Interplay between cardiometabolic risk factors in metabolic dysfunction-associated steatotic liver disease: Clinical evidence on cardiovascular disease

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, is the most common liver disease, with a prevalence of 38% in the adult population. MASLD is defined as steatotic liver disease with at least one cardiometabolic risk factor and the absence of harmful alcohol intake. Individuals with MASLD have a high percentage of cardiometabolic comorbidities such as obesity, dyslipidemia, diabetes, and hypertension. Therefore, these patients are at increased risk for the occurrence of cardiovascular disease (CVD), which is the leading cause of death in MASLD patients. There is evidence suggesting links between MASLD and insulin resistance, systemic inflammation, oxidative stress, and endothelial dysfunction in the development of CVD, such as arrhythmia (e.g., atrial fibrillation), atherosclerotic heart disease, cardiomyopathy (e.g., left ventricular dysfunction and hypertrophy), heart failure, venous thrombosis, cardiac conduction defects, and peripheral artery disease. In this review, we highlight how cardiometabolic risk factors link MASLD to the development of CVD, considering insulin resistance, systemic inflammation, oxidative stress, and endothelial dysfunction. Therapeutic strategies are also considered.

Key Words: Metabolic dysfunction-associated steatotic liver disease; Diagnostic criteria; Cardiometabolic comorbidities; Insulin resistance; Systemic inflammation; Oxidative stress; Endothelial dysfunction; Cardiovascular disease; Therapeutic strategies

Core Tip: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease, mostly prevalent in Latin America, associated with the development of cardiovascular disease (CVD). Its management and treatment can be challenging, especially in advanced stages (fibrosis and cirrhosis); thus, this disease should be treated by a multidisciplinary team of hepatologists, cardiologists, and nutritionists (among others) in order to reduce liver-related and cardiovascular risk factors. This comprehensive review provides insight into the clinical evidence of the connection between MASLD and CVD through cardiometabolic risk factors.

INTRODUCTION

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver condition globally and is defined as steatotic liver greater than 5% and includes the presence of at least 1 of 5 cardiometabolic risk factors, such as: (1) Overweight or obesity; (2) Prediabetes or type 2 diabetes (T2D); (3) High blood pressure; (4) High plasma triglycerides; and (5) Low plasma high-density lipoprotein cholesterol (HDL-C). The criteria for adults and children are shown in Table 1[1,2]. Additionally, MASLD includes a category termed metabolic and alcohol-related/associated liver disease, which includes individuals with MASLD who consume greater amounts of alcohol (140-350 g/week for females and 210-420 g/week for males, respectively) but do not meet the criteria for alcohol-associated/related liver disease[1]. The overall global prevalence of MASLD is estimated at 38%. The reported prevalence of MASLD and metabolic dysfunction-associated steatohepatitis (MASH) in middle-aged Americans is 38% and 14%, respectively, and MASLD prevalence is higher in men (40%) than women (26%); meanwhile, the prevalence of MASLD is highest in Latin America (44%), then the Middle East and North Africa (36%), South Asia (34%), Southeast Asia (33%), East Asia (29%), and Asia Pacific (28%), and lowest in Western Europe (25%)[2-5]. By 2040, the global prevalence of MASLD is expected to reach more than 55%[6,7].

Table 1 Metabolic dysfunction-associated steatotic liver disease diagnostic criteria for adults and children.

Adult criteria	Children criteria
Overweight or obesity, BMI ≥ 25 kg/m2 and ≥ 23 kg/m2 for Asia OR WC ≥ 94 cm (M) and ≥ 80 cm (F) for Europeans OR ≥ 90 cm (M) and ≥ 80 cm (F) for South Asians and Chinese OR ≥ 85 cm (M) and ≥ 90 cm (F) for Japanese	Overweight or obesity, BMI ≥ 85th percentile for age/sex (BMI z score ≥ +1) OR WC ≥ 95th percentile OR ethnicity adjusted equivalent
Prediabetes, HbA1c: 5.7%-6.4% OR fasting plasma glucose: 100-125 mg/dL OR 2-hour plasma glucose during OGTT: 140-199 mg/dL OR T2D: HbA1c ≥ 6.5% OR fasting plasma glucose ≥ 126 mg/dL OR 2-hour plasma glucose during OGTT ≥ 200 mg/dL or treatment for T2D	Prediabetes, HbA1c: 5.7%-6.4% OR fasting plasma glucose: 100-125 mg/dL OR 2-hour plasma glucose during OGTT: 140-199 mg/dL OR T2D: HbA1c ≥ 6.5% OR fasting plasma glucose ≥ 126 mg/dL OR 2-hour plasma glucose during OGTT ≥ 200 mg/dL or treatment for T2D
Blood pressure ≥ 130/85 mmHg OR treatment for hypertension	Blood pressure age < 13 year, BP ≥ 95th percentile OR ≥ 130/85 mmHg; age ≥ 13 years, ≥ 130/85 mmHg OR treatment for hypertension
Plasma triglycerides ≥ 150 mg/dL OR lipid-lowering treatment	Plasma triglycerides age < 10 years, ≥ 100 mg/dL; age ≥ 10 years, ≥ 150 mg/dL OR lipid-lowering treatment
Plasma HDL-cholesterol ≤ 40 mg/dL (M) and ≤ 50 mg/dL (F) OR lipid-lowering treatment	Plasma HDL-cholesterol ≤ 40 mg/dL OR lipid-lowering treatment

Steatotic liver disease: Hepatic steatosis determined by imaging or biopsy. Presence of at least 1 of 5 cardiometabolic criteria without other causes of steatosis. BMI: Body mass index; F: Female; M: Male; WC: Waist circumference; HbA1c: Glycated hemoglobin; OGTT: Oral glucose tolerance test; T2D: Type 2 diabetes; HDL: High-density lipoprotein; BP: Blood pressure.

Major risk factors for MASLD are centered on metabolic syndrome, including obesity. Due to the increasing incidence of obesity worldwide, obesity-associated metabolic diseases, such as insulin resistance, T2D, dyslipidemia, hypertension, and MASLD, have also increased along with changes in lifestyle, diet, social environment, and an aging population[8,9]. There is a strong consensus that obesity represents the primary clinical risk factor for MASLD, though the accumulation of visceral fat serves as an even more powerful predictor. Individuals with overweight (70%) and obesity (75%) present a two-fold increase in MASLD prevalence compared to individuals without obesity[6,10,11]. In addition to obesity, multiple complex interacting pathways among risk factors influence the development and progression of the pathophysiology of MASLD (Table 2). Dyslipidemia and hypertension are common in patients with MASLD. Insulin resistance increases plasma glucose levels and lipolysis in adipose tissue, which in turn produces elevated levels of circulating free fatty acids (FFAs), and the development of T2D is strongly associated with the progression of MASLD[2,10,12]. In individuals with prediabetes, the prevalence of MASLD varies between 41% and 56%, and the global prevalence of MASLD and MASH is approximately doubled in people with T2D (55%-70%) for MASLD and 30%-40% for MASH, while 14% of patients with T2D have advanced fibrosis and 6% have cirrhosis. It is estimated that MASH is present in 12%-40% of patients with MASLD, 15%-25% progress to cirrhosis, and approximately 7% of patients with cirrhosis develop hepatocellular carcinoma (HCC). Figure 1 illustrates the global prevalence of liver disease progression and histological criteria, respectively[3,4,6,11,13,14].

Figure 1 The schematic highlights the histological transitions and clinical outcomes. Redrawn and modified by the authors. Clinical data and progression rates are adapted from Stefan et al[308] (Cell Metab 2023) and Younossi et al[6] (Clin Mol Hepatol 2025). Citation: Stefan N, Schick F, Birkenfeld AL, Häring HU, White MF. The role of hepatokines in NAFLD. Cell Metab 2023; 35: 236-252. Copyright ©The Author(s) 2023. Published by Elsevier Inc. (Supplementary material). Younossi ZM, Kalligeros M, Henry L. Epidemiology of metabolic dysfunction-associated steatotic liver disease. Clin Mol Hepatol 2025; 31: S32-S50. Copyright ©The Author(s) 2025. Published by the Korean Association for the Study of the Liver. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported License (https://creativecommons.org/Licenses/by-nc/3.0/). MASLD: Metabolic dysfunction-associated steatotic liver disease; MASH: Metabolic dysfunction-associated steatohepatitis; HCC: Hepatocellular carcinoma; T2D: Type 2 diabetes.

Table 2 Overview of risk factors associated to metabolic dysfunction-associated steatotic liver disease.

Obesity-associated risk factors of MASLD
Lifestyle choices: Poor dietary habits; Less physical activity
Inherent risk factors: Genetic predisposition; Race/ethnicity (hispanic race); Sex (men); Epigenetic influences
Influence of metabolic factors: Dyslipidemia; Insulin resistance; Type 2 diabetes; Hypertension
Pathological processes: Gut microbiota; Adipokine imbalance; Systemic inflammation; Oxidative stress; Immune system imbalance; Hepatic steatosis

MASLD: Metabolic dysfunction-associated steatotic liver disease.

According to the analyses of a large tertiary care non-alcoholic fatty liver disease (NAFLD) cohort and data from the population-based Nutrition Examination Survey (NHANES III), the comparison of MASLD with NAFLD was found to have very high concordance and almost identical outcomes, but approximately 5% of patients with NAFLD did not meet the criteria for MASLD[2,6]. However, significant limitations exist, and this transition should be taken with caution due to changes in diagnostic criteria, alcohol inclusion, and population categorization. Therefore, this review uses the MASLD nomenclature to refer to previous studies with NAFLD.

MASLD has the potential to advance to MASH, formerly termed non-alcoholic steatohepatitis (NASH), a state in which hepatic fat accumulation is coupled with lobular inflammation (usually in acinar zone 3, and the inflammation is followed by infiltration) and portal inflammation (usually mild), hepatocellular ballooning, with or without fibrosis, and progresses to cirrhosis and HCC, which may culminate in hepatic decompensation and finally death[10,15]. Currently, MASLD represents a significant economic burden on global health, and MASH-related cirrhosis is widely considered to be the primary indication for liver transplantation. HCC ranks as the sixth most prevalent malignancy globally and stands as the fourth chief cause of oncology-related deaths, with MASLD estimated to cause up to 32% of HCC cases[15-17].

Obesity-associated metabolic complications like systemic inflammation, oxidative stress, and insulin resistance, which are interrelated with vascular endothelial dysfunction and promote atherosclerosis, diabetes, and cardiovascular disease (CVD). Importantly, MASLD and CVD share these metabolic complications associated with obesity. Insulin resistance acts as the central pathophysiological bridge between MASLD and CVD by promoting chronic inflammation, atherogenic dyslipidemia, and vascular damage[9,10,18]. Several clinical studies have recognized MASLD as an independent risk factor for CVD, mainly advanced MASLD, and the death of patients with MASLD is caused by CVD rather than MASLD[4,12]. MASLD is associated with the development of several CVDs, including atherosclerotic heart disease, hypertension, valvular heart disease, cardiomyopathy, cardiac valve deformation, left ventricular (LV) diastolic dysfunction (LVDD) and hypertrophy, cardiac valvular calcification, enhanced epicardial fat thickness, cardiac arrhythmias [mainly permanent atrial fibrillation (AF)], and heart failure (HF)[4,6,8,12,19]. It should not be surprising to find a link between MASLD and CVD due to their associations with common metabolic risk factors, including obesity, hyperlipidemia, and diabetes, which may lead to an increased risk of cardiovascular implications. Insulin resistance is probably the main mechanism by which MASLD increases CVD risk, but others play a critical role, such as systemic inflammation, endothelial dysfunction, oxidative stress, adipose tissue dysfunction (dysregulation of adipokines), and atherogenic dyslipidemia, as well as the activation of the renin-angiotensin-aldosterone system (RAAS), intestinal dysbiosis, and genetic and epigenetic factors. Additionally, endothelial dysfunction is a pivotal contributor to the pathogenesis of numerous CVDs, such as hypertension, atherosclerosis, ischemic heart disease, stroke, myocardial infarction, peripheral artery disease (PAD), and HF[4,20,21]. In this review, we discuss the obesity- and diabetes-associated cardiometabolic risk factors connecting MASLD and CVD, with a focus on insulin resistance, systemic inflammation, systemic oxidative stress, and endothelial dysfunction. The CVDs analyzed include hypertension, atherosclerosis, stroke, coronary artery disease (CAD) [also known as coronary heart disease (CHD)], and myocardial infarction.

CARDIOMETABOLIC RISK FACTORS ASSOCIATED WITH MASLD

MASLD is closely related to cardiometabolic risk factors, and these are strongly associated with higher CVD-associated and all-cause mortality risks. Table 3 outlines the relationships and mechanisms connecting these factors.

Table 3 Network of cardiometabolic risk factors between metabolic dysfunction-associated steatotic liver disease and cardiovascular disease.

Factor	Key drivers/mechanisms	Relationship to MASLD and CVD
Obesity and visceral fat	High energy intake leads to hypertrophy of adipocytes in the adipose tissue	BMI and waist circumference positively correlate with MASLD progression. Visceral adipose tissue mediates the majority of cardiometabolic risk by promoting insulin resistance
Insulin resistance	Disruption of metabolic pathways in muscle, liver, and adipose tissue. Driven by hyperinsulinemia and lipotoxicity	Creates a vicious cycle with hepatic steatosis. Insulin resistance exacerbates dyslipidemia and endothelial dysfunction and is the most important factor driving atherosclerotic CVD
Dyslipidemia	Increased VLDL-cholesterol synthesis, elevated triglycerides, and reduced HDL-cholesterol (atherogenic profile)	Enhance atherogenesis. Affects a high percentage of MASLD/MASH patients. Promotes plaque formation and increased risk of myocardial infarction
Systemic inflammation	Secretion of pro-inflammatory adipokines (TNF-α, IL-6, CRP) and reduced adiponectin	Cytokines from the diseased liver drain into circulation, intensifying a systemic pro-inflammatory state that leads to CVD. Promotes vascular injury, atherosclerosis
Oxidative stress	Imbalance between ROS and antioxidants (e.g., low glutathione)	High ROS levels cause mitochondrial dysfunction and hepatocyte apoptosis, leading to fibrosis (MASH). Promotes plaque instability
Endothelial dysfunction	Reduced nitric oxide bioavailability and increased ADMA or endothelin-1	An early event linking MASLD to CVD. Correlates with the severity of liver steatosis and arterial stiffening. Promotes thrombosis
Hypertension	Activation of the RAAS and sympathetic nervous system	Bidirectional relationship: Hypertension aggravates liver damage, while MASLD influences high blood pressure development

VLDL: Very low-density lipoprotein; HDL: High-density lipoprotein; TNF-α: Tumor necrosis factor-alpha; IL-6: Interleukin-6; CRP: C-reactive protein; ROS: Reactive oxygen species; ADMA: Asymmetric dimethylarginine; RAAS: Renin-angiotensin-aldosterone system; MASLD: Metabolic dysfunction-associated steatotic liver disease; BMI: Body mass index; CVD: Cardiovascular disease; MASH: Metabolic dysfunction-associated steatohepatitis.

Obesity is strongly linked to MASLD and CVD

A diagnosis of obesity is established when an individual’s body mass index (BMI) exceeds 30 kg/m². Based on this metric, the condition is categorized into class I (30-34.9 kg/m²), class II (35-39.9 kg/m²), and class III (≥ 40 kg/m²). However, BMI serves as an imperfect metric for obesity, as it fails to account for individual body composition compartments, most notably the relative proportions of fat, muscle, and bone. Consequently, measuring waist circumference (WC) and the waist-to-hip ratio has been proposed to more accurately assess visceral fat volume, as both metrics serve as superior predictors of mortality and morbidity compared to BMI[9,10,22].

Obesity has escalated into an epidemic and emerged as a critical public health challenge, associated with substantial healthcare expenditures across numerous nations. The obesity world federation reported that approximately 2 billion people will be obese by 2035 and that the number of obese children could double by 2035; furthermore, the number of boys could reach 208 million, and the number of girls could increase by 175 million[6,10]. Obese children have a higher risk of cardiometabolic comorbidities and a higher risk of cardiovascular morbidity and mortality in adulthood[23,24]. Individuals with class I obesity have a high/very high cardiovascular risk; this risk escalates to very high for class II and extremely high for class III among Caucasian cohorts[22]. Obesity is an important risk factor for endothelial dysfunction, heart attacks, and cerebrovascular accidents (strokes), the most prevalent forms of CVD[10,20]. Furthermore, the accumulation of surplus ectopic fat within cardiac tissue leads to dilated cardiomyopathy, systolic dysfunction, or both[25]. Furthermore, obesity contributes to the development of systemic oxidative stress and low-grade chronic systemic inflammation due to the accumulation of fat in adipose tissue, whose expansion promotes the secretion of pro-inflammatory adipokines and decreases the release of the anti-inflammatory mediator adiponectin. This microenvironment, together with insulin resistance, is the major factor responsible for the pathogenesis of obesity[9,10]. Obesity is the main risk factor for MASLD, and both BMI and WC are positively correlated with the risk of MASLD development and progression[6,10,11,26]. In line with this, a meta-analysis demonstrated that individuals with obesity face a 3.5-fold higher risk of MASLD development. Furthermore, MASLD prevalence correlates directly with BMI, rising from under 10% in individuals with a healthy weight (18.5-25 kg/m²) to roughly 50% in Americans presenting with a BMI of 35 kg/m²[27,28]. Projections indicate that MASLD affects 80%-90% of obese adults and 40%-70% of obese children. Although 5%-8% of individuals with MASLD are lean, they show insulin resistance and an excess of visceral adipose tissue (VAT)[29-31]. MASLD in lean individuals could be influenced by genetic factors, and the disease is expected to be less severe than in patients with obesity and MASLD[32,33]. Patients with non-obese MASLD exhibited less severe histological features of MASH, a lower frequency of advanced fibrosis, and a decreased prevalence of diabetes[34,35].

