-metabolic adults and children, but the genetic impact on NAFLD-CKD association is still a matter of debate. The aim of the study was to investigate the impact of PNPLA3, transmembrane 6 superfamily member 2 (TM6SF2), membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and glucokinase regulatory protein (GCKR) gene variants rather than metabolic syndrome features on renal function in a large population of NAFLD patients. The present study is a post hoc analysis of the Plinio Study (ClinicalTrials.gov: NCT04036357). PNPLA3, TM6SF2, MBOAT7 and GCKR genes were analyzed by using real-time PCR with TaqMan probes. Glomerular filtration rate (GFR) was estimated with CKD-EPI. We analyzed 538 NAFLD; 47.2% had GFR < 90 mL/min/1.73 m2 while 5.9% had GFR < 60 mL/min/1.73 m2. The distribution of genotypes was superimposable according to GFR cut-offs. Results from the multivariable regression model did not show any correlation between genotypes and renal function. Conversely, metabolic syndrome was highly associated with GFR < 90 mL/min/1.73 m2 (odds ratio (OR): 1.58 [1.10−2.28]) and arterial hypertension with GFR < 60 mL/min/1.73 m2 (OR: 1.50 [1.05−2.14]). In conclusion, the association between NAFLD and CKD might be related to the shared metabolic risk factors rather than the genetic NAFLD background.

Statin liver safety in non-alcoholic fatty liver disease: A systematic review and metanalysis.

AIMS: Statin liver safety in non-alcoholic fatty liver disease (NAFLD) patients is not well defined. We analysed differences in liver function tests, including alanine transaminase aminotransferase (ALT), aspartate transaminase (AST) and gamma-glutamyl transpeptidase (GGT) in NAFLD patients treated or not treated with statins. METHODS: We performed a systematic review of MEDLINE via PubMed and EMBASE databases and metanalysis of clinical studies investigating levels of ALT, AST and GGT in NAFLD according to statin treatment. Mean difference (MD) and percentage MD were calculated between the two groups. RESULTS: We included 22 studies with 2345 NAFLD patients. Overall, 16 were before-after interventional, five were cross-sectional and one was combined cross-sectional/interventional study. In all interventional studies, except one, patients had raised ALT, AST and GGT at baseline. Interventional studies showed reduced ALT values with an MD reduction of -27.2 U/L (95% CI -35.25/-19.15) and a percentage MD reduction of -35.41% (95% CI -44.78/-26.04). Also, AST values were reduced after statin treatment in interventional studies with an MD of -18.82 U/L (95% CI -25.63/-12.02) (percentage -31.78%, 95% CI -41.45/-22.11). Similarly, GGT levels were reduced after statin treatment with an MD of -19.93 U/L (95% CI -27.10/-12.77) (percentage -25.57%, 95% CI -35.18/-15.97). Cross-sectional studies showed no difference in AST and GGT values between patients treated with and without statins. CONCLUSION: In interventional studies, ALT, AST and GGT were reduced after statin treatment with a percentage mean difference of -35.41%, -31.78% and -25.57%, respectively, while observational studies showed a null effect, suggesting liver safety of statins in NAFLD patients.

Prevention and Management of Type II Diabetes Chronic Complications: The Role of Polyphenols (Mini-Review).

The numerous complications of diabetes may be at least in part generated by the oxidative stress associated with the constant state of hyperglycemia. Polyphenols are plant-based secondary metabolites that have high potentials in the prevention and treatment of some diseases, in particular those that involve oxidative stress, such as complications of diabetes. The purpose of this narrative review is to show the main evidence regarding the role of polyphenols in treating and preventing these complications. For the bibliographic research, the papers published up to March 15, 2021, were considered, and the search terms included words relating to polyphenols, their classes and some more known compounds in association with the complications of diabetes. There are numerous studies showing how polyphenols are active against endothelial damage induced by diabetes, oxidative stress and hyperinflammatory states that are at the origin of the complications of diabetes. Compounds such as flavonoids, but also anthocyanins, stilbenes or lignans slow the progression of kidney damage, prevent ischemic events and diabetic nephropathy. Many of these studies are preclinical, in cellular or animal models. The role of polyphenols in the prevention and treatment of diabetes complications is undoubtedly promising. However, more clinical trials need to be implemented to understand the real effectiveness of these compounds.

