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Perspective Chapter: Metabolic Dysfunction-Associated Steatotic Liver Disease as an Emerging Cardiovascular Risk Factor – Pathophysiology, Implications and Clinical Perspectives

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Diana-Ruxandra Hădăreanu, Cristina Florescu, Anca Mihu-Marinescu, Veronica Gheorman, Edme-Roxana Mustafa, Adina-Dorina Glodeanu, Rodica Pădureanu, Diana-Maria Trașcă, Ion-Cristian Efrem, Vlad Pădureanu, Sorina Ionelia Stan, Iulian-Alin-Silviu Popescu and Viorel Biciușcă

Submitted: 12 May 2025 Reviewed: 11 June 2025 Published: 07 July 2025

DOI: 10.5772/intechopen.1011513

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Steatosis - Causes and Treatment [Working Title]

Dr. Costin Teodor Streba

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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic liver disease globally and is now recognized as a key cardiometabolic disorder. Beyond hepatic involvement, MASLD is independently associated with increased risks of coronary artery disease, stroke, arrhythmias, and heart failure, even after adjusting for traditional cardiovascular risk factors. Its pathophysiology involves insulin resistance, visceral adiposity, systemic inflammation, and oxidative stress, which collectively contribute to both hepatic fibrosis and cardiovascular disease (CVD). Diagnostic strategies have evolved to include non-invasive tools—such as the Fibrosis-4 Index and Enhanced Liver Fibrosis test, transient elastography, NT-proBNP, coronary artery calcium scoring, and echocardiography—to facilitate early identification of patients at dual hepatic and cardiovascular risk. Complementing these efforts, a novel pathophysiological staging framework for systemic metabolic disorder has been proposed to stratify disease severity and personalize treatment approaches. Management is increasingly multidimensional, combining lifestyle intervention with pharmacologic therapies such as GLP-1 receptor agonists, SGLT2 inhibitors, statins, and novel agents like resmetirom. Given the shared pathophysiological mechanisms between MASLD and CVD, integrated care approaches across hepatology, cardiology, and endocrinology are essential. Recognizing MASLD as a systemic disease enables earlier interventions that may prevent both hepatic progression and adverse cardiovascular outcomes.

Keywords

  • metabolic dysfunction-associated steatotic liver disease
  • cardiovascular risk
  • cardiometabolic risk
  • cardiovascular disease
  • metabolic syndrome
  • metabolic disease
  • multidisciplinary management

1. Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), has increasingly gained attention as a major contributor to global morbidity. MASLD is characterized by excessive hepatic fat accumulation in individuals with metabolic dysfunction, excluding secondary causes such as alcohol abuse. The shift in nomenclature reflects a more accurate understanding of the disease’s association with metabolic syndrome, type 2 diabetes mellitus (T2DM), and obesity. Notably, recent studies underscore the strong connection between MASLD and cardiovascular disease (CVD), making MASLD not just a liver-specific pathology but a systemic disorder with profound cardiovascular implications [1].

Importantly, MASLD is increasingly recognized not only as a hepatic disorder but as a systemic condition with significant cardiovascular implications [2]. Multiple studies have demonstrated a robust association between MASLD and CVD, highlighting its role as an independent cardiometabolic risk factor [3]. This reconceptualization allows for earlier identification of individuals at elevated risk for atherosclerotic cardiovascular events and facilitates a more integrated clinical approach.

The cardiovascular burden associated with MASLD has grown substantially over the past three decades. Data from US national surveys reveal that the prevalence of CVD among individuals with MASLD rose from 8.7% in the 1990s to more than 17% by 2020, emphasizing the urgent need for early cardiometabolic surveillance and targeted interventions [4]. Reflecting this shift in clinical understanding, international guidelines now incorporate MASLD into cardiovascular risk stratification frameworks. The European Association for the Study of the Liver (EASL) recommends routine cardiovascular screening in patients with MASLD and endorses a multidisciplinary approach to address coexisting metabolic disorders [5]. Similarly, the American Heart Association recognizes MASLD as a risk-enhancing factor for atherosclerotic CVD in its latest scientific statement [6]. These evolving guidelines signal a growing consensus on the need to treat MASLD as a systemic disease, with implications for cardiology, endocrinology, and hepatology.

2. Pathophysiological mechanisms linking MASLD and CVD

The pathophysiological interplay between MASLD and CVD is complex and multifactorial (Figure 1) [7]. MASLD embodies a systemic metabolic disorder characterized by insulin resistance, inflammation, oxidative stress, and hemodynamic disturbances that collectively foster CVD (Table 1). Insulin resistance promotes hepatic de novo lipogenesis while impairing fatty acid oxidation [8]. This metabolic shift leads to hepatic steatosis and a proatherogenic lipid profile—marked by elevated triglycerides, small dense low-density lipoprotein cholesterol particles, and reduced high-density lipoprotein cholesterol levels [9]—all of which contribute to atherosclerotic risk [10]. Beyond dyslipidemia, MASLD is a chronic inflammatory state. Elevated levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 exacerbate vascular injury and promote endothelial dysfunction. Recent evidence supports a “multi-hit” model in which oxidative stress, lipotoxicity, and adipokine imbalance work synergistically to accelerate subclinical atherosclerosis and impair endothelial homeostasis [11].

Figure 1.

Interplay between metabolic dysfunction-associated steatotic liver disease and cardiovascular disease.

MechanismDescriptionClinical relevanceEvidence
Insulin ResistanceReduces fatty acid oxidation and increases de novo lipogenesis.Promotes hepatic steatosis and systemic metabolic dysfunction.Common in >80% of MASLD patients.
Oxidative StressMitochondrial dysfunction and reactive oxygen species production aggravate liver injury.Triggers inflammation and endothelial damage.Linked to early atherosclerosis.
Chronic InflammationIncreased cytokines (IL-6 and TNF-α) activate immune responses.Drives endothelial dysfunction and plaque instability.Highly sensitive C-reactive protein levels observed in MASLD.
Endothelial DysfunctionImpaired nitric oxide signaling and increased endothelin-1/asymmetric dimethylarginine.Leads to arterial stiffness and hypertension.Reduced flow-mediated dilation in MASLD.
Genetic VariantsPNPLA3 and TM6SF2 variants modulate lipid metabolism and inflammation.Influence severity of hepatic and possibly cardiac disease.Common in certain ethnic populations.

Table 1.

Summary of key mechanisms linking metabolic dysfunction-associated steatotic liver disease to cardiovascular disease.

Abbreviations: MASLD, metabolic dysfunction-associated steatotic liver disease.

Oxidative stress further aggravates endothelial injury by disrupting nitric oxide signaling, leading to reduced vasodilation, arterial stiffness, and enhanced plaque formation [12]. This is compounded by a hypercoagulable state and ectopic fat accumulation in epicardial and perivascular tissues, which promote inflammation, ventricular remodeling, and a heightened risk of arrhythmias [3].

Furthermore, genetic variants such as PNPLA3 and TM6SF2 exacerbate hepatic lipid retention and systemic inflammatory signaling [13]. These alterations are associated with left ventricular hypertrophy, myocardial fibrosis, and coronary artery calcification in patients with MASLD [11]. These interrelated mechanisms underscore how MASLD serves as both a marker and mediator of CVD, and the PNPLA3 genetic polymorphism is a key modulator in this interplay [14]. However, carriers of PNPLA3 variants may develop liver disease without a corresponding increase in cardiovascular events, suggesting a need for more nuanced risk stratification in clinical settings [15]. Other genetic predispositions like TM6SF2 also influence the extent of CVD risk, albeit in variable directions depending on their metabolic expression profiles [16].

Together, these interdependent mechanisms position MASLD not merely as a marker of systemic dysfunction but as a direct contributor to the pathogenesis of CVD.

3. Cardiovascular risk and comorbidities

The association between MASLD and CVD has been consistently demonstrated across diverse populations and is now regarded as one of the most clinically relevant extrahepatic manifestations of this disease [17]. Numerous epidemiological studies have demonstrated that individuals with MASLD are at an elevated risk of both subclinical and overt cardiovascular conditions, including coronary artery disease, cerebrovascular disease, and heart failure, even after adjusting for conventional cardiovascular risk factors, suggesting that MASLD may exert an independent pathogenic role in CVD development [10]. In contrast, another large study examining whether NAFLD independently contributes to cardiovascular risk found that, after adjusting for traditional risk factors, the associations were no longer significant [18]. However, CVD risk assessment remains important in patients with MASLD.

Cardiac structural and functional abnormalities frequently accompany MASLD. These include left ventricular hypertrophy, diastolic dysfunction, and left atrial enlargement—features associated with the development of heart failure with preserved ejection fraction (HFpEF), a phenotype increasingly prevalent in patients with metabolic disorders. Subclinical markers of atherosclerosis, such as coronary artery calcification [19] and increased carotid intima-media thickness (CIMT) [20], are also significantly more prevalent in MASLD. Beyond atherosclerosis and myocardial remodeling, MASLD has also been linked to electrophysiological disturbances. Patients demonstrate higher risks of atrial fibrillation, QTc prolongation, and ventricular arrhythmias [21, 22, 23]. The mechanisms underlying these arrhythmogenic risks likely include myocardial fat infiltration, autonomic imbalance, and systemic inflammation. Overall, CVD remains the leading cause of mortality in patients with MASLD, far exceeding liver-related complications, thus necessitating a proactive, integrated cardiovascular risk assessment strategy in clinical practice [10].

Large-scale studies have further validated the association between MASLD and CVD. A meta-analysis involving over 34,000 individuals demonstrated that MASLD confers a 65% increased risk of cardiovascular events, including myocardial infarction and stroke. Particularly concerning is the growing evidence from younger populations, where MASLD is now associated with premature atherosclerosis and increased rates of ischemic stroke and heart failure [24]. These findings were confirmed by a UK Biobank study involving more than 325,000 individuals reporting that MASLD was independently associated with a 35% increased risk of myocardial infarction and a 26% increased risk of stroke [12]. The cardiovascular manifestations in MASLD are often the primary cause of mortality in this population [25]. Additionally, NAFLD is independently associated with valvular heart conditions, particularly aortic valve sclerosis, and mitral annulus calcification. In a population-based analysis from the Study of Health in Pomerania, involving 2212 participants, hepatic steatosis was linked to a 33% increase in the odds of aortic valve sclerosis, even after adjustment for confounding factors [26]. Supporting these findings, a more recent investigation in 180 individuals with T2DM demonstrated that NAFLD posed a threefold increase in the likelihood of developing aortic valve sclerosis [27]. Similarly, a separate study assessing 247 diabetic patients found a significant association between NAFLD and the presence of aortic valve sclerosis or mitral annulus calcification [28].

Moreover, biopsy-confirmed MASLD patients in a Swedish cohort had up to a 2.15-fold increase in CVD risk, while a separate meta-analysis reported a 45% increased risk of major adverse cardiovascular events, rising to 2.54-fold in individuals with advanced fibrosis [29]. Increased liver stiffness (rather than hepatic fat alone) is linked to higher atrial fibrillation prevalence, underscoring the importance of fibrosis as a shared pathophysiological thread between hepatic and cardiac dysfunction [30].

Finally, in a nationwide cohort from Korea, individuals with MASLD had significantly higher incidence of cardiovascular events, including both fatal and non-fatal myocardial infarction and stroke, compared to those without. They also found that MASLD, MASLD with increased alcohol intake, and alcoholic liver disease conferred progressively greater CVD risk, emphasizing the additive effect of alcohol and metabolic dysfunction on cardiovascular burden [31].

Taken together, these findings support the growing recognition of MASLD as an early and independent marker of CVD, highlighting the critical importance of early screening, risk stratification, and intervention.

