# The Basics of Metabolic Dysfunction-Associated Steatotic Liver Disease for Cardiologists

Muhammad Shahzeb Khan, Syed Sarmad Javaid, Amreen Dinani, Kara Wegermann, Ambarish Pandey, Ankeet S Bhatt, Mark Muthiah, Harriette G.C. van Spall, Faiez Zannad, Javed Butler, et al.

<figure><img src="image_1.png" /></figure>

## To cite this version:

Muhammad Shahzeb Khan, Syed Sarmad Javaid, Amreen Dinani, Kara Wegermann, Ambarish Pandey, et al. The Basics of Metabolic Dysfunction-Associated Steatotic Liver Disease for Cardiologists. JACC. Advances, 2025, 86 (20), pp.1861-1884. 10.1016/j.jacc.2025.08.100. hal-05371439

HAL Id: hal-05371439

https://hal.univ-lorraine.fr/hal-05371439v1

Submitted on 18 Nov 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>
# The Basics of Metabolic Dysfunction-Associated Steatotic Liver Disease for Cardiologists

## Pathophysiology, Diagnosis, and Treatment

Muhammad Shahzeb Khan, MD, MSc,ª,ᵇ,ᶜ Syed Sarmad Javaid, MBBS,ᵈ Amreen Dinani, MD,ᵉ,*f

Kara Wegermann, MD,ª Ambarish Pandey, MD,ʰ Ankeet S. Bhatt, MD, MBA, ScM,ᵢ,ⱼ Mark

Muthiah, MBBS,⁵,¹,⁻¹⁾ Harriette G.C. Van Spall, MD, MPH,ⁿ Faiez Zannad, MD, PhD,º Javed Butler, MD, MPH, MBA,ª Michael L. Volk, MD,ρ Marat Fudim, MD, MHSq

## Author Affiliations

a Baylor Scott and White Research Institute, Dallas, Texas, USA

b Department of Medicine, Baylor School of Medicine, Temple, Texas, USA

c Division of Cardiology, Heart Hospital Plano, Plano, Texas, USA

d Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.

e Division of Gastroenterology, Duke University, Durham, North Carolina, USA

f Division of Liver Diseases, Icahn School of Medicine at Mount Sinai New York, New York, USA

g Department of Medicine, Division of Gastroenterology and Hepatology, Duke University, Durham, North Carolina, USA.

h Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA

i Division of Research, Kaiser Permanente San Francisco Medical Center, San Francisco, California, USA.

j Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, California, USA.
k Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore.

l Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

m National University Centre for Organ Transplantation, National University Health System, Singapore.

n Department of Medicine and Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.

o Centre d'Investigations Cliniques Plurithématique 1433, Université de Lorraine, Nancy, France.

p Department of Internal Medicine, Baylor Scott and White Central Texas, Temple, Texas, USA.

q Division of Cardiology, Duke University Medical Center, Durham, North Carolina, USA.

**Short Title:** MASLD and CVD: A Cardiologist's Guide

**ADDRESS FOR CORRESPONDENCE:** Dr Muhammad Shahzeb Khan, The Heart Hospital Plano, 1100 Allied Drive, Plano, Texas 75024, USA. E-mail: Shahzeb.Khan@Bswhealth.org. OR Dr Marat Fudim, Division of Cardiology, Duke University Medical Center, 2301 Erwin Road, Durham, North Carolina 27710, USA. E-mail: [marat.fudim@duke.edu](mailto:marat.fudim@duke.edu).

**FUNDING SUPPORT AND AUTHOR DISCLOSURES:** No funding was received for this study. Dr Khan has received fees from Bayer, Boehringer Ingelheim, and Novartis. Dr Van Spall serves on a trial executive committee for Novo Nordisk. Dr. Dinani is a consultant for Guidepoint and Kinetix. Dr Pandey has received grant funding (to the institution) from Applied Therapeutics, Gilead Sciences, Ultromics, Myovista, and Roche; has served as a consultant for and/or received honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, Roche Diagnostics, Sarfez Therapeutics, Edwards Lifesciences, Merck, Bayer, Novo Nordisk, Alleviant, and Axon Therapies; has received nonfinancial support from Pfizer and Merck; is a consultant for Palomarin Inc with stocks
compensation; and has received research support from the National Institute on Aging GEMSSTAR Grant (1R03AG067960-01), the National Institute on Minority Health and Disparities (R01MD017529), and the National Heart, Lung, and Blood Institute (NHLBI) (R21HL169708). Dr Bhatt has received research grant support to his institution from NIH/NHLBI, NIH/National Institute on Aging, the American College of Cardiology Foundation, and the Centers for Disease Control and Prevention; and has received consulting fees from Novo Nordisk, Merck, and Sanofi. Dr Butler has served as a consultant for Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, Cardiorem, CSL Bearing, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Regeneron, Renibus, Roche, Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultrromics, Vifor, and Zoll. Dr Zannad has received personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, BMS, CVRx, Cambrian, Cardior, Cereno Pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, Novo Nordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, and USA2; has stock options at G3Pharmaceutical and equities at Cereno, Cardiorenal, and Eshmoun Clinical Research; and is the founder of Cardiovascular Clinical Trialists. Dr Fudim is supported by American Heart Association Grant 17MCPRP33460225 and NIH T32 Grant 5T32HL007101; and is a consultant for Coridea and Galvani. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
ABSTRACT

Metabolic dysfunction-associated steatotic liver disease (MASLD) is now recognized as a multisystem disease closely linked to cardiovascular disease, which is the leading cause of death in this population. MASLD and cardiovascular disease share overlapping pathophysiological mechanisms including insulin resistance, chronic inflammation, oxidative stress and endothelial dysfunction that not only drive the progression of each disease but may also potentiate one another. Recent initiatives, such as the cardiovascular-kidney-metabolic health framework and the cardiovascular-renal-hepatic-metabolic model, underscore the importance of integrated, multidisciplinary care for managing multisystemic conditions like MASLD. In this context, cardiologists who frequently encounter MASLD-related comorbidities such as diabetes and obesity are well positioned to lead efