Cardiovascular Implications in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A State-of-the-Art Review

Author's summary

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has rapidly emerged as the most prevalent chronic liver disease globally, with significant and underappreciated implications for cardiovascular morbidity and mortality. In this comprehensive review, we synthesize the latest evidence linking MASLD to cardiovascular outcomes, highlight advances in diagnostic and risk stratification approaches, discuss emerging therapeutic strategies targeting the cardio-hepatic axis, and outline critical gaps in knowledge and future research directions. Our review is distinguished by its integrated focus on MASLD within the newly updated disease framework, incorporation of emerging cardiometabolic therapies, and emphasis on multidisciplinary management strategies.

Abstract

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is the most prevalent chronic liver disease globally and a key driver of cardiometabolic morbidity. Beyond hepatic manifestations, MASLD significantly elevates the risk of cardiovascular disease (CVD)—including myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality—through overlapping mechanisms such as visceral adiposity, insulin resistance, inflammation, oxidative stress, and dyslipidemia. Epidemiologic data demonstrate a consistent and independent association between MASLD and adverse cardiovascular outcomes. Subclinical changes in vascular structure and function precedes overt events, underscoring the need for early detection and proactive risk stratification. While glucagon-like-peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors offer dual hepatic and cardiovascular benefits, recent trials have revealed nuances in efficacy across patient populations, particularly in heart failure with preserved ejection fraction and cirrhotic cohorts. Non-invasive diagnostics—including elastography, magnetic resonance elastography, magnetic resonance imaging-derived proton density fat fraction, and machine learning–based tools—are enhancing the precision of MASLD staging and risk assessment. However, implementation remains variable, and cost-effectiveness in CVD screening is underexplored. This review synthesizes current knowledge on the MASLD–CVD interface, critically appraises existing evidence, and identifies gaps in mechanistic understanding, diagnostics, and therapeutics. We advocate for an integrated, multidisciplinary framework combining hepatology and cardiology expertise to optimize patient care in this evolving disease landscape.

INTRODUCTION

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has rapidly evolved from a hepatology-focused diagnosis to a major systemic disease at the center of the global cardiometabolic epidemic. As the most prevalent chronic liver disease worldwide, MASLD affects nearly one-third of the global adult population, a trend fueled by the rising burden of obesity, type 2 diabetes mellitus, and metabolic syndrome. Once thought to be a benign condition, MASLD is now recognized as a dynamic, progressive disorder with implications far beyond the liver. A growing body of literature suggests that MASLD is intimately linked to multisystem injury, with the cardiovascular system being its most frequent and fatal target.¹⁾,²⁾,³⁾,⁴⁾

Cardiovascular complications, including myocardial infarction, stroke, and heart failure, frequently occur before hepatic events manifest, reflecting the silent yet pervasive nature of the MASLD–cardiovascular disease (CVD) axis. Shared pathophysiologic mechanisms—including systemic inflammation, insulin resistance, dyslipidemia, endothelial dysfunction, and coagulation abnormalities—create a milieu conducive to both hepatic fibrosis and vascular injury. Genetic polymorphisms such as PNPLA3 and TM6SF2 further modulate this interplay, influencing both hepatic progression and atherogenesis. Postmenopausal women may be particularly vulnerable due to the loss of estrogen’s hepatoprotective and vasoprotective effects, shifting their risk profile. Longitudinal studies and meta-analyses have consistently shown that individuals with MASLD have a significantly increased risk of incident and fatal cardiovascular events, even after adjusting for conventional risk factors.⁵⁾,⁶⁾,⁷⁾

Despite this evidence, MASLD remains underappreciated in cardiovascular risk stratification algorithms and clinical practice guidelines. Similarly, cardiologists often overlook the presence of underlying hepatic steatosis or fibrosis in patients presenting with CVD. This bidirectional knowledge gap between hepatology and cardiology hinders early identification of high-risk individuals and delays the implementation of appropriate therapeutic interventions.⁴⁾,⁵⁾,⁸⁾,⁹⁾ For example, statins—which reduce cardiovascular risk—are often underutilized in MASLD patients due to unsubstantiated fears of hepatotoxicity, despite growing safety data.

Given the growing prevalence of MASLD and its disproportionate cardiovascular burden, there is an urgent need to reframe MASLD as a multisystem disorder with far-reaching clinical implications. This review explores the epidemiology, pathophysiology, and clinical consequences of the MASLD–CVD axis. We also examine emerging diagnostic and therapeutic approaches, highlight knowledge gaps, and propose integrated care strategies aimed at improving patient outcomes through multidisciplinary collaboration.

EPIDEMIOLOGY

The epidemiologic link between MASLD and CVD has reshaped its clinical identity, positioning MASLD as a systemic metabolic risk factor rather than an isolated hepatic disorder. A growing body of evidence demonstrates that individuals with MASLD are at significantly elevated risk for major cardiovascular events—including myocardial infarction, ischemic stroke, heart failure, and cardiovascular death—across diverse global populations. These associations persist independently of traditional risk factors, underscoring MASLD’s direct contribution to cardiovascular morbidity (Table 1).⁷⁾,¹⁰⁾,¹¹⁾

Table 1. Summary of key epidemiological studies linking MASLD and cardiovascular disease.

Study	Population	Key findings	Hazard ratio	Notes	Ref.
Nationwide cohort (>7 million adults)	General population	MASLD associated with increased CVD incidence; risk increases with number of metabolic risk factors	1.39	Regression of MASLD linked to reduced CVD risk	7)
Young adult cohort	Young adults	MASLD increases risk of MI, stroke, heart failure	1.23 (MI), 1.12 (Stroke), 1.18 (HF)	Higher risk in females and obese individuals	11)
Meta-analysis (129 studies)	Diverse global cohorts	MASLD increases pooled cardiovascular event risk	1.43	Robust across populations	10)

Summary of major epidemiological studies demonstrating the association between MASLD and increased cardiovascular risk.

CVD = cardiovascular disease; HF = heart failure; MASLD = Metabolic Dysfunction-Associated Steatotic Liver Disease; MI = myocardial infarction.

Large-scale cohort studies have provided robust quantification of this risk. A landmark national analysis of over 7 million adults found a hazard ratio (HR) of 1.39 for CVD events among those with MASLD, even after adjusting for age, sex, diabetes, hypertension, and obesity. Notably, the magnitude of risk scaled with the number of coexisting cardiometabolic traits. Additionally, dynamic changes in hepatic phenotype proved prognostically significant—incident MASLD during follow-up increased CVD risk, while resolution of MASLD corresponded to a lower future risk—underscoring its role as both a marker and modulator of cardiovascular outcomes.⁵⁾,¹²⁾

Further studies in young adults reinforced these concerns, linking MASLD in early life with substantially elevated risk of major adverse cardiovascular events (MACE). Adjusted HRs reached 1.23 for myocardial infarction, 1.12 for ischemic stroke, and 1.18 for heart failure. These risks were amplified among women and individuals with obesity, suggesting subgroup vulnerabilities that merit targeted intervention. Notably, women with MASLD may experience a greater relative increase in cardiovascular risk than men, especially following menopause. This may be partly due to the decline in estrogen’s hepatoprotective and vasoprotective effects, which amplifies metabolic and vascular vulnerability. These findings highlight the possibility that MASLD may contribute to premature CVD morbidity and mortality beginning early in the lifespan.⁵⁾,¹¹⁾,¹²⁾