Role of visceral adiposity accumulation in MASLD

Excess white adipocyte tissue, in visceral fat depots, induces inflammation by altering adipokine production and can lead to the development of many chronic metabolic diseases, including insulin resistance, metabolic syndrome, T2D, MASLD, MASH, CVD, and certain cancers. Adipose tissue is composed of diverse cell populations, predominantly adipocytes, preadipocytes, endothelial cells, and immune cells. In the context of chronic caloric surplus, this tissue sequesters the excess energy as triglycerides, which triggers either an expansion in cell number (hyperplasia) or an increase in individual cell volume (hypertrophy)[9,10,36]. It is important to note that not all excess fat contributes to disease risk equally; VAT poses a greater clinical threat than subcutaneous adipose tissue (SAT) because visceral adipocytes secrete proteins that drive inflammation, dyslipidemia, hypertension, and atherosclerosis. Studies indicate that visceral fat during obesity mediates the majority of cardiometabolic risk and mortality independent of other cardiovascular risk factors (CVRFs)[2,37]. Using a community-based prospective cohort over a period of 4.6 years, associations between magnetic resonance imaging (MRI)-quantified areas of VAT and SAT and incident MASLD were assessed in 2830 participants aged 55-70 years. The cumulative incidence of MASLD correlated positively with larger areas of both VAT and SAT in both sexes. However, these relationships were more pronounced in males than in females, particularly among individuals under the age of 60[38]. Therefore, this study suggests that it is important to consider sex and age when identifying at-risk populations and preventive and therapeutic strategies for MASLD. Furthermore, VAT demonstrated a significant correlation with hepatic steatosis as quantified by the controlled attenuation parameter, a relationship that remained independent of both BMI and sex[39]. In line with previous studies, VAT, SAT, and fat in muscle compartments are elevated in patients with moderate-to-severe hepatic steatosis relative to those presenting with mild steatosis[40]. Concurrently, separate investigations from Korea and Japan demonstrated an association between VAT and fibrosis severity in individuals with MASLD[41,42]. Preis et al[43] showed a correlation of SAT and VAT with insulin resistance; however, VAT was more strongly correlated with insulin resistance than SAT. The excess VAT was associated with insulin resistance after adjustment for SAT and BMI[43]. A cross-sectional study comprising 100 patients with T2D and 100 non-T2D controls, matched for age, sex, and BMI, reported that the mean liver stiffness measurement was significantly elevated in the T2D cohort (5.53 kPa vs 4.79 kPa, P < 0.001). Furthermore, the VAT area was significantly larger in individuals with T2D than in those without the condition[44]. In patients with T2D, higher VAT independent of BMI was associated with dyslipidemia[45]. Furthermore, the deposition of ectopic fat within the cardiac structure causes dilated cardiomyopathy, systolic dysfunction, or both, whereas fat cell accumulation in peripheral vasculature drives arterial stiffness. Epicardial adipose tissue, situated next to the coronary arteries and myocardium, produces significantly higher concentrations of reactive oxygen species (ROS) than SAT in patients with CVD[46-49]. These studies indicate that the VAT area is an important determinant of hepatic steatosis and the severity of fibrosis in obese individuals.

Obesity-related dyslipidemia contributes to the progression of MASLD and CVD

Dyslipidemia is a recognized pathogenic factor for MASLD and affects 69% of these patients, while in MASH patients it affects 72%. In addition, mixed hyperlipidemia is reported in 50% of individuals with MASLD and isolated hypertriglyceridemia is reported in 27%, whereas hypercholesterolemia is present in 17%, and a trend toward elevated triglyceride levels and reduced HDL-C levels is present in the atherogenic lipid profile of patients with MASLD[5,50]. Among patients with obesity and T2D, those with MASLD exhibit more severe hyperinsulinemia and dyslipidemia, alongside heightened insulin resistance in both adipose and hepatic tissues, relative to their counterparts without MASLD[51]. Dyslipidemia is an important cause of CVD, especially atherosclerotic CVD (ASCVD). Patients with dyslipidemia have an increased risk of hypertension [odds ratio (OR) = 3.05, 95% confidence interval (CI): 2.36-3.90][52]. Within a Japanese cohort, age, obesity (defined as BMI ≥ 25 kg/m²), and hypertriglyceridemia emerged as primary predictors for the onset of hepatic steatosis, with hypertension playing a slightly less significant role[53]. Moreover, fasting hypertriglyceridemia is a predictor of increased risk for cardiovascular mortality (OR = 1.8, 95%CI: 1.31-2.49), cardiovascular events (CVE) (OR = 1.37, 95%CI: 1.23-1.53), and myocardial infarction (OR = 1.31, 95%CI: 1.15-1.49)[54]. In MASLD, the presence of dyslipidemia is associated with the development of CAD. Furthermore, BMI, WC, and levels of triglycerides and gamma-glutamyl transferase serve as reliable indicators for MASLD and its associated comorbidities[55].

The liver is central to lipoprotein metabolism; however, in the context of MASLD, intrahepatic lipid buildup intensifies due to metabolic irregularities. These include heightened lipolysis, increased hepatic uptake of FFAs, and elevated very low density lipoprotein cholesterol (VLDL-C) synthesis, alongside diminished FFA oxidation and triglyceride export. Moreover, individuals with MASLD exhibit a five-fold increase in de novo lipogenesis, which hastens the progression of steatosis, relative to those without the condition. Excess circulating FFAs and triglycerides are the hallmark features of MASLD. Liver fat levels originate predominantly from the accelerated lipolysis of adipose tissue triglycerides, followed by smaller contributions from dietary fats, sugars, and de novo lipogenesis[30,56,57]. Impaired suppression of adipocyte lipolysis and the elevated FFA concentrations associated with abdominal obesity provoke vascular endothelial dysfunction. Hyperinsulinemia also contributes to hepatic de novo lipogenesis, and increased triglyceride synthesis and decreased fatty acid catabolism contribute to MASLD and dyslipidemia. Interestingly, the increased risk of hyperglycemia and dyslipidemia is independent of visceral fat mass in MASLD[21,25]. The association between hepatic lipid content and hyperlipidemia or dyslipidemia has been documented in pediatric and adolescent populations[58]. Specifically, an increased amount of fat in the liver correlated with elevated insulin resistance, triglycerides, and total cholesterol, a relationship that persisted regardless of BMI and even when lipid levels remained within a normal physiological range. Similarly, hepatic steatosis was independently associated with insulin resistance and triglycerides in adolescents with obesity[21]. Additionally, increased concentrations of triglycerides and low-density lipoprotein (LDL) cholesterol, alongside diminished HDL-C levels, are common among children with MASLD[21]. Therefore, MASLD promotes atherogenic dyslipidemia, consisting of elevated levels of triglycerides and LDL-C and a decrease in HDL-C, and a high concentration of apolipoprotein B100, leading to a significantly increased CV risk[56,59]. Increased non-HDL-C/HDL-C levels have been reported to be independently associated with a high risk of MASLD and liver fibrosis in the United States population[60]. A study using lipidomics analysis in obese children with MASLD found in plasma a significant increase in phosphatidylethanolamines and a significant decrease in phosphatidylcholines, lyophosphatidylcholines, and lyophosphatidylethanolamines[61]. Abnormal lipoprotein levels have been reported in MASLD, such as elevated levels of apolipoprotein B100 (atherogenic lipoprotein), apolipoprotein B48 (a major structural component of chylomicrons, and its high levels reflect postprandial lipemia), and apolipoprotein C-III (which potentially facilitates the secretion of chylomicrons and VLDL-C while suppressing the activity of both lipoprotein and hepatic lipases); and decreased levels of lipoproteins such as apolipoprotein A-I (particularly in patients with liver fibrosis, it is the main structural component of HDL-C and important for reverse cholesterol transport) and apolipoprotein F (low levels of hepatic apolipoprotein F expression are related to an atherogenic lipid profile)[62]. The apolipoprotein B/A1 ratio is considered to be predictive of CVD outcomes in patients with overweight or obesity[63]. On the other hand, lipoprotein (a) [Lp(a)] is associated with an increased CVD risk independently of other CVD risk factors, and the presence of MASLD is inversely associated with elevated Lp(a) concentrations[56]. Endothelial function was evaluated via flow-mediated dilation (FMD) alongside measurements of HDL-C and triglyceride levels before and after three sequential meals in men with T2D and metabolic syndrome. The study found that MASLD was linked to postprandial HDL-C-triglyceride enrichment, which correlated strongly with impairments in both HDL-C and endothelial function[64]. Excessive LDL-C particles enter the subendothelial space via the endothelial barrier and are oxidized to form oxidized LDL (oxLDL), promoting an increase in ROS levels, inflammation, and the development of atherosclerotic plaques[56,57]. Specifically, oxLDL causes the lining of the blood vessels (endothelium) to produce adhesion molecules like vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), which recruit inflammatory white blood cells into the vessel wall. Once there, these cells, along with interleukins and other inflammatory signals, encourage vascular smooth muscle cells (VSMCs) to multiply and move. This increases the buildup of fat and fibrous material, leading to the formation of atherosclerosis[65]. The heightened cardiovascular risk observed in individuals with MASLD is, at least in part, attributable to atherogenic dyslipidemia, given that these lipid irregularities serve as independent indicators of CVD-related morbidity and mortality[56]. Therefore, obesity and MASLD are both associated with impaired lipid metabolism.

Systemic inflammation drives the development of MASLD and CVD

Systemic inflammation is common in metabolic disorders, such as MASLD and T2D, and may play a crucial role in the development of MASLD-associated extrahepatic complications. Lipotoxicity, oxidative stress, endoplasmic reticulum (ER) stress, and gut microbiota dysbiosis represent the primary drivers of systemic inflammation. These pathways are further modulated by a person’s unique genetic and epigenetic landscape[21,66,67]. Adipose tissue inflammation is frequently found in abdominal obesity, T2D, and MASLD. This tissue serves a significant endocrine role, discharging a variety of adipokines that include hormones, cytokines, and chemokines[21,66,67]. When adipocytes are hypertrophied by adiposity in adipose tissue, macrophages polarize toward the M1 phenotype and release various adipokines and pro-inflammatory signaling molecules. This triggers a persistent, low-level systemic inflammatory state that facilitates the development of insulin resistance, T2D, and metabolic syndrome[57,66,68]. During the formation of adipocyte hypertrophy in obesity, oxygen delivery to the fat cells can become compromised, resulting in cellular hypoxia, adipocyte death, and the recruitment of macrophages into the adipose tissue. Under these conditions, adipose tissue increases the secretion of pro-inflammatory adipokines, including leptin, plasminogen activator inhibitor 1 (PAI-1), visfatin, and resistin, as well as proinflammatory cytokines [such as tumor necrosis factor (TNF)-α, retinol-binding protein 4, interleukin (IL)-1β, IL-6, IL-8, IL-12, and IL-23]. Regarding the secretion of inflammatory mediators from adipose tissue during MASLD, meta-analytic data show that elevated blood concentrations of C-reactive protein (CRP), IL-1β, IL-6, TNF-α, and ICAM-1 are associated with increased risk of MASLD[69]. Adipose tissue also releases endothelial-derived substances, including ICAM-1, which potentially contribute to the pathogenesis of CVD in individuals with overweight or obesity[25]. TNF-α is derived primarily from macrophages rather than adipocytes; notably, the density of macrophages within fat tissue shows a direct positive correlation with adipocyte volume and overall weight[70]. This cytokine facilitates both the initial development of MASLD and its progression into MASH[67]. Furthermore, in animal models, TNF-α triggers the excessive synthesis of hepatic VLDL-C (containing apolipoprotein B100) by driving liver insulin resistance. Both TNF-α and IL-6 are linked to the presence of hypertriglyceridemia. Inflammatory mediators, including TNF-α, IL-6, IL-1, interferon (IFN)-α, and IFN-γ, trigger triglyceride production in HepG2 cells while promoting lipolysis within adipocytes. In clinical settings, circulating TNF-α and IL-6 show an inverse relationship with HDL-C concentrations in both healthy subjects and CVD patients; conversely, levels of the anti-inflammatory cytokine IL-10 are positively associated with plasma HDL-C. Notably, TNF-α, IL-6, and IL-1 stimulate HepG2 cells to synthesize and release phospholipase A2, an enzyme that hastens atherosclerotic progression, as reviewed previously[67]. During systemic inflammation caused by metabolic disorders (e.g., MASLD) and accumulation of epicardial adipose tissue, inflammatory mediators, such as TNF-α, IL-6, IL-8, and leptin, are released, exacerbating inflammation and negatively affecting the myocardial structure and electrical remodeling, thus increasing the risk of CVD[71,72]. According to a meta-analysis, elevated systemic concentrations of IL-6 and CRP correlate with a heightened susceptibility to AF within the general public and among post-coronary artery bypass graft patients. These biomarkers also serve as indicators for AF relapse following catheter ablation or electrical cardioversion[73]. Furthermore, the absence of IL-6 diminishes LV hypertrophy and the dysfunction typically induced by pressure overload, suggesting that IL-6 signaling plays a vital role in the enlargement of cardiac myocytes. In clinical practice, systemic concentrations of both IL-6 and high-sensitivity CRP (hs-CRP) serve as independent predictors of CVD risk[4]. In line with this, elevated IL-6 levels in obese individuals aggravate insulin resistance and CVD risk in those subjects[25]. Conversely, leptin facilitates the synthesis of various pro-inflammatory cytokines, including TNF-α, IL-2, IL-6, IL-18, and IFN-γ. This hormone is a marker of obesity and its comorbidities, such as T2D and CVD, with angiogenic and atherogenic effects and prothrombotic activity[25]. Leptin has several roles; in MASLD, it activates adenosine monophosphate-activated protein kinase in hepatic cells, a process that facilitates lipid β-oxidation and glycolysis while suppressing lipogenesis. Meanwhile, leptin-deficient mice did not progress to fibrosis during diet-induced steatohepatitis or following chronic toxic liver damage (via carbon tetrachloride); additionally, they showed no upregulation of collagen-I despite experiencing hepatic injury comparable to their genetic counterparts[67,74]. In the context of obesity, elevated leptin levels have been linked to extended platelet aggregation, arterial thrombosis, and reduced arterial compliance, alongside the stimulation of VSMC migration and proliferation. PAI-1, a factor that inhibits fibrinolysis, is secreted by the liver and VAT. Working in conjunction with inflammatory mediators like IL-6, TNF-α, and CRP, it drives oxidative stress and endothelial impairment, ultimately fostering the development of atherosclerosis and CVD[25]. Systemic insulin resistance in obese individuals with MASLD is associated with increased plasma PAI-1 levels. Furthermore, abundant expression of pro-inflammatory macrophages and cluster of differentiation (CD) 4+ and CD8+ T-cells, as well as several pro-inflammatory cytokines, has been described in the subcutaneous abdominal adipose tissue of obese patients with MASLD[75]. Low adiponectin levels are an independent risk factor for MASLD; they are inversely associated with MASLD and predicts its grade and severity. Circulating adiponectin concentrations exhibit an inverse relationship with triglycerides and a direct correlation with HDL-C. Furthermore, diminished adiponectin levels are linked to the presence of CVD, T2D, and dyslipidemia. Adiponectin regulates fat lipid metabolism by inhibiting lipolysis and enhancing the oxidation of fatty acids and the uptake of glucose via adenosine monophosphate-activated protein kinase activation in skeletal muscle and hepatic tissues; this process, in turn, optimizes insulin sensitivity and lipoprotein profiles. Systemic adiponectin concentrations show a direct positive relationship with insulin sensitivity. A decreased adiponectin level may contribute to the development of necroinflammatory forms of MASLD. Furthermore, adiponectin induces activation of lipoprotein lipase, thus enhancing VLDL-C clearance and decreasing plasma triglyceride levels. Therefore, it exhibits a protective role against insulin resistance, CVD, and atherosclerosis. Adiponectin also decreases the inflammation in macrophages, epithelial cells, and vascular smooth muscle[67,76-79]. Increased serum resistin in MASLD is related to liver disease severity[67]. MASLD, regardless of whether it is graded as mild or moderate-to-severe, serves as an independent predictor of elevated hs-CRP and fibrinogen concentrations. Furthermore, cardiovascular risk scores are significantly linked to the simultaneous presence of MASLD and increased levels of these inflammatory markers. In addition, the presence of more pronounced low-grade inflammation, quantified by fasting serum hs-CRP, serves as an independent predictor of elevated cardiometabolic risk. In children with overweight or obesity, this inflammatory state also correlates with more advanced insulin resistance, dyslipidemia, and MASLD[21,80].

Excessive hepatic lipid accumulation induces oxidative stress and lipid peroxidation, triggering the release of inflammatory mediators, including IL-6, TNF-α, fetuin-A, CRP, and fibrinogen. The lipid accumulations include FFAs, diacylglycerols, ceramides, and long-chain fatty acyl-coenzyme A synthetase (ACS), which culminate in inflammation within hepatocytes. In MASLD, hepatic lipogenesis is activated, and its main product is the saturated fatty acid palmitate, which induces inflammation and ER stress. Furthermore, elevated hepatic lipogenesis exhibits a robust association with insulin resistance and an unfavorable cardiometabolic risk profile[11,55,81]. In the fatty liver, FFAs induce TNF-α expression through activation of nuclear factor-kappa B (NF-κB), which, along with the release of inflammatory mediators from dysfunctional adipose tissue, such as monocyte chemoattractant protein-1 (MCP-1), IL-6, and TNF-α, and gut-derived endotoxins in diabetic patients with MASLD, activates Kupffer cells and release more hepatic inflammatory mediators (IL-1β, IL-6, and TNF-α) to promote liver damage and inflammation. Hepatocellular injury further promotes apoptotic and necrotic death pathways in the hepatocytes, and the persistence of this pathological process ultimately leads to hepatic stellate cell activation, collagen deposition, and liver fibrosis (MASH)[11,30,59]. It is understandable that cytokines released by the diseased liver drain into the systemic circulation and intensify the obesity-induced pro-inflammatory state, further increasing the risk of ASCVD. TNF-α facilitates programmed cell death (apoptosis), new blood vessel formation (angiogenesis), and blood clot development (thrombogenesis) within both endothelial cells and myocytes, indicating their involvement in the pathogenesis of cardiac diseases. IL-1β triggers endothelial inflammation and enhances the autocrine release of platelet-derived growth factor, thereby driving smooth muscle cell proliferation and the pathogenesis of atherosclerosis. Furthermore, IL-1β prompts the production of IL-6 within smooth muscle cells and various other cell types, a process linked to an elevated risk of CVD. Within hepatocytes, IL-6 induces the synthesis of PAI-1 and fibrinogen, which together facilitate the development of thrombi. Additionally, IL-6 prompts macrophages to release the chemokine IL-8, an action that triggers angiogenesis and the development of arterial plaques. Fetuin-A, a 64-kDa glycoprotein primarily synthesized by the liver and secreted into the bloodstream, serves as a vital in vivo inhibitor of vascular calcification. Nevertheless, fetuin-A levels correlate with endothelial impairment and carotid atherosclerosis, as well as an increased susceptibility to T2D, ischemic stroke, and myocardial infarction[21,55,81-83]. Consistent with this, the blockade of these signaling cascades and the mitigation of inflammation related to obesity can ameliorate cardiomyopathy, myocardial infarction, and atherosclerosis in animal studies. In a similar fashion, obstructing NF-κB-driven inflammatory signaling has been demonstrated to alleviate cardiac damage within mouse models of MASH[21]. Taken together, these data provide evidence that inflammatory markers from adipose tissue and liver under conditions of obesity and MASLD act synergistically to contribute to the observed systemic inflammation and connect MASLD to CVD.

