Metabolic dysfunction-associated steatotic liver disease (MASLD) is a potential independent risk factor for cardiovascular disease (CVD)-associated and all-cause mortalities as they share common risk factors. We investigated the association between cardiometabolic risk factors for MASLD and CVD-associated and all-cause mortality risks in middle-aged and older Korean adults.

We used data from the Korean Genome and Epidemiology Study, a population-based prospective cohort study. Five cardiometabolic risk factors were assessed. MASLD was defined as liver steatosis with a fatty liver index (FLI) ≥60 and at least one cardiometabolic risk factor. The non-MASLD group included individuals with a FLI <60 or FLI ≥60 without cardiometabolic risk factors. The primary outcomes were CVD-associated and all-cause mortalities. Cox proportional hazard models were used to evaluate the association between cardiometabolic risk factors for MASLD and mortalities, adjusting for covariates. Multivariable Cox regression analysis revealed that the MASLD group had increased CVD-associated and all-cause mortality risks compared to the non-MASLD group. The presence of three or more and one or more cardiometabolic risk factors significantly increased the CVD-associated and all-cause mortality rate, respectively. The combination of hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), and high glucose concentrations significantly increased both CVD-associated (hazard ratio [HR] 3.64; 95 % confidence interval [CI] 1.44-9.22; p = 0.006) and all-cause (HR 4.57; 95 % CI: 1.74-12.05; p = 0.002) mortality risks.

Cardiometabolic risk factors for MASLD are strongly associated with higher CVD-associated and all-cause mortality risks, highlighting the need to manage hypertriglyceridemia, low HDL-C, and high glucose concentrations.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is rising among reproductive-aged individuals and in pregnancy. MASLD in pregnancy does increase such risks as gestational diabetes, preeclampsia, and preterm birth. Although routine screening for MASLD has not been established in pregnancy, individuals with metabolic comorbidities, such as type 2 diabetes mellitus, should be evaluated by liver imaging and liver panel. Preconception counseling should address potential risks as well as need for optimized metabolic health before and during pregnancy. Fibrosis assessment should ideally be completed before pregnancy, to identify cases of cirrhosis that may warrant additional preconception management, such as variceal screening, as well as comanagement with maternal-fetal medicine specialists. In patients with MASLD, aspirin is advised at 12 weeks of gestational age to lower preeclampsia risk. In the absence of cirrhosis, no additional blood test monitoring is needed. In the general population, breastfeeding has beneficial effects on metabolic health in birthing parents and offspring and thus should be encouraged in the setting of MASLD, including access to enhanced lactation support. Research needs include evaluation of the long-term risks of MASLD in pregnancy on metabolic health in birthing parents and infants, as well as safety data for MASLD-directed therapies during pregnancy and lactation.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed nonalcoholic fatty-liver disease, is an important and rising health issue with a link with atherosclerotic cardiovascular (CV) disease (CVD), affecting ∼25-30 % of the adults in the general population; in patients with diabetes, its prevalence culminates to ∼70 %; its evolutive form, nonalcoholic steatohepatitis, is estimated to be the main cause of liver transplantation in the future. MASLD is a multisystem disease that affects, besides the liver, extra-hepatic organs and regulatory pathways; it raises the risk of type 2 diabetes mellitus (T2D), CVD, and chronic kidney disease; the disease may also progress to hepatocellular carcinoma. Its diagnosis requires hepatic steatosis and at least one cardiometabolic risk factor and the exclusion of both significant alcohol consumption and other competing causes of chronic liver disease. Beyond CV events, associated metabolic comorbidities comprise obesity (∼50 %), T2D (∼20 %), hyperlipidemia (∼70 %), hypertension (∼40 %), and metabolic syndrome (∼40 %). Among the various clinical events, CV events mostly determine prognosis as they are the leading cause of death in these patients. Regarding management, statins exert beneficial effects in improving liver injury; silybin, derived from Silybum marianum, has some protective effects; lifestyle modification, such as weight loss, dietary changes, physical exercise, and abstention from alcohol use combined with optimal management of comorbidities are most helpful. Bariatric surgery may be an option in persons with MASLD and obesity. Adults with non-cirrhotic MASLD and significant liver fibrosis may be candidates for targeted treatment with resmetirom, which has histological efficacy on steatohepatitis and fibrosis with an acceptable safety and tolerability profile, whereas, no MASLD-targeted pharmacotherapy can be beneficial in the cirrhotic stage, whereby other measures may include metabolic drugs, nutritional counseling, surveillance for portal hypertension and hepatocellular carcinoma, and finally, liver transplantation in decompensated cirrhosis.

Cardiovascular disease (CVD) is the leading cause of death among patients with non-alcoholic fatty liver disease (NAFLD). This study investigates the association between high-sensitivity cardiac troponin (hs-cTn) levels and mortality in adults at risk of NAFLD in a representative U.S. population sample.

Among participants aged 18 years and older in the 1999-2004 National Health and Nutrition Examination Survey, we measured high-sensitivity troponin T using a single assay (Roche) and high-sensitivity troponin I using three assays (Abbott, Siemens, and Ortho). Myocardial injury was identified by elevated levels of hs-cTn. Mortality outcomes were determined through linkage with the National Death Index database, with follow-up until December 31, 2019. A multivariable Cox proportional hazards model was used to evaluate the associations between myocardial injury and mortality in the NAFLD population. Sensitivity analyses were conducted to assess the robustness of the main findings.

A total of 2581 at risk of NAFLD were included in this observational study, with myocardial injury identified in 7.01%. Over a median follow-up of 16.7 years, 937 all-cause deaths occurred, including 319 cardiovascular disease-related deaths. NAFLD individuals with myocardial injury had worse survival rates at 5, 10, and 15 years compared to those without myocardial injury. After adjusting for baseline characteristics, myocardial injury was associated with an increased risk of all-cause mortality (adjusted Hazard Ratio [aHR] 1.785, 95% CI 1.494-2.134, P < 0.001) and cardiovascular mortality (aHR 2.155, 95% CI 1.606-2.893, P < 0.001).