Meta-analyses have confirmed the breadth and strength of these associations. A pooled analysis of 129 studies revealed a HR of 1.43 for CVD events in MASLD compared to non-MASLD individuals, with generalizability across regions, populations, and study designs. Longitudinal cohorts further demonstrated that elevated liver enzymes—common surrogates of hepatic inflammation or fibrosis—were independently associated with increased all-cause and cardiometabolic-specific mortality. Even modest biochemical indicators of liver injury may therefore signal considerable cardiovascular risk.¹⁰⁾,¹³⁾,¹⁴⁾

These observations are supported by a biologically coherent framework. Shared mechanisms—including visceral adiposity, systemic inflammation, oxidative stress, endothelial dysfunction, insulin resistance, thrombogenicity, and gut dysbiosis—create a pro-atherogenic environment in MASLD. The co-localization of these features in MASLD patients provides a compelling pathophysiologic explanation for the elevated cardiovascular risk observed. It is important to acknowledge that many studies evaluating the MASLD–CVD link are subject to residual confounding, particularly from conditions such as obstructive sleep apnea, sarcopenia, and sedentary behavior, which independently increase cardiovascular risk.⁶⁾,¹⁵⁾,¹⁶⁾,¹⁷⁾

Emerging evidence suggests that this risk is proportional to liver disease severity. Individuals with advanced hepatic fibrosis carry a significantly higher burden of CVD than those with isolated steatosis, highlighting the need for careful fibrosis staging and ongoing surveillance. The parallel progression of MASLD and CVD points to a synergistic relationship, wherein each disease may amplify the other over time.¹⁵⁾,¹⁸⁾

Given the overwhelming epidemiologic signal, proactive cardiovascular risk management is imperative for all patients with MASLD. This includes early implementation of lifestyle interventions and pharmacotherapies that confer dual hepatic and cardiovascular benefit. Glucagon-like-peptide 1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 inhibitors (SGLT2is), for example, have demonstrated promise in reducing cardiovascular events while improving liver outcomes. Regular cardiovascular risk assessment should also become routine in MASLD care, enabling earlier detection of subclinical disease.¹⁹⁾,²⁰⁾,²¹⁾

In summary, MASLD is a major, independent driver of CVD risk. The strength, consistency, and biological plausibility of this relationship demand a shift in clinical mindset—from viewing MASLD solely through a hepatology lens to recognizing it as a central player in cardiometabolic disease. As MASLD prevalence rises globally, addressing its cardiovascular consequences will be essential to reducing long-term morbidity and mortality. This necessitates a shift in framing MASLD as a multisystem disease requiring coordinated cardiology-hepatology care.

PATHOPHYSIOLOGY

The link between MASLD and CVD is driven by a convergence of interrelated mechanisms that extend well beyond hepatic injury (Figure 1 and Table 2). These include visceral adiposity, insulin resistance, systemic inflammation, endothelial dysfunction, oxidative stress, and dysregulated lipid and glucose metabolism—collectively fostering an environment that promotes atherosclerosis, cardiac remodeling, and vascular injury.⁵⁾,¹⁶⁾,²²⁾

Figure 1. Pathophysiological link between MASLD and cardiovascular disease risk. This conceptual framework illustrates the mechanistic pathways connecting MASLD to increased cardiovascular disease risk. Hepatic lipid accumulation leads to increased free fatty acid flux, triggering oxidative stress and systemic inflammation via cytokines (e.g., TNF-α, IL-6, CRP). These processes exacerbate insulin resistance and dyslipidemia—characterized by elevated triglycerides, small dense LDL particles, and reduced HDL cholesterol. The resulting atherogenic environment promotes endothelial dysfunction, plaque formation, and a prothrombotic state, culminating in plaque instability and heightened cardiovascular risk. Additional emerging contributors include gut dysbiosis, genetic polymorphisms (PNPLA3, TM6SF2), and lipotoxic inflammatory spillover, reinforcing the liver-heart axis as a critical therapeutic target.

CRP = C-reactive protein; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; IL-6 = interleukin-6; LDL = low-density lipoprotein; MASLD = Metabolic Dysfunction-Associated Steatotic Liver Disease; ROS = reactive oxygen species; TNF-α = tumor necrosis factor-α.

Table 2. Pathophysiological mechanisms linking MASLD and cardiovascular disease.

Mechanism	Impact
Visceral adiposity	Promotes insulin resistance and hepatic steatosis
Insulin resistance	Exacerbates dyslipidemia, endothelial dysfunction
Chronic low-grade inflammation	Promotes vascular injury, atherosclerosis
Oxidative stress	Damages endothelial cells and promotes plaque instability
Endothelial dysfunction	Impairs vascular homeostasis, promotes thrombosis
Prothrombotic state	Increases risk of acute cardiovascular events
Dyslipidemia and postprandial hyperlipemia	Enhance atherogenesis
Gut dysbiosis	Induces systemic inflammation and metabolic disturbances
Genetic predisposition (e.g., PNPLA3, TM6SF2)	Modifies lipid metabolism and inflammation

Pathophysiological processes connecting MASLD to cardiovascular disease through metabolic, inflammatory, and vascular pathways.

MASLD = Metabolic Dysfunction-Associated Steatotic Liver Disease.

At the core is visceral adiposity, which functions as an active endocrine organ. It secretes pro-inflammatory cytokines and adipokines, including tumor necrosis factor-α, interleukin-6, resistin, and leptin, while reducing protective adiponectin levels. This proinflammatory state exacerbates insulin resistance and increases free fatty acid flux to the liver, promoting steatosis and hepatic lipotoxicity. The result is a metabolic milieu characterized by increased hepatic gluconeogenesis, impaired fatty acid oxidation, and systemic hyperinsulinemia—all of which amplify cardiovascular risk. Recent studies also implicate the hepatokine FGF21, which exerts anti-inflammatory and metabolic effects and may directly influence vascular remodeling, further connecting hepatic dysfunction to cardiovascular pathology.⁵⁾,²³⁾

Hepatic insulin resistance contributes further to systemic metabolic disruption. In MASLD, hepatocytes develop resistance to insulin’s regulatory effects on glucose production and lipid metabolism, driving hyperglycemia and hypertriglyceridemia. This cascade increases small dense low-density lipoprotein (LDL) particles, reduces high-density lipoprotein, and contributes to atherogenic dyslipidemia. Concurrently, hepatic production of prothrombotic factors such as plasminogen activator inhibitor-1 and fibrinogen promotes a hypercoagulable state that elevates thrombotic risk.¹⁵⁾,²³⁾,²⁴⁾,²⁵⁾,²⁶⁾

Inflammation is another critical mediator. Hepatic steatosis activates resident Kupffer cells and recruits monocytes, which perpetuate local and systemic inflammation via cytokine signaling. The spillover of inflammatory mediators into circulation leads to endothelial activation, reduced nitric oxide availability, and increased vascular permeability. Endothelial dysfunction—hallmarked by impaired vasodilation, arterial stiffness, and enhanced leukocyte adhesion—represents a key early step in the pathogenesis of atherosclerosis. Variants in genes such as PNPLA3, TM6SF2, and MBOAT7 are well-established drivers of hepatic steatosis and fibrosis, and may also influence cardiovascular phenotypes through lipid remodeling and inflammatory signaling.²⁷⁾,²⁸⁾,²⁹⁾