Role of oxidative stress in MASLD and CVD

Oxidative stress reflects an imbalance between ROS and cellular antioxidant defense, leading to a failure of cellular functions and eventually cell death. There are several cell types that are sources of ROS, including phagocytic cells, VSMCs, endothelial cells, and mononuclear cells. Specifically, multiple organelles and molecules generate ROS in the cell, including mitochondria, ER, peroxisomes, and lysosomes, as well as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), cytochrome P450 enzymes, xanthine oxidase, endothelial nitric oxide synthase (eNOS), myeloperoxidase, cyclooxygenases, lipoxygenases, and heme proteins[49,84-87]. To mitigate the effects of ROS, cells employ various antioxidant defense mechanisms. These encompass enzymatic systems like catalase, glutathione peroxidase (GPx), thioredoxin reductase, and superoxide dismutase (SOD), the latter of which exists in three isoforms: Copper (Cu)/zinc (Zn) SOD, manganese SOD, and extracellular SOD. Additionally, antioxidant molecules such as glutathione, coenzyme Q, and vitamins A, B1, B2, and C play a crucial role in these strategies[85,86]. High levels of ROS are generated by the deterioration of the electron transport chain, which leads to a leakage of electrons that react with oxygen to generate superoxide anion (O₂^-). Due to leakage of electrons, the membrane potential dissipates, causing a decrease in adenosine triphosphate synthesis. ROS interact with various biomolecules, leading to structural and functional impairments; specifically, they target proteins to form carbonyls, lipids to generate malondialdehyde (MDA) and 4-hydroxynonenal, and DNA to produce 8-hydroxy-2’-deoxyguanosine[87,88].

Obesity contributes to the development of systemic oxidative stress and demonstrates a direct correlation with adipose tissue volume in both human and rodent populations. Central adiposity is correlated with reduced antioxidant capacity in obese adults. Furthermore, SOD and GPx activities are reduced in obese individuals compared to non-obese individuals. In the plasma of adult patients with morbid obesity, there is an impaired antioxidant capacity. The primary catalysts for oxidative stress stemming from obesity likely involve modified nutritional states, chronic inflammatory processes, and elevated levels of blood glucose and lipids. For instance, in cultured adipocytes with hyperglycemia, ROS accumulation is strongly induced. In line with this in vitro study, streptozotocin-treated hyperglycemic mice show enhanced oxidative DNA damage in adipose tissue. Therefore, an influx of excess nutrients elevates the mitochondrial substrate load in adipocytes, increasing the production of ROS. Under obesity, an excess of FFAs like palmitate drives ROS production through the protein kinase C (PKC)-dependent activation of NADPH oxidase within endothelial and smooth muscle cells. This heightened ROS generation is further linked to the abnormal expression of adipokines in adipose tissue. Moreover, adipose tissues in obese individuals exhibit elevated levels of mitochondrial oxidative stress markers, specifically lipid peroxidation products, protein carbonyls, and MDA[49,89,90]. Meanwhile, in obese mice, adipose tissue shows increased expression of NADPH oxidase and decreased SOD and GPx, leading to lipid peroxidation and elevated hydrogen peroxide production. Therefore, NADPH oxidase is involved in the elevation of ROS generation in obese adipose tissue, and NOX4 is particularly crucial for ROS production in adipocytes[89]. Oxidative stress and inflammation are closely related. Oxidative stress activates the NF-κB and mitogen-activated protein kinase (MAPK) pathways, which suppresses anti-inflammatory adipokines while boosting the expression of pro-inflammatory cytokines within adipose tissue[49]. In patients with MASLD, a reduction of antioxidant capacity in hepatocytes was reported. The enzymatic (catalase, CuZn-SOD, and GPx) and non-enzymatic antioxidant systems (glutathione, thioredoxin, α-tocopherol, and coenzyme Q10, or ubiquinone) are reduced in the serum, plasma, and liver[87,91], while other studies reported unchanged or elevated expression of antioxidant capacity in early MASLD and advanced MASLD[86]. The ratio of oxLDL/oxidized HDL (oxHDL) is strongly associated with MASLD in adults, and oxLDL is involved in the development of CVD in adults with MASLD[92,93]. An elevated oxHDL and oxHDL/HDL-C ratio in adolescents with MASLD compared to their peers without MASLD but with obesity or normal weight suggests increased oxidative stress in adolescents with MASLD that is independent of obesity, suggesting a potential increased risk of CVD[94]. Independent of metabolic syndrome, diabetes, and obesity, individuals with MASLD exhibit elevated oxidative stress biomarkers, specifically serum soluble NOX2-derived peptide and urinary 8-iso-prostaglandin F_2α. Furthermore, these levels demonstrate a positive correlation with the progression of hepatic steatosis severity[95]. In a cross-sectional study, elevated oxidative stress markers (assessed as the oxidative stress index) in obese adolescents with MASLD were associated with insulin resistance[90]. Moreover, elevated oxidative stress was independently associated with MASLD in Asian Indians without and with T2D[96]. The antioxidant glutathione, a tripeptide synthesized from the amino acids cysteine, glycine, and glutamic acid, has been reported to be low in the liver of MASLD patients and further decreased by insulin resistance[4]. Research indicates that circulating fetuin-A concentrations are elevated in diabetic individuals concurrently affected by MASLD. ER stress is frequently observed in the hepatic tissue of obese subjects; notably, ER stress triggered by elevated palmitate and glucose levels upregulates fetuin-A expression, thereby promoting the progression of insulin resistance[97,98]. Overproduction of ROS and oxidative stress caused by triglycerides and FFAs in the liver can lead to hepatic inflammation, mitochondrial dysfunction, hepatocyte apoptosis, and activation of stellate cells leading to fibrogenesis (MASH). Furthermore, de novo lipogenesis in the liver has also been related to ER stress in hepatocytes[84,87,98]. During MASLD, nuclear factor erythroid-derived 2-like 2 (Nrf2), a transcriptional regulator of antioxidant proteins (e.g., glutathione and thioredoxin), is downregulated, promoting the progression of fatty accumulation, inflammation, and fibrosis in the liver[4,87,99,100].

Oxidative stress and inflammation have been shown to decrease cardiac contractility in preclinical studies. These pathological mechanisms are linked to both diastolic and systolic impairment in MASLD patients, ultimately resulting in compromised cardiac contractility. In addition, oxidative stress impairs the function of the β-adrenergic receptor system, causing cardiomyocyte apoptosis, thus affecting the cardiovascular system in MASLD. Oxidative stress drives programmed cell death in cardiomyocytes via signaling cascades involving the activation of protein kinase B (Akt/PKB), p38, c-Jun N-terminal kinase (JNK), and extracellular regulated protein kinases 1/2[87]. Numerous studies indicate that oxidative stress plays a pivotal role in triggering the molecular signaling pathways responsible for cardiac hypertrophy, remodeling, and programmed cell death. Oxidative stress contributes to hypertension, dyslipidemia, diabetes, atherosclerosis, myocardial infarction, angina pectoris, HF, cardiac arrhythmia, and ischemia-reperfusion injury[85,87].

Insulin resistance and diabetes are a central link between MASLD and CVD

The main insulin-resistant tissues are skeletal muscle, liver, heart, and adipose tissue. During nutrient intake, insulin is released from the pancreas, and signals are sent to the liver, which promotes de novo lipogenesis, suppresses fatty acid oxidation, and induces triglyceride esterification and secretion; however, in insulin resistance, these metabolic pathways are disrupted. Various mechanisms and conditions have been implicated in insulin resistance, including elevated levels of leptin and reduced levels of adiponectin, as well as inflammation, mitochondrial dysfunction, hyperinsulinemia, lipotoxicity, and gut dysbiosis, which are related to obesity[2,9,21,73]. Insulin resistance is driven by various enzymes, including PKC, JNK-1, and inhibitor of kappa kinase beta (IKK-β). These enzymes catalyze the serine phosphorylation of insulin receptor substrate (IRS) at particular serine and threonine residues. This modification impairs glucose uptake and glycogen synthase activity while reducing the phosphorylation of forkhead box protein O, ultimately triggering hepatic gluconeogenesis. Moreover, inflammatory mediators like IL-6, IL-1β, and TNF-α can trigger the serine phosphorylation of IRS-1 via the mammalian target of rapamycin, S6K, IKK-β, and JNK-1 pathways, thereby promoting the onset of insulin resistance. TNF-α and IL-6 also stimulate the NF-κB pathway, which upregulates mediators of inflammation that cause insulin resistance[25,101,102]. In the liver, mammalian target of rapamycin complex 1 is critical for lipid biosynthesis because it is involved in insulin signaling. When surplus carbohydrates and triglycerides build up within adipose and hepatic tissues, insulin binds to its receptor to trigger a signaling cascade that stimulates phosphatidylinositol 3-kinase (PI3K), which in turn activates protein kinase B (Akt/PKB). Following this, Akt enhances the transcription of genes involved in lipid synthesis, glycolysis, and the absorption of glucose[103]. The process of lipolysis, typically suppressed by insulin, becomes hyperactive during insulin-resistant conditions, leading to an elevation in FFA concentrations, most notably diacylglycerol, ceramides, and acyl-CoAs. These have been reported to exacerbate the inhibition of insulin signaling by activating protein kinases such as PKC, JNK-1, and IKK-β. Furthermore, when FFAs accumulate in the liver and induce gluconeogenesis and VLDL-C overproduction, they also induce mitochondrial β-oxidation to limit FFAs that increase hepatic oxidative stress and liver damage, including mitochondrial dysfunction and ER stress, and finally aggravate insulin resistance[101,102]. Results from a cross-sectional serum analysis indicate that heightened oxidative stress biomarkers in obese adolescents suffering from MASLD are linked to the presence of insulin resistance[90]. In liver biopsies obtained from 37 obese and nondiabetic individuals, the concentration of diacylglycerol within cytoplasmic lipid droplets correlates with insulin resistance and demonstrates a robust correlation with the activation of hepatic PKC-ε[104]. When insulin resistance is established in the liver or T2D conditions, there is hyperinsulinemia and hyperglycemia, consequently driving de novo lipogenesis through two pathways: Insulin-mediated activation via sterol regulatory element-binding protein-1c (which increases the expression of critical lipogenic genes like stearoyl-CoA desaturase, acetyl-CoA carboxylase, and fatty acid synthase) and glucose-mediated activation via carbohydrate response element binding protein (which triggers genes such as acetyl-CoA carboxylase, fatty acid synthase, and liver pyruvate kinase); as a result, hepatic de novo lipogenesis is significantly accelerated in MASLD patients[4,59,102]. Therefore, there is a vicious cycle between hepatic steatosis and insulin resistance, which drives further fat accumulation in the liver, leading to both MASLD and T2D.

Insulin resistance affects enzymes such as lipoprotein lipase and hepatic lipase; individuals with greater insulin resistance have lower circulating levels of lipoprotein lipase and higher levels of hepatic triglyceride lipase, while increased hepatic lipase activity has been reported in obesity and insulin resistance states. Therefore, low levels of lipoprotein lipase activity increase VLDL-C and intermediate-density lipoprotein cholesterol and reduce HDL-C. Furthermore, increased hepatic lipase activity associated with insulin resistance may increase atherogenic lipoproteins and small-dense LDL[105-108]. Of note, there are controversial studies suggesting that MASLD can develop in the absence of obesity and insulin resistance. However, alternative research has underscored that insulin resistance remains a defining attribute of MASLD, even among individuals with a lean body habitus[55,59]. In fact, insulin resistance predicts the development of MASLD in young people and is probably the most important factor driving liver inflammation that leads to fibrosis in addition to genetic factors. Patients with T2D have a higher rate of MASLD, MASH, and advanced fibrosis compared to non-diabetic individuals[109-111]. The occurrence of single nucleotide polymorphisms within the patatin-like phospholipase domain-containing protein 3 (PNPLA3) could be related to the role of insulin in the development of MASLD. Other genetically determined risk factors for MASLD include transmembrane 6 superfamily member 2 protein (TM6SF2), glucokinase regulatory protein (GCKR), protein phosphatase 1 regulatory subunit 3B (PPP1R3B), lysophospholipase-like 1 (LYPLAL1), membrane-bound O-acyltransferase domain-containing 7 (MBOAT7), and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13). These genes regulate the mobilization of triglycerides from lipid droplets (PNPLA3), secretion of LDLs (TM6SF2), de novo lipogenesis (GCKR), regulation of liver glycogen metabolism (PPP1R3B), lipid metabolism and fat distribution (LYPLAL1), hepatic phosphatidylinositol acyl-chain remodeling (MBOAT7), and bioactive lipid and estradiol signaling (HSD17B13)[6,11,59]. In a cohort of Chinese adults, the PNPLA3 GG genotype was found to synergize with body weight fluctuations to worsen hepatic steatosis; conversely, it appeared to lower the risk of developing T2D among metabolically unhealthy individuals, defined by a homeostatic model assessment of insulin resistance (HOMA-IR) of at least 2.5 or central obesity (WC ≥ 90 cm for men and ≥ 80 cm for women)[112]. A study reported that obese patients with MASLD showed insulin resistance in adipose tissue, liver, and skeletal muscle, and patients with greater insulin resistance in adipose tissue tended to have more severe liver fibrosis (but not necroinflammation)[113]. Furthermore, insulin resistance within adipose tissue serves as a predictor for the degree of liver fibrosis in individuals with both MASLD and T2D[114]. While MASLD is frequently linked to insulin resistance and abdominal obesity, it is the underlying metabolic dysfunction, rather than the accumulation of liver fat itself, that accounts for the cardiovascular risk in this population[115]. Importantly, insulin resistance exacerbated by MASLD predisposes patients to atherogenic dyslipidemia, the production of pro-inflammatory, profibrogenic, and vasoactive mediators, which can contribute to cardiac and arrhythmic disorders. Furthermore, insulin resistance is the most important factor driving ASCVD. It should be noted that the metabolic dysfunction itself, rather than hepatic steatosis, may explain the cardiovascular risk in these individuals. Insulin resistance compromises the release of endothelial nitric oxide, exacerbates oxidative stress within the endothelium, intensifies mitochondrial dysfunction, and amplifies the inflammatory response; all these alterations lead to endothelial dysfunction and vascular remodeling. Insulin resistance can induce cardiac hypertrophy, which disrupts normal myocardial function and accelerates myocardial strain and HF[20,21].

T2D is characterized by deficient insulin production alongside insulin resistance in peripheral tissues, specifically the liver, adipose tissue, and skeletal muscle. In obese populations, the condition arises when pancreatic β-cells fail to compensate for diminished insulin sensitivity, resulting in elevated blood glucose. As of 2022, the global prevalence among adults reached roughly 828 million, a surge of 630 million cases since 1990. In this year, the age-standardized diabetes prevalence in the world was around 14% for both women and men[25,116]. Typically, MASLD and T2D coexist and act synergistically to drive adverse outcomes in patients. MASLD increases the risk of developing T2D twofold over a median period of five years. It has been reported that 78% of patients with MASLD develop T2D or impaired glucose tolerance, and individuals with MASLD and diabetes have a 2-4-fold increased risk of CVD. In this respect, MASLD in patients with diabetes makes it difficult to achieve good blood glucose control, which can accelerate extrahepatic complications. T2D accelerates the advancement of MASLD into more critical hepatic conditions, including MASH, cirrhosis, and HCC. T2D can increase the risk of CVD by promoting increased levels of oxidative stress and inflammation. It is noteworthy that T2D operates in tandem with hypertension and obesity to heighten the likelihood of CVD[29,50,59]. The link between T2D and MASLD was first identified following observations that elevated alanine aminotransferase (ALT) levels served as a predictor for future T2D in Pima Indian populations[117]. In addition, another cohort study also reported that aspartate aminotransferase (AST) and ALT independently predict T2D[118]. However, the majority of patients with T2D and MASLD (between 80% and 85%) have normal serum levels of liver enzymes; this aligns with previous research indicating that MASH, extensive fibrosis, or cirrhosis can occur even when liver enzyme concentrations appear relatively standard, as reviewed by Anstee et al[119]. A study showed that serum leptin and leptin resistance correlate with MASLD in patients with T2D[120]. Of note, patients with MASLD have twice the risk of developing T2D than those without MASLD. This risk escalates in correlation with rising liver fat and fibrosis scores; notably, the co-existence of insulin resistance, MASLD, and an elevated BMI (overweight or obesity) amplifies the likelihood of developing T2D fourteenfold. The worldwide prevalence of MASLD in T2D was reported to be as high as 55%, with the highest rates in Europe (68%) and West Asia (67%), while the lowest prevalence was in Africa (30%), 78% of obese patients with T2D have MASLD, while 37% of patients with T2D have MASH, respectively. Additionally, in patients with both T2D and MASLD who were evaluated via biopsy, the calculated prevalence of advanced hepatic fibrosis reached 17%[11,57,102,121]. Among individuals with T2D, MASLD is robustly linked to microvascular diabetic sequelae, including chronic renal disease and proliferative or laser-managed retinopathy. MASLD is also independently associated with early LVDD in patients with T2D[119,122]. Several studies have shown an association between MASLD and CVD risk in patients with diabetes[123-126], while other studies reported no association[127,128]. Possible explanations for these controversial findings could be the small sample size, diagnostic methods for MASLD, comorbidities, study duration, and follow-up periods. On the other hand, MASLD increases the risk of death among patients with T2D, with advanced age, high CRP, CVD, chronic kidney disease, high fibrosis-4 (FIB-4), and active smoking being independent predictors of mortality among those with MASLD and T2D. The most common causes of death in patients with MASLD with T2D are malignancy, liver-related complications, and ischemic heart disease. Individuals with MASLD and diabetes, whether lean or obese, have increased risks of all-cause mortality and CVD-related mortality[129-131]. Of concern, both T2D and MASLD are increasingly prevalent in young adults under 40 years of age, with deaths from T2D and MASLD projected to increase by 158.6% and 158.4%, respectively, between 2019 and 2050[57]. Therefore, it is recommended to screen patients with MASLD for T2D and evaluate patients with MASLD and diabetes, regardless of the presence of obesity, to be considered for therapy and avoid the risk of death among these patients.

Endothelial dysfunction is an early event in the link between MASLD and CVD

Endothelial dysfunction is defined by the diminished synthesis and bioavailability of nitric oxide (NO), a molecule known for its anti-atherogenic properties, with the presence or absence of an imbalance between endothelium-derived contracting and relaxing factors. The development of this pathological condition is influenced by a decrease in NOS, an increase in asymmetric dimethylarginine (ADMA), elevated blood homocysteine, reduced vascular tone, and increased oxidative stress. Several pathophysiological conditions can alter endothelial function, including hypercholesterolemia (e.g., oxidatively modified lipoproteins), hyperglycemia (advanced glycation end products, ROS), metabolic syndrome (e.g., advanced glycation end products, ROS, adipokines), hypertension (e.g., angiotensin-II, ROS), aging (e.g., advanced glycation end products, cell senescence), pro-inflammatory cytokines (e.g., IL-1β, IL-6, CRP, TNF-α), and exposure to specific drugs (e.g., psychostimulants, chemotherapy drugs, high-dose steroids), which can induce molecular mechanisms that regulate NO bioavailability[65,82,132]. Furthermore, activated lipolysis in adipose tissue and high FFA levels observed in abdominal obesity promote vascular endothelial dysfunction, while the accumulation of fat cells in peripheral vessels causes an increase in vascular stiffness. Numerous inflammatory cytokines induced during obesity can cause endothelial dysfunction and induce atherogenesis and thromboembolism. In addition, elevated leptin concentrations during obesity act on adrenal gland receptors to trigger aldosterone release, which causes salt and water retention; consequently, obesity facilitates hypertension and endothelial impairment driven by leptin-induced aldosterone secretion. Obesity also promotes vascular hyperreactivity to angiotensin II and increases endothelin 1 levels, potentially leading to vasoconstriction, inflammation, and even vascular remodeling[21,25]. Markers of blood vessel damage, specifically PAI-1 and von Willebrand factor, decline after weight loss. This shift strongly indicates that the health of the endothelium is improving[133]. There are various techniques to detect endothelial function, and FMD is one of the most widely used. This technique assesses endothelium-dependent vasodilation by utilizing an ultrasound transducer to measure the response following a stimulus of transient shear stress. Numerous studies have been conducted evaluating the association of MASLD and FMD, including meta-analysis, which have reported that patients with MASLD exhibit a significant reduction of FMD (endothelial dysfunction) and a marked impairment in brachial artery flow-mediated vasodilation relative to healthy control subjects. This reduction correlates with the histological features of MASLD. Furthermore, endothelial dysfunction is present in both the portal vein and the systemic circulation, and MASLD has been identified as an independent determinant of FMD in multivariate analysis[55,134-137]. It seems that endothelial dysfunction may depend on the stage of steatosis. However, it could imply that the liver disease and vascular damage are concurrent results of a systemic inflammatory environment rather than a linear cause-effect chain. In this regard, obese children with simple steatosis, unlike those with steatohepatitis, appear to have intact vascular function. Crucially, increased levels of hepatic steatosis correlate with more profound endothelial impairment as measured by FMD; furthermore, FMD values are significantly diminished in patients with MASH compared to those with isolated steatosis[134,138,139]. Patients with MASLD and endothelial dysfunction show elevated levels of E-selectin, impaired eNOS, accumulation of endothelin-1, and ADMA (an endogenous inhibitor of eNOS), indicating diastolic dysfunction and a positive link to CVD[21,140]. Endothelin-1 triggers vasoconstriction, increases vascular smooth muscle tone, and stimulates the proliferation of these cells while promoting inflammation, thrombosis, and the uncoupling of eNOS. During uncoupling, eNOS-derived NO interacts with surplus superoxide (O₂^-), producing peroxynitrite (ONOO^-). As a highly reactive oxidant with cytotoxic effects, peroxynitrite encourages vasoconstriction and reduces NO bioavailability, thereby impairing vasodilation and driving endothelial dysfunction. During MASLD, systemic inflammation triggers the synthesis and release of various cardiokines, including transforming growth factor-β1, angiotensin II, endothelin-1, and urotensin II; the elevation of these factors is directly linked to the generation of ROS. In addition, endothelin-1 enhances the expression and function of arginase-2 within both endothelial cells and macrophages. This upregulation facilitates the production of ROS in the vascular lining, triggering inflammation and disrupting vascular tone in individuals with MASLD. By competing with eNOS for its shared substrate, L-arginine, arginase-2 effectively limits the bioavailability of NO. Angiotensin II is a potent activator of NADPH oxidase 1 and 2 (NOX1 and NOX2) in the endothelium and heart, contributing significantly to ROS production. Patients with MASLD have high activity of NOX1 and NOX2, major players in endothelial O₂^- formation and H₂O₂ production. Elevated intraluminal pressure due to obesity-related hypertension can also promote the formation of O₂^- and ONOO^-. Angiotensin II further exacerbates endothelial impairment through its vasoconstrictive properties, which diminish soluble guanylyl cyclase levels and subsequently disrupt the NO/cyclic guanosine monophosphate signaling pathway[62,87,141]. As the primary site for homocysteine production within the methionine cycle, the liver plays a critical role in MASLD; consequently, the elevated homocysteine levels found in these patients may facilitate injury to both cardiomyocytes and the endothelial lining. Consequently, elevated homocysteine concentrations represent an additional etiological driver of endothelial impairment in MASLD, as they inhibit the synthesis of NO. Furthermore, intrahepatic dysfunction is also described in MASLD; however, it occurs in the absence of inflammation or fibrosis, which may suggest an early event that could drive disease progression[62,82,142].

Under physiological conditions, insulin can participate in the production of NO that mediates the vasodilatory, anti-inflammatory, and antithrombotic effects of a healthy endothelium. However, insulin resistance is associated with endothelial dysfunction, which is a major pathogenic factor in arterial hypertension, atherosclerosis, and CAD. Furthermore, endothelial insulin resistance is linked to diabetic cardiovascular complications, including atherosclerosis. FMD has also been associated with an elevated risk of acute coronary syndrome and ischemic stroke[21,87,143,144]. A significant consequence of hepatic insulin resistance is its physiological link to vascular insulin resistance. Mice with liver-specific insulin receptor knockout subsequently developed aortic insulin resistance, as well as endothelial dysfunction and inflammation, which was associated with the downregulation of both the PI3K/Akt/eNOS and p42/44 MAPK signaling cascades[145]. In insulin resistance, the PI3K/Akt pathway is impaired, while other pathways related to insulin signaling remain unaltered, including the Ras/MAPK pathway, resulting in an imbalance between insulin functions conducted by the PI3K pathways and MAPK. This alteration promotes reduced eNOS activation and therefore decreased NO production, resulting in endothelial dysfunction. Moreover, while the lack of insulin receptors specifically in the endothelium does not alter lipid profiles or systemic insulin sensitivity, it significantly accelerates atherosclerosis through the inactivation of eNOS. In line with this, obesity-centered therapies that aim to enhance insulin sensitivity are frequently linked to the restoration of endothelial function or augmented vascular insulin sensitivity[4,143,146]. A study explored FMD in patients with T2D with and without MASLD and reported that MASLD is associated with endothelial dysfunction in patients with T2D[147]. Endothelial dysfunction has been reported in several models of liver disease, including cirrhosis, ischemia-reperfusion, and endotoxemia. Intrahepatic and mesenteric endothelial dysfunction is also well known. Patients with MASLD show marked eNOS dysfunction and endothelial dysfunction, which may contribute to increased cardiovascular risk and CVE (e.g., atherosclerosis), the latter caused by portal hypertension originating from vascular hypertension that is favored by endothelial dysfunction. Maintaining endothelial wall integrity is a cornerstone of prevention against atherosclerotic vascular disease. While circulating bone marrow-derived endothelial progenitor cells (EPCs) typically repair damage to the endothelial monolayer, MASLD patients exhibit reduced plasma EPC concentrations, which are linked to increased arterial stiffness and impaired endothelial function[82,87,143,148-150]. The pro-inflammatory state and elevated oxidative stress in individuals with MASLD may cause endothelial dysfunction and induce vascular inflammation, which promotes atherosclerotic plaque formation and the activation of mechanisms that can lead to changes in cardiac structure and diastolic dysfunction. In summary, NO plays a critical role in modulating vascular tone, preventing platelet aggregation, and limiting the proliferation of VSMCs. Compromised endothelium-mediated vasodilation has been documented in the renal, coronary, and forearm vessels of individuals suffering from hypertension, dyslipidemia, diabetes, and CAD[85,151]. Therefore, assessment of endothelial dysfunction in patients with MASLD is essential for the prevention of systemic cardiovascular damage.

Hypertension and MASLD exhibit a bidirectional relationship

Hypertension is a multifaceted condition resulting from the intricate interplay of genetic, epigenetic, and environmental influences. It is characterized by increased systemic arterial pressure and can significantly affect several vital organs, including the heart, brain, and kidneys. Estimates suggest that hypertension affects 31.5% of the adult population in low- and middle-income nations (totaling 1.04 billion), compared to a prevalence of 28.5% in high-income countries (amounting to 349 million). Hypertension is the leading cause of mortality and disability worldwide, accounting for 14% of all deaths. This disease is closely related to metabolic disorders such as obesity, hyperglycemia, and dyslipidemia, forming metabolic syndrome[152,153]. Hypertension and MASLD have a bidirectional relationship independent of traditional cardiometabolic risk factors: While hypertension could aggravate the progression of liver damage, MASLD could influence the development of hypertension[14,154]. Several studies have shown an association between MASLD and hypertension, but these studies have considerable heterogeneity in the criteria used for the diagnosis of MASLD. Notably, two prospective epidemiological studies conducted in France and Germany with follow-up period of 9 years and 5 years, respectively, concluded that patients with MASLD have a 2-3 higher higher risk of developing hypertension[155-158]. However, because hypertension also aggravates liver damage, it is unclear if MASLD is a direct cause or a parallel manifestation of shared metabolic dysfunction. A retrospective cohort study reported that the development of incident MASLD is associated with an increased risk of hypertension even after adjustment for multiple confounders (OR = 1.60, 95%CI: 1.30-1.96; P < 0.001)[159]. In addition to primary hypertension, MASLD is also associated with secondary hypertension. Individuals with MASLD exhibit a greater frequency and higher risk of chronic kidney disease, a condition in which enduring renal damage leads to the development of severe hypertension[160]. Individuals with hypertension have a 50% risk of developing MASLD, and 40%-60% of people with MASLD have hypertension, while patients with MASH have 68% hypertension. Interestingly, patients with hypertension have higher levels of liver fat than those without hypertension. The prevalence and incidence of hypertension increase with fibrosis progression, as reported in an Italian study, a large meta-analysis, and NHANES data, reaching peak frequency and occurrence among those with F4 fibrosis (cirrhosis); furthermore, the presence of both MASLD and hypertension concurrently exerts a more profound influence on the likelihood of fibrosis development[6,160-164].

MASLD may induce systemic inflammation, activation of the RAAS-sympathetic nervous system (SNS), and insulin resistance, all of which contribute to the development of hypertension. Leptin-mediated sympathetic activation is implicated in obesity-induced hypertension. Furthermore, decreased adiponectin levels and increased leptin levels in patients with MASLD may contribute to the increase in blood pressure. RAAS activation and angiotensin II are critical mediators of hypertension. The angiotensin-converting enzyme/angiotensin II/angiotensin II type 1 receptor pathway activates NADPH oxidase in myocardial cells, which increases ROS generation. ROS can subsequently activate MAPKs (extracellular signal-regulated kinase, JNK, and p38-MAPK) and the NF-κB signaling pathway, leading to cardiac remodeling. In patients with MASLD, the systemic expression of pro-inflammatory cytokines such as CRP, TNF-α, and IL-6 may promote SNS activation and thus induce hypertension. The activation of SNS is related to a variety of CVD, including arrhythmias, diastolic dysfunction, myocardial cell hypertrophy, and cardiac remodeling. Several studies have shown a strong association between inflammation and the development of hypertension. However, a small number of studies have determined the efficacy of anti-inflammatory treatment of hypertension in MASLD[29,81,155,165]. Some clinical studies have been conducted using natural product antioxidants and have reported a reduction in inflammatory indices and blood pressure in patients with MASLD[166,167]. In obese patients, visceral fat is associated with activation of the RAAS in adipose tissue. Moreover, the SNS triggers hepatic VLDL-C-triglyceride production, which facilitates arterial plaque formation, thereby narrowing vessels and elevating blood pressure. Clinically, individuals with dyslipidemia face a three-fold higher risk of hypertension compared to healthy controls (OR = 3.05, 95%CI: 2.36-3.90). Additionally, the rs5186 A1166C gain-of-function mutation in the AGTR1 gene has been identified as a genetic correlate of hypertension in patients with MASLD[21,29]. Hepatic insulin resistance has been shown to predict the development of hypertension. However, less than 50% of hypertensive individuals have impaired insulin sensitivity[20,168]. RAAS-SNS activation is thought to promote insulin resistance and liver inflammation, ultimately contributing to the development of MASLD. Nevertheless, the precise contribution of insulin resistance to the pathogenesis of hypertension remains a subject of ongoing debate. Chronic hyperinsulinemia in rodents can induce hypertension through a RAAS-dependent mechanism. In contrast, in human patients with insulinomas (elevated insulin levels), hyperinsulinemia does not appear to influence blood pressure; furthermore, administering insulin to individuals with type I diabetes has been shown to lower blood pressure rather than raise it. Insulin resistance could induce hypertension through an increase in FFAs, which facilitate the accumulation of perivascular adipose tissue adjacent to the vasculature and the renal sinus. Furthermore, hypertension is one of the main risk factors for CVD and affects approximately 30% of the world’s population[29,155,169]. Data from the World Health Organization (WHO) suggests that hypertension is the primary cause of roughly 54% of stroke instances and 47% of ischemic heart disease cases worldwide[170]. These findings suggest that elevated insulin levels act in concert with other risk factors such as obesity, MASLD, and hyperlipidemia, as well as augmented homocysteine levels, gut dysbiosis, and oxidative stress, to contribute to the development of hypertension. Figure 2 illustrates the interrelationship between cardiometabolic risk factors and MASLD in the induction of CVD.

Figure 2 Interrelationship of the metabolic and pathophysiological factors between metabolic dysfunction-associated steatotic liver disease, adipose tissue metabolism, insulin resistance, and the development of cardiovascular disease. MASLD: Metabolic dysfunction-associated steatotic liver disease; RAAS: Renin-angiotensin-aldosterone system; SNS: Sympathetic nervous system.

MASLD MAY BE AN INDEPENDENT RISK FACTOR FOR CVD

Research utilizing ultrasound to identify steatosis has explored the relationship between MASLD and CVD. One analysis of an extensive North American cohort revealed that individuals with MASLD exhibit a greater frequency of both CVRFs and clinical events. However, the CVD mortality rate during a 14-year follow-up period did not increase in these patients[171]. Another study carried out in Japanese patients with MASLD and a 5-year follow-up period reported a higher incidence of CVD events compared with healthy individuals (5.2% vs 1.0%; P < 0.001), establishing MASLD as an independent predictor of CVD[124]. In addition, a meta-analysis of 34 studies with 164494 participants reported an increased risk of CVD in MASLD patients, but the prevalence of MASLD was not associated with mortality from CVE in this analysis, suggesting that MASLD was an independent risk factor for the incidence of CVE[172]. In a large meta-analysis of observational studies, Targher et al[173] a found 64% increased risk of fatal and non-fatal CVE in patients with MASLD. Additionally, a systematic review and meta-analysis demonstrated that MASLD patients face a markedly elevated risk of clinical CVEs and a greater likelihood of cardiovascular-related death than those in the control group[174]. A worldwide epidemiological meta-analysis of MASLD patients uncovered a striking mortality rate: 4.79 deaths from CVD compared to 0.77 deaths from liver-related causes per 1000 person-years[175]. Of note, some analyses have shown that after adjusting for common CVRFs, MASLD persists as an autonomous predictor for CVD, regardless of other traditional risk factors[176,177]. However, within a clinical setting, it remains challenging to untangle these overlapping pathologies and establish MASLD as a standalone contributor to cardiovascular risk.

Because MASLD is strongly associated with metabolic syndrome, Hamaguchi et al[178] proposed that the elevated cardiovascular risk observed in MASLD patients stems from metabolic syndrome rather than being a direct result of liver fat accumulation. This is explained by the severity of MASLD being commonly associated with a higher incidence of CVD risk factors such as dyslipidemia, impaired fasting glucose/T2D, and hypertension, which is one of the most common metabolic syndrome-related disorders. However, a primary care study in Germany revealed that MASLD is associated with a higher risk of CHD and myocardial infarction, independent of underlying metabolic risk factors such as diabetes, obesity, arterial hypertension, or hyperlipidemia. Furthermore, MASLD is significantly associated with AF in individuals up to age 60[179]. MASLD and obesity are independent risk factors for CVD, and both have a significant synergistic effect on CVD risk[180]. Among the mechanisms linking CVD risk with MASLD are atherogenic dyslipidemia, cytokine abnormalities, low-grade chronic inflammation, oxidative stress, insulin resistance, endothelial dysfunction, and prothrombotic mechanisms[14,56,181]. Furthermore, inflammation and oxidative stress induced by MASLD may contribute to cardiac insulin resistance and cardiac fibrosis, promoting altered cardiac structure and HF[66,182]. Regarding cardiac structure abnormalities, patients with MASLD showed a higher prevalence of LV hypertrophy, LVDD, reduced early diastolic relaxation (e’) velocity, higher LV filling pressure (E/e’ ratio), and a higher prevalence of aortic valve sclerosis (an independent indicator of atherosclerosis), valve dysfunction, myocardial hypertrophy, and, consequently, HF. Moreover, patients with MASLD who are obese, hypertensive, or diabetic also have impaired LV systolic function[50,183]. CVD is the primary cause of mortality in patients with MASLD (34%). Estimates of all-cause mortality at 15 years in individuals with MASLD were 25% in those without cirrhosis, 75% in those with compensated cirrhosis, and 85% in those with decompensated cirrhosis[184,185]. CVD is the most common cause of death in patients with T2D (up to two-thirds of all deaths), and elevated glycated hemoglobin (HbA1c) levels are strongly correlated with an increased risk of heart disease and overall mortality[186,187]. Patients with MASLD, and particularly those with its advanced form MASH, are at a high risk for atherosclerotic and ischemic heart disease, ASCVD, arrhythmia, stroke, and HF, encompassing a heightened susceptibility to venous thrombosis within both the portal and systemic circulations for individuals with MASH-related cirrhosis[16,56,188,189]. Obesity and metabolic syndrome are well-known risk factors for venous thromboembolism. The activities of various coagulation factors such as FVIII, FIX, FXI, and FXII are increased in patients with MASLD and correlate with the features of insulin resistance[190]. Established indicators of CVD within the MASLD population encompass endothelial impairment, accelerated pulse wave velocity, coronary artery calcification (CAC), and hypertension. Furthermore, this clinical profile includes aortic valve sclerosis, diastolic dysfunction, the presence of atherosclerotic plaques, and a measurable increase in carotid intima-media thickness (CIMT)[20,50]. Additionally, the identification of cardiovascular biomarkers, including CRP, D-dimer, B-type natriuretic peptides, and cardiac troponins I and T, has provided essential tools for the clinical detection and treatment of atherosclerosis, myocardial infarction, and acute coronary syndrome, as well as thrombosis and ischemic heart conditions[189]. Taken together, studies demonstrate an association between MASLD and CVD, influenced by metabolic disorders such as obesity, dyslipidemia, hypertension, and diabetes.

