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

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].

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].

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].

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.