This large, nationally representative study demonstrates that myocardial injury, defined by elevated hs-cTn levels, is independently associated with increased all-cause and cardiovascular mortality risks in the adult population at risk of NAFLD in the United States. This association persisted after adjusting for various factors and in patients without pre-existing cardiovascular disease. The Siemens hs-cTn I assay demonstrated the strongest association with all-cause mortality. These findings highlight the potential of hs-cTn as a valuable prognostic marker in NAFLD patients, even in those without clinically apparent cardiovascular disease. Routine hs-cTn assessment may aid in risk stratification and guide targeted interventions to reduce mortality risk in this population.

Background: Over the last two decades, a fair number of echocardiographic studies have investigated the influence of metabolic dysfunction-associated steatotic liver disease (MASLD) on myocardial strain and strain rate parameters assessed by speckle tracking echocardiography (STE) in individuals without overt heart disease, reporting not univocal results. We aimed at analyzing the main findings of these studies. Methods: All studies examining conventional echoDoppler parameters by transthoracic echocardiography (TTE) and left ventricular (LV) mechanics [LV-global longitudinal strain (GLS), LV-global strain rate in systole (GSRs), in early diastole (GSRe) and late diastole (GSRl)] by STE in MASLD patients without known heart disease vs. healthy individuals, were searched on PubMed, Embase and Scopus databases. The primary endpoint was to quantify the effect of MASLD on LV-GLS in individuals without overt cardiac disease. Continuous data [LV-GLS, LV-GLSRs, LV-GLSRe, LV-GLSRl and left ventricular ejection fraction (LVEF)] were pooled as the standardized mean difference (SMD) comparing MASLD cohorts with healthy controls. Results: A total of 11 studies were included, totaling 1348 MASLD patients and 6098 healthy controls. Overall, MASLD showed a medium effect on LV-GLS (SMD -0.6894; 95%CI -0.895, -0.472, p < 0.001) and LV-GLSRs (SMD -0.753; 95%CI -1.501, -0.006, p = 0.048), a large effect on LV-GLSRe (SMD -0.837; 95%CI -1.662, -0.012, p = 0.047) and a small and not statistically significant effect on LV-GLSRl (SMD -0.375; 95%CI -1.113, 0.363, p = 0.319) and LVEF (SMD -0.134; 95%CI -0.285, 0.017, p = 0.083). The overall I2 statistic was 86.4%, 89.4%, 90.9%, 89.6% and 72.5% for LV-GLS, LV-GLSRs, LV-GLSRe, LV-GLSRl and LVEF studies, respectively, indicating high between-study heterogeneity. Egger's test for LV-GLS studies gave a p value of 0.11, 0.26, 0.40, 0.32 and 0.42 for LV-GLS, LV-GLSRs, LV-GLSRe, LV-GLSRl and LVEF studies, respectively, thus excluding publication bias. Meta-regression analysis excluded any correlation between potential confounders and LV-GLS in MASLD individuals (all p > 0.05). Sensitivity analysis confirmed the robustness of study results. Conclusions: MASLD has a medium effect on LV-GLS, independently of demographics, anthropometrics and the cardiovascular disease burden. STE analysis may allow early detection of subclinical LV systolic dysfunction in MASLD patients, potentially identifying those who may develop heart failure later in life.

Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of heart failure cases, with increasing prevalence due to aging and risk factors such as hypertension and obesity. Liver dysfunction is common in HFpEF and may impact prognosis. This systematic review and meta-analysis aimed to evaluate the prognostic value of liver function markers (albumin, bilirubin, AST, ALT, ALP) in HFpEF patients.

A systematic search of PubMed, Embase, Web of Science, and Scopus was conducted for studies assessing the association of liver markers with adverse outcomes in HFpEF. The primary outcome was a composite of heart failure-related hospitalization or death. Hazard ratios (HR) were pooled using a random-effects model, and heterogeneity was assessed using the I² statistic.

Twenty studies involving 30,623 patients were included. Serum albumin, the main marker of our study, was significantly associated with a reduced risk of adverse outcomes in a meta-analysis of 16 studies (HR 0.71, 95% CI: 0.61-0.83; I² = 87%). After excluding outliers, heterogeneity decreased (I² = 23%), and the association remained significant (HR 0.75, 95% CI: 0.69-0.82). Although no significant associations were found for AST, ALT, ALP, or bilirubin with adverse outcomes, the limited number of studies for these markers may have contributed to the lack of statistical significance.

Higher serum albumin levels predict better outcomes in HFpEF, while other liver function markers showed limited prognostic utility. Serum albumin may serve as a valuable marker for risk stratification in HFpEF.

In early-stage breast cancer, steatotic liver disease (SLD) is associated with increased recurrence, cardiovascular events, and non-cancer death. Endocrine therapy (ET) increases the risk of SLD. The impact of cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) on SLD and prognostic association in metastatic breast cancer is unknown. We characterized the presence of SLD, risk factors, and treatment outcomes of SLD in metastatic HR+/HER2- breast cancer receiving CDK4/6i.

This single institution, retrospective, cohort study included patients with metastatic HR+/HER2- breast cancer receiving first-line ET and CDK4/6i from January 2018 to June 2022. SLD was defined as a Liver Attenuation Index (LAI) > 25 HU on contrast-enhanced CT scans and/or > 10 HU on plain CT scans. Univariable binary-logistic regression was used to assess associations with SLD. Time to treatment failure (TTF) and overall survival (OS) were analyzed using Cox proportional hazards modeling.

Among 87 patients with a median age of 58 years and 65.5% postmenopausal, 50 (57.5%) had SLD at anytime (24 at baseline, 26 acquired). SLD at baseline was statistically associated with post-menopausal status. It was quantitatively but not statistically associated with age > 65, diabetes, smoking, and HER2-low. SLD at anytime was statistically significantly associated with longer TTF (median 470 vs 830.5 days, HR = 0.38, p < 0.001). No significant differences in OS or grade 3/4 adverse events were observed between groups.

This study demonstrated a high prevalence of SLD in this population, with SLD presence correlated with longer TTF. SLD may be an indicator of better outcomes in metastatic HR+/HER2- breast cancer patients treated with CDK4/6i.

The purpose of this systematic review and meta-analysis is to investigate the association of metabolic dysfunction-associated steatotic liver disease (MASLD) with arterial stiffness and enlighten on potential cardiometabolic co-factors.

A literature search in PubMed/Medline, Embase, Scopus, and Web of Science databases was conducted. All the observational studies comparing arterial stiffness indices between adults with Non-alcoholic Fatty Liver Disease (NAFLD), Metabolic Dysfunction Associated-Fatty Liver Disease (MAFLD), or MASLD and apparently healthy individuals with normal liver function were included. Pulse wave velocity (PWV) and augmentation index (AIx) were mainly used as arterial stiffness indices.

Fourty one unique studies were included in the systematic review, with 27 deemed eligible for meta-analysis. Patients with MASLD had increased carotid-femoral PWV (14 studies, Mean difference (MD): 0.96 m/s, 95% confidence interval (CI) 0.65-1.27, p < 0.001) compared with healthy individuals. This finding was independent from body mass index, triglycerides, high-density lipoprotein, systolic blood pressure, and fasting plasma glucose. Moreover, patients with MASLD had higher brachial-ankle PWV (13 studies, MD: 78.14 cm/s, 95% CI 60.37-95.90, p < 0.001) and AIx (7 studies, MD: 3.85%, 95% CI 0.87-6.82, p = 0.0195) compared with controls.

MASLD is correlated with increased arterial stiffness. This relation is unaffected by common cardiometabolic risk factors.

PROSPERO (ID: CRD42023468258).

EFCAB4B is an evolutionarily conserved protein that encodes for the Rab GTPase Rab46, and the CRAC channel modulator, CRACR2A. Previous genome wide association studies have demonstrated the association of EFCAB4B variants in the progression of non-alcoholic fatty liver disease (NAFLD). In this study we show that mice with global depletion of Efcab4b -/- have significantly larger livers than their wild-type (WT) counterparts. We performed RNA-sequencing (RNA-seq) analysis of liver tissues to investigate differential global gene expression among Efcab4b -/- and WT mice. Of the 69 differentially expressed genes (DEGs), analyses of biological processes found significant enrichment in liver and bile development, with 6 genes (Pck1, Aacs, Onecut1, E2f8, Xbp1, and Hes1) involved in both processes. Specific consideration of possible roles of DEGs or their products in NAFLD progression to (NASH) and hepatocarcinoma (HCC), demonstrated DEGs in the livers of Efcab4b -/- mice had roles in molecular pathways including lipid metabolism, inflammation, ER stress and fibrosis. The results in this study provide additional insights into molecular mechanisms responsible for increasing susceptibility of liver injuries associated with EFCAB4B.

Valsartan (VAL) is commonly prescribed for patients with cardiovascular disease (CVD) to lower blood pressure, reduce heart failure risk, and prevent heart attacks or strokes by blocking the effects of angiotensin II. Many patients with CVD also suffer from metabolic dysfunction-associated steatohepatitis (MASH), which disrupts several xenobiotic transporters, affecting the pharmacokinetics of numerous drugs. Medications used in patients to treat comorbidities associated with MASH may be subject to this altered disposition and potential toxicity. This study aimed to assess how MASH alters the pharmacokinetics of VAL using a rodent model that mimics human MASH. MASH was induced in rats via a methionine- and choline-deficient (MCD) diet. Rats received VAL-a substrate of organic anion-transporting polypeptide (OATP) 1B1/1B3 and reported for multidrug resistance-associated protein-2-(2 mg/kg) through intravenous injection to isolate hepatic transport processes, and bile, serum, and liver concentrations measured using liquid chromatography-tandem mass spectrometry. Consistent with MASH progression, MCD rats presented with more gross pathology, including increased liver-to-body weight ratios, along with macrosteatosis, hepatocyte ballooning, and lobular inflammation. In MCD rats, the expression of Oatp1b2 was significantly reduced, and Mrp2 was internalized, resulting in higher systemic exposure to VAL compared with controls. Additionally, cumulative biliary excretion of VAL was lower in MCD rats. To further assess VAL disposition in MASH, transport kinetics were evaluated in human embryonic kidney 293 cells overexpressing OATP1B1 or OATP1B3, revealing similar affinity for VAL between both transporters. These findings suggest that changes in OATP function in MASH may alter VAL pharmacokinetics, which may have implications for personalized treatments. SIGNIFICANCE STATEMENT: Although expression of drug transporters in metabolic dysfunction-associated steatohepatitis (MASH) has been explored, the combined effect between MASH and genetic loss of transporters on the disposition of sartan drugs has not been determined. This study applied liquid chromatography-tandem mass spectrometry analyses and immunohistological staining to assess drug disposition and identify alterations to drug transporters in rodents on a methionine- and choline-deficient diet. The observations made in this study have significant implications regarding its disposition in the context of hepatic dysfunction associated with MASH.

Patients receiving statin therapy still suffer from adverse cardiovascular events. Metabolic (dysfunction)-associated fatty liver disease (MAFLD) is a newly proposed concept that shares common metabolic risk factors with cardiovascular disease. This study aimed to investigate the association between MAFLD and adverse cardiovascular outcomes in coronary heart disease (CHD) patients with LDL-C<1.8 mmol/L.

CHD patients with LDL-C<1.8 mmol/L were divided into MAFLD and non-MAFLD groups. Propensity score matching (PSM) was used to control for baseline differences between the two groups. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCEs). All MAFLD patients were further stratified into two groups with and without advanced liver fibrosis, according to the Fibrosis-4 (FIB-4) index cutoffs, and the associations between advanced liver fibrosis status and cardiovascular outcomes were analyzed. After PSM, 800 MAFLD and 800 non-MAFLD patients with LDL-C<1.8 mmol/L were analyzed. MAFLD patients exhibited a significantly greater cumulative incidence and risk of MACCEs than non-MAFLD patients (9.6 % versus 6.6 %, p < 0.05; HR 1.48, 95 % CI 1.04-2.1, p < 0.05). Among MAFLD patients with LDL-C<1.8 mmol/L, advanced liver fibrosis staged by the FIB-4 index was associated with an elevated risk for MACCEs (HR 2.91, 95 % CI 1.17-7.19, p < 0.05), all-cause mortality, myocardial infarction (MI) and stent thrombosis.

MAFLD was an independent risk factor for adverse cardiovascular outcomes in CHD patients with LDL-C<1.8 mmol/L. Additionally, advanced liver fibrosis predicts increased risks for adverse cardiovascular events among MAFLD patients. These findings suggest that MAFLD and liver fibrosis screening and management contribute to the residual cardiovascular risk of CHD patients.