Oxidative stress mediated platelet activation in patients with congenital analbuminemia: Effect of albumin infusion.

BACKGROUND AND AIMS: Congenital analbuminemia is a rare autosomal recessive inherited disorder characterized by strongly decreased concentration, or complete absence, of serum albumin (SA). Several lines of evidence indicate that SA has anti-thrombotic effect. In vivo platelet function and the role of oxidative stress (OS) in platelet aggregation promotion have never been studied in analbuminaemic patients. PATIENTS AND METHODS: We report two cases of congenital analbuminemia in a 38-year-old male and in a 67-year-old woman. We analyzed platelet activation (PA) and OS at baseline and 2 h after 40 g human albumin infusion. PA was evaluated as platelet aggregation, sCD40L and surface αIIbß3 integrin and P-selectin expression. OS was evaluated measuring serum sNOX2dp, and 8-iso-PGF2α. FINDINGS: Analbuminemic patients displayed higher platelet aggregation, markers of PA and of OS. Albumin infusion reduced platelet activation by reducing oxidative stress.

Nonalcoholic Fatty Liver Disease and the Kidney: A Review.

Nonalcoholic fatty liver disease (NAFLD) is associated with several extrahepatic manifestations such as cardiovascular disease and sleep apnea. Furthermore, NAFLD is reported to be associated with an increased risk of incident chronic kidney disease (CKD). Inflammation and oxidative stress are suggested to be the key factors involved in the inflammatory mechanisms and pathways linking NAFLD to CKD and are responsible for both the pathogenesis and the progression of CKD in NAFLD patients. This review aims to provide a more comprehensive overview of the association between CKD and NAFLD, also considering the effect of increasing severity of NAFLD. A PubMed search was conducted using the terms "non-alcoholic fatty liver disease AND kidney". In total, 537 articles were retrieved in the last five years and 12 articles were included in the qualitative analysis. Our results showed that CKD developed more frequently in NAFLD patients compared to those without NAFLD. This association persisted after adjustment for traditional risk factors and according to the severity of NAFLD. Therefore, patients with NAFLD should be considered at high risk of CKD. Intensive multidisciplinary surveillance over time is needed, where hepatologists and nephrologists must act together for better and earlier treatment of NAFLD patients.

Open Issues in the Transition from NAFLD to MAFLD: The Experience of the Plinio Study.

Metabolic associated fatty liver diseases (MAFLD) definition was proposed to identify fatty liver condition associated to metabolic disorders and to replace non-alcoholic fatty liver disease (NAFLD). We aimed to explore the effect of the application of the new MAFLD criteria on a pre-existing cohort of NAFLD patients. The consequences of the reclassification were investigated by applying the MAFLD criteria to a prospective cohort (The Plinio Study) of dysmetabolic patients examined for the presence of NAFLD. In the Plinio cohort, 795 patients had NAFLD and 767 of them (96.5%) were reclassified as MAFLD patients. Out of these, 94.9% had overweight/obesity or diabetes, while the remaining were lean and had metabolic dysregulation defined by the presence of at least two metabolic risk abnormalities. By contrast, 3.5% of the NAFLD patients were reclassified as no-MAFLD due to the absence of overweight/obesity, diabetes, or metabolic risk abnormalities. The only significant difference between the NAFLD and MAFLD groups was the higher prevalence of subjects with BMI ≥ 25 kg/m2 in the latter (88.6% vs. 92%; p = 0.018). In the cohort, 68 subjects were defined as "lean NAFLD". Of these, 40 were reclassified as MAFLD and 28 as no-MAFLD. In conclusion, when applying MAFLD criteria to the Plinio cohort, there is a substantial overlap between NAFLD and MAFLD diagnosis. However, some specific subgroups of patients, such as those currently defined as lean NAFLD, were excluded by the new MAFLD definition.

Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors Reduce Platelet Activation Modulating ox-LDL Pathways.

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.