Oxidative stress further compounds the vascular injury seen in MASLD. Excess reactive oxygen species generated in fatty hepatocytes and macrophages contribute to mitochondrial dysfunction, lipid peroxidation, and cytokine release. This environment fosters the formation of oxidized LDL and perpetuates vascular inflammation. Studies have linked markers of oxidative stress in MASLD with increased carotid intima-media thickness (CIMT) and coronary artery calcification—established precursors of clinical CVD.³⁾,¹⁶⁾,³⁰⁾,³¹⁾,³²⁾

Additional pathways include gut-liver axis alterations and microbiome dysbiosis. Increased intestinal permeability and endotoxemia due to microbial translocation have been observed in MASLD and are associated with both hepatic inflammation and systemic immune activation. Emerging data also implicate bile acid signaling and fibroblast growth factor pathways in MASLD-related cardiometabolic dysfunction. One key molecule linking this axis is trimethylamine N-oxide, a gut microbiota–derived metabolite that promotes endothelial dysfunction and atherosclerosis, and is increasingly recognized as a shared biomarker in MASLD and CVD.³³⁾,³⁴⁾,³⁵⁾

Together, these mechanisms illustrate that MASLD is not merely a hepatic disorder, but a driver of systemic inflammation, vascular injury, and cardiac remodeling. Recognizing these shared pathophysiologic roots reinforces the need for integrated approaches in diagnosing and managing both MASLD and CVD. However, many studies exploring mechanistic pathways in MASLD may be confounded by coexisting conditions such as obstructive sleep apnea, sarcopenia, and sedentary behavior, which independently contribute to cardiovascular pathology.

ROLE OF FIBROSIS SEVERITY IN CARDIOVASCULAR DISEASE RISK

Fibrosis severity in MASLD is increasingly recognized as a pivotal determinant of cardiovascular risk. While simple steatosis is associated with elevated morbidity, progression to hepatic fibrosis markedly amplifies systemic consequences (Figure 2). Emerging data underscore a dose-dependent relationship between fibrosis burden and both subclinical vascular changes and overt cardiovascular events. Data also suggests that fibrogenesis may itself contribute to cardiovascular injury by promoting systemic inflammation, matrix remodeling, and vascular stiffness—independent of metabolic comorbidities.¹⁸⁾,¹⁹⁾

Figure 2. Role of fibrosis in cardiovascular risk stratification among patients with MASLD. This illustration highlights the association between hepatic fibrosis severity and CVD risk in MASLD. As liver disease progresses from steatosis to early and late-stage fibrosis, cardiovascular risk increases—often beginning with subclinical vascular abnormalities. Elevated FIB-4 scores (>2.67) are associated with a fourfold increased risk of CVD, including CAD progression and ischemic stroke. Fibrosis acts as a key amplifier of CVD risk, reflecting systemic inflammation, vascular injury, and metabolic dysfunction. Hepatic fibrogenesis may serve as an early biomarker for cardiovascular screening and risk stratification in MASLD.

aOR = adjusted odds ratio; CAD = coronary artery disease; CVD = cardiovascular disease; FIB-4 = fibrosis-4; MASLD = Metabolic Dysfunction-Associated Steatotic Liver Disease.

A recent systematic review and meta-analysis demonstrated that even early-stage fibrosis correlates with heightened risk of subclinical atherosclerosis, with a pooled odds ratio of 2.18. Cardiovascular risk increases progressively across fibrosis stages, with studies showing HRs ranging from 1.5 in early fibrosis (F1) to over 3.5 in advanced fibrosis (F3–F4), independent of traditional cardiometabolic risk factors.⁵⁾,¹⁵⁾,³⁶⁾

Non-invasive fibrosis indices—particularly the Fibrosis-4 (FIB-4) score and liver stiffness measured via transient elastography—have shown strong predictive value. These markers correlate with surrogate endpoints of atherosclerosis, such as increased CMIT and moderate to severe coronary artery stenosis. In multiple cohorts, elevated FIB-4 scores and liver stiffness values independently predicted the presence and progression of coronary artery disease, reinforcing their utility in risk stratification. It is important to note that the performance of non-invasive fibrosis tools like FIB-4 and liver stiffness measurement can vary by body mass index (BMI), age, and diabetic status, potentially reducing predictive accuracy in lean MASLD or those with insulin resistance.³⁷⁾,³⁸⁾,³⁹⁾,⁴⁰⁾

Prospective studies provide further support for fibrosis as a prognostic biomarker. In one cohort, a FIB-4 score >2.67 was associated with a 4-fold increase in the incidence of cardiovascular events compared to patients without significant fibrosis. Similarly, biopsy-proven advanced fibrosis independently predicted incident CVD even after adjusting for conventional risk factors, suggesting that hepatic scarring confers incremental risk above and beyond established metabolic drivers.³⁸⁾,⁴¹⁾

The impact of fibrosis is not confined to hepatic or coronary pathology. Among hypertensive patients, MASLD-related fibrosis has been linked to increased all-cause mortality and ischemic stroke, with HRs rising by 91% and 42%, respectively, in individuals with high-risk fibrosis profiles. These findings expand the scope of fibrosis-related risk across multiple vascular territories.⁴⁾,¹⁵⁾,⁴²⁾

Data from the Framingham Heart Study further highlighted the systemic relevance of hepatic fibrosis. Liver stiffness assessed by vibration-controlled transient elastography was positively associated with a broad cluster of cardiovascular risk factors, including central obesity, metabolic syndrome, hypertension, dyslipidemia, and insulin resistance. These associations emphasize that hepatic fibrosis acts not only as a marker of liver disease progression but as a cardiometabolic amplifier with systemic implications.⁴⁰⁾,⁴³⁾,⁴⁴⁾,⁴⁵⁾

Taken together, these findings support the integration of fibrosis staging into cardiovascular risk assessment frameworks for MASLD. Identifying patients with advanced fibrosis provides an opportunity for aggressive risk factor modification, early implementation of cardioprotective therapies, and targeted surveillance aimed at reducing both hepatic and cardiovascular morbidity and mortality.

SUBCLINICAL CARDIOVASCULAR CHANGES IN METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE

CVD in MASLD frequently develops insidiously, with pathologic alterations often preceding clinical manifestations by years. A growing body of evidence underscores the presence of subclinical cardiovascular abnormalities in individuals with MASLD, detectable through advanced imaging modalities and vascular function assessments (Figure 3). Identifying these early changes is critical for risk stratification and for initiating preventive interventions before irreversible atherosclerotic or myocardial injury occurs.²²⁾

Figure 3. Imaging modalities for detecting subclinical cardiovascular disease in MASLD. This figure depicts non-invasive imaging techniques used to identify subclinical cardiovascular disease in patients with MASLD. Cardiovascular abnormalities in MASLD include subclinical atherosclerosis, vascular remodeling, and myocardial steatosis—often present before overt clinical symptoms. Coronary artery calcium scoring via CT scan detects coronary plaque burden, while carotid ultrasound assesses intima-media thickness and plaque formation. Magnetic resonance spectroscopy identifies myocardial fat deposition. These modalities offer insight into early vascular and cardiac changes in MASLD and may guide risk stratification and timely interventions.

CT = computed tomography; MASLD = Metabolic Dysfunction-Associated Steatotic Liver Disease; MRI = magnetic resonance imaging.

One of the most validated indicators of subclinical atherosclerosis is the coronary artery calcium (CAC) score, obtained via non-contrast computed tomography (CT). A CAC score >100 is commonly associated with a >2-fold increased risk of coronary events in MASLD patients. Multiple population-based studies have consistently demonstrated that patients with MASLD exhibit significantly elevated CAC scores compared to controls without steatosis. Importantly, this association persists even after adjustment for age, sex, diabetes, and hypertension, suggesting that MASLD confers additional cardiovascular risk beyond traditional factors.⁴⁶⁾

CIMT, measured via high-resolution ultrasonography, offers another noninvasive marker of early vascular disease. Increased CIMT has been observed in MASLD patients and correlates with markers of hepatic steatosis, fibrosis stage, and insulin resistance. CIMT is also associated with endothelial dysfunction and arterial stiffness—2 hallmarks of early atherosclerosis. MASLD patients often exhibit CIMT values exceeding 0.8 mm, which have been linked to early atherosclerotic changes and increased cardiovascular event rates.⁴⁷⁾

In addition to structural changes, MASLD is linked to functional myocardial alterations. Cardiac magnetic resonance imaging (MRI) and speckle-tracking echocardiography have revealed impairments in left ventricular strain, increased left atrial volume, and subtle diastolic dysfunction in MASLD patients, even in the absence of overt heart disease. These findings suggest subclinical cardiomyopathy driven by shared metabolic and inflammatory pathways.⁵⁾,⁴⁸⁾

Microvascular dysfunction is another critical component. Endothelial dysfunction—characterized by impaired nitric oxide–mediated vasodilation—has been documented in MASLD and is believed to contribute to impaired coronary flow reserve and myocardial perfusion abnormalities. Biomarkers of endothelial injury, including asymmetric dimethylarginine and soluble intercellular adhesion molecule-1, are elevated in MASLD and correlate with disease severity.¹⁾,⁵⁾

Recent machine learning–based models integrating demographics, labs, and liver stiffness measurements have demonstrated high accuracy in predicting MACE in MASLD populations, offering scalable tools for early identification of at-risk individuals.

Collectively, these subclinical abnormalities provide compelling evidence that MASLD initiates cardiovascular injury well before the onset of symptomatic disease. Incorporating advanced imaging and vascular biomarkers into MASLD evaluation may enhance early detection of at-risk individuals and support more aggressive cardiovascular risk mitigation strategies. However, interpretation of subclinical changes must consider coexisting conditions such as obstructive sleep apnea, sarcopenia, and chronic inflammation, which may independently influence vascular remodeling and stiffness.⁵⁾

CLINICAL CARDIOVASCULAR OUTCOMES IN METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE

The clinical burden of MASLD extends well beyond hepatic complications, with CVD representing the leading cause of morbidity and mortality in this population. While epidemiologic data establish a strong association between MASLD and elevated cardiovascular risk, clinical outcome studies provide compelling evidence that MASLD actively contributes to a diverse spectrum of cardiovascular pathologies, including myocardial infarction, ischemic stroke, heart failure, arrhythmias, and cardiovascular death (Figure 4 and Table 3).⁷⁾,¹⁰⁾

Figure 4. Clinical cardiovascular outcomes associated with MASLD. This figure summarizes the spectrum of cardiovascular outcomes linked with MASLD. Individuals with MASLD—especially young adults, women, and those with obesity—have elevated risks of MI, stroke, HF, and atrial fibrillation. The risk of cardiovascular events rises proportionally with the burden of coexisting cardiometabolic risk factors. Compared to individuals without hepatic steatosis, those with MASLD exhibit a 39% increased hazard for CVD events. MASLD is associated with multivessel coronary artery disease, vulnerable plaques, large-artery and cardioembolic strokes, and frequent hospitalizations due to HF and arrhythmias. Notably, regression of MASLD correlates with reduction in CVD risk, reinforcing the importance of early detection and management.

CAD = coronary artery disease; CVD = cardiovascular disease; HF = heart failure; MASLD = Metabolic Dysfunction-Associated Steatotic Liver Disease; MI = myocardial infarction.

Table 3. Cardiovascular outcomes associated with MASLD.

Outcome	Description
Myocardial infarction	Increased coronary plaque burden and vulnerability
Ischemic stroke	Elevated risk due to atherosclerosis and prothrombotic states
Heart failure	Predominantly heart failure with preserved ejection fraction
Arrhythmias	Increased prevalence of atrial fibrillation linked to myocardial fibrosis
Cardiovascular mortality	Elevated all-cause and CVD-specific death rates in MASLD populations

Major clinical cardiovascular outcomes associated with MASLD, illustrating the systemic impact of hepatic metabolic dysfunction.

CVD = cardiovascular disease; MASLD = Metabolic Dysfunction-Associated Steatotic Liver Disease.

Numerous large-scale cohort studies have reported increased rates of MACE in individuals with MASLD. In a nationwide cohort of over 7 million adults, MASLD was associated with a 39% higher hazard of cardiovascular events compared to those without hepatic steatosis. The risk increased in proportion to the number of concurrent cardiometabolic risk factors. Longitudinal data further revealed that development of MASLD during follow-up conferred a higher future CVD risk, whereas disease regression was associated with risk reduction—highlighting the dynamic interplay between hepatic metabolic dysfunction and cardiovascular health.¹⁰⁾

The cardiovascular impact of MASLD is not limited to middle-aged or elderly populations. In a cohort of young adults, MASLD was associated with increased incidence of myocardial infarction (HR, 1.23), ischemic stroke (HR, 1.12), and heart failure (HR, 1.18), with risk disproportionately elevated among women and individuals with obesity. These findings suggest that MASLD contributes to early-onset cardiovascular pathology, raising serious implications for long-term health outcomes and healthcare costs. This burden may be particularly pronounced in women, who demonstrate an elevated susceptibility to heart failure with preserved ejection fraction (HFpEF) in the context of MASLD. The transition through menopause, accompanied by a decline in estrogen’s vasodilatory and anti-inflammatory effects, may contribute to increased microvascular dysfunction and cardiac remodeling.¹¹⁾,¹²⁾

Meta-analyses reinforce these observations. A comprehensive synthesis of 129 studies yielded a pooled HR of 1.43 for cardiovascular events in MASLD patients, confirming the consistency and strength of this association across diverse populations and methodologies. Importantly, subclinical vascular abnormalities—such as increased CAC and CIMT—are also more common in MASLD, suggesting that vascular injury begins long before overt clinical disease develops.¹⁰⁾,²²⁾

The cardiovascular phenotypes associated with MASLD are diverse. Myocardial infarction is among the most prevalent outcomes, with patients demonstrating higher rates of both initial and recurrent events. Imaging studies, including coronary angiography and CT angiography, reveal greater plaque burden, higher CAC scores, and increased prevalence of high-risk plaque morphologies in MASLD, even after adjusting for conventional risk factors. Multi-vessel disease is more frequent in this group, further elevating clinical risk.⁴⁹⁾

The incidence of ischemic stroke is also heightened. MASLD contributes to atherogenic dyslipidemia, systemic inflammation, endothelial dysfunction, and a prothrombotic state—all of which drive cerebrovascular risk. Studies show increased rates of both large-artery and cardioembolic strokes in this population, underscoring the need for early vascular risk detection and intervention.⁷⁾

Heart failure, particularly HFpEF, is an increasingly recognized complication of MASLD. Mechanistic data implicate myocardial steatosis, microvascular dysfunction, increased ventricular stiffness, and systemic inflammation in the pathogenesis of HFpEF among MASLD patients. Observational cohorts confirm a significantly higher incidence of heart failure independent of other risk factors, expanding the clinical footprint of MASLD. These observations parallel epidemiologic trends showing disproportionately higher rates of HFpEF among postmenopausal women with MASLD.⁵⁰⁾,⁵¹⁾

Arrhythmias—especially atrial fibrillation—are more common in MASLD, likely due to a combination of autonomic imbalance, myocardial fibrosis, inflammation, and structural remodeling. Even after adjusting for obesity, hypertension, and diabetes, MASLD remains independently associated with atrial fibrillation, raising important considerations for stroke prevention and anticoagulation strategies.⁵²⁾

Beyond contributing to incident events, MASLD also worsens outcomes in patients with established CVD. In cohorts with preexisting coronary artery disease or heart failure, the presence of MASLD correlates with increased hospitalization, recurrence, and mortality. Elevated liver enzymes—often surrogates for active hepatic inflammation—are independently associated with both all-cause and cardiovascular-specific mortality in this setting. Recognizing this, both the American Association for the study of liver diseases (AASLD) and American College of Cardiology/American Heart Association now recommend statins for primary and secondary prevention of cardiovascular events in patients with MASLD, including those with compensated cirrhosis, based on strong outcome data and favorable hepatic safety profiles.⁵⁾,⁵³⁾

Collectively, these data affirm that MASLD is not a passive bystander but an active driver of CVD. The steatotic and inflamed liver promotes systemic metabolic dysfunction, vascular inflammation, plaque instability, myocardial impairment, and electrical remodeling. These processes increase the incidence, complexity, and lethality of cardiovascular conditions. However, outcome data for pharmacologic agents must be interpreted cautiously. For example, while glucagon-like-peptide 1 receptor agonists (GLP-1 RAs) reduce cardiovascular events in type 2 diabetes, randomized trials in HFpEF cohorts have yielded mixed mortality outcomes. Statin therapy, though generally safe in MASLD, still warrants individualized assessment in patients with advanced fibrosis or decompensated liver disease. Moreover, while resmetirom demonstrates histologic improvement in MASLD, cardiovascular event data are pending from ongoing trials.⁵⁾

Recognizing MASLD as a key contributor to cardiovascular outcomes mandates a shift in clinical management. Routine cardiovascular risk screening should be integrated into MASLD care, with aggressive targeting of modifiable risk factors including dyslipidemia, insulin resistance, obesity, and hypertension. Pharmacologic therapies with dual hepatic and cardiovascular benefits—such as GLP-1 receptor agonists and SGLT2 inhibitors—may help mitigate this parallel disease trajectory. Importantly, these interventions may be most impactful when guided by subclinical risk markers, such as CAC and myocardial strain abnormalities, which precede clinical events and allow for earlier intervention.¹⁵⁾

METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE IN SPECIAL POPULATIONS: YOUNG ADULTS AND WOMEN

Although MASLD has traditionally been regarded as a condition of middle-aged and older adults, recent shifts in epidemiology highlight its increasing prevalence in younger populations. The global rise in obesity, insulin resistance, and sedentary behavior among adolescents and young adults has contributed to earlier onset of MASLD, raising concern for premature cardiometabolic disease. In female patients, hormonal status critically influences MASLD-related cardiovascular outcomes. Premenopausal women may be relatively protected due to estrogen’s hepatoprotective and vasodilatory effects, which modulate lipid metabolism, inflammation, and endothelial function. In contrast, postmenopausal transition is associated with increased visceral adiposity, hepatic steatosis, and endothelial dysfunction—factors that collectively enhance cardiometabolic risk.⁵⁴⁾,⁵⁵⁾

Early-onset MASLD is associated with a disproportionately high risk of subclinical and clinical CVD. Young adults with MASLD demonstrate increased CAC scores and CIMT compared to their age-matched peers, suggesting early vascular remodeling and atherogenesis. Longitudinal data indicate that MASLD during youth accelerates cardiovascular trajectories, predisposing individuals to premature myocardial infarction, stroke, and heart failure. Importantly, hepatic steatosis in early adulthood has been linked to elevated cardiovascular mortality decades later, independent of conventional risk factors.¹⁰⁾,²²⁾,⁵⁶⁾,⁵⁷⁾

Women also represent a high-risk subgroup with unique MASLD-associated cardiovascular implications. While premenopausal women are generally protected from CVD, this advantage diminishes or reverses in the presence of MASLD. Epidemiologic studies reveal that MASLD confers a greater relative increase in cardiovascular risk in women than in men. The transition through menopause, which alters insulin sensitivity and lipid metabolism, may exacerbate MASLD’s systemic effects. Moreover, despite comparable body mass indices, women with MASLD often exhibit greater visceral adiposity and inflammatory dysregulation—factors that intensify cardiovascular vulnerability.⁵⁸⁾,⁵⁹⁾,⁶⁰⁾

A notable cardiovascular outcome in women with MASLD is HFpEF, a phenotype more common among females. The overlap between MASLD, metabolic syndrome, and HFpEF suggests shared pathophysiology, including systemic inflammation, myocardial stiffness, and endothelial dysfunction. Additionally, MASLD may interact with pregnancy-related conditions—such as gestational diabetes and preeclampsia—further compounding lifetime cardiovascular risk in women.⁵⁰⁾,⁵¹⁾

These trends underscore the need for MASLD-specific cardiovascular screening protocols tailored to young adults and women. Traditional risk calculators may underestimate risk in these populations, leading to missed opportunities for early intervention. Proactive diagnosis and aggressive risk factor modification in these special populations may significantly reduce the long-term burden of cardiometabolic disease. This may include earlier cardiovascular risk screening in perimenopausal women, and targeted prevention approaches that address hormonal and metabolic shifts during menopause.

DIAGNOSTIC APPROACHES AND RISK STRATIFICATION IN METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE

As the intersection between MASLD and CVD becomes increasingly evident, early detection and precise risk stratification are critical to mitigating long-term complications. Advances in non-invasive diagnostics, imaging modalities, and machine learning have expanded the clinical toolkit, enabling individualized assessments of hepatic and cardiovascular risk.

Diagnostic approaches

Insulin resistance markers such as homeostasis model assessment insulin resistance and the lipid accumulation product provide early diagnostic clues and predict CVD outcomes in MASLD. These indices reflect the central role of metabolic dysfunction in the pathogenesis of both hepatic and cardiovascular injury (Figure 5, Tables 4 and 5).⁶¹⁾

Figure 5. Diagnostic tools and risk stratification strategies in MASLD. This figure outlines a multi-tiered approach to diagnosing and stratifying cardiometabolic risk in patients with and without MASLD. In undiagnosed individuals, insulin resistance markers such as HOMA-IR and LAP scores, along with machine learning-based models, help predict steatosis and CVD risk. In patients with MASLD, integration of cardiometabolic criteria with data-driven phenotyping enhances prediction of MACE. Steatosis and fibrosis severity are assessed using imaging modalities such as MRI-PDFF, transient elastography, and MRE. Longitudinal follow-up of fibrosis progression involves composite scoring systems (e.g., aMAP, LSM-plus, Agile 3+/4, FAST, SAFE) and biochemical profiling. Accurate stratification is challenged by variable performance across populations, particularly in those with obesity, diabetes, or inflammation.

CVD = cardiovascular disease; ELF = enhance liver fibrosis; FIB-4 = fibrosis-4; HOMA-IR = homeostasis model assessment insulin resistance; LAP = lipid accumulation product; MACE = major adverse cardiovascular events; MASLD = Metabolic Dysfunction-Associated Steatotic Liver Disease; MRE = magnetic resonance elastography; MRI-PDFF = magnetic resonance imaging-derived proton density fat fraction.

Table 4. Diagnostic tools and risk stratification models in MASLD.

Tool/model	Purpose	Key features
HOMA-IR, LAP	Insulin resistance detection	Useful early markers
MRI-PDFF	Liver fat quantification	High sensitivity and specificity
Fibroscan®, MRE, FIB-4, ELF	Fibrosis staging	Non-invasive assessment
aMAP, LSM-Plus models	Advanced fibrosis and cirrhosis detection	Combines clinical and imaging data
Machine learning algorithms	Risk prediction	Integrates routine clinical data
Agile 3+, Agile 4, SAFE scores	Fibrosis stratification	Outperform traditional NITs
Cluster analysis	Phenotyping MASLD	Identifies CVD-predominant subtypes

Diagnostic and risk stratification tools employed in MASLD to assess liver severity and cardiovascular risk.

CVD = cardiovascular disease; ELF = enhance liver fibrosis; FIB-4 = fibrosis-4; HOMA-IR = homeostasis model assessment insulin resistance; LAP = lipid accumulation product; MASLD = Metabolic Dysfunction-Associated Steatotic Liver Disease; MRE = magnetic resonance elastography; MRI-PDFF = magnetic resonance imaging-derived proton density fat fraction; NIT = non-invasive fibrosis test.

Table 5. Therapeutic strategies for MASLD and cardiovascular risk reduction.

Intervention	Mechanism	Benefits
Mediterranean diet	Anti-inflammatory, metabolic improvement	Reduces steatosis and CVD risk
Physical activity	Enhances insulin sensitivity	Decreases liver fat and CVD risk
GLP-1 receptor agonists	Weight loss, insulin sensitization	Reduces liver fat, cardiovascular events
SGLT2 inhibitors	Glycemic and BP control	Reduces steatosis, improves heart failure outcomes
PPAR agonists	Lipid metabolism modulation	Improves NASH histology
Statins	LDL-C reduction	Decreases cardiovascular events, safe in MASLD
Resmetirom	THR-β agonist	Reduces liver fat, potential cardiometabolic benefits
Bariatric surgery	Weight loss, metabolic reset	Resolves MASLD, reduces major CVD events

Summary of lifestyle, pharmacological, and surgical interventions for MASLD and their cardiovascular benefits.

BP = blood pressure; CVD = cardiovascular disease; GLP-1 = glucagon-like-peptide 1; LDL-C = low-density lipoprotein cholesterol; MASLD = Metabolic Dysfunction-Associated Steatotic Liver Disease; NASH = non-alcoholic steatohepatitis; PPAR = peroxisome proliferator-activated receptor; SGLT2 = sodium-glucose co-transporter-2; THR-β = thyroid hormone receptor.

Phenotyping through data-driven cluster analysis has revealed subtypes of MASLD with varying risks for liver progression and cardiovascular complications. Certain phenotypes are more prone to metabolic dysfunction-associated steatohepatitis (MASH) or advanced fibrosis, while others primarily manifest with CVD or diabetes. This heterogeneity highlights the need for personalized diagnostic algorithms.⁶²⁾

Baseline cardiometabolic burden—including central obesity, dyslipidemia, hypertension, and hyperglycemia—strongly predicts MACE in MASLD. Importantly, improvement in these parameters (e.g., weight loss or glycemic control) correlates with reduced cardiovascular risk, supporting dynamic risk reassessment over time.⁶³⁾

Artificial intelligence offers novel predictive capabilities. Machine learning models using basic clinical inputs—such as age, sex, platelet count, albumin, and bilirubin—demonstrate high accuracy in predicting MASH, fibrosis, and cirrhosis. These tools provide scalable, personalized risk predictions beyond traditional scores.⁶⁴⁾,⁶⁵⁾,⁶⁶⁾

Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) has become the gold standard for non-invasive liver fat quantification. It offers high diagnostic precision for MASLD, MASH, and fibrotic MASH, and outperforms liver biopsy in feasibility and safety. While MRE and MRI-PDFF provide excellent granularity, their use in routine cardiometabolic risk screening remains limited by cost-effectiveness concerns. In contrast, transient elastography is portable, relatively affordable, and has demonstrated clinical utility in CVD risk stratification when combined with fibrosis biomarkers. Cost-effectiveness models generally favor transient elastography-first algorithms, reserving MRE/MRI for inconclusive or high-risk cases.⁶⁷⁾,⁶⁸⁾

Fibrosis staging is essential for prognosis. Established non-invasive fibrosis tests—including FIB-4, enhance liver fibrosis (ELF), serum Pro-C3, transient elastography (FibroScan^®, Echosens, Paris, France), and magnetic resonance elastography—accurately identify patients at risk for advanced fibrosis. These tools also predict mortality and cardiovascular complications, reinforcing the systemic implications of hepatic scarring.⁶⁹⁾,⁷⁰⁾

Risk stratification

Risk stratification now encompasses both hepatic and cardiovascular endpoints. The degree of hepatic steatosis correlates with subclinical vascular disease, suggesting that liver fat burden may serve as an early marker for endothelial injury. Imaging modalities like MRI-PDFF provide quantitative risk metrics.⁸⁾,⁷¹⁾

Survival classification and regression tree models stratify patients based on age and metabolic burden, identifying high-risk subgroups more effectively than conventional calculators. These models integrate complex, multidimensional variables into actionable clinical predictions.⁴⁾

Longitudinal monitoring adds another layer. Risk is influenced not only by baseline status but by trends in metabolic health. Dynamic assessments better capture evolving risk than static snapshots, facilitating timely intervention.⁷²⁾

Newer composite scores outperform traditional tools. The aMAP score (age, male sex, albumin, platelets, liver stiffness) and LSM-plus model show strong performance in identifying significant fibrosis and cirrhosis. Agile 3+, Agile 4, and the FAST score integrate liver stiffness, clinical variables, and biomarkers to refine fibrosis staging and predict MACE. Comparative studies suggest that Agile 3+ and FAST outperform FIB-4 in obese or diabetic populations, particularly in detecting advanced fibrosis where alanine aminotransferase levels may be normal. However, in lean MASLD, the FIB-4 may retain value due to its simplicity and validated cutoffs. Importantly, diabetes status, BMI, and age can significantly influence the accuracy and false positive rates of these scores, emphasizing the need for population-tailored application.⁷³⁾,⁷⁴⁾,⁷⁵⁾

The SAFE score, when paired with elastography, outperforms FIB-4 and APRI for detecting significant fibrosis (F≥2). Early detection enables prompt interventions to reduce hepatic progression and cardiovascular risk.⁶⁸⁾,⁷⁶⁾

Biochemical phenotyping may offer additional stratification value. Distinct patterns—hepatocellular, cholestatic, and mixed—are associated with different risks for cirrhosis and mortality. For example, a cholestatic profile predicts worse outcomes, enabling clinicians to identify high-risk patients with simple lab values.³¹⁾

Together, these tools form a robust framework for MASLD management. By combining imaging, machine learning, biochemical profiling, and continuous monitoring, clinicians can deliver precision care that addresses the dual hepatic and cardiovascular threat posed by MASLD.

THERAPEUTIC IMPLICATIONS: MANAGEMENT OF METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE AND CARDIOVASCULAR RISK

Managing MASLD requires a comprehensive, multidisciplinary strategy targeting the shared metabolic, inflammatory, and fibrotic pathways underlying both hepatic and cardiovascular injury. Lifestyle modification remains foundational, but the expanding landscape of pharmacologic agents, emerging therapeutics, surgical interventions, and precision monitoring offers new opportunities to mitigate both liver disease progression and cardiovascular morbidity and mortality (Figure 6).²¹⁾,⁷⁷⁾,⁷⁸⁾

Figure 6. Management strategies for cardiovascular disease in MASLD. This diagram illustrates current and emerging approaches to managing CVD in patients with MASLD. Core strategies focus on optimizing metabolic health through lifestyle interventions, including adherence to a Mediterranean diet, sustained weight loss, and regular physical activity (≥150 minutes per week). Pharmacologic therapies such as GLP-1 receptor agonists, SGLT2 inhibitors, PPARα agonists, and statins contribute to improved insulin sensitivity, lipid profiles, glucose control, blood pressure management, and plaque stabilization. Emerging therapies—including multivitamins, combination drug regimens, bariatric surgery, and predictive machine learning models—are under investigation to further personalize treatment. A multimodal strategy targeting both hepatic and cardiovascular pathology offers the greatest potential for improving outcomes in MASLD.

GLP-1 = glucagon-like-peptide 1; LDL = low-density lipoprotein; MASLD = Metabolic Dysfunction-Associated Steatotic Liver Disease; PPARα = peroxisome proliferator-activated receptor α; SGLT2 = sodium-glucose co-transporter-2.

Lifestyle modifications

Lifestyle intervention remains the cornerstone of MASLD therapy. Weight loss—achieved through dietary modification and increased physical activity—substantially reduces hepatic steatosis, enhances insulin sensitivity, and attenuates systemic inflammation. Among dietary patterns, the Mediterranean diet—emphasizing whole grains, fruits, vegetables, olive oil, legumes, nuts, and lean protein—has shown robust efficacy in reducing liver fat and improving cardiometabolic profiles. Adherence to this diet improves lipid levels, glycemic control, and inflammatory biomarkers, reinforcing its dual hepatic and cardiovascular benefit.⁷⁹⁾,⁸⁰⁾,⁸¹⁾

Exercise is equally critical. Guidelines recommend ≥150 minutes per week of moderate-intensity aerobic activity such as brisk walking, cycling, or swimming. Physical activity reduces liver fat, improves visceral adiposity and insulin sensitivity, and enhances cardiovascular fitness—even independent of weight loss. Given its low cost and broad benefit, structured lifestyle intervention should be prioritized in all MASLD patients, irrespective of fibrosis stage or comorbidities.²¹⁾,⁸²⁾

Pharmacologic interventions

Pharmacotherapy serves as a valuable adjunct, particularly in patients with advanced fibrosis, cardiometabolic comorbidities, or suboptimal response to lifestyle changes.

GLP-1 RAs such as liraglutide and semaglutide are leading candidates in MASLD pharmacotherapy. These agents induce significant weight loss, reduce hepatic steatosis, and dampen systemic inflammation. Large clinical trials demonstrate cardiovascular risk reduction, decreased heart failure hospitalizations, and improved glycemic control. GLP-1 RAs are now regarded as first-line agents for patients with MASLD and concomitant obesity, type 2 diabetes, or established CVD. Emerging data also support their hepatoprotective potential.

SGLT2i, including empagliflozin and dapagliflozin, improve hepatic and cardiovascular outcomes through multiple mechanisms. They reduce steatosis and fibrosis, promote weight loss, and lower blood pressure and glucose. A large nationwide cohort study demonstrated that SGLT2i were associated with reduced risk of liver fibrosis progression and hepatic decompensation in patients with type 2 diabetes and MASLD, suggesting a possible disease-modifying effect.⁸³⁾,⁸⁴⁾,⁸⁵⁾,⁸⁶⁾ In patients with MASLD and coexisting diabetes, heart failure, or chronic kidney disease, SGLT2i provide substantial cardioprotective and nephroprotective effects.⁸⁷⁾,⁸⁸⁾,⁸⁹⁾,⁹⁰⁾,⁹¹⁾

Peroxisome proliferator-activated receptor (PPAR) agonists—including PPAR-γ (pioglitazone) and PPAR-α (fenofibrate)—modulate lipid metabolism, insulin resistance, and hepatic inflammation. Pioglitazone, in particular, has shown histologic improvements in steatohepatitis and fibrosis. However, risks such as fluid retention and weight gain warrant caution in select patients, especially those with heart failure.⁸⁾,⁹²⁾

Statins, long underused in MASLD due to concerns over hepatotoxicity, are now recognized as safe and essential. They lower LDL cholesterol, stabilize plaque, and reduce cardiovascular events, even in patients with compensated cirrhosis. Recent consensus guidelines from the AASLD and major cardiology societies now explicitly recommend statins for both primary and secondary cardiovascular prevention in MASLD, citing favorable benefit-risk profiles. Their use should not be withheld due to hepatic enzyme elevations in the absence of decompensation.⁹³⁾,⁹⁴⁾

Resmetirom, a liver-targeted thyroid hormone receptor-β agonist, is an emerging therapy that reduces hepatic fat and fibrosis. It may also favorably modulate lipid metabolism, offering promise as a dual-action agent for MASLD and cardiovascular prevention. AASLD guidelines support its consideration in patients with significant fibrosis.⁹⁵⁾,⁹⁶⁾,⁹⁷⁾,⁹⁸⁾

EMERGING THERAPIES AND COMBINATORIAL STRATEGIES

Combination therapy is gaining traction. Concurrent use of GLP-1 RAs with SGLT2i or PPAR agonists may offer synergistic benefits, tackling obesity, insulin resistance, dyslipidemia, and hepatic inflammation in a multifaceted manner. Such polytherapies reflect the complex pathophysiology of MASLD and its overlap with systemic metabolic dysfunction. Several promising agents are currently in advanced clinical development for MASLD and MASH, with potential cardiovascular benefits. Resmetirom, a selective thyroid hormone receptor-β agonist, has demonstrated improvements in hepatic steatosis and atherogenic lipid profiles in Phase III trials, although long-term cardiovascular outcomes are still under investigation. Lanifibranor, a pan-PPAR agonist, has shown reductions in steatosis, inflammation, and fibrosis, with potential cardiometabolic synergy. Incretin-based agents such as tirzepatide (GLP-1/glucose-dependent insulinotropic polypeptide dual agonist) and survodutide (GLP-1/glucagon dual agonist) not only reduce liver fat but have demonstrated weight loss and cardiovascular benefit in diabetes and obesity trials. FGF21 analogs like pegozafermin and efruxifermin are under investigation for both hepatic and systemic metabolic improvements, including lipid modulation and insulin sensitization. These agents reflect a paradigm shift toward therapies that target both hepatic and cardiovascular axes in MASLD.¹⁵⁾,⁸⁵⁾,⁹⁹⁾,¹⁰⁰⁾,¹⁰¹⁾

SURGICAL INTERVENTIONS

In patients with severe obesity and advanced liver disease, bariatric surgery represents a potent intervention. Procedures such as Roux-en-Y gastric bypass and sleeve gastrectomy yield profound, sustained weight loss, improve hepatic steatosis, and resolve non-alcoholic steatohepatitis. They also reduce incident MACE and cardiovascular mortality. Bariatric surgery should be considered in MASLD patients with obesity and poor response to medical therapy, especially when type 2 diabetes or fibrosis coexist.¹⁰²⁾,¹⁰³⁾

RISK STRATIFICATION AND MONITORING

Ongoing assessment is crucial for tailoring treatment and anticipating progression. Non-invasive monitoring tools—including transient elastography, MRI-PDFF, FIB-4, and ELF score—offer reproducible, scalable means to evaluate hepatic steatosis and fibrosis.⁷⁰⁾,¹⁰⁴⁾,¹⁰⁵⁾

Machine learning algorithms incorporating clinical, imaging, and biochemical data enable personalized prediction of liver and cardiovascular outcomes. These tools stratify patients according to progression risk, supporting early escalation of therapy or referral to subspecialty care.¹⁰⁶⁾,¹⁰⁷⁾,¹⁰⁸⁾

GAPS IN KNOWLEDGE AND FUTURE DIRECTIONS

Despite significant strides in understanding MASLD and its systemic cardiovascular impact, critical knowledge gaps persist. Addressing these limitations is imperative to optimize diagnostics, personalize treatment, and improve outcomes for the growing global population affected by MASLD.

Pathophysiological mechanisms

The association between MASLD and CVD is well-established, yet the underlying pathophysiology remains incompletely elucidated. Mechanisms such as visceral adiposity, chronic inflammation, oxidative stress, endothelial dysfunction, insulin resistance, dyslipidemia, gut dysbiosis, and prothrombotic states have all been implicated. However, the inter-relationships among these pathways—and their temporal sequence across hepatic and CVD progression—are poorly understood.

There remains a pressing need for mechanistic studies incorporating tissue-level profiling, advanced imaging, and multi-omics analyses to better characterize the cardio-hepatic axis. Understanding how and when MASLD instigates vascular injury could identify novel therapeutic targets and enable earlier intervention before irreversible damage occurs.

Diagnostic tools

Non-invasive diagnostic tools such as transient elastography and MRI-PDFF have improved MASLD staging. However, their performance can be limited in high-risk populations—especially those with severe obesity, diabetes, or systemic inflammation. Moreover, these tools primarily assess hepatic outcomes and often lack predictive accuracy for cardiovascular events.

The next generation of diagnostics must be more comprehensive, integrating liver disease evaluation with cardiometabolic risk profiling. Combining imaging data with circulating biomarkers and predictive algorithms could yield more accurate and individualized prognostic models. Additionally, most risk stratification models—including aMAP and LSM-plus—require broader validation across ethnically and geographically diverse populations.

Future efforts should also develop dynamic models that update risk based on changes in liver fibrosis, metabolic parameters, and patient behavior over time, thereby providing real-time decision support in clinical practice.

Therapeutic interventions

While agents such as GLP-1 RAs, SGLT2 inhibitors, and PPAR agonists have shown promise, many MASLD patients still lack effective, targeted therapy. The long-term cardiovascular safety and efficacy of newer agents like resmetirom remain to be established in large outcome trials.

Combination therapy targeting multiple pathogenic pathways—including hepatic steatosis, inflammation, fibrosis, and endothelial dysfunction—represents an attractive future direction. Rational design of such combination regimens will require greater mechanistic clarity, along with trials powered for both hepatic and cardiovascular endpoints.

Longitudinal studies

Most existing evidence linking MASLD to CVD arises from cross-sectional or retrospective cohorts. Prospective longitudinal studies are urgently needed to clarify disease trajectories, identify temporal risk windows, and inform the optimal timing of interventions.

These studies should examine how dynamic changes in liver histology, metabolic health, and lifestyle behaviors influence long-term cardiovascular outcomes. Such data are essential to move from associative to causal inference and to establish evidence-based screening and treatment thresholds.

Multidisciplinary models

Given its multisystemic nature, MASLD care should be delivered via integrated, multidisciplinary teams involving hepatologists, cardiologists, endocrinologists, primary care clinicians, dietitians, and behavioral specialists. However, such care models remain underdeveloped and inconsistently implemented.

Future research should focus on developing, testing, and scaling team-based models that are effective, cost-conscious, and adaptable to different healthcare systems. Outcome-driven care pathways can ensure timely intervention, reduce fragmentation, and improve both hepatic and cardiovascular endpoints.

In summary, to advance MASLD-CVD care, future efforts must prioritize prospective, longitudinal cohort studies with harmonized cardiovascular endpoints and stratification by liver fibrosis stage. Multidisciplinary care models involving hepatology, cardiology, and endocrinology should be developed. We propose a management algorithm (Figure 7) that integrates hepatic fibrosis staging, metabolic comorbidities, and cardiovascular risk scores (e.g., atherosclerotic cardiovascular disease [ASCVD], QRISK3) to guide interventions. For instance, statins should be initiated in all MASLD patients with ASCVD ≥7.5% irrespective of mild transaminitis, while SGLT2i or GLP-1RA can be prioritized in patients with coexisting diabetes and early steatohepatitis. This integrated approach can close the bidirectional care gap.

Figure 7. MASLD-CVD co-management framework. Evidence-based algorithm integrating MASLD severity and cardiovascular risk to guide statin initiation, antidiabetic drug selection, specialty referral, and longitudinal monitoring. Adapted from AASLD, ACC, ADA, and recent trial evidence.

ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; CVD = cardiovascular disease; FIB-4 = fibrosis-4; GLP-1 RA = glucagon-like-peptide 1 receptor agonist; HFpEF = heart failure with preserved ejection fraction; MASLD = Metabolic Dysfunction-Associated Steatotic Liver Disease; OSA = obstructive sleep apnea; SGLT2 = sodium-glucose co-transporter-2; T2DM = diabetes mellitus type 2; TE = transient elastography; TMAO = trimethylamine N-oxide.

PRECISION MEDICINE

The heterogeneity of MASLD highlights the limitations of a one-size-fits-all approach. Precision medicine, leveraging genomics, transcriptomics, proteomics, and metabolomics, holds immense promise for individualized diagnosis and treatment.¹⁰⁹⁾,¹¹⁰⁾,¹¹¹⁾

Multi-omics profiling can help identify patients at highest risk for progression or poor treatment response and facilitate targeted therapeutic development. Integration of molecular phenotyping into clinical practice may allow earlier diagnosis, better risk stratification, and tailored therapy based on underlying disease biology.¹⁰⁹⁾,¹¹¹⁾,¹¹²⁾

Artificial intelligence and machine learning

AI and ML offer transformative potential in MASLD. These tools can synthesize diverse data sources—electronic health records, imaging, laboratory data, and omics—to uncover novel patterns predictive of disease progression or treatment response.⁶⁴⁾,¹¹³⁾

AI-driven clinical decision support systems may enhance diagnostic accuracy, stratify patients by multidimensional risk, and personalize therapeutic strategies. The next challenge lies in validating these algorithms across diverse clinical settings and embedding them seamlessly into routine care.¹¹¹⁾,¹¹³⁾

Public health initiatives

MASLD is a global epidemic fueled by rising rates of obesity, diabetes, and sedentary lifestyles. Public health responses must prioritize primary prevention through promotion of healthy diet, physical activity, and early metabolic screening.

Population-wide strategies—ranging from school-based wellness initiatives to policy interventions addressing food security and urban design—will be essential. Education campaigns, early detection programs, and community-based screening for high-risk individuals could substantially reduce future MASLD burden and its cardiovascular sequelae.¹⁰⁶⁾,¹¹⁴⁾,¹¹⁵⁾,¹¹⁶⁾

CONCLUSION

MASLD is now recognized as a major contributor to cardiovascular morbidity and mortality, yet many critical questions remain unanswered. Advancing our understanding of its mechanisms, improving diagnostic and predictive tools, developing more effective therapies, and implementing longitudinal, multidisciplinary, and precision-based care are essential to changing the course of this disease.

By bridging these knowledge gaps, we can shift MASLD from a silent, systemic threat to a preventable and treatable condition—transforming the outlook for millions of patients worldwide.