4. MASLD, obesity and cardiovascular risk

Recognizing MASLD as a cardiovascular risk factor has substantial implications for clinical practice. Risk stratification models now integrate hepatic fibrosis as a prognostic factor, given that advanced fibrosis correlates strongly with cardiovascular outcomes. The CARDIA study revealed that individuals maintaining high cardiovascular health from young adulthood to midlife have significantly lower odds of developing MASLD. Those with decreasing cardiovascular health trajectories were at markedly higher risk for hepatic steatosis by year 25 of follow-up, highlighting the importance of longitudinal cardiovascular monitoring in MASLD prevention [32].

A shared dysmetabolic environment links NAFLD and CVD through mechanisms involving obesity, hypertension, dyslipidemia, and insulin resistance [33].

The natural course of MASLD is significantly influenced by coexisting cardiometabolic conditions. Among these, T2DM is the strongest determinant of fibrosis progression and hepatocellular carcinoma. This dual burden is associated with a 1.5–2-fold increase in the incidence of myocardial infarction and stroke. T2DM also increases the likelihood of developing advanced fibrosis and poses a higher risk of liver-related events and mortality [5]. In a Minnesota cohort, ischemic heart disease accounted for 25% of all deaths among MASLD patients, underscoring the need for proactive, integrated cardiometabolic management [34].

On the other hand, obesity, particularly visceral adiposity, plays a central role in the development and progression of MASLD. Visceral obesity arises as a consequence of impaired expandability and dysfunction of subcutaneous adipose tissue [35]. Visceral fat is highly metabolically active and functions as an endocrine organ, releasing adipokines and pro-inflammatory cytokines that contribute to insulin resistance, hepatic steatosis, and systemic inflammation [11]. Notably, elevated body mass index (BMI) correlates with increased risks of hepatic decompensation, cirrhosis, and hepatocellular carcinoma. Moreover, while a direct causal relationship between MASLD and hypertension has yet to be confirmed, it is postulated that MASLD may promote the development of hypertension through mechanisms involving low-grade chronic inflammation and hepatic insulin resistance [36]. In turn, hypertension and dyslipidemia additively accelerate fibrosis progression. The cumulative impact of multiple metabolic risk factors produces a synergistic escalation in disease severity, underscoring the need for holistic cardiometabolic management [5].

The “portal hypothesis” offers mechanistic insight into the role of visceral fat: free fatty acids and inflammatory mediators are directly delivered via the portal vein to the liver, promoting hepatic insulin resistance and lipogenesis. This may explain why visceral, rather than subcutaneous adiposity is more strongly linked to both MASLD and cardiovascular complications [37].

Adipokine dysregulation is another hallmark of MASLD-related cardiovascular risk. In affected individuals, adiponectin—an insulin-sensitizing and anti-inflammatory adipokine—is typically suppressed, while leptin levels are elevated. Leptin promotes fibrogenesis and atherogenesis, thereby contributing to vascular inflammation and endothelial dysfunction [3].

The pathophysiological effects of obesity in MASLD extend beyond metabolic dysfunction to direct myocardial involvement. Patients often exhibit subclinical myocardial changes, including diastolic dysfunction and atrial remodeling, which predispose them to atrial fibrillation and HFpEF. These manifestations reflect myocardial remodeling driven by chronic inflammation and ectopic fat deposition within cardiac tissue [38].

Obesity phenotypes significantly influence cardiovascular risk. Patients with metabolically unhealthy obesity have increased visceral fat, hepatic steatosis, and insulin resistance, while those with metabolically healthy obesity may still carry elevated cardiovascular risk if visceral adiposity is high. Risk stratification should thus focus on fat distribution and metabolic profile rather than BMI alone [39].

NAFLD has also been correlated with increased epicardial adipose tissue (EAT) thickness. EAT not only shows an independent association with NAFLD, but its volume appears to increase in parallel with the severity of hepatic steatosis, suggesting its potential role in the interplay between liver pathology and cardiovascular risk [40]. Multiple cardiovascular alterations in obesity, including concentric left ventricular remodeling, impaired relaxation, and increased right ventricular afterload, are aggravated by systemic inflammation and neurohormonal activation [41]. Obesity also increases pulmonary vascular resistance and raises pulmonary artery pressures, mechanisms that may culminate in right heart dysfunction and HFpEF [42]. More than 80% of individuals with HFpEF are either overweight or obese, and HFpEF is anticipated to become the predominant phenotype of heart failure in the coming years [43]. Cardiac fibrosis has emerged as a hallmark of obesity-related cardiac dysfunction. Fibrotic remodeling of the myocardium contributes to left ventricular hypertrophy, diastolic dysfunction, and arrhythmias. Elevated levels of pro-fibrotic mediators, including TGF-β and thrombospondin-1, are found in obese individuals, and their expression correlates with the severity of myocardial remodeling [39]. Severe obesity induces profound changes in myocardial metabolism. Increased fatty acid oxidation, decreased glucose oxidation, and mitochondrial inefficiency contribute to impaired cardiac energy production. These metabolic derangements, in turn, promote functional cardiac decline and an increased risk of heart failure [42]. Moreover, studies show that even non-obese individuals with MASLD have comparable, if not higher, cardiovascular risk compared to their obese counterparts [11].

5. Diagnostic assessment

The evolving understanding of MASLD as a systemic condition with cardiovascular implications has prompted a shift toward integrated diagnostic strategies. Current guidelines advocate for a stepwise, risk-based screening strategy to identify patients with MASLD who are at risk for advanced fibrosis and liver-related outcomes [5].

5.1 Hepatic risk assessment

Non-invasive scoring systems such as the Fibrosis-4 (FIB-4) index and NAFLD Fibrosis Score (NFS) are widely used for evaluating hepatic fibrosis in MASLD patients. In addition, advanced imaging modalities such as transient elastography and magnetic resonance elastography allow for precise quantification of liver stiffness and steatosis. In primary care settings, early identification of MASLD using a two-step algorithm—FIB-4 followed by transient elastography—is now recommended. This model has been adopted across several European countries to enhance screening efficiency and timely referral to hepatology. Importantly, the model includes integrated care pathways with lifestyle and pharmacologic intervention aligned with cardiovascular risk profiles [44].

Emerging biomarkers, including cytokeratin-18 and the enhanced liver fibrosis (ELF) score, may further refine cardiovascular risk prediction. These tools provide a holistic view of hepatic and cardiometabolic health, reinforcing the need for integrated care pathways [32]. The latest EASL-EASD-EASO 2024 guidelines support the use of FIB-4 index as a first-line tool, followed by vibration-controlled transient elastography or magnetic resonance elastography for fibrosis staging [5].

Additionally, steatosis prediction indices like the lipid accumulation product (LAP), and fatty liver index (FLI) offer clinicians predictive insight into both hepatic and CVD risk. When combined with imaging, these indices enhance predictive accuracy and can facilitate early identification of MASLD patients requiring cardiometabolic monitoring [45].

5.2 Cardiovascular risk assessment

Accurate cardiovascular evaluation is critical to identify high-risk patients early and guide therapeutic decisions [3]. Clinical assessment begins with detailed history taking for symptoms such as chest pain, dyspnea, syncope, or palpitations, which may indicate underlying ischemic heart disease or arrhythmias. Physical examination should evaluate blood pressure, as well as 24-h blood pressure monitoring, BMI, and waist circumference to gauge visceral adiposity [5]. Resting electrocardiography can identify left ventricular hypertrophy, arrhythmias, and prior myocardial infarction [46].

Biochemical markers are gaining prominence for cardiovascular risk stratification in MASLD [47]. Several tests are recommended to detect CVD, including high-sensitivity C-reactive protein, serum ferritin, and NT-proBNP [5]. High-sensitivity C-reactive protein is an indicator of low-grade systemic inflammation and correlates with endothelial dysfunction and atherosclerosis [48]. NT-proBNP is a useful indicator of cardiac stress and is independently associated with cardiovascular mortality in the general population [49], and combining it with FIB-4 enhances risk stratification in patients with MASLD [5]. Additional markers such as fasting insulin, apolipoprotein B, and lipoprotein(a) can further refine cardiometabolic profiling [50, 51].

The liver-derived fibrosis scores have also demonstrated utility in predicting cardiovascular outcomes. Elevated scores are independently associated with a greater incidence of major adverse cardiovascular event, including myocardial infarction and ischemic stroke, atrial fibrillation, as well as subtle impairments in myocardial strain [52], suggesting these tools may serve dual roles in both hepatic and cardiovascular risk stratification.

5.3 Non-invasive cardiovascular imaging

Non-invasive imaging plays a central role in evaluating subclinical CVD in MASLD. Transthoracic echocardiography frequently reveals diastolic dysfunction, left ventricular hypertrophy and left atrial dilation in patients with MASLD or metabolic syndrome. These alterations reflect early myocardial remodeling linked to systemic inflammation and ectopic fat accumulation [38].

CIMT is a validated marker of early atherosclerosis and correlates strongly with hepatic steatosis severity. CIMT is elevated in MASLD and metabolic syndrome patients and is associated with increased risk of ischemic stroke and acute coronary events [11]. A 2023 meta-analysis covering over 16,000 cases confirmed a significant association between NAFLD and increased CIMT, supporting CIMT as a surrogate endpoint in cardiovascular risk assessment for this population [53].

Coronary artery calcium (CAC) scoring provides a quantitative measure of coronary atherosclerosis burden. In MASLD patients, elevated CAC scores are independently predictive of myocardial infarction and all-cause mortality. CAC can be integrated into global risk scores for the reclassification of patients with intermediate cardiovascular risk [54]. Finally, coronary computed tomography angiography with pericoronary fat attenuation index (FAI) is a novel imaging modality for detecting vascular inflammation. Elevated FAI values reflect perivascular adipose inflammation and have been associated with higher risks of acute coronary syndrome in MASLD [55, 56].

Collectively, these diagnostic strategies highlight the value of integrated hepatic and cardiovascular screening in MASLD. By combining non-invasive tools with early intervention, clinicians can effectively reduce the dual burden of hepatic and CVD [5].

In addition, in patients with advanced MASLD undergoing liver transplant evaluation, structured cardiac screening using transthoracic echocardiography, followed by dobutamine stress echocardiography, cardiac magnetic resonance stress imaging, or coronary computed tomography angiography is recommended based on the presence of clinical risk factors and findings in baseline tests, with consequent cardiology referral and multidisciplinary discussion (Table 2) [5].

Tool/TestRoleKey findings in MASLD/Obesity
Clinical
Physical Exam, electrocardiographyInitial risk screeningIdentifies arrhythmias, left ventricular hypertrophy, central obesity
Biochemical
NT-proBNP, High-sensitivity C-reactive protein, FerritinAssess cardiac stress and inflammationElevated in CVD and MASLD; predicts mortality
FIB-4 index, ELF score, NFSLiver fibrosis and CV riskHigher scores linked with major adverse cardiovascular events
Imaging
EchocardiographyAssess cardiac functionDetects diastolic dysfunction, left ventricular hypertrophy
CIMTAssess subclinical atherosclerosisPredicts stroke
CAC scoreQuantify coronary plaqueElevated in MASLD; predicts myocardial infarction
Liver stiffness (elastography)Fibrosis assessmentAssociated with higher CV risk
Coronary computed tomography angiography + FAIDetect coronary inflammationHigh-fat attenuation index predicts acute coronary syndromes in MASLD

Table 2.

Cardiovascular evaluation in MASLD.

Abbreviations: CAC, coronary artery calcium; CIMT, carotid intima-media thickness; CV, cardiovascular; CVD, cardiovascular disease; ELF, enhanced liver fibrosis; FAI, fat attenuation index; FIB-4, Fibrosis-4; MASLD, metabolic dysfunction-associated steatotic liver disease; NFS, non-alcoholic fatty liver disease fibrosis score.


6. Clinical staging of systemic metabolic disorder

Systemic metabolic disorder represents a cluster of interrelated metabolic abnormalities, including insulin resistance, dyslipidemia, and visceral obesity, that progressively damage the liver, heart, and kidneys. Recognizing the complexity and overlapping nature of these dysfunctions, the European Atherosclerosis Society has just proposed a pathophysiology-based clinical staging system to enhance early detection, stratification, and treatment personalization for patients with metabolic diseases. Traditional approaches often treat individual metabolic risk factors in isolation. However, these conditions frequently coexist and contribute synergistically to morbidity and mortality. The three-stage staging system aims to address this gap by offering a structured framework for understanding disease progression and optimizing management strategies across medical disciplines. Stage 1 encompasses early metabolic alterations without overt organ damage. Patients typically present with features such as overweight/obesity, insulin resistance or pre-diabetes, liver steatosis, atherogenic dyslipidemia, or hypertension. Stage 2 involves the onset of organ-specific injury, including T2DM, early chronic kidney disease, subclinical atherosclerosis, metabolic-associated steatohepatitis, or asymptomatic diastolic dysfunction. Finally, stage 3 reflects advanced organ failure or clinical disease, such as HFpEF, advanced kidney disease, cirrhosis, or atherosclerotic CVD. Each stage is identified through the specific clinical and laboratory assessments presented above [57].

7. Therapeutic strategies

The management of MASLD should prioritize both hepatic and cardiovascular risk reduction through a combination of lifestyle modifications and pharmacological interventions. Given the shared pathophysiology between MASLD and CVD, therapies that address both metabolic and hepatic targets are increasingly emphasized in clinical guidelines [5, 58].

Lifestyle interventions remain the cornerstone of MASLD therapy. Caloric restriction, adherence to a Mediterranean diet [59], and engagement in moderate-intensity aerobic physical activity for at least 150 minutes per week are associated with significant improvements in cardiovascular outcomes [60]. Sustained weight loss of ≥10% is particularly effective in reversing hepatic fibrosis and improving cardiometabolic health [5, 10].

Among pharmacologic strategies (Table 3), glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown substantial promise. These agents promote weight loss and glycemic control while also improving cardiovascular outcomes, offering a dual benefit in MASLD management [61, 62]. Recent consensus guidelines support the use of GLP-1 RAs—including semaglutide and liraglutide—in patients with a BMI ≥27 kg/m2 and coexisting cardiovascular risk factors such as MASLD [38].

Drug/ClassMechanism of actionHepatic effectCardiovascular effectApproval status
GLP-1 RAsIncretin mimeticReduces steatosis and inflammationImproves CV outcomesApproved for diabetes, obesity
SGLT2 inhibitorsInhibits renal glucose reabsorptionReduces liver fat and alanine transaminaseReduces heart failure and atherosclerosisApproved for diabetes
StatinsInhibit HMG-CoA reductaseMay reduce fibrosisStrong atherosclerosis benefitWidely approved
ResmetiromThyroid hormone receptor-beta agonistImproves steatosisReduces low-density lipoprotein cholesterolApproved for Metabolic dysfunction-associated steatohepatitis (F2–F3)
PioglitazonePPAR-γ agonistImproves non-alcoholic steatohepatitis histologyNeutral or beneficial effectApproved for diabetes

Table 3.

Pharmacologic treatments for MASLD and their cardiovascular effects.

Abbreviations: CV, cardiovascular; GLP-1 RA, glucagon-like peptide-1 receptor agonists; SGLT2, sodium-glucose cotransporter-2.


In addition to GLP-1 RAs, sodium-glucose cotransporter-2 (SGLT2) inhibitors remain the cornerstone pharmacological agents due to their beneficial effects on hepatic steatosis, insulin resistance, and cardiovascular outcomes [63].

Statins are another key pharmacologic intervention with proven cardiovascular benefits. Historically underutilized in MASLD due to concerns about hepatotoxicity, accumulating evidence confirms their safety and efficacy in this population. Statins not only reduce cardiovascular mortality but may also offer hepatic benefits, including anti-inflammatory and antifibrotic effects [64].

Furthermore, novel pharmacotherapies are now entering clinical practice. Resmetirom, a thyroid hormone receptor-beta agonist, is the first FDA-approved treatment for metabolic dysfunction-associated steatohepatitis with stage F2–F3 fibrosis. It has demonstrated substantial improvements in hepatic histology and lipid metabolism, representing a major advancement in dual-targeted therapy [65].

Lanifibranor, a pan-PPAR agonist currently under investigation, and pemafibrate, a selective PPAR-alpha modulator, also show promise in improving both hepatic and cardiovascular parameters. These agents represent the evolving pharmacologic landscape aimed at concurrently addressing steatosis, inflammation, fibrosis, and dyslipidemia [66].

Finally, bariatric surgery remains an effective intervention for eligible patients with severe obesity and MASLD. Beyond inducing significant and sustained weight loss, bariatric surgery improves insulin sensitivity, reduces hepatic inflammation and fibrosis, and lowers long-term cardiovascular risk [67].

Recognizing that MASLD exists within a broader spectrum of systemic metabolic dysfunction, recent staging frameworks have emphasized the importance of tailoring therapeutic strategies according to disease severity and organ involvement.

Management strategies differ significantly across the stages of systemic metabolic disorder. In stage 1, the primary focus is on lifestyle modifications aimed at preventing disease progression. As the condition advances to stage 2, interventions must become more aggressive, often incorporating pharmacologic agents such as GLP-1 RAs and SGLT2 inhibitors that address both metabolic dysfunction and emerging organ-specific complications. By stage 3, when clinical disease is established, a multidisciplinary approach is crucial. This typically involves coordinated care among cardiologists, hepatologists, nephrologists, and endocrinologists to manage complex systemic manifestations and mitigate further deterioration [57].

Together, these strategies highlight the growing capacity for MASLD treatment to address both liver-specific pathology and its systemic cardiovascular consequences.

8. Conclusions

MASLD is now firmly recognized as a multisystem disorder with substantial cardiovascular implications. More than a hepatic condition, MASLD is a central component of the metabolic disease spectrum—interacting with obesity, insulin resistance, T2DM, and systemic inflammation to promote CVD. Growing evidence confirms that MASLD independently increases the risk of coronary artery disease, stroke, arrhythmias, and heart failure—even in the absence of traditional risk factors. Given the strong interplay between hepatic and cardiovascular health, diagnostic approaches should combine liver fibrosis staging with cardiovascular risk assessment using tools like FIB-4 index, transient elastography, NT-proBNP, CAC scoring, and echocardiography. This integrated strategy enables earlier detection of high-risk patients and more effective, individualized interventions. Importantly, the recently proposed pathophysiological staging framework for systemic metabolic disorder offers a structured approach to categorize disease severity and guide stage-specific management. By stratifying patients into progressive stages based on metabolic dysfunction and organ involvement, this model facilitates targeted interventions, from lifestyle changes in early stages to pharmacologic and multidisciplinary care in advanced disease. Ultimately, MASLD should be managed as a cardiometabolic disease. Collaborative care across hepatology, cardiology, endocrinology, and primary care is essential to reduce its burden. Early detection and comprehensive intervention remain key to improving long-term cardiovascular outcomes and survival.

References

  1. 1. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Journal of Hepatology. 2023;79:1542-1556
  2. 2. Zhou XD, Cai J, Targher G, Byrne CD, Shapiro MD, Sung KC, et al. Metabolic dysfunction-associated fatty liver disease and implications for cardiovascular risk and disease prevention. Cardiovascular Diabetology. 2022;21:270
  3. 3. Zheng H, Sechi LA, Navarese EP, Casu G, Vidili G. Metabolic dysfunction-associated steatotic liver disease and cardiovascular risk: A comprehensive review. Cardiovascular Diabetology. 2024;23:346
  4. 4. Zhang Y, Zhang X, Huang C, Zhu L. Trends and disparities in cardiovascular disease in US adults with metabolic dysfunction-associated steatotic liver disease. Biomedicine. 2025;13(4):956. Available from: https://www.mdpi.com/2227-9059/13/4/956
  5. 5. Tacke F, Horn P, Wong VWS, Ratziu V, Bugianesi E, Francque S, et al. EASL-EASD-EASO clinical practice guidelines on the management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Obesity Facts. 2024;17(4):374-444
  6. 6. Barton Duell P, Welty FK, Miller M, Hammond G, Ahmad Z, Cohen DE, et al. Nonalcoholic fatty liver disease and cardiovascular risk: A scientific statement from the American heart association. Arteriosclerosis, Thrombosis, and Vascular Biology. 2022;42(6):E168-E185
  7. 7. Yanai H, Adachi H, Hakoshima M, Iida S, Katsuyama H. Metabolic-dysfunction-associated steatotic liver disease—Its pathophysiology, association with atherosclerosis and cardiovascular disease, and treatments. International Journal of Molecular Sciences. 2023;24:15473
  8. 8. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: Pathophysiology and clinical implications. Gastroenterology. 2012;142(4):711-725.e6. Available from: https://www.sciencedirect.com/science/article/pii/S0016508512001606
  9. 9. DeFilippis AP, Blaha MJ, Martin SS, Reed RM, Jones SR, Nasir K, et al. Nonalcoholic fatty liver disease and serum lipoproteins: The multi-ethnic study of atherosclerosis. Atherosclerosis. 2013;227(2):429-436. Available from: https://www.sciencedirect.com/science/article/pii/S0021915013000580
  10. 10. Stahl EP, Dhindsa DS, Lee SK, Sandesara PB, Chalasani NP, Sperling LS. Nonalcoholic fatty liver disease and the heart: JACC state-of-the-art review. Journal of the American College of Cardiology. 2019;73:948-963
  11. 11. Ionescu VA, Gheorghe G, Bacalbasa N, Diaconu CC. Metabolic dysfunction-associated steatotic liver disease: Pathogenetic links to cardiovascular risk. Biomolecules. 2025;15:163
  12. 12. Targher G, Byrne CD, Tilg H. MASLD: A systemic metabolic disorder with cardiovascular and malignant complications. Gut. 2024;73:691-702
  13. 13. Lauridsen BK, Stender S, Kristensen TS, Kofoed KF, Køber L, Nordestgaard BG, et al. Liver fat content, non-alcoholic fatty liver disease, and ischaemic heart disease: Mendelian randomization and meta-analysis of 279 013 individuals. European Heart Journal. 2018;39(5):385-393. DOI: 10.1093/eurheartj/ehx662
  14. 14. Gutiérrez-Cuevas J, Santos A, Armendariz-Borunda J. Pathophysiological molecular mechanisms of obesity: A link between mafld and Nash with cardiovascular diseases. International Journal of Molecular Sciences. 2021;22:11629
  15. 15. Santos RD, Valenti L, Romeo S. Does nonalcoholic fatty liver disease cause cardiovascular disease? Current knowledge and gaps. Atherosclerosis. 2019;282:110-120
  16. 16. Mellemkjær A, Kjær MB, Haldrup D, Grønbæk H, Thomsen KL. Management of cardiovascular risk in patients with metabolic dysfunction-associated steatotic liver disease. European Journal of Internal Medicine. 2024;122:28-34
  17. 17. Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66(6):1138-1153
  18. 18. Alexander M, Loomis AK, Van Der Lei J, Duarte-Salles T, Prieto-Alhambra D, Ansell D, et al. Non-alcoholic fatty liver disease and risk of incident acute myocardial infarction and stroke: Findings from matched cohort study of 18 million European adults. The BMJ. 2019;367:l5367
  19. 19. Park HE, Kwak MS, Kim D, Kim MK, Cha MJ, Choi SY. Nonalcoholic fatty liver disease is associated with coronary artery calcification development: A longitudinal study. Journal of Clinical Endocrinology and Metabolism. 2016;101(8):3134-3143
  20. 20. Kang JH, Cho KI, Kim SM, Lee JY, Kim JJ, Goo JJ, et al. Relationship between nonalcoholic fatty liver disease and carotid artery atherosclerosis beyond metabolic disorders in non-diabetic patients. Journal of Cardiovascular Ultrasound. 2012;20(3):126-133
  21. 21. Mantovani A. Nonalcoholic fatty liver disease (Nafld) and risk of cardiac arrhythmias: A new aspect of the liver-heart axis. Journal of Clinical and Translational Hepatology. 2017;5:134-141
  22. 22. Hung CS, Tseng PH, Tu CH, Chen CC, Liao WC, Lee YC, et al. Nonalcoholic fatty liver disease is associated with QT prolongation in the general population. Journal of the American Heart Association. 2015;4(7):e001820
  23. 23. Käräjämäki AJ, Pätsi OP, Savolainen M, Kesäniemi YA, Huikuri H, Ukkola O. Non-alcoholic fatty liver disease as a predictor of atrial fibrillation in middle-aged population (OPERA study). PLoS One. 2015;10(11):e0142937
  24. 24. Chung GE, Yu SJ, Yoo JJ, Cho Y, Lee KN, Shin DW, et al. Metabolic dysfunction-associated steatotic liver disease increases cardiovascular disease risk in young adults. Scientific Reports. 2025;15(1):5777
  25. 25. Kasper P, Martin A, Lang S, Kütting F, Goeser T, Demir M, et al. NAFLD and cardiovascular diseases: A clinical review. Clinical Research in Cardiology. 2021;110:921-937
  26. 26. Markus MRP, Baumeister SE, Stritzke J, Dorr M, Wallaschofski H, Volzke H, et al. Hepatic steatosis is associated with aortic valve sclerosis in the general population: The study of health in pomerania (SHIP). Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33(7):1690-1695
  27. 27. Bonapace S, Valbusa F, Bertolini L, Pichiri I, Mantovani A, Rossi A, et al. Nonalcoholic fatty liver disease is associated with aortic valve sclerosis in patients with type 2 diabetes mellitus. PLoS One. 2014;9(2):e88371
  28. 28. Mantovani A, Pernigo M, Bergamini C, Bonapace S, Lipari P, Valbusa F, et al. Heart valve calcification in patients with type 2 diabetes and nonalcoholic fatty liver disease. Metabolism. 2015;64(8):879-887. Available from: https://www.sciencedirect.com/science/article/pii/S0026049515001080
  29. 29. Simon TG, Roelstraete B, Hagström H, Sundström J, Ludvigsson JF. Non-alcoholic fatty liver disease and incident major adverse cardiovascular events: Results from a nationwide histology cohort. Gut. 2022;71(9):1867. Available from: http://gut.bmj.com/content/71/9/1867.abstract
  30. 30. Ma G, Xu G, Huang H. Correlation between metabolic dysfunction-associated steatotic liver disease and subclinical coronary atherosclerosis in eastern China. Diabetology and Metabolic Syndrome. 2025;17(1):16
  31. 31. Moon JH, Jeong S, Jang H, Koo BK, Kim W. Metabolic dysfunction-associated steatotic liver disease increases the risk of incident cardiovascular disease: A nationwide cohort study. EClinicalMedicine. 2023;65:102292
  32. 32. Park SW, Ning H, Carnethon MR, VanWagner LB. Cardiovascular health trajectories and prevalent metabolic dysfunction-associated steatotic liver disease in midlife: The CARDIA study. Journal of the American Heart Association. 2025;14(8):1. DOI: 10.1161/JAHA.124.037948
  33. 33. Muzurović E, Peng CCH, Belanger MJ, Sanoudou D, Mikhailidis DP, Mantzoros CS. Nonalcoholic fatty liver disease and cardiovascular disease: A review of shared cardiometabolic risk factors. Hypertension. 2022;79:1319-1326
  34. 34. Wakabayashi SI, Tamaki N, Kimura T, Umemura T, Kurosaki M, Izumi N. Natural history of lean and non-lean metabolic dysfunction-associated steatotic liver disease. Journal of Gastroenterology. 2024;59(6):494-503. DOI: 10.1007/s00535-024-02093-z
  35. 35. Després JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444(7121):881-887. DOI: 10.1038/nature05488
  36. 36. Zhao YC, Zhao GJ, Chen Z, She ZG, Cai J, Li H. Nonalcoholic fatty liver disease: An emerging driver of hypertension. Hypertension. 2020;75:275-284
  37. 37. Lopez-Jimenez F, Almahmeed W, Bays H, Cuevas A, Di Angelantonio E, le Roux CW, et al. Obesity and cardiovascular disease: Mechanistic insights and management strategies. A joint position paper by the world heart federation and world obesity federation. European Journal of Preventive Cardiology. 2022;29(17):2218-2237
  38. 38. Koskinas KC, Van Craenenbroeck EM, Antoniades C, Blüher M, Gorter TM, Hanssen H, et al. Obesity and cardiovascular disease: An ESC clinical consensus statement. European Journal of Preventive Cardiology. 2024;45(38):4063-4098
  39. 39. Preda A, Carbone F, Tirandi A, Montecucco F, Liberale L. Obesity phenotypes and cardiovascular risk: From pathophysiology to clinical management. Reviews in Endocrine and Metabolic Disorders. 2023;24:901-919
  40. 40. Fracanzani AL, Pisano G, Consonni D, Tiraboschi S, Baragetti A, Bertelli C, et al. Epicardial adipose tissue (EAT) thickness is associated with cardiovascular and liver damage in nonalcoholic fatty liver disease. PLoS One. 2016;11(9):e0162473
  41. 41. Borlaug BA, Jensen MD, Kitzman DW, Lam CSP, Obokata M, Rider OJ. Obesity and heart failure with preserved ejection fraction: New insights and pathophysiological targets. Cardiovascular Research. 2022;118:3434-3450
  42. 42. Piché ME, Tchernof A, Després JP. Obesity phenotypes, diabetes, and cardiovascular diseases. Circulation Research. 2020;126:1477-1500
  43. 43. Borlaug BA, Sharma K, Shah SJ, Ho JE. Heart failure with preserved ejection fraction: JACC scientific statement. Journal of the American College of Cardiology. 2023;81:1810-1834
  44. 44. Lionis C, Papadakis S, Anastasaki M, Aligizakis E, Anastasiou F, Francque S, et al. Practice recommendations for the management of MASLD in primary care: Consensus results. Diseases. 2024;12(8):180
  45. 45. Laeeq T, Tun KM. Metabolic dysfunction-associated steatotic liver disease and cardiovascular disease. Clinical Liver Disease. 2024;23:e0181
  46. 46. Visseren FLJ, MacH F, Smulders YM, Carballo D, Koskinas KC, Bäck M, et al. ESC Guidelines on cardiovascular disease prevention in clinical practice. European Heart Journal. 2021;42:3227-3337
  47. 47. Kazi IN, Kuo L, Tsai E. Noninvasive methods for assessing liver fibrosis and steatosis. Gastroenterology & Hepatology. 2024;20:21-29
  48. 48. Kirkgöz K. C-reactive protein in atherosclerosis—More than a biomarker, but not just a culprit. Reviews in Cardiovascular Medicine. 2023;24:297
  49. 49. Ciardullo S, Cannistraci R, Muraca E, Zerbini F, Perseghin G. Liver fibrosis, NT-ProBNP and mortality in patients with MASLD: A population-based cohort study. Nutrition, Metabolism and Cardiovascular Diseases. 2024;34(4):963-971
  50. 50. Ballestri S, Mantovani A, Baldelli E, Lugari S, Maurantonio M, Nascimbeni F, et al. Liver fibrosis biomarkers accurately exclude advanced fibrosis and are associated with higher cardiovascular risk scores in patients with NAFLD or viral chronic liver disease. Diagnostics. 2021;11(1):98
  51. 51. Lamarche B, Tchernof A, Mauriège P, Cantin B, Dagenais GR, Lupien PJ, et al. Fasting insulin and Apolipoprotein B levels and low-density lipoprotein particle size as risk factors for ischemic heart disease. JAMA. 1998;279(24):1955-1961. DOI: 10.1001/jama.279.24.1955
  52. 52. Lee J, Vali Y, Boursier J, Spijker R, Anstee QM, Bossuyt PM, et al. Prognostic accuracy of FIB-4, NAFLD fibrosis score and APRI for NAFLD-related events: A systematic review. Liver International. 2021;41(2):261-270
  53. 53. Khoshbaten M, Maleki SH, Hadad S, Baral A, Rocha AV, Poudel L, et al. Association of nonalcoholic fatty liver disease and carotid media-intima thickness: A systematic review and a meta-analysis. Health Science Reports. 2023;6:e1554
  54. 54. Kramer CK, Zinman B, Gross JL, Canani LH, Rodrigues TC, Azevedo MJ, et al. Coronary artery calcium score prediction of all cause mortality and cardiovascular events in people with type 2 diabetes: Systematic review and meta-analysis. BMJ. 2013;346:f1654
  55. 55. Yuvaraj J, Lin A, Nerlekar N, Munnur RK, Cameron JD, Dey D, et al. Pericoronary adipose tissue attenuation is associated with high-risk plaque and subsequent acute coronary syndrome in patients with stable coronary artery disease. Cells. 2021;10(5):1143
  56. 56. van der Bijl P, Kuneman JH, Bax JJ. Pericoronary adipose tissue attenuation: diagnostic and prognostic implications. European Heart Journal Cardiovascular Imaging. 2022;23:E537-E538
  57. 57. Romeo S, Vidal-Puig A, Husain M, Ahima R, Arca M, Bhatt DL, et al. Clinical staging to guide management of metabolic disorders and their sequelae: A European atherosclerosis society consensus statement. European Heart Journal. 2025:1-29. DOI: 10.1093/eurheartj/ehaf314/8125503
  58. 58. Marx N, Federici M, Schütt K, Müller-Wieland D, Ajjan RA, Antunes MJ, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. European Heart Journal. 2023;44(39):4043-4140
  59. 59. He K, Li Y, Guo X, Zhong L, Tang S. Food groups and the likelihood of non-alcoholic fatty liver disease: A systematic review and meta-analysis. British Journal of Nutrition. 2020;124:1-13
  60. 60. Khurshid S, Al-Alusi MA, Churchill TW, Guseh JS, Ellinor PT. Accelerometer-derived “weekend warrior” physical activity and incident cardiovascular disease. JAMA. 2023;330(3):247-252
  61. 61. Alfaris N, Waldrop S, Johnson V, Boaventura B, Kendrick K, Stanford FC. GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: A narrative review. eClinicalMedicine. 2024;75:102782
  62. 62. Nevola R, Epifani R, Imbriani S, Tortorella G, Aprea C, Galiero R, et al. GLP-1 receptor agonists in non-alcoholic fatty liver disease: Current evidence and future perspectives. International Journal of Molecular Sciences. 2023;24:1703
  63. 63. Genua I, Cusi K. Pharmacological approaches to nonalcoholic fatty liver disease: Current and future therapies. Diabetes Spectrum. 2024;37(1):48-58
  64. 64. Bernhard J, Galli L, Speidl WS, Krychtiuk KA. Cardiovascular risk reduction in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis. Current Cardiology Reports. 2025;27:28
  65. 65. Mousa AM, Mahmoud M, AlShuraiaan GM. Resmetirom: The first disease-specific treatment for MASH. International Journal of Endocrinology. 2025;2025:6430023
  66. 66. Lange NF, Graf V, Caussy C, Dufour JF. PPAR-targeted therapies in the treatment of non-alcoholic fatty liver disease in diabetic patients. International Journal of Molecular Sciences. 2022;23(8):4305
  67. 67. Sasaki A, Nitta H, Otsuka K, Umemura A, Baba S, Obuchi T, et al. Bariatric surgery and non-alcoholic fatty liver disease: Current and potential future treatments. Frontiers in Endocrinology. 2014;5:164

Written By

Diana-Ruxandra Hădăreanu, Cristina Florescu, Anca Mihu-Marinescu, Veronica Gheorman, Edme-Roxana Mustafa, Adina-Dorina Glodeanu, Rodica Pădureanu, Diana-Maria Trașcă, Ion-Cristian Efrem, Vlad Pădureanu, Sorina Ionelia Stan, Iulian-Alin-Silviu Popescu and Viorel Biciușcă

Submitted: 12 May 2025 Reviewed: 11 June 2025 Published: 07 July 2025