MASLD and atherosclerosis

Atherosclerosis is a common etiologic factor for CVD and is characterized by the development of neointimal plaques in large arteries, hardening of the arteries, and narrowing of the lumen. Atherosclerosis causes CVE such as myocardial infarction and stroke. The composition of atherosclerotic plaques changes through specific processes such as lipid deposition, inflammation, fibrosis, and calcification[191]. The stimulation of the RAAS and the subsequent rise in angiotensin II levels drive vasoconstriction and oxidative stress. This process also triggers the endothelial overproduction of ICAM-1, VCAM-1, P-selectin, and MCP-1, thereby hastening the progression of atherosclerosis[62,81]. Standard modalities for visualizing plaques comprise ultrasonography, MRI, and computed tomography (CT). Additionally, vascular inflammation can be assessed through nuclear imaging techniques, specifically ¹⁸F-fluorodeoxyglucose positron emission tomography and single-photon emission CT. In addition, plaque size can be assessed by measuring CIMT or arterial stiffness via brachial-ankle pulse wave velocity (ba-PWV)[191,192]. Several studies and meta-analyses have shown that MASLD is a significant risk factor for atherosclerosis in the coronary and carotid arteries. MASLD is associated with an increased risk of increased CIMT or plaques, arterial stiffness, CAC, and endothelial dysfunction (one of the earliest indicators of atherosclerosis). Moreover, MASLD has a strong association with subclinical atherosclerosis, including elevated ba-PWV and CIMT[50,173,176,193-196]. In addition to MASLD, arterial stiffness is associated with CVRFs such as age, obesity, dyslipidemia, T2D, hypertension, smoking, and metabolic syndrome and may independently predict CVD morbidity and mortality[56]. The CAC score indicates both plaque burden and the severity of atherosclerosis in coronary arteries and is linked with adverse cardiovascular outcomes[197]. MASLD is associated with a high CAC score (even among patients with BMI < 25 kg/m²), independent of the presence of common CVRFs and metabolic syndrome, and MASLD severity is strongly associated with early carotid atherosclerosis, independent of traditional CVRFs. Elevated levels of liver enzymes, including AST, have further been linked to higher coronary artery calcium scores (OR = 1.77, 95%CI: 1.19-2.34). CIMT is also increased in MASLD independent of dyslipidemia and hypertension[50,160,191]. A systematic review and meta-analysis determined that MASLD serves as a predictor for elevated CAC scores, regardless of the presence of traditional risk factors[198]. Furthermore, the CAC score is also correlated well with MASLD severity[199,200]. One study found that MASLD was independently associated with CAC score only in patients with diabetes and higher HbA1c ≥ 7%, after adjustment for confounders[201], whereas another study found no relationship between MASLD and coronary, aortic, or carotid calcium or CIMT in diabetic patients[128]. A cross-sectional study reported that MASLD is not associated with increased CIMT but is associated with carotid and lower limb atherosclerotic plaque independent of CVRFs and metabolic syndrome in Chinese patients with T2D[202]. One prospective investigation noted that elevated baseline CIMT and ba-PWV correlate with a higher risk of MASLD onset. Furthermore, ba-PWV stands as an autonomous predictor of both new-onset MASLD and increased fibrosis risk, according to nonalcoholic fatty liver disease fibrosis score, FIB-4, and AST to platelet ratio index assessments[203]. However, several investigations found that MASLD was not significantly linked to subclinical atherosclerosis, assessed via ba-PWV, carotid-femoral pulse wave velocity, or specific CAC thresholds (cutoff > 10), once other risk factors were controlled for[204-206]. While the majority of research has prioritized CAC, one specific analysis examined various vascular sites, including the carotid, iliac, and renal arteries, as well as the thoracic aorta and mesenteric systems. Interestingly, this study identified a correlation between MASLD and calcification within the celiac trunk and thoracic aorta, yet found no such link regarding the coronary arteries[207]. Consequently, the findings indicate that individuals with MASLD have an increased vulnerability to calcification across multiple arterial systems. In fact, abdominal aortic calcification is also associated with MASLD[56]. Notably, a pair of studies indicated that MASLD correlates more strongly with noncalcified plaques than with calcified ones; the former are characterized by a higher susceptibility to rupture, leading to subsequent CVE[206,208]. A study showed that MASLD is more significantly associated with CAC compared with abdominal obesity[209], while another study suggested that obesity attenuates the relationship between MASLD and subclinical atherosclerosis[210]. Young adults with MASLD associated with overweight/obesity were found to have an increased risk of developing CAC in middle age[211]. In addition, MASLD without overt atherosclerosis risk factors may be involved in the development of cerebral atherosclerotic disease[212]. In summary, multiple large-scale studies and meta-analyses consistently show that MASLD is independently associated with markers such as increased CAC and CIMT.

MASLD and stroke

Literature regarding the link between MASLD and stroke remains limited. However, existing research indicates that MASLD patients face a 1.68-fold increase in ischemic stroke risk compared to the general public. Specifically, MASLD has been correlated with a 2.51 higher likelihood (95%CI: 1.92-3.28) of experiencing an ischemic event[50,188]. A meta-analysis of 20 observational studies suggested that MASLD increases the risk of stroke[213]. Moreover, a retrospective study including MASLD patients, who were analyzed in 5 clusters, noted that according to multivariate analysis, individuals categorized in cluster 3 (characterized by severe insulin resistance) and cluster 4 [marked by high Lp(a) levels] faced a significantly higher risk of stroke[214]. Additionally, a prospective analysis of the United Kingdom Biobank, encompassing 325129 participants over a median of 12.8 years, confirmed that MASLD is linked to a greater incidence of stroke[215]. A meta-analysis demonstrated that a progressive increase in the severity of hepatic steatosis is tied to a significantly higher risk of stroke development among those with MASLD. The incidence of stroke in MASLD was 5.04% (95%CI: 2.74%-9.09%), while the incidence of ischemic stroke in MASLD was 6.05% (95%CI: 2.93%-12.07%), and the incidence of hemorrhagic stroke was 2.22% (95%CI: 0.22%-18.77%)[216]. In a Chinese study group of 79905 individuals monitored over a median of 10.34 years, MASLD patients exhibited a 16% greater risk of ischemic stroke (95%CI: 1.07-1.26) than those unaffected by the condition[217]. To evaluate if cardiovascular risk differs between lean and non-lean MASLD phenotypes, a systematic review and meta-analysis synthesized data from 33 studies, encompassing a combined population of 10592851 individuals. Research indicated that MASLD is associated with a heightened likelihood of ischemic stroke, yielding an OR of 1.6 (95%CI: 1.2-2.1)[218]. MASLD was reported to have no impact on disability and death after the stroke. However, patients with a first stroke episode showed a high prevalence of MASLD, particularly at intermediate ages[219]. Therefore, patients with MASLD are at high risk of CV outcomes, including an increased risk of stroke.

MASLD and CAD

CAD, also known as CHD, is a condition where the major blood vessels in the heart get narrow and stiff due to the buildup of atherosclerotic plaque. Perivascular adipose tissue surrounding coronary arteries induces a pro-inflammatory state, and the accumulation of this tissue influences the prevalence, severity, and progression of CAD independently of visceral obesity[170]. The presence of hepatic steatosis is strongly associated with an increased risk of CAD. MASLD per se is an independent predictor of significant CAD, and CAD is an important cause of death in patients with MASLD[16,55]. In 244 Brazilian patients, 63% were found to have CAD and 42% to have MASLD. Notably, 44% of individuals with CAD were concurrently diagnosed with MASLD, highlighting a robust link between these conditions. A subsequent regression analysis validated this connection, demonstrating that MASLD is significantly tied to CAD, insulin resistance, and elevated BMI[131]. Synthesizing data from six studies involving 25837 individuals, a meta-analysis determined that MASLD patients face a significantly elevated risk of clinical CVEs [relative risk (RR) = 1.77; 95%CI: 1.26-2.48, P < 0.001]. Furthermore, the analysis revealed a more than twofold increase in the risk of CAD (RR = 2.26; 95%CI: 1.04-4.92, P < 0.001)[220]. Interestingly, a pair of investigations indicated that the lack of coronary calcification is not sufficient to rule out the existence of clinically significant CAD[221,222]. Among MASLD patients with elevated liver fibrosis markers, both the FIB-4 and nonalcoholic fatty liver disease fibrosis scores were found to be autonomous predictors of CAD, remaining significant even after controlling for sex and established CVRFs. Additionally, individuals with MASLD and CAD were more likely to be hypertensive, have a longer duration of diabetes, and be older[223,224]. It is worth noting that patients with MASLD showed a greater propensity to develop CAD in the following 10 years, even without diabetes or hypertension[225,226].

MASLD correlates with various indicators of CHD, most notably central adiposity and insulin resistance. CHD is a progressive disease that begins with coronary atherosclerosis in the early stages and progresses to become established CAD[227]. Of note, CAC is an important marker of subclinical CHD, and several underlying pathogenetic mechanisms are recognized between MASLD and CHD, including oxidative stress, systemic/vascular inflammation, atherogenic dyslipidemia, endothelial dysfunction, and coagulopathy[56]. New research indicates a correlation between CHD and MASLD that persists even after accounting for shared cardiometabolic risk factors[170,181,228]. MASLD is an independent risk factor for CHD regardless of the degree of hepatic steatosis and affects the CHD severity[229]. Moreover, MASLD is associated with increased severity of angiographic CHD, independent of other CVRFs[230]. A meta-analysis reported that the prevalence of CHD was 45% in patients with MASLD and concluded that steatosis is related to CHD involvement and that moderate-to-severe steatosis is related to clinical CAD[231]. Findings from the RISC study demonstrated that fatty liver correlates with an elevated 10-year CHD risk profile, a relationship that remains significant even among subjects who are non-hypertensive and non-diabetic[55]. Importantly, diabetes in MASLD can accelerate the development of CHD[232], because insulin resistance is linked to atherogenesis, increased progression of atherosclerotic lesion, and augmented plaque vulnerability. Acute coronary syndromes are a manifestation of CHD. Several studies have been conducted to investigate MASLD in acute coronary syndromes[124,233,234], particularly in acute myocardial infarction (AMI). Collectively, the combination of metabolic risk factors, insulin resistance, and rapid atherogenesis in MASLD patients may act synergistically to promote extensive coronary plaque accumulation and more advanced arterial narrowing.

MASLD and myocardial infarction

AMI is one of the leading causes of mortality worldwide and represents an important socioeconomic burden[235]. MASLD increases the risk of myocardial infarction independently of established risk factors[236,237]. However, a cohort study involving 18 million European adults found that the link between MASLD, as documented in standard electronic health records, and the occurrence of AMI or stroke was relatively weak, with hazard ratios hovering near 1.2[238]. Myocardial infarction is associated with high mortality rates. Approximately 22% of patients with AMI have MASLD, and both obese and non-obese MASLD are independent predictors of all-cause mortality following AMI, with a higher risk of mortality in the group with MASLD without obesity[236]. Therefore, MASLD influences the development of myocardial infarction.

MASLD and HF

MASLD and HF share several risk factors, such as obesity, diabetes, hypertension, and metabolic syndrome[220,239-241]. In particular, factors related to obesity and T2D are considered a possible link between MASLD and the development of HF[10,150]. These factors include insulin resistance and impaired glucose and lipid metabolism, resulting in increased myocardial fatty acid oxidation (less efficient than glucose metabolism) that leads to alterations in cardiac energy metabolism and cardiac dysfunction, contributing to the development of HF. Importantly, there is also evidence that elevated activation of the RAAS, an important mediator of cardiac remodeling and HF progression, plays an additional role alongside cardiac ROS in the interaction between MASLD and HF[239,242]. Pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) and decreased plasma levels of adiponectin resulting from VAT dysfunction may not only be involved in the progression of MASLD but may also affect the coronary arteries and promote HF[67,68,73,76]. The prevalence of HF increases dramatically with age, especially among people over 60 years old (10% in this population), with HF with preserved ejection fraction being more common than HF with reduced ejection fraction (HFrEF) (5% vs 3.5%)[239]. MASLD is strongly associated with the risk of HF and with a higher cumulative incidence of HF[243], and the intensity of the risk appears to be directly proportional to the severity of MASLD, especially the level of liver fibrosis. Patients with MASLD exhibited a risk for HF fourfold higher than those without MASLD[244]. A study with 96576 participants and a median follow-up of 14.0 years reported that MASLD significantly increased the risk of HF in women, especially young women[245]. A Japanese nationwide epidemiological study including 3279918 participants examined the association between MASLD and the incidence of HF and found a HR for HF of 1.73 (95%CI: 1.69-1.76) for MASLD after adjusting for the cardiometabolic confounders[246]. An extensive meta-analysis encompassing cohort studies of roughly 11 million people demonstrated that MASLD patients carry a 36% higher RR of developing future HF, even after accounting for other cardiometabolic risk factors. Interestingly, this study also found that simple steatosis was associated with an increased risk of HF[247].

Several studies have reported an association between MASLD and impaired diastolic function after adjusting for HF risk factors[122,248-251]. MASLD correlates with subclinical myocardial remodeling, a relationship that persists regardless of conventional HF risk factors or measures of adiposity. The research established that MASLD is potentially linked to the development of LV hypertrophy, altered LV geometry, and compromised myocardial strain, independent of established cardiovascular risk profiles[252]. In addition, MASLD is linked to progressive, subclinical alterations in LV structure and function, an association largely explained by the presence of obesity[253]. Research has indicated a correlation between MASLD and the presence of LVDD[254,255]. The risk of LVDD and remodeling increases with the progression of MASLD[248]. Accordingly, in pediatric and adolescent populations with obesity, MASLD is characterized by early-stage diastolic and systolic impairment of the left ventricle; these dysfunctions are notably more pronounced in individuals diagnosed with MASH[256]. Concurrently, a stepwise increase in the risk of LVDD based on the severity of fibrosis is particularly evident among non-obese individuals[257].

MASLD and arrhythmias

Arrhythmias are heart diseases characterized by a disruption in the electrical signals that regulate heart rhythm, causing the heart to beat too fast (tachycardia, > 100 bpm), too slow (bradycardia, < 60 bpm), or irregularly. They are classified by where they begin in the heart (atria vs ventricles): (1) Supraventricular arrhythmias (top chamber disorders), originate in the atria (upper chambers) or the atrioventricular node (the electrical gateway to the ventricles). Examples include AF, atrial flutter, and atrial tachycardia; (2) Ventricular arrhythmias (lower chamber disorders), these occur in the ventricles and are often more dangerous or life-threatening (e.g., ventricular tachycardia and ventricular fibrillation, both of which are tachycardias); (3) Bradyarrhythmias (slow heart rhythm disorders, where the heart rate is less than 60 bpm); for example, sick sinus syndrome and heart block; and (4) Inherited/genetic arrhythmia syndromes, often causing sudden death in young people (e.g., long QT syndrome, Brugada syndrome, both irregular arrhythmias)[258-260].

MASLD is associated with an increased risk of cardiac arrhythmias such as AF and heart rate corrected QT (QTc) interval prolongation, which predispose individuals to life-threatening ventricular arrhythmias, which may explain why people with MASLD have a higher risk of CV mortality[20,170,177,232,239,261-265]. AF consists of an irregular and rapid electrical and mechanical activation of the atria, which promotes hemodynamic changes and remodeling of the structure of the left atrium. AF represents one of the most prevalent global arrhythmias, affecting 0.51% of the world’s population and significantly increasing the likelihood of systemic stroke and HF[266-268]. Obesity, dyslipidemia, obstructive sleep apnea, hyperthyroidism, smoking, hypertension, insulin resistance, diabetes, CAD, and HF are major risk factors of AF. Patients with MASLD exhibit elevated levels of inflammatory cytokines and oxidative stress, which can promote cardiac autonomic dysfunction and, consequently, cardiac arrhythmias such as AF[266,269]. Research using various animal models has demonstrated that proinflammatory cytokines, specifically TNF-α, IL-1β, and IL-17, are capable of triggering cardiac arrhythmias[267]. MASLD is associated with systemic inflammation, and elevated serum CRP levels have been observed in patients with MASLD. Furthermore, an elevated CRP level is a significant predictor of the development of incident AF[270,271]. Several epidemiological studies and meta-analyses have suggested an association between MASLD and AF[177,232,261,262,265,272,273]. During an average follow-up period of 29 months, patients with MASLD exhibited significantly elevated rates of arrhythmia recurrence following catheter ablation for AF[262]. Another study reported that MASLD was independently associated with the risk of AF and also reported a twice as high incidence of AF in patients with MASLD[265]. A meta-analysis encompassing six longitudinal cohort studies and 614763 subjects revealed that MASLD correlates with a roughly 20% higher risk of new-onset AF (adjusted HR = 1.19; 95%CI: 1.04-1.31) over a 10-year median period. Furthermore, MASLD accounts for an estimated 5% of incident AF cases within the general population[261]. The investigators determined that the correlation between MASLD and AF is explained, in part, by the presence of overlapping cardiometabolic risk factors. Two recent meta-analyses also provide evidence that MASLD is associated with an increased risk of AF (OR = 1.27, 95%CI: 1.18-1.37, 95% prediction interval: 1.07-1.52)[273], and MASLD is significantly associated with a higher long-term risk of developing incident AF[272]. MASLD predisposes patients to AF, regardless of known risk factors for atherosclerosis[274]. Additionally, patients with MASLD and advanced hepatic fibrosis had a higher risk of AF[275]. However, one study utilizing CT scans to quantify liver fat content found no significant link to increased AF prevalence or incidence over a 12-year period after controlling for typical risk factors. The researchers highlighted, however, that their analysis may have lacked the statistical power necessary to identify significant correlations within this relatively young cohort[276]. In addition, two different studies demonstrated that ultrasound-diagnosed MASLD is associated with a higher prevalence and incidence of AF in patients with T2D[264,277]. Another retrospective study with 330 outpatients with T2D without preexisting AF showed that MASLD serves as an autonomous predictor for a higher frequency of ventricular arrhythmias among those with T2D[263]. A systematic review and meta-analysis indicated that MASLD correlates with a doubled risk of prevalent AF, with this association being particularly pronounced among individuals with T2D[278]. On the other hand, research indicates that fat surrounding the heart (epicardial fat) is an independent risk factor for AF. This link appears to be even more significant than the risks posed by belly fat or overall obesity[266]. In addition, pericardial adipose tissue releases proinflammatory cytokines that trigger local arrhythmogenic changes and facilitate the development of AF. Within cardiac tissue, angiotensin II stimulates transforming growth factor-β-driven fibrosis; this process leads to the structural and electrical remodeling of the left atrium, ultimately predisposing the patient to AF[279]. Interestingly, inter-atrial thickness and left atrial thickness index were found to be independently associated with incident AF in MASLD[16]. There is also an association of MASLD with diastolic dysfunction, which is known to induce AF[266]. The pathological link between MASLD and AF involves systemic inflammation, impaired insulin sensitivity, oxidative stress, and the accumulation of epicardial adipose tissue[267]. Consequently, individuals with both MASLD and T2D represent a high-priority risk group, as they face the greatest likelihood of experiencing adverse CVE and mortality.