Background: Non-alcoholic fatty liver disease (NAFLD), more recently redefined as metabolic-associated fatty liver disease (MAFLD), is now recognized as the most prevalent cause of chronic liver disease. Its strong association with cardiovascular disease (CVD) underscores its emerging role in global morbidity and mortality. Objective: This review critically examines the pathophysiological mechanisms that link NAFLD/MAFLD with CVD. It focuses on shared metabolic disturbances, inflammatory pathways, and alterations in the gut microbiota that contribute to hepatic and cardiovascular pathology. Review and Gaps: Current evidence highlights insulin resistance, dyslipidemia, systemic inflammation, and gut dysbiosis as pivotal factors connecting NAFLD/MAFLD to CVD. Despite these insights, inconsistencies in diagnostic criteria and a lack of validated non-invasive biomarkers hinder a clear understanding of the causal relationship between liver and cardiovascular diseases. Conclusions: Addressing these knowledge gaps through standardized diagnostic protocols and large-scale longitudinal studies is essential. Improved biomarker validation and clearer delineation of the underlying mechanisms will improve cardiovascular risk stratification and enable more personalized therapeutic strategies for patients with NAFLD/MAFLD.

The link between cardiovascular disease (CVD) and metabolic dysfunction-associated steatotic liver disease (MASLD) is well-established at both the epidemiological and pathophysiological levels. Among the common pathophysiological mechanisms involved in the development and progression of both diseases, oxidative stress and inflammation, insulin resistance, lipid metabolism deterioration, hepatokines, and gut dysbiosis along with genetic factors have been recognized to play a pivotal role. Pharmacologic interventions with drugs targeting common modifiable cardiometabolic risk factors, such as T2DM, dyslipidemia, and hypertension, are a reasonable strategy to prevent CVD development and progression of MASLD. Recently, a novel drug for metabolic dysfunction-associated steatohepatitis (MASH), resmetirom, has shown positive effects regarding CVD risk, opening new opportunities for the therapeutic approach of MASLD and CVD. This review provides current knowledge on the epidemiologic association of MASLD to CVD morbidity and mortality and enlightens the possible underlying pathophysiologic mechanisms linking MASLD with CVD. The role of cardiometabolic drugs such as anti-hypertensive drugs, hypolipidemic agents, glucose-lowering medications, acetylsalicylic acid, and the thyroid hormone receptor-beta agonist in the progression of MASLD is also discussed. Metformin failed to prove beneficial effects in MASLD progression. Studies on the administration of thiazolinediones in MASLD suggest effectiveness in improving steatosis, steatohepatitis, and fibrosis, while newer categories of glucose-lowering agents such as GLP-1Ra and SGLT-2i are currently being tested for their efficacy across the whole spectrum of MASLD. Statins alone or in combination with ezetimibe have yielded promising results. The conduction of long-duration, large, high-quality, randomized-controlled trials aiming to assess by biopsy the efficacy of cardiometabolic drugs to reverse MASLD progression is of great importance.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is correlated with an increased cardiovascular risk, independent of other traditional risk factors. The mechanisms underlying this pathogenic link are complex yet remain incompletely elucidated. Among these, the most significant are visceral adiposity, low-grade inflammation and oxidative stress, endothelial dysfunction, prothrombotic status, insulin resistance, dyslipidemia and postprandial hyperlipemia, gut dysbiosis, and genetic mutations. Cardiovascular diseases are the leading cause of death in patients with MASLD. These patients have an increased incidence of coronary artery disease, carotid artery disease, structural and functional cardiac abnormalities, and valvulopathies, as well as arrhythmias and cardiac conduction disorders. In this review, we present the latest data on the association between MASLD and cardiovascular risk, focusing on the pathogenic mechanisms that explain the correlation between these two pathologies. Given the high rates of cardiovascular morbidity and mortality among patients with MASLD, we consider it imperative to raise awareness of the risks associated with this condition within the general population. Further research is essential to clarify the mechanisms underlying the increased cardiovascular risk linked to MASLD. This understanding may facilitate the identification of new diagnostic and prognostic biomarkers for these patients, as well as novel therapeutic targets.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global health concern, and it is not only the keystone precursor of eventual liver-related morbidity, but it also places patients at considerably higher cardiovascular risk, which is still a leading cause of death in these patients. The most important common underlying pathophysiological mechanisms in these diseases are primarily related to insulin resistance, chronic inflammation and oxidative stress. The presence of MASLD with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) elevates the risk for poor outcomes, thus this review highlights a method to the therapeutic approaches. Given the intertwined nature of MASLD, T2DM, and CVD, there is an urgent need for therapeutic strategies that address all three conditions. Although lifestyle changes are important as treatment, medication plays a crucial role in managing hyperglycemia, enhancing liver function and lowering cardiovascular risk. The onset and progression of MASLD should be addressed through a multifaceted therapeutic approach, targeting inflammatory, immune, metabolic, oxidative stress, hormonal and gutaxis pathways, alongside the treatment strategies for T2DM. In this review, we discuss the effects of antidiabetic drugs with an impact on both liver outcomes and cardiovascular risk in patients affected by MASLD, T2DM and CDV.

We investigated the risk of cardiovascular events, all-cause mortality, and liver-related mortality according to the presence of metabolic syndrome (MetS) and fatty liver index (FLI). In this retrospective longitudinal population-based cohort study, we used Korean National Health Insurance Service data from 2009 to 2012. Nonalcoholic fatty liver disease (NAFLD) was defined as FLI ≥ 60. Risk of all-cause mortality, liver-related mortality, and major adverse cardiovascular events (MACE) including myocardial infarction (MI), stroke, heart failure (HF), and cardiovascular disease (CVD)-related mortality was assessed according to the presence of MetS and FLI among adults (aged 40 to 80 years) who underwent health examinations (n = 769,422). During a median 8.59 years of follow up, 44,356 (5.8%) cases of MACE, 24,429 (3.2%) cases of all-cause mortality, and 1114 (0.1%) cases of liver-related mortality were detected in the entire cohort. When the FLI < 30 without MetS group was set as a reference, the FLI ≥ 60 with MetS group had the highest risk of MACE (adjusted hazard ratio [aHR] 2.05, 95% confidence interval [CI] 1.98-2.13) and all-cause mortality (aHR 1.96, 95% CI 1.86-2.07). The risk of liver-related mortality (aHR 10.71, 95% CI 8.05-14.25) was highest in the FLI ≥ 60 without MetS group. The FLI ≥ 60 with MetS group had a higher risk of MACE (aHR 1.39, 95%CI 1.28-1.51), a lower risk of liver-related mortality (aHR 0.44, 95%CI 0.33-0.59), and no significant difference in all-cause mortality compared with the FLI ≥ 60 without MetS group. The FLI ≥ 60 with MetS group was associated with the highest risk of MACE and the FLI ≥ 60 without MetS group had the highest risk liver-related mortality, but there was no significant difference in all-cause mortality between two groups. In conclusion, as FLI levels increase, the risk of MACE increases, and the risk increases additively in the presence of MetS. The risk of liver-related mortality increases with higher FLI levels, the effect of high FLI on increased risk is more significant in groups without MetS compared to those with MetS.

Nonalcoholic fatty liver disease (NAFLD) is prone to complicated cardiovascular disease, and we aimed to identify patients with NAFLD who are prone to developing stable coronary artery disease (CAD).

We retrospectively recruited adults who underwent coronary computed tomography angiography (CTA). A total of 127 NAFLD patients and 127 non-NAFLD patients were included in this study. Clinical features and imaging parameters were analysed, mainly including pericardial adipose tissue (PAT), pericoronary adipose tissue (PCAT), and radiomic features of 6792 PCATs. The inflammatory associations of NAFLD patients with PAT and PCAT were analysed. Clinical features (model 1), CTA parameters (model 2), the radscore (model 3), and a composite model (model 4) were constructed to identify patients with NAFLD with stable CAD. The presence of NAFLD resulted in a greater inflammatory involvement in all three coronary arteries (all P < 0.01) and was associated with increased PAT volume (r = 0.178**, P < 0.05). In the presence of NAFLD, the mean CT value of the PAT was significantly correlated with the fat attenuation index (FAI) in all three vessels and had the strongest correlation with the RCA FAI (r = 0.55, p < 0.001). A total of 9 radiomic features were screened by LASSO regression to calculate radiomic scores. In the model comparison, model 4 had the best performance of all models (AUC 0.914 [0.863-0.965]) and the highest overall diagnostic value of the model (sensitivity: 0.814, specificity: 0.941).

NAFLD correlates with PAT volume and PCAT inflammation. Furthermore, combining clinical features, CTA parameters, and radiomic scores can improve the efficiency of early diagnosis of stable CAD in patients with NAFLD.

Non-alcoholic fatty liver disease (NAFLD), linked to sedentary lifestyles and metabolic dysfunction, is highly prevalent. Exercise is an established intervention, but the relative efficacy of different exercise modalities remains unclear. The aim of this study was to compare the effects of moderate-intensity continuous aerobic training and High-Intensity Interval Training (HIIT) on physical fitness, biochemical parameters, and liver function in NAFLD patients.

Sixty NAFLD patients (32 males, 28 females; age: 49.7±8.7 years; BMI: 31.1±3.3 kg/m2) were randomized into HIIT, aerobic training, and control cohorts. The HIIT cohort performed 4-minute high-intensity intervals at 85-95% of peak heart rate, interspersed with 3-minute active recovery at 60-70% of peak heart rate for 30-40 minutes per session. The aerobic training cohort performed continuous exercise at 60-70% of peak heart rate for 45-60 minutes per session. Both intervention cohorts underwent 12 weeks of supervised training, thrice weekly. Before and after the intervention, assessments included cardiorespiratory fitness, muscular strength, flexibility, lipid profile, liver enzymes, inflammatory markers, insulin sensitivity, and oxidative stress markers.

Compared to controls, both exercise cohorts showed significant improvements in cardiorespiratory fitness, muscular strength, and flexibility. However, HIIT elicited superior enhancements in cardiorespiratory fitness and muscular strength. Biochemically, both exercise cohorts exhibited reductions in triglycerides, low-density lipoprotein (LDL) cholesterol, liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST]), inflammatory markers (C-reactive protein [CRP], interleukin-6 [IL-6]), insulin resistance (homeostatic model assessment of insulin resistance [HOMA-IR]), and oxidative stress markers (malondialdehyde [MDA], protein carbonyl). Notably, HIIT yielded more substantial improvements in these parameters.

HIIT and traditional aerobic training are effective in improving physical fitness and ameliorating biochemical indicators in NAFLD patients. Notably, HIIT appears to be more advantageous in enhancing cardiorespiratory fitness, muscular strength, and metabolic, inflammatory, and oxidative stress profiles, suggesting its potential as a time-efficient and effective exercise modality for managing NAFLD.

The combination of alcohol and a low-carbohydrate, high-protein, high-fat atherogenic diet (AD) increases the risk of lethal arrhythmias in apolipoprotein E/low-density lipoprotein receptor double-knockout (AL) mice with metabolic dysfunction-associated steatotic liver disease (MASLD). This study investigates whether left ventricular (LV) myocardial interstitial fibrosis (MIF), formed during the progression of metabolic dysfunction-associated steatohepatitis (MASH), contributes to this increased risk. Male AL mice were fed an AD with or without ethanol for 16 weeks, while age-matched AL and wild-type mice served as controls. Liver and heart tissues were analyzed, and susceptibility to lethal arrhythmias was assessed through histopathology, fluorescence immunohistochemistry, RNA-Seq, RT-PCR, and lethal arrhythmia-evoked test. Ethanol combined with an AD significantly induced LV MIF in MASH-affected AL mice, as shown by increased fibrosis-related gene expression, Sirius-Red staining, and elevated collagen 1a1 and 3a1 mRNA levels, alongside a higher incidence of lethal arrhythmias. Cardiac myofibroblasts exhibited sympathetic activation and produced elevated levels of fibrosis-promoting factors. This study highlights the role of cardiac myofibroblasts in LV MIF, contributing to an increased incidence of lethal arrhythmias in MASH-affected AL mice fed ethanol and AD, even after the alcohol was fully metabolized on the day of consumption.

Non-alcoholic fatty liver disease (NAFLD) is closely related to metabolic syndrome and remains a major global health burden. The increased prevalence of obesity and type 2 diabetes mellitus (T2DM) worldwide has contributed to the rising incidence of NAFLD. It is widely believed that atherosclerotic cardiovascular disease (ASCVD) is associated with NAFLD. In the past decade, the clinical implications of NAFLD have gone beyond liver-related morbidity and mortality, with a majority of patient deaths attributed to malignancy, coronary heart disease (CHD), and other cardiovascular (CVD) complications. To better define fatty liver disease associated with metabolic disorders, experts proposed a new term in 2020 - metabolic dysfunction associated with fatty liver disease (MAFLD). Along with this new designation, updated diagnostic criteria were introduced, resulting in some differentiation between NAFLD and MAFLD patient populations, although there is overlap. The aim of this review is to explore the relationship between MAFLD and ASCVD based on the new definitions and diagnostic criteria, while briefly discussing potential mechanisms underlying cardiovascular disease in patients with MAFLD.

Metabolic dysfunction-associated steatohepatitis (MASH) represents a critical stage in the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), significantly increasing the risk of cirrhosis, hepatocellular carcinoma (HCC), and liver-related mortality. Despite the rising global prevalence of MASLD, gaps in understanding the pathophysiological mechanisms driving MASH to cirrhosis persist, leading to challenges in early diagnosis, prevention, and treatment. This review explores the current knowledge on MASH, focusing on its pathophysiology, clinical management, and treatment strategies in the advanced stages. The role of metabolic dysfunction, portal hypertension, decompensation, and HCC occurrence is highlighted, alongside an evaluation of therapeutic options including lifestyle intervention, bariatric surgery, pharmacological therapies and liver transplantation. Furthermore, we emphasize the need for a multidisciplinary care approach to improve patient outcomes and address the complex metabolic and hepatic interplay in MASLD. Bridging these gaps will require an integrated effort combining advanced diagnostic tools, novel treatments, and comprehensive care strategies.

A global increase in nonalcoholic fatty liver disease (NAFLD) prevalence has been observed in the last decade. This study assesses knowledge, awareness, and clinical practice gaps of hepatologists and non-hepatologists in NAFLD management across hospitals in China.

A web-based quantitative survey was conducted, and participants included hepatologists (gastroenterologists and infectious disease specialists) and non-hepatologists (internal medicine specialists, cardiologists, and pharmacists) from various hospitals across China.

In total, 1627 healthcare practitioners (HCPs) responded to the survey. This included 658 hepatologists and 969 non-hepatologists. In comparison to 92.6% hepatologists, only 58.0% of non-hepatologists were aware of NAFLD. A higher proportion of hepatologists (82.8%) performed screening for NAFLD compared to non-hepatologists (56.9%). Majority of the hepatologists (70%) and non-hepatologists (67%) were aware of the four primary recommendations for managing NAFLD. Only 11% of hepatologists did not manage NAFLD patients, mainly because they felt they did not have enough time (66.7%). Of the 36% non-hepatologists who did not manage NAFLD, 78.4% stated that NAFLD is not their specialty, and 38.6% were not familiar with the treatment options.

Most hepatologists were aware of and agreed to performing screening for NAFLD compared to non-hepatologists. Both hepatologists and non-hepatologists exhibited similar level of understanding on NAFLD management. However, a small percentage of both hepatologists and non-hepatologists admitted that they did not manage NAFLD patients because they were not familiar with available treatment options. This underscores the importance of further educating HCPs involved in managing NAFLD.

Glucose metabolism status (GMS) is linked to non-alcoholic fatty liver disease (NAFLD). Higher levels of advanced glycation end products (AGEs) are observed in people with type 2 diabetes mellitus (T2DM) and NAFLD. We examined the association between GMS, non-invasive tests and AGEs, with liver steatosis and fibrosis.

Data from The Maastricht Study, a population-based cohort, were analysed. Participants with alcohol overconsumption or missing data were excluded. GMS was determined via an oral glucose tolerance test. AGEs, measured by skin autofluorescence (SAF), were assessed using an AGE Reader. Associations of GMS and SAF with the fibrosis-4 score (FIB-4), Forns index (FI) and fatty liver index (FLI) were investigated using multivariable linear regression, adjusted for sociodemographic, lifestyle and clinical variables.

1955 participants (56.6%) were analysed: 598 (30.6%) had T2DM, 264 (13.5%) had pre-diabetes and 1069 (54.7%) had normal glucose metabolism. Pre-diabetes was significantly associated with FLI (standardised regression coefficient (Stβ) 0.396, 95% CI 0.323 to 0.471) and FI (Stβ 0.145, 95% CI 0.059 to 0.232) but not FIB-4. T2DM was significantly associated with FLI (Stβ 0.623, 95% CI 0.552 to 0.694) and FI (Stβ 0.307, 95% CI 0.226 to 0.388) but not FIB-4. SAF was significantly associated with FLI (Stβ 0.083, 95% CI 0.036 to 0.129), FI (Stβ 0.106, 95% CI 0.069 to 0.143) and FIB-4 (Stβ 0.087, 95% CI 0.037 to 0.137).

The study showed that adverse GMS and higher glycaemia are positively associated with steatosis. FI, but not FIB-4, was related to adverse GMS concerning fibrosis. This study is the first to demonstrate that SAF is positively associated with steatosis and fibrosis.

Steatotic liver disease is the overarching term for conditions characterised by abnormal lipid accumulation in the liver (liver or hepatic steatosis). Steatotic liver disease encompasses what was previously termed non-alcoholic fatty liver disease (NAFLD), which is now called metabolic dysfunction-associated steatotic liver disease (MASLD). Additionally, steatotic liver disease includes alcohol-related liver disease (ALD) and MetALD, the new classification for the overlap between MASLD and ALD, and rare causes of liver steatosis. Cirrhosis is globally the 11th leading cause of death, and steatotic liver disease has become the leading cause of cirrhosis in the EU and USA. Steatotic liver disease affects around 30% of the global population and is mainly driven by obesity, type 2 diabetes, and alcohol intake, but only a minor proportion with steatotic liver disease progress to cirrhosis. The presence and progression of liver fibrosis led by hepatic inflammation is the main predictor of liver-related death across the entire spectrum of steatotic liver diseases. A combination of recent advancements of widely available biomarkers for early detection of liver fibrosis together with considerable advancements in therapeutic interventions offer the possibility to reduce morbidity and mortality in patients with steatotic liver disease. This Seminar covers the recent reclassification of steatotic liver disease and how it reflects clinical practice and prognosis. For early detection of liver fibrosis, we propose a collaborative diagnostic framework between primary care and liver specialists. Lastly, we discuss current best practices for managing steatotic liver disease, we explore therapeutic targets across the spectrum of steatotic liver diseases, and we review the pipeline of drugs in development for MASLD.

The rising prevalence of obesity-related illnesses, such as metabolic steatotic liver disease (MASLD), represents a significant global public health concern. This disease affects approximately 30 % of the adult population and is the result of metabolic abnormalities rather than alcohol consumption. Additionally, MASLD is associated with an increased risk of cardiovascular disease (CVD), chronic liver disease, and a variety of cancers, particularly gastrointestinal cancers. Clonal hematopoiesis (CH) is a biological state characterized by the expansion of a population of blood cells derived from a single mutated hematopoietic stem cell. The presence of CH in the absence of a diagnosed blood disorder or cytopenia is known as clonal hematopoiesis of indeterminate potential (CHIP), which itself increases the risk of hematological malignancies and CVD. Steatotic liver disease may also complicate the clinical course of cancer patients receiving antineoplastic agents, a condition referred to as chemotherapy induced steatohepatitis (CASH). This review will present an outline of the various aspects of MASLD, including complications. Furthermore, it will summarize the existing knowledge on the emerging association between CHIP and MASLD and present the available data on patient cases with concurrent MASLD and hematological neoplasms. Finally, it will provide a brief overview of the chemotherapeutic drugs associated with CASH, the underlying pathophysiologic mechanisms and their clinical implications.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major public health concern that is exacerbated by the obesity pandemic. Dietary interventions have the potential to alleviate obesity-associated MASLD through variable mechanisms, including optimizing the gut microbiota. Previously, we reported that soy protein concentrate (SPC) with low or high levels of isoflavone (LIF or HIF) protected young obese Zucker rats from developing liver steatosis. The current study was designed to test whether SPC-LIF and SPC-HIF diets would reverse liver steatosis and alter fecal microbial composition in adult obese Zucker rats with existing steatosis.

Six-week-old male obese Zucker rats (n = 26) were fed a casein control diet (CAS) for 8 weeks and 7 rats were randomly selected and sacrificed to confirm liver steatosis. The remaining rats were randomly assigned to receive CAS, SPC-LIF, or SPC-HIF diet (n = 6-7/group) for an additional 10 weeks.

Compared to CAS diet, feeding SPC-LIF and SPC-HIF diets resulted in significantly lower liver weight, liver steatosis score, and liver microvesicular score (p < 0.05), but did not lead to difference in body weight, liver macrovesicular score, serum ALT, or serum AST. Isoflavone levels (e.g., LIF vs. HIF) did not affect any of these measurements except in the SPC-HIF group, which had an additional decrease in liver weight (p < 0.05) compared to the SPC-LIF group. The SPC-HIF group also had significantly higher levels of the aglycone forms of daidzein, genistein, and equol as well as the total levels of daidzein, genistein, and equol compared to SPC-LIF or CAS diet fed rats (p < 0.05). The distribution of microbial communities based on measures of beta diversity of both SPC-LIF and SPC-HIF groups were significantly different to that of the CAS group (p ≤ 0.005). Alpha-diversity did not differ between any of the groups.

Taken together, dietary soy protein can reverse liver steatosis in adult Zucker rats, and the reversal of steatosis is accompanied by alterations in gut microbial composition.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is regarded as a liver manifestation of metabolic syndrome. It is linked to insulin resistance, obesity, and diabetes mellitus, all of which increase the risk of cardiovascular complications. Endothelial dysfunction (EnD) constitutes the main driver in the progression of atherosclerosis and coronary artery disease (CAD). Several pathophysiological alterations and molecular mechanisms are involved in the development of EnD in patients with NAFLD. Our aim is to examine the association of NAFLD and CAD with the parallel assessment of EnD, discussing the pathophysiological mechanisms and the genetic background that underpin this relationship. This review delves into the management of the condition, exploring potential clinical implications and available medical treatment options to facilitate the deployment of optimal treatment strategies for these patients.

We previously reported that Oxy210, an oxysterol-based drug candidate, exhibits antifibrotic and anti-inflammatory properties. We also showed that, in mice, it ameliorates hepatic hallmarks of non-alcoholic steatohepatitis (NASH), including inflammation and fibrosis, and reduces adipose tissue inflammation. Here, we aim to investigate the effects of Oxy210 on atherosclerosis, an inflammatory disease of the large arteries that is linked to NASH in epidemiologic studies, shares many of the same risk factors, and is the major cause of mortality in people with NASH.

Oxy210 was studied in vivo in APOE*3-Leiden.CETP mice, a humanized mouse model for both NASH and atherosclerosis, in which symptoms are induced by consumption of a high fat, high cholesterol "Western" diet (WD). Oxy210 was also studied in vitro using two cell types that are important in atherogenesis: human aortic endothelial cells (HAECs) and macrophages treated with atherogenic and inflammatory agents.

Oxy210 reduced atherosclerotic lesion formation by more than 50% in hyperlipidemic mice fed the WD for 16 weeks. This was accompanied by reduced plasma cholesterol levels and reduced macrophages in lesions. In HAECs and macrophages, Oxy210 reduced the expression of key inflammatory markers associated with atherosclerosis, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), chemokine (C-C motif) ligand 2 (CCL2), vascular cell adhesion molecule-1 (VCAM-1), and E-Selectin. In addition, cholesterol efflux was significantly enhanced in macrophages treated with Oxy210.

These findings suggest that Oxy210 could be a drug candidate for targeting both NASH and atherosclerosis, as well as chronic inflammation associated with the manifestations of metabolic syndrome.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed nonalcoholic fatty liver disease (NAFLD), poses a significant global health challenge due to its increasing prevalence and strong association with cardiovascular disease (CVD). This comprehensive review summarizes the current knowledge on the MASLD-CVD relationship, compares analysis of how different terminologies for fatty liver disease affect cardiovascular (CV) risk assessment using different diagnostic criteria, explores the pathophysiological mechanisms connecting MASLD to CVD, the influence of MASLD on traditional CV risk factors, the role of noninvasive imaging techniques and biomarkers in the assessment of CV risk in patients with MASLD, and the implications for clinical management and prevention strategies. By incorporating current research and clinical guidelines, this review provides a comprehensive overview of the complex interplay between MASLD and cardiovascular health.

Metabolic dysfunction associated steatotic liver disease (MASLD) contributes to the cardiometabolic diseases through multiple mechanisms. Fatty liver index (FLI) has been formulated as a non-invasive, convenient, and cost-effective approach to estimate the degree of MASLD. The current study aims to evaluate the correlation between FLI and the prevalent cardiometabolic multimorbidity (CMM), and to assess the usefulness of FLI to improve the detection of the prevalent CMM in the general population.

26,269 subjects were enrolled from the National Health and Nutrition Examination Survey 1999-2018. FLI was formulated based on triglycerides, body mass index, γ -glutamyltransferase, and waist circumference. CMM was defined as a history of 2 or more of diabetes mellitus, stroke, myocardial infarction.

The prevalence of CMM was 10.84%. With adjustment of demographic, anthropometric, laboratory, and medical history covariates, each standard deviation of FLI leaded to a 58.8% risk increase for the prevalent CMM. The fourth quartile of FLI had a 2.424 times risk for the prevalent CMM than the first quartile, and a trend towards higher risk was observed. Smooth curve fitting showed that the risk for prevalent CMM increased proportionally along with the elevation of FLI. Subgroup analysis demonstrated that the correlation was robust in several conventional subpopulations. Receiver-operating characteristic curve analysis revealed an incremental value of FLI for detecting prevalent CMM when adding it to conventional cardiometabolic risk factors (Area under the curve: 0.920 vs. 0.983, P < 0.001). Results from reclassification analysis confirmed the improvement from FLI.

Our study demonstrated a positive, linear, and robust correlation between FLI and the prevalent CMM, and our findings implicate the potential usefulness of FLI to improve the detection of prevalent CMM in the general population.

Nonalcoholic fatty liver disease (NAFLD) is a disease process that is gaining increasing recognition. The global prevalence of NAFLD is increasing in parallel with growing rates of risk factors for NAFLD such as hypertension, obesity, diabetes, and metabolic syndrome. NAFLD has been referred to as a risk factor for cardiovascular disease (CVD). As CVD is the leading cause of morbidity and mortality worldwide, there are constant efforts to describe and alleviate its risk factors. Although there is conflicting data supporting NAFLD as a causative or associative factor for CVD, NAFLD has been shown to be associated with structural, electrical, and atherosclerotic disease processes of the heart. Shared risk factors and pathophysiologic mechanisms between NAFLD and CVD warrant further explication. Pathologic mechanisms such as endothelial dysfunction, oxidative stress, insulin resistance, genetic underpinnings, and gut microbiota dysregulation have been described in both CVD and NAFLD. The mainstay of treatment for NAFLD is lifestyle intervention including physical exercise and hypocaloric intake in addition to bariatric surgery. Investigations into various therapeutic targets to alleviate hepatic steatosis and fibrosis by way of maintaining the balance between lipid synthesis and breakdown. A major obstacle preventing the success of many pharmacologic approaches has been the effects of these medications on CVD risk. The future of pharmacologic treatment of NAFLD is promising as effective medications with limited CVD harm are being investigated.

There is an unmet clinical need for pharmacologic treatment for metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocyte cell death is a hallmark of this highly prevalent chronic liver disease, but the dominant type of cell death remains uncertain. Here we report that ferroptosis, an iron-catalyzed mode of regulated cell death, contributes to MASLD. Unsupervised clustering in a cohort of biopsy-proven MASLD patients revealed a subgroup with hepatic ferroptosis signature and lower glutathione peroxidase 4 (GPX4) levels. Likewise, a subgroup with reduced ferroptosis defenses was discerned in public transcriptomics datasets. Four weeks of choline-deficient L-amino acid-defined high-fat diet (CDAHFD) induced MASLD with ferroptosis in mice. Gpx4 overexpression did not affect steatohepatitis, instead CDAHFD protected from morbidity due to hepatocyte-specific Gpx4 knockout. The ferroptosis inhibitor UAMC-3203 attenuated steatosis and alanine aminotransferase in CDAHFD and a second model, i.e., the high-fat high-fructose diet (HFHFD). The effect of monounsaturated and saturated fatty acids supplementation on ferroptosis susceptibility was assessed in human HepG2 cells. Fat-laden HepG2 showed a drop in ferroptosis defenses, increased phosphatidylglycerol with two polyunsaturated fatty acid (PUFA) lipid tails, and sustained ferroptosis sensitivity. In conclusion, this study identified hepatic ferroptosis as a detrimental factor in MASLD patients. Unexpectedly, non-PUFA supplementation to hepatocytes altered lipid bilayer composition to maintain ferroptosis sensitivity. Based on findings in in vivo models, ferroptosis inhibition represents a promising therapeutic target in MASLD.

Mitral annulus calcification is a chronic degenerative condition affecting the fibrous base of the mitral valve. Historically viewed as an age-related phenomenon, recent studies suggest it is driven by active mechanisms involving systemic inflammation, hemodynamic stress, abnormal calcium-phosphorus metabolism, and lipid accumulation. Despite often being asymptomatic and incidentally detected, its clinical relevance stems from its strong association with increased cardiovascular disease risk, higher cardiovascular mortality, and elevated overall mortality.

This article investigates the complexities and controversies surrounding mitral annular calcification as a potential embolic source, focusing on its diagnosis, its relationship with systemic inflammation, and its links to metabolic and chronic disorders.

The findings highlight that mitral annular calcification is not merely a passive marker of aging but an active indicator of atherosclerotic burden with significant implications for cardiovascular health.

Mitral annulus calcification should be recognized as an important factor in cardiovascular risk assessment, offering insight into systemic inflammatory processes and metabolic dysregulation.