QTc interval prolongation, often linked to bradycardia, serves as a potent electrocardiographic predictor of ventricular arrhythmias and sudden cardiac death. The QT interval has been associated with cardiac and metabolic disorders, such as obesity, hypertension, diabetes, and CAD[66,280]. Insulin resistance, commonly in MASLD, can promote a decrease in potassium, which affects the prolongation of ventricular repolarization[170]. Several studies suggest that MASLD is associated with QTc interval prolongation in both patients with T2D and the general population[281,282]. In addition, MASLD is related to non-fatal ventricular arrhythmias, such as premature ventricular beats[263]. In a large cross-sectional study, MASLD and the extent of its progression were found to be autonomous predictors for a higher risk of existing heart block among hospitalized individuals with T2D[283]. The frequent occurrence of heart rhythm disorders in patients with MASLD likely drives structural changes in the heart and functional impairment, ultimately predisposing individuals to major adverse CVEs (MACE), which is exacerbated by other comorbidities such as diabetes in this population.

MASLD and peripheral arterial disease

PAD is a vascular condition characterized by the stenosis of arteries, which compromises blood delivery to the extremities. PAD is considered as a manifestation of systemic atherosclerosis and is therefore considered equivalent to CHD and serves as a robust indicator of CVD and death, irrespective of whether the patient is symptomatic[56,284]. There are few studies on MASLD in patients with PAD. An observational study with 102115 Chinese adult participants reported that the prevalence of PAD [diagnosed by ankle-brachial index (ABI)] was higher in patients with MASLD[285]. In patients with MASLD and T2D, the prevalence of PAD was significantly higher compared to that in patients with diabetes without MASLD[123,286]. In addition, individuals with T2D and abnormal liver function tests exhibited a greater frequency of PAD than those with liver enzyme levels within the standard range[287]. In patients with MASLD followed for a median of 13 years, PAD was associated with a significantly higher incidence of all-cause death (1.8, 95%CI:1.4-2.4) and cardiovascular mortality (HR = 2.5, 95%CI: 1.5-4.3), independent of CVRFs[288]. Current guidelines strongly recommend CVD screening in patients with MASLD, and the use of ABI measurement in routine clinical practice may be indicated to reduce morbidity or mortality from PAD. Table 4 shows clinical studies of the association between MASLD and CVD. In summary, the strength of the evidence linking MASLD to various cardiovascular manifestations indicates a stronger association with subclinical atherosclerosis, where MASLD is an independent predictor of CAC and CIMT. The link between MASLD and AF is supported by systemic inflammation (IL-6, CRP), providing a clear mechanistic basis for this association. There is strong evidence (Framingham Heart Study) that MASLD increases the risk of incident HF. Meanwhile, controversial associations between MASLD and CVD include stroke, and the associations with vascular calcification are attenuated after adjusting for VAT, suggesting that the fat around the organs might be a more direct driver than the fat inside the liver.

Table 4 Representative clinical studies on the association between metabolic dysfunction-associated steatotic liver disease and cardiovascular disease.

Ref.	Country, year	Type of study	Population, diagnostic method	Main outcomes
Subclinical atherosclerosis and arterial stiffness
Kim et al[193]	South Korea, 2012	Cross-sectional study	4023 subjects (ultrasonography)	CAC scores were associated with a higher prevalence of MASLD (OR = 1.84, 95%CI: 1.61-2.10). CAC scores were significantly associated with MASLD (OR = 1.28, 95%CI: 1.04-1.59) independent of visceral adiposity
Huang et al[196]	China, 2012	Cross-sectional study	8632 participants (ultrasonography)	MASLD had remarkably higher CIMT and ba-PWV compared to the control group (0.594 ± 0.105 mm vs 0.578 ± 0.109 mm and 1665 ± 424 cm/second vs 1558 ± 430 cm/second)
Targher et al[173]	Italy, 2016	Meta-analysis	16 studies; 34043 adult individuals (imaging or histology)	MASLD had a higher risk of fatal and/or non-fatal CVD events (OR = 1.64, 95%CI: 1.26-2.13). Severe MASLD had more development of fatal and non-fatal CVD events (OR = 2.58, 95%CI: 1.78-3.75)
Zhou et al[194]	China, 2018	Systematic review and meta-analysis)	26 studies; 85395 participants (ultrasonography, computed tomography, or biopsy)	MASLD was independently associated with subclinical atherosclerosis (OR = 1.60, 95%CI: 1.45-1.78). MASLD also increased the risk of carotid artery intima-media thickness/plaques, arterial stiffness, CAC, and endothelial dysfunction with OR and 95%CIs of 1.74 (1.47-2.06), 1.56 (1.24-1.96), 1.40 (1.22-1.60), and 3.73 (0.99-14.09), respectively
Wong et al[195]	Singapore, 2018	Meta-analysis	64 studies; 172385 participants (ultrasonography, liver biopsy, CT, MRS, or FLI)	MASLD was associated with increased CIMT (OR 2.00, 95%CI: 1.56-2.56). MASLD was also associated with any coronary calcification (OR = 1.21, 95%CI: 1.12-1.32) and the development/progression of CAC (OR = 1.26, 95%CI: 1.04-1.52)
Liu et al[199]	United States, 2012	Cross-sectional study	2884 participants (CT)	Liver attenuation was inversely associated with CAC in data adjusted for age and sex (OR = 0.84, 95%CI: 0.7-0.9). Fatty liver was associated with CAC independent of abdominal VAT or BMI in African Americans
Guo et al[202]	China, 2017	Cross-sectional study	8571 patients	The prevalence of carotid (56.5% vs 44.5%) and lower limb plaque (56.2% vs 48.7%) and carotid (11.2% vs 6.8%) and lower limb stenosis (15.1% vs 10.3%) were significantly higher in diabetic patients with MASLD compared to those without it (P < 0.001)
Lee et al[206]	South Korea, 2018	Cross-sectional study	5121 individuals (ultrasonography)	Atherosclerotic plaque (OR = 1.18, 95%CI: 1.03-1.35) and non-calcified plaque (OR = 1.27, 95%CI: 1.08-1.48) were significantly higher in MASLD. There was a significant association of FLI ≥ 30 with non-calcified plaque (OR = 1.37, 95%CI: 1.14-1.65) and NFS ≥ -1.455 with non-calcified plaque (OR = 1.20, 95%CI: 1.08-1.42)
Park et al[208]	South Korea, 2019	Retrospective cohort	488 subjects (FibroScan)	CAP ≥ 222 dB/m was independently associated with the presence of coronary plaques (OR = 1.624, 95%CI: 1.047-2.518). CAP ≥ 222 dB/m was significantly associated with non-calcified plaque (OR = 3.528, 95%CI: 1.463-8.511)
VanWagner et al[210]	United States, 2014	Cross-sectional study	2424 participants (CT)	MASLD was associated with CAC (OR = 1.33, 95%CI: 1.001-1.82) and AAC (OR = 1.74, 95%CI: 1.29-2.35). However, these associations were attenuated after adjustment for VAT (CAC OR = 1.05, 95%CI: 0.74-1.48; AAC OR = 1.20, 95%CI: 0.86-1.67)
Cerebrovascular disease and stroke
Wang et al[213]	China, 2022	Meta-analysis	18 studies; 17031672 participants (ultrasonography, CT, MRI, or FLI)	MASLD was associated with a mildly increased risk of stroke (OR = 1.18, 95%CI: 1.08-1.30)
Chen et al[215]	China, 2023	Large prospective cohort study	325129 participants years (FLI)	MASLD was significantly associated with myocardial infarction (HR = 1.35, 95%CI: 1.29-1.41) or stroke (HR = 1.26, 95%CI: 1.18-1.33)
Tang et al[216]	Singapore, 2022	Meta-analysis	30 studies; 7951 patients (biopsy, ultrasonography, CT)	In individuals with MASLD, the incidence of stroke was 5.04% (95%CI: 2.74%-9.09%)
Mahfood Haddad et al[174]	United States, 2017	Systematic review and meta-analysis	6 studies; 25837 patients (elevated transaminases without imaging confirmation)	MASLD had a significantly higher risk of CVE compared to controls (RR = 1.77, 95%CI: 1.26-2.48), while clinical CAD (RR = 2.26, 95%CI: 1.04-4.92) and ischemic stroke (RR = 2.09, 95%CI: 1.46-2.98) were also increased
Alon et al[273]	Italy, 2022	Systematic review and meta-analysis	3254 records; 20 studies (ultrasonography, CT, ICD codes, FLI)	MASLD was associated with an increased risk of MI (OR = 1.66, 95%CI: 1.39-1.99, 95%PI: 0.84-3.30), IS (OR = 1.41, 95%CI: 1.29-1.55, 95%PI: 1.03-1.93), AF (OR = 1.27, 95%CI: 1.18-1.37, 95%PI: 1.07-1.52), and HF (OR = 1.62, 95%CI: 1.43-1.84, 95%PI: 1.04-2.51)
Coronary artery disease and myocardial infarction
Lu et al[223]	China, 2022	Retrospective cross-sectional study	1346 patients (ultrasonography)	The FIB-4 score and NFS were independently associated with CAD. The AST to platelet ratio index was not a significant factor for CAD
Namakchian et al[224]	Iran, 2023	Prospective study	1664 patients (ultrasonography)	FIB-4 score independently correlates with CAD in patients with MASLD
Gastaldelli et al[225]	Italy, 2009	Prospective, observational, cohort study	1307 subjects; 19 centers in 14 European countries (FLI)	FLI was associated with increased CHD risk (r = 0.48)
Wong et al[230]	China, 2011	Prospective cohort study	612 patients (ultrasonography)	After adjusting for demographic and metabolic factors, MASLD (OR = 2.31, 95%CI: 1.46-3.64) remained independently associated with CAD
Toh et al[231]	Singapore, 2022	Meta-analysis	38 articles; 67070 patients (ultrasonography or CT)	The prevalence of CHD was higher in patients with moderate to severe steatosis (37.5%, 95%CI: 15.0%-67.2%) than in those with mild steatosis (29.6%, 95%CI: 13.1%-54.0%)
Emre et al[234]	Turkey, 2015	Prospective cohort study	186 patients (ultrasonography)	Patients with an MASLD score ≥ 3 were more likely to have absent myocardial perfusion (MBG 0/1, 37% vs 12%), absent STR (27% vs 9%), and a higher in-hospital MACE rate (31% vs 8%)
Koh et al[236]	Singapore, 2025	Retrospective observational cohort	5702 patients (HSI)	Non-obesity MASLD had the highest risk of heart failure (P = 0.034), cardiogenic shock (P < 0.001), and all-cause long-term mortality (P = 0.019). The non-obesity MASLD (HR = 1.400, 95%CI: 1.077-1.820, P = 0.012) and obesity MASLD phenotypes (HR = 1.222, 95%CI: 1.005-1.485, P = 0.044) were independently associated with long-term all-cause mortality
Sinn et al[237]	South Korea, 2020	Retrospective cohort analysis	111492 adults over 40 years old (ultrasonography)	Myocardial infarction had an incidence rate of 0.3 cases per 1000 person-years. The age-, sex-, and year-of-visit-adjusted HR for incident myocardial infarction comparing participants with MASLD with those without it was 2.14 (95%CI: 1.59-2.89)
Alexander et al[238]	England, 2019	Matched cohort study	120795 adults (method not reported)	After adjustment for age and smoking, the pooled HR for AMI was 1.17 (95%CI: 1.05-1.30)
Heart failure and structural heart changes
Houghton et al[220]	England, 2019	Cross-sectional study	96 sedentary patients (MRS)	Diastolic variability and systolic variability [LF/HF-SBP (n/1); 2.3 (1.7) vs 3.4 (1.5), P < 0.01] were impaired in patients with MASLD when compared to controls
Targher et al[240]	Italy, 2021	Observational study	356 individuals (ultrasonography)	Individuals with T2D and MASLD (OR = 4.29, 95%CI: 1.90-10.6) and individuals with MASLD alone (OR = 3.41, 95%CI: 1.59-7.29) had an increased risk of having cardiac sympathetic/parasympathetic imbalance
Roderburg et al[243]	Germany, 2023	Retrospective cohort study	173966 patients (method not reported)	MASLD was significantly associated with a subsequent diagnosis of HF (HR = 1.34, 95%CI: 1.28-1.39)
Wu et al[245]	China, 2024	Prospective cohort	96576 participants (ultrasonography)	MASLD was associated with a higher risk of HF (HR = 1.45, 95%CI: 1.31-1.63). In women, MASLD was associated with an 84% increased risk of HF (HR = 1.84, 95%CI: 1.43-2.37), while in men, the risk was 36% (HR = 1.36, 95%CI: 1.20-1.53)
Li et al[247]	China, 2022	A meta-analysis of observational studies	6 cohort studies; 10979967 participants (CT, FLI, biopsy)	In the unadjusted model, MASLD had a greater risk of incident HF (HR = 1.47, 95%CI: 1.25-1.75, I2 = 99%), compared with those without MASLD
Mantovani et al[122]	Italy, 2015	Cross-sectional study	222 patients (ultrasonography)	Patients with MASLD had a remarkably greater prevalence of mild and/or moderate LVDD compared with those without MASLD (71% vs 33%, P < 0.001)
Jung et al[248]	South Korea, 2017	Cross-sectional study	20821 participants (ultrasonography)	The mild and moderate-to-severe MASLD had higher OR for abnormal LV relaxation (mild group 1.29, 95%CI: 1.15-1.46; moderate-to-severe group 1.95, 95%CI: 1.61-2.35) and increased relative wall thickness (> 0.42; mild group 1.26, 95%CI: 1.05-1.52; moderate-to-severe group 1.46, 95%CI: 1.08-1.95)
Fallo et al[249]	Italy, 2009	Observational cross-sectional study	86 patients (ultrasonography)	Patients with MASLD had a similar prevalence of LVH compared to patients without MASLD but a higher prevalence of diastolic dysfunction (62.5% vs 21.1%, P < 0.001), as defined by E/A ratio < 1 and an E-wave deceleration time > 220 ms
Chiu et al[251]	United States, 2020	Cross-sectional study	2356 Framingham Heart Study participants (CT)	MASLD was associated with LV mass (β = 1.45, 95%CI: 0.01-2.88), LV wall thickness (β = 0.01, 95%CI: 0.00-0.02), mass volume ratio (β = 0.02, 95%CI: 0.01-0.03), mitral peak velocity (E) (β = 0.83, 95%CI: 0.31-1.36) and LV filling pressure (E/e’ ratio) (β = 0.16, 95%CI: 0.09-0.23); and inversely associated with global systolic longitudinal strain (β = 0.20, 95%CI: 0.07-0.33), diastolic annular velocity (e’) (β = -0.12, 95%CI: -0.22 to -0.03), and E/A ratio (β = -0.01, 95%CI: -0.02 to -0.00)
VanWagner et al[253]	United States, 2020	Large population-based prospective study	1827 participants (CT)	MASLD had higher LV mass, relative wall thickness, incident LV hypertrophy, and abnormal LV geometry vs non-MASLD (P < 0.02). MASLD had impaired LV relaxation (E/A ratio 1.1 vs 1.2), higher LV filling pressures (E/e’ ratio 7.9 vs 7.2), worse longitudinal strain (-13.9% vs -15.3%), and lower LV ejection fraction (58.9% vs 60.2%, P < 0.01)
VanWagner et al[254]	United States, 2015	Cross-sectional analysis	2713 participants (CT)	MASLD had lower early diastolic relaxation (e’) velocity (10.8 ± 2.6 cm/second vs 11.9 ± 2.8 cm/second), higher LV filling pressure (E/e’ ratio: 7.7 ± 2.6 vs 7.0 ± 2.3), and worse absolute GLS (14.2% ± 2.4% vs 15.2% ± 2.4%) than non-MASLD (P < 0.0001 for all)
Arrhythmias and conduction disorders
Cai et al[261]	China, 2020	Meta-analysis of cohort studies	6 studies; 614673 participants (ultrasonography, CT, FLI)	MASLD was associated with an increased risk of AF (RR = 1.65, 95%CI: 1.23-2.20, I2 = 63.0%). After adjustment for multiple cardiometabolic risk factors, the association was still higher than that in non-MASLD (RR = 1.19, 95%CI: 1.04-1.31, I2 = 54.0%)
Donnellan et al[262]	United States, 2020	Retrospective cohort study	267 patients (ultrasonography, CT, MRI)	MASLD was independently associated with increased rates of arrhythmia recurrence (HR = 3.01, 95%CI: 1.98-4.68, P < 0.0001)
Mantovani et al[263]	Italy, 2016	Retrospective, cross-sectional design	330 patients (ultrasonography)	MASLD was associated with a 35-fold increased risk of ventricular arrhythmias (OR = 3.47, 95%CI: 1.65-7.30)
Targher et al[264]	Italy, 2013	Prospective study	400 patients (ultrasonography)	MASLD was associated with an increased risk of incident AF (OR = 4.49, 95%CI: 1.6-12.9)
Käräjämäki et al[265]	Finland, 2015	Prospective study	958 subjects (ultrasonography)	MASLD was an independent predictor of AF (adjusted OR = 1.88, 95%CI: 1.03-3.45)
Mantovani et al[272]	Italy, 2025	Systematic review and meta-analysis)	16 retrospective cohort studies; approximately 19.5 million participants (liver biopsy, imaging techniques, blood-based scores)	MASLD was significantly associated with an increased risk of developing incident AF (HR = 1.20, 95%CI: 1.10-1.32, I2 = 92%). This risk did not appear to further increase with the severity of liver fibrosis (n = 3 studies, HR = 1.22, 95%CI: 1.18-1.26, I2 = 10%)
Roh et al[274]	South Korea, 2020	Cross-sectional analysis	334280 healthy individuals (FLI)	AF was significantly higher in subjects with higher FLIs. Adjusted HRs indicated that a higher FLI was independently associated with an increased risk for AF (HR between Q4 and Q1 = 1.35, 95%CI: 1.11-1.63)
Targher et al[277]	Italy, 2013	Cross-sectional analysis	702 patients with T2D (ultrasonography)	MASLD was associated with an increased risk of prevalent AF (OR = 3.04, 95%CI: 1.54-6.02)
Mantovani et al[278]	Italy, 2019	Meta-analysis	9 cross-sectional and longitudinal studies; 364919 individuals (ultrasonography, biopsy, FLI)	5 cross-sectional studies showed that MASLD was associated with an increased risk of prevalent AF (OR = 2.07, 95%CI: 1.38-3.10, I2 = 54.7%) 4 longitudinal studies showed that MASLD was independently associated with a 10-year increased risk of incident AF only in T2D patients (n = 1 study; HR = 4.96, 95%CI: 1.42-17.28)
Targher et al[281]	Italy, 2014	Cross-sectional analysis	400 outpatients with T2D (ultrasonography)	MASLD was associated with an increased QTc interval (OR = 2.16, 95%CI: 1.4-3.4). Adjusted OR = 2.26, 95%CI: 1.4-3.7
Hung et al[282]	Taiwan, 2015	Cross-sectional analysis	31116 participants (ultrasonography)	Mild, moderate, and severe MASLD were associated with an increased risk for QTc prolongation (OR = 1.11, 95%CI: 1.01-1.21; OR = 1.61, 95%CI: 1.36-1.9; and OR = 1.31, 95%CI: 1.16-2.24), respectively, in women, and (OR = 1.11, 95%CI: 1.01-1.21; OR = 1.39, 95%CI: 1.22-1.59; and OR = 1.87, 95%CI: 1.16-2.24), respectively, in men
Mantovani et al[283]	Italy, 2017	Single-center, retrospective design	751 patients with T2D (ultrasonography)	Patients with MASLD had a remarkably higher prevalence of any persistent heart block than those without MASLD (31.3% vs 16.7%, P < 0.001). MASLD was associated with an increased risk of prevalent heart block (adjusted OR = 3.04, 95%CI: 1.81-5.10)
Peripheral artery disease
Song et al[285]	China, 2023	Prospective cohort study	6833 participants (ultrasonography)	MASLD was associated with a higher risk of the presence of PAD (adjusted OR = 1.30, 95%CI: 1.19-1.42). MASLD at baseline was associated with a higher risk of incident PAD (adjusted HR = 1.67, 95%CI: 1.17-2.38)
Ciardullo et al[288]	Italy, 2022	Cross-sectional complex survey	3094 participants aged 40 years or older (FLI)	PAD was associated with a higher risk of all-cause (1.8, 95%CI: 1.4-2.4) and cardiovascular mortality (HR = 2.5, 95%CI: 1.5-4.3) after adjustment

CT: Computed tomography; MRI: Magnetic resonance imaging; MRS: Magnetic resonance spectroscopy; FLI: Fatty liver index; ICD: International statistical classification of diseases; T2D: Type 2 diabetes; HSI: Hepatic steatosis index; CAC: Coronary artery calcification; MASLD: Metabolic dysfunction-associated steatotic liver disease; OR: Odds ratio; CI: Confidence interval; CIMT: Carotid intima-media thickness; ba-PWV: Brachial-ankle pulse wave velocity; CVD: Cardiovascular disease; VAT: Visceral adipose tissue; BMI: Body mass index; NFS: Non-alcoholic fatty liver disease fibrosis score; CAP: Controlled attenuation parameter; AAC: Abdominal aortic calcification; HR: Hazard ratio; CVE: Cardiovascular events; RR: Relative risk; PI: Prediction interval; MI: Myocardial infarction; IS: Ischemic stroke; HF: Heart failure; AF: Atrial fibrillation; FIB-4: Fibrosis-4; CAD: Coronary artery disease; AST: Aspartate aminotransferase; CHD: Coronary heart disease; MBG: Myocardial blush grade; STR: ST-segment resolution; MACE: Major adverse cardiovascular events; AMI: Acute myocardial infarction; LF: Low frequency; HF: High frequency; SBP: Systolic blood pressure; LV: Left ventricular; LVDD: Left ventricular diastolic dysfunction; LVH: Left ventricular hypertrophy; GLS: Global longitudinal strain; QTc: Heart rate-corrected QT; PAD: Peripheral artery disease.

THERAPEUTIC STRATEGY TARGETING MASLD AND REDUCING CVD RISK

A therapeutic strategy for MASLD aimed at reducing CVD risk requires a holistic and multidisciplinary approach. This strategy focuses on reversing liver fat accumulation and managing metabolic comorbidities to lower the risk of atherosclerosis, HF, and arrhythmias. The cornerstone of this strategy is based on the following three approaches: Intensive lifestyle modifications, pharmacological management of MASLD/MASH, and biomarkers and screening of cardiometabolic risk in MASLD/MASH.

Intensive lifestyle modifications

Adopting healthy lifestyle habits continues to be the fundamental pillar of management for MASLD patients across all BMI categories, as they provide benefits for both hepatic and cardiovascular health. Lifestyle intervention includes weight loss, dietary changes, physical exercise, and discouraging alcohol consumption and tobacco use, which can reduce metabolic overload, adipose tissue dysfunction, and cardiovascular risk[2,289,290]. A weight loss of 7%-10% has been shown to improve hepatic steatosis, inflammation, and fibrosis, including the reversal of cardiac abnormalities. Furthermore, long-term weight reduction enhances insulin sensitivity and attenuates systemic inflammation, consequently diminishing cardiovascular risk among the MASLD population. However, maintaining a steady weight loss is often difficult. The Look AHEAD study was focused on achieving 10% weight loss, but 42% of these participants were able to sustain the weight loss at 4 years, and another study reported 21% regained the weight back to baseline within 1.5 years. Obese people tend to regain the weight once the weight control program has been interrupted[289-291].

Dietary modification plays an important role as a strategy for cardiovascular risk management in MASLD patients. Patients with MASLD or MASH must avoid foods high in added sugar, cholesterol, saturated fats, refined carbohydrates, red meat, ultra-processed foods, sweetened juices, and high-fructose corn syrup, as these have inflammatory potential and worsen these diseases. Conversely, diets with antioxidant and anti-inflammatory properties, as well as the Mediterranean diet, are highly recommended for managing MASLD and reducing the risk of CVD. The Mediterranean dietary pattern is characterized by a high intake of plant-based foods, including fruits, vegetables, legumes, and whole grains, with olive oil as the primary lipid source, complemented by a moderate intake of seafood, dairy products, and poultry. This diet improves hepatic steatosis, insulin resistance, and CVRFs even in the absence of significant weight loss. In addition, the dietary approaches to stop hypertension diet is highly suitable for patients with coexisting hypertension and metabolic syndrome[2,289,290,292]. Nutritional management for individuals with MASLD or MASH should incorporate vitamin E-rich foods, specifically nuts, seeds, vegetable oils, and leafy greens, alongside lean animal proteins and seafood. Vitamin E has antioxidant, anti-inflammatory, and antiapoptotic properties and protects against MASLD and MASH, particularly in individuals with T2D. In cases of MASH characterized by bridging fibrosis or cirrhosis, vitamin E therapy correlates with a lower incidence of mortality, liver transplantation, and hepatic decompensation. However, the clinical utility of vitamin E is constrained by potential adverse effects, such as increased all-cause mortality, hemorrhagic stroke, and prostate malignancy, which preclude its standardized administration. Coffee consumption has a protective association with MASLD and fibrosis in several observational studies. Notably, coffee intake exhibited an inverse correlation with mortality rates stemming from chronic liver disease and HCC[2,292]. Nutritional interventions should be customized based on an individual’s metabolic and nutritional profile to effectively manage and mitigate conditions such as obesity, MASLD, MASH, T2D, and CVD. The fundamental objective of these dietary regimens is the restriction of caloric intake to facilitate weight reduction and enhance insulin sensitivity. Dietary plans should be monitored and adjusted based on parameters such as weight, WC, and liver and cardiovascular biomarkers (ALT, AST, blood glucose, lipid profile, HbA1c, blood pressure, CRP, and brain natriuretic peptide), which is crucial for the effective management of MASLD and cardiovascular risk[289,290].

Exercise, with or without diet, influences the improvement of the muscle-liver axis. Physical activity is essential to manage cardiovascular risk in patients with MASLD because it lowers blood pressure and improves lipid profile, contributes to weight loss, reduces liver fat, and provides other metabolic benefits independent of weight reduction. In patients with T2D and MASLD, physical activity reduces liver fat content and visceral adiposity, enhances insulin sensitivity, and decreases HbA1c levels, further supporting its role in metabolic control. According to the American Heart Association and the World Health Organization, it is recommended to engage in physical activity for 150 minutes or more per week, consisting of either moderate aerobic exercise or 75 minutes of high-intensity training weekly, supplemented by a minimum of two resistance-training sessions to maximize cardiovascular protection. This exercise regimen is advised for the MASLD population, particularly individuals presenting with metabolic comorbidities like hypertension, obesity, or diabetes. Exercise regimens, encompassing aerobic training (such as jogging or cycling) and resistance exercises (like weightlifting), are proven to diminish hepatic fat and optimize metabolic markers. For those with MASLD, consistent activity retards the transition to steatohepatitis/MASH and fibrosis while bolstering cardiovascular health, primarily by enhancing endothelial performance and mitigating vascular inflammation. It is imperative that physical activity programs are tailored to the patient’s specific functional limits and existing comorbidities, including musculoskeletal issues or CVD[289,292].

Abstaining from tobacco and alcohol is vital due to their detrimental impact on metabolic syndrome, hepatic pathology, and cardiac failure. Specifically, immoderate alcohol intake triggers oxidative stress within the liver, thereby intensifying the severity of underlying MASLD. People with MASLD who consume alcohol suffer consequences such as liver problems, higher overall mortality, increased cancer incidences, and cardiovascular problems, in particular CAD. Patients with significant fibrosis or cirrhosis should strictly abstain from alcohol consumption. However, low or moderate alcohol consumption may not have harmful effects or may even have protective effects on overall mortality, MASLD, and steatohepatitis. Ethanol intake potentially elevates the risk of HCC in obese populations. The clinical significance of alcohol remains a subject of debate; however, certain research indicates that minimal daily consumption might provide cardioprotective effects[2,292,293]. Smoking is associated with MASLD, liver fibrosis, and liver cancer. Tobacco use in patients with T2D increases the risk of hepatic fibrosis and metabolic syndrome. Smoking cessation reduces HF risk[2,289].

Pharmacological management of MASLD/MASH and comorbidities

Pharmacological interventions are critical in managing MASLD and cardiovascular risk, especially in treating MASLD in patients with T2D, dyslipidemia, or hypertension.

Resmetirom: A selective hepatic thyroid hormone receptor-beta agonist that was approved by the Food and Drug Administration in March 2024 for the treatment of adults with non-cirrhotic MASH and significant liver fibrosis (F2-F3). Resmetirom is effective against steatohepatitis and fibrosis, preventing their progression to cirrhosis. Resmetirom significantly reduces liver enzymes and cardiovascular risk markers, such as atherogenic lipoproteins, including apolipoprotein C-III, Lp(a), and VLDL-C, as shown in the MAESTRO-NAFLD trial and in the MAESTRO-NASH trial[2,289,294]. In the United States, the prescribed dosage for resmetirom is weight-contingent: 80 mg daily for patients weighing under 100 kg and 100 mg for those exceeding that threshold. It is important to note that a dose reduction is required if the patient is also taking a moderate inhibitor like clopidogrel. In addition, the co-administration of resmetirom and statins should be precluded, or the statin dosage attenuated, to mitigate the risk of statin-related toxicity[2,294]. Resmetirom has moderate side effects, mostly gastrointestinal (nausea and diarrhea), with good overall safety and tolerability. Resmetirom treatment is recommended in patients evaluated on non-invasive tests (NITs) measuring liver stiffness, such as vibration-controlled transient elastography (VCTE) with scores ranging from 8 kPa to 15 kPa, magnetic resonance elastography (MRE) readings between 3.1 kPa and 4.4 kPa, or histologically confirmed fibrosis at stages F2-F3 via liver biopsy. Resmetirom is contraindicated in cases of advanced cirrhosis, specifically for patients with a VCTE stiffness exceeding 20 kPa or an MRE reading above 5 kPa, excessive alcohol consumption (more than 20-30 g per day for both sexes), or active thyroid disease. Studies are ongoing to determine the optimal duration of therapy and long-term cardiovascular outcome data, including prevention of progression to cirrhosis[289,294].

Glucagon-like peptide-1 receptor agonists: Glucagon-like peptide-1 (GLP-1) increases insulin and decreases glucagon secretion, reducing blood sugar levels. GLP-1 also delays gastric emptying, creating a feeling of satiety. GLP-1 receptor agonists (GLP-1RAs) are recommended in patients with overweight/obesity, MASLD, T2D, MASH, and liver fibrosis, including those with MASH and compensated cirrhosis, due to their positive impact on cardiometabolic outcomes. GLP-1RAs exert their beneficial effects by modulating the gut-liver axis, reducing liver enzyme levels, steatosis, and fibrosis. GLP-1RAs also exert anti-inflammatory effects in the T2D population, manifesting independently of any fluctuations in glycemic control or body mass[289,290]. Obese patients with MASLD can be pharmacologically treated to reduce body weight and improve MASLD with GLP-1RAs such as semaglutide and liraglutide; tirzepatide (a dual agonist of GLP-1 and glucose-dependent insulinotropic polypeptide: GIP); and orlistat. Semaglutide and tirzepatide have shown beneficial effects on cardiovascular and renal outcomes. Both semaglutide and liraglutide help patients with T2D or obesity by lowering blood sugar, encouraging weight loss, and decreasing the risk of heart attacks and strokes[2,289,294].

Semaglutide marks the first GLP-1RA to receive United States Food and Drug Administration approval for MASH management, becoming the second authorized therapeutic for this condition overall, following resmetirom. Administered as a weekly subcutaneous injection, specifically at a 2.4 mg dose for obesity, it achieves weight reduction of up to 15% over a 68-week period, leading to clinical improvements in MASLD. In a clinical trial focusing on MASH, an 18-month course of semaglutide achieved the resolution of steatohepatitis, though it failed to show a significant reduction in fibrosis. Furthermore, semaglutide markedly lowers the incidence of CVEs among obese individuals who do not have diabetes. Semaglutide is associated with a reduction in MACEs, even in obese patients without diabetes[2,289,290,294]. In individuals with compensated MASH-related cirrhosis, semaglutide did not significantly improve fibrosis or MASH resolution. However, patients lost more weight and had lower levels of triglycerides and VLDL-C, and those with T2D also experienced reductions in HbA1c levels[295].

Liraglutide (3 mg/day, subcutaneously) is recommended to treat T2D and moderate obesity and induces weight loss of up to 5%-6% after 56 weeks; it also reduces CVEs in patients with T2D or obesity. Liraglutide demonstrates histological efficacy in MASH and exerts a favorable influence on cardiovascular risk profiles by mitigating hepatic steatosis, despite a lack of significant fibrosis regression. In the LEADER and SUSTAIN-6 studies, liraglutide reduces the occurrence of MACE in patients with T2D at high CVD risk[2,289,290,294].

Tirzepatide: Is a GLP-1/GIP receptor agonist administered once weekly to individuals with T2D, overweight, or obese. Administered on a weekly basis, a 5 mg dose of tirzepatide resulted in a 16% reduction in body weight over 72 weeks, whereas the 15 mg weekly dosage achieved a weight loss of 22.5%. In patients with T2D, tirzepatide lowers both liver and visceral fat. It has also proven to be more effective at helping patients lose weight and improving the health of liver tissue in cases of MASH. Tirzepatide has better effects on reducing HbA1c and more lasting weight loss compared to semaglutide, supporting its cardiometabolic relevance[2,289,290,294].

Peroxisome proliferator-activated receptor agonists: Pioglitazone [peroxisome proliferator-activated receptor (PPAR-γ) agonist] and lanifibranor (pan-PPAR agonist) significantly improve CVD risk factors associated with MASLD. Pioglitazone reduces blood glucose levels and insulin resistance and improves lipid metabolism, providing cardiovascular protection in patients with T2D and atherosclerotic disease. Furthermore, it enhances hepatic histological markers in MASLD and provides a defense against both microvascular and macrovascular cardiovascular complications, acting as a stabilizing agent for atherosclerotic plaques[289,290,294]. Pioglitazone represents a suitable therapeutic candidate for individuals presenting with T2D and MASLD, particularly those characterized by insulin resistance, elevated triglycerides and LDL-C, and increased abdominal adiposity. Controversial studies of pioglitazone on MASH have been reported. Pioglitazone improves steatosis, resolves MASH, and improves fibrosis. In the context of MASH, it mitigates necroinflammation by altering adipose tissue distribution, specifically by shifting the visceral-to-subcutaneous fat ratio, and elevating adiponectin concentrations. Nevertheless, while the drug enhances the histological markers of steatohepatitis, it lacks a definitive impact on fibrosis regression, even with extended therapy spanning three years. The guidelines suggest the use of pioglitazone in diabetic individuals with MASH, but advise against its use to treat MASLD without biopsy-proven MASH. However, its side effects (increased body weight, fluid retention, HF, and bone loss) have limited its development for MASH[2,289,290,294].

Sodium-glucose co-transporter-2 inhibitors: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are indicated for the management of T2D, HF, and chronic kidney disease, owing to their established cardioprotective and renoprotective advantages. They also have beneficial hepatic effects (improving ALT and intrahepatic triglyceride content) because they induce renal glucosuria, weight loss, blood pressure reduction, as well as a decrease in fat mass, specifically within the visceral and abdominal subcutaneous compartments, thereby providing a defense against significant CVEs, such as HF[2,289,290]. While SGLT2 inhibitors are indicated for T2D, specific agents such as empagliflozin and dapagliflozin have received further regulatory approval for the management of HF and chronic kidney disease. In patients with T2D, empagliflozin and dapagliflozin reduce liver fat content, and ALT levels are reduced by empagliflozin. Moreover, empagliflozin and dapagliflozin have been shown to decrease HF hospitalizations and MACEs across both diabetic and non-diabetic populations. Consequently, these agents are particularly beneficial for MASLD patients, who frequently present with a high burden of cardiometabolic risk factors. Additionally, SGLT2 inhibitors elevate circulating concentrations of adiponectin and glucagon while simultaneously lowering uric acid levels. These agents also mitigate oxidative stress and systemic inflammation, providing therapeutic advantages for individuals with T2D and MASLD[2,289,290]. There are studies with inconsistent results regarding improvements in liver fibrosis. However, SGLT2 inhibitors provide therapeutic value for patients with HFrEF and concurrent MASLD, as they diminish cardiovascular mortality and HF admissions while enhancing glycemic regulation, insulin sensitivity, and fatty acid oxidation[4,5]. Prudence is required when prescribing SGLT2 inhibitors to individuals with advanced kidney dysfunction, as these agents may be entirely contraindicated in severe cases. Furthermore, the 2024 European Association for the Study of the Liver-European Association for the Study of Diabetes-European Association for the Study of Obesity Clinical Practice Guidelines advise against utilizing this drug class as a primary, targeted treatment for MASH[2,289].

Statins: Current clinical practice guidelines advocate for the use of statins to manage hyperlipidemia in individuals with MASLD and confirmed CVD. Furthermore, they are indicated for those at elevated cardiovascular risk, encompassing patients with obesity, T2D, and metabolic syndrome. Statins are safe in individuals with MASLD, with no risk of hepatotoxicity, and improve liver biochemistry. Statins reduce oxidative stress, inflammation, and endothelial insulin resistance and improve endothelial dysfunction, but clinical data remain limited[2,289,292,294]. Clinical guidelines suggest the use of moderate- to high-intensity statin therapy in patients with MASLD who have dyslipidemia or elevated cardiovascular risk, except in cases of decompensated cirrhosis or acute liver failure. The administration of statins is associated with a decreased incidence of MASLD, MASH, and liver fibrosis. Furthermore, in patients with cirrhosis, statin use has been shown to lower the risk of hepatic decompensation, overall mortality, and the development of HCC[2,289,294]. Elevated ALT levels can be induced by statin treatment in 3% of patients, and no progression of liver fibrosis has been reported. Statins prevent both cardiovascular and liver-related complications in MASLD patients. However, the therapeutic effectiveness of statins specifically for MASH remains unconfirmed, given the absence of large-scale randomized controlled trials that utilize histological assessment as a primary endpoint. Should statin therapy prove insufficient for MASLD management, alternative agents, either as monotherapy or in tandem, may be explored. These include ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, inclisiran, and bempedoic acid for LDL-C reduction, alongside fibrates, omega-3 fatty acids, or icosapent ethyl for addressing hypertriglyceridemia, despite a scarcity of disease-specific data. It is important to note that co-administering statins and fibrates is generally discouraged owing to the elevated risk of myopathy[2,289,294].

Metformin: Metformin remains a cornerstone for T2D treatment, particularly as many of these patients concurrently present with MASLD and atherosclerosis. It provides significant cardiometabolic benefits, including a decreased incidence of cardiovascular complications and an improvement in overall survival rates among overweight individuals with T2D. Metformin exerts hepatoprotective effects by inhibiting gluconeogenesis and liponeogenesis via adenosine monophosphate-activated protein kinase activation. Additionally, it mitigates systemic inflammation, elevates GLP-1 concentrations, enhances peripheral glucose utilization, optimizes lipid oxidation, and reshapes the composition of the gut microbiota[289,290]. Metformin can reduce liver fat content and decrease transaminase levels in individuals with MASLD and T2D without a significant effect on fibrosis and resolution of MASH. These effects are attributed to the reduction of systemic inflammation, the improvement of endothelial function, and the decrease of atherogenic risk factors, which are important in MASLD, where CVD is the leading cause of mortality[2,289,290,294]. Metformin can reduce the risk of HCC development[292,294]. The current guidelines consider metformin safe for diabetic patients with liver disease but do not recommend metformin for the treatment of MASLD itself. However, metformin is a pragmatic therapeutic option in MASLD patients with elevated cardiovascular risk[289,290].

Other therapeutic targets: Pharmacological agents with anti-inflammatory properties, specifically corticosteroids and pentoxifylline, have demonstrated potential in mitigating hepatic inflammation. Furthermore, aspirin may exert a protective effect by slowing the advancement of fibrosis in the MASLD population. Since MASLD is linked to AF and a hypercoagulable state, antithrombotic interventions, including aspirin and oral anticoagulants, may lower cardiovascular risk while simultaneously slowing liver scarring. The use of beta-blockers and angiotensin receptor blockers is recommended to treat both hypertension and HF. Although beta-blockers may mask hypoglycemic symptoms in individuals with concurrent MASLD and T2D, angiotensin receptor blockers and ACE inhibitors appear advantageous owing to their inherent anti-inflammatory and antifibrotic characteristics[293,296].

Biomarkers and screening of cardiometabolic risk in MASLD/MASH

The role of metabolic and hepatic biomarkers is fundamental to assess the risk and progression of MASLD and MASH. The first strategy involves the identification of at-risk patients with obesity, T2D, and metabolic syndrome. Weight loss (10% of body weight reduction) is critical to reducing steatosis, MASLD, and cardiometabolic risk in obese patients, which can be achieved through dietary interventions (hypocaloric diet), structured exercise programs (comprising 150-300 minutes of moderate-intensity or 75-150 minutes of high-intensity physical activity per week), or bariatric surgery. Obesity can be diagnosed using assessments like BMI, WC, and waist to height ratio, while dyslipidemia is evaluated through a lipid profile from fasting plasma (triglycerides, LDL-C, and HDL-C). According to the European Society of Cardiology, cholesterol level goals for patients with MASLD are defined as follows: LDL-C < 2.6 mmol/L (100 mg/dL), for low/moderate CVD risk, < 1.8 mmol/L (70 mg/dL) for high risk, and < 1.4 mmol/L (55 mg/dL) for very high risk. Meanwhile, the goals for blood pressure are all patients (blood pressure < 140/90 mmHg) and high-risk CVD patients (blood pressure < 130/80 mmHg); and for T2D, all patients (HbA1c < 53 mmol/mol or 7%). In addition, several biomarkers have been proposed for their utility in monitoring MASLD development, including transaminase enzymes, which indicate liver damage but do not distinguish between different stages of MASLD and MASH; lipid biomarkers (ceramides, sphingolipids, FFAs, phospholipids, and omega-3 polyunsaturated fatty acids); inflammatory markers (hs-CRP, TNF-α, and IL-6); insulin resistance indicators (HOMA-IR and adiponectin); and hepatic function markers (cytokeratin 18 and gamma-glutamyl transferase)[2,297-299]. T2D acts as a catalyst for the advancement of liver disease, driving the transition from simple steatosis toward fibrosis, cirrhosis, and ultimately, HCC. Therefore, active monitoring of liver function in patients with T2D is recommended. Clinicians confirm the presence of T2D or insulin resistance by assessing fasting plasma glucose and HbA1c levels, or through an oral glucose tolerance test. Additional diagnostic metrics include 2-hour post-load glucose, fasting plasma insulin, C-peptide concentrations, and the HOMA-IR index. The therapeutic goals for patients with T2D are HbA1c < 7%, prevention of microvascular and macrovascular complications, and organ protection (heart, kidney, and liver)[2,300]. Atherosclerosis is assessed through a complete blood count, platelets, Lp(a), and, according to clinical evaluation, can be considered fibrinogen, homocysteine, von Willebrand factor antigen, CIMT, Echo-Doppler plaque instability, and CAC. Importantly, individuals with MASLD should also be screened annually for T2D, hyperlipidemia, hypertension, and overweight/obesity[2,291]. MRI-derived proton density fat fraction is widely regarded as the benchmark for the non-invasive assessment of hepatic steatosis. It demonstrates high diagnostic accuracy in identifying MASLD, MASH, and fibrotic MASH. Individuals with MASLD, T2D, and metabolic syndrome should undergo assessment using NITs, a process vital for stratifying patients into low-, intermediate-, or high-risk categories for advanced fibrosis, which serves as a primary predictor of long-term prognosis in MASLD. Preliminary screening via NITs involves the calculation of FIB-4 and the nonalcoholic fatty liver disease fibrosis score. Should these metrics suggest a high probability of advanced disease, confirmatory elastography techniques, such as VCTE or MRE, are indicated[297,301,302]. Owing to its widespread availability, cost-effectiveness, and high negative predictive value for ruling out advanced fibrosis (≥ F3-F4), the FIB-4 index is advocated as a primary screening instrument for individuals with metabolic risk factors, including T2D and obesity. For patients aged 65 years and younger, a FIB-4 score below 1.3 signifies a low likelihood of advanced fibrosis, whereas scores ranging from 1.3 to 2.67 fall into an indeterminate category. A score exceeding 2.67 indicates a high probability of advanced disease, necessitating further diagnostic evaluation or a referral to a hepatology specialist. When FIB-4 results fall within the indeterminate range, clinicians should employ additional risk stratification via VCTE (e.g., FibroScan^®) or a secondary blood-based fibrosis panel. Should these diagnostic findings prove contradictory, a liver biopsy is indicated to reach a definitive conclusion. VCTE assesses the velocity of mechanical waves traveling through hepatic tissue to calculate the liver stiffness measurement. A liver stiffness value (LSV) below 8.0 kPa offers a high negative predictive value for ruling out advanced fibrosis (≥ F3-F4), whereas values of 8.0 kPa or higher signify an increased risk, necessitating a referral to a hepatology specialist. MRE is recommended in instances where VCTE results are either inconclusive or technically unreliable. This imaging modality has proven to be an exceptionally precise tool for measuring liver fibrosis and is further linked to markers of systemic inflammation and endothelial dysfunction, key contributors to CVD. Nevertheless, its clinical adoption is constrained by significant expenses and the necessity for specialized hardware. An MRE-derived LSV exceeding 3.5 kPa indicates the likely presence of advanced fibrosis, while a measurement greater than 4.4 kPa is highly indicative of cirrhosis. MRI-derived iron-corrected T1 can identify at-risk MASH. Moreover, MRE is more sensitive and accurate than transient elastography for detecting significant fibrosis and cirrhosis. Beyond its capacity for the precise quantification of hepatic steatosis and metabolic flux, magnetic resonance spectroscopy facilitates cardiovascular risk stratification, especially among patients with dyslipidemia or insulin resistance. Magnetic resonance spectroscopy is capable of detecting increased myocardial triglycerides and lactate, markers of cardiac stress and potential ischemia, while also identifying lipid-dense atherosclerotic plaques in the arteries that drive CAD and cerebrovascular accidents[291,296,301,302]. The enhanced liver fibrosis (ELF) test is recognized as a second-line NIT option, used for advanced fibrosis when it is suspected. ELF scoring ≥ 11.3 can predict future CVD and liver-related events in the general population. ELF score assesses levels of hyaluronic acid, procollagen III amino-terminal peptide, and tissue inhibitor of metalloproteinases-1, all of which indicate extracellular matrix remodeling during fibrogenesis. Compared to the FIB-4 index and the NAFLD fibrosis score, ELF demonstrates superior sensitivity and specificity in forecasting liver-related outcomes, including the development of cirrhosis and associated clinical complications[291,302]. Additional fibrosis markers, the AST to platelet ratio index, the steatosis-associated fibrosis estimator score, the Forns index, and the Hepamet fibrosis score (HFS) are also noninvasive tools to evaluate hepatic fibrosis. Both the Forns index and HFS have demonstrated a significant association with cardiovascular risk, providing clinicians with effective instruments for risk stratification within the context of chronic liver disease[296,302].

Since cardiovascular complications often determine the clinical outcomes of MASLD, current guidelines recommend screening for CVD using standard ASCVD prediction tools. For instance, the predicting risk of CVD events (PREVENT) calculator is a tool that takes into account chronic kidney disease and metabolic comorbidities to provide 10- and 30-year prognostic estimates for ASCVD and HF. If it is required for refining the individual’s ASCVD risk or for guidance of treatment decisions, CT coronary artery calcium scoring can be used to aid in prediction of CVD events in patients with MASLD. Other scoring systems for assessing CVD risk in patients with MASLD include the Framingham risk score and the ASCVD risk score (ASCVD); nevertheless, current clinical practice guidelines refrain from endorsing a definitive risk-stratification instrument. For individuals with severe MASLD and symptoms suggestive of underlying CAD, coronary CT angiography (CCTA) may be considered. However, routine CT-derived coronary artery calcium score or CCTA is not recommended based on the presence of MASLD alone. A CAC score exceeding 100 often correlates with a more than twofold rise in coronary event risk among those with MASLD. CIMT, assessed via high-resolution ultrasonography, serves as a marker for early-stage vascular pathology. In MASLD cohorts, elevated CIMT measurements are linked to the severity of hepatic steatosis, the stage of fibrosis, and underlying insulin resistance. CIMT also demonstrates an association with endothelial impairment and arterial rigidity, both of which are definitive characteristics of early-stage atherosclerosis. In patients with MASLD, common CIMT measurements surpassing a threshold of 0.8 mm are associated with early atherosclerotic changes and increased CVE rates. MASLD is associated with functional remodeling of the myocardium. Advanced imaging techniques, such as MRI and speckle-tracking echocardiography, have identified reduced LV strain, left atrial enlargement, and subclinical diastolic impairment in MASLD cohorts, even among those without clinically evident heart disease. Echocardiography is used to assess early diastolic relaxation velocity, filling pressures, global longitudinal strain, regional wall motion abnormalities, valvular abnormalities, and epicardial adipose tissue in symptomatic individuals with MASLD[291,299,303].

SUMMARY AND PROSPECTS

MASLD is considered a complex disease characterized by diverse genetic variations among patients, environmental factors, and metabolic and pathophysiological conditions such as dyslipidemia, dysregulation of adipokine expression, inflammation, oxidative stress, insulin resistance, liver steatosis, and gut dysbiosis, which interact to determine the phenotype and progression of the disease[10]. Obesity-driven visceral adiposity and insulin resistance serve as the primary drivers, leading to an atherogenic lipid profile and endothelial dysfunction. Patients with MASLD have multiple risk factors for the development of CVD, including obesity, dyslipidemia, hypertension, T2D, and chronic kidney disease. Indeed, a wealth of clinical evidence suggests that CVD represents a leading driver of both morbidity and mortality among the MASLD population. In addition, MASLD and T2D share a sophisticated, reciprocal association; this interplay drives hepatic fibrogenesis, insulin resistance, endothelial dysfunction, and finally, cardiovascular manifestations. The diseased liver acts as a source of pro-inflammatory cytokines and pro-thrombotic factors that directly accelerate atherosclerosis. Another frequent comorbidity in MASLD is hypertension, which increases the risk of HF, peripheral arterial occlusive disease, and cardiac arrhythmias, especially AF. Further research is warranted to optimize HF identification in patients with MASLD and quantify its prognostic impact, thereby guiding clinicians toward more effective therapeutic selections. The fundamental pathways connecting MASLD to CVD are multifaceted, involving the concurrent interplay of dyslipidemia, dysregulation of adipokine expression, insulin resistance, systemic inflammation, oxidative stress, endothelial dysfunction, coagulation disorders, RAAS and SNS activation, and gut microbiota dysbiosis; see Figure 3[66,170]. Patients with MASLD often develop coronary atherosclerosis, and cardiac alterations (especially cardiac remodeling and hypertrophy), which, along with AF, promote the development of HF[239]. Several studies have evaluated MASLD as an independent risk factor for cardiometabolic disorders and CVD. For instance, some studies show a clear association between MASLD and cardiovascular risk in diabetic patients; others have not reported such a relationship. Discrepancies in results may be due to variations in sample size, MASLD diagnostic methods, and the length of follow-up periods in clinical studies. Given the prevalence of AF and HF in patients with MASLD, cardiologists and hepatologists should consider screening these patients for signs and symptoms of CVD, particularly those with T2D and hypertension, to reduce morbidity and mortality in patients with MASLD. In addition, multidisciplinary collaboration involving clinical nutritionists, psychologists, and physical rehabilitation therapists is essential. Integrating food banks, farmers' markets, low-cost public gyms, exercise programs, and personalized diets can help MASLD patients reverse liver fibrosis and avoid developing CVD. Notably, CVD remains the primary cause of death in this population, outstripping liver-related mortality.

Figure 3 Pathophysiological mechanisms that link metabolic dysfunction-associated steatotic liver disease to cardiovascular disease. MASLD: Metabolic dysfunction-associated steatotic liver disease; RAAS: Renin-angiotensin-aldosterone system; SNS: Sympathetic nervous system; CAC: Coronary artery calcification; CAD: Coronary artery disease; CHD: Coronary heart disease; ACS: Acute coronary syndrome; PAD: Peripheral artery disease; CVD: Cardiovascular disease; AF: Atrial fibrillation; QTc: Heart rate-corrected QT; HFpEF: Heart failure with preserved ejection fraction; LV: Left ventricular; LVH: Left ventricular hypertrophy.

Currently, resmetirom remains the only pharmacological therapy approved by the Food and Drug Administration specifically for non-cirrhotic MASH, and there are no specialized clinical protocols for managing CVD uniquely within the MASLD population; there is a necessity for optimized multidisciplinary diagnostic and management strategies. Therefore, a proactive and holistic approach should be considered to improve outcomes in patients with MASLD and CVD, as well as to assess the long-term impacts of these two diseases. The therapeutic approach centers on achieving weight reduction alongside the aggressive management and mitigation of CVRFs. In patients with MASLD and CVRFs, a lifestyle intervention is recommended to induce weight loss through diet (especially a Mediterranean diet), the use of herbal and plant-based medicines with protective properties targeting CVRFs, and exercise[304,305]. To manage hyperlipidemia, statins are indicated as the primary therapeutic intervention, complemented by the administration of antihypertensive and antidiabetic agents to address hypertension and diabetes, respectively. Global health projections suggest that by 2050, the adult population affected by overweight and obesity will escalate to 3.8 billion (3.39-4.04), while the prevalence of diabetes is expected to surpass 1.31 billion (1.22-1.39) individuals[306,307]. Driven by the worldwide surge in obesity and T2D, the prevalence of MASLD and CVD is projected to rise. Consequently, there is a critical need for robust preventive strategies, diagnostic screening, and potent therapeutic interventions to mitigate the illness and death associated with the MASLD population.

Future studies must focus on definitively isolating the independent contribution of MASLD from shared metabolic risk factors like visceral fat. This requires more rigorous longitudinal designs that include advanced imaging to track the progression of both liver fibrosis and vascular damage simultaneously. Prospects include the development and broader implementation of therapies with dual benefits, specifically GLP-1RAs and SGLT2 inhibitors, which have demonstrated significant potential in enhancing hepatic metabolic function alongside cardiovascular health. Incorporating liver health assessments into routine cardiovascular risk stratification could facilitate earlier intervention. Further investigation into the liver-heart axis is required, specifically regarding how hepatokines and gut microbiota-derived metabolites influence cardiac remodeling and arrhythmogenesis.

CONCLUSION

In conclusion, a definitive association exists between MASLD and obesity, dyslipidemia, insulin resistance, T2D, and hypertension; these represent traditional CVRFs and heighten prothrombotic risk. While the direct causality between MASLD and CVD remains a subject of ongoing discussion, an extensive body of research has confirmed a robust correlation between MASLD, particularly in its more severe stages, and diverse cardiovascular pathologies, including atherosclerosis, cardiomyopathy (LV dysfunction and hypertrophy), cardiac arrhythmias such as AF, venous thrombosis, and cardiac conduction defects. In addition, MASLD acts as a significant driver of CVD through systemic pathways. Both MASLD and CVD are growing public health problems, and CVD remains the leading cause of death among patients with MASLD and T2D. The associations between MASLD and subclinical atherosclerosis, AF, and HF are often independent of traditional risk factors, although they are significantly exacerbated by the presence of T2D and obesity. Notably, MASLD presents both a diagnostic and therapeutic challenge. The use of non-invasive screening methods and the participation of multi-disciplinary team members play a critical role in the timely identification and intervention of both MASLD and its comorbidities in high-risk patients. Managing obesity-related complications through lifestyle interventions and pharmacological therapies for obesity-associated comorbidities is the key therapeutic intervention for patients with MASLD, which contributes to improving cardiometabolic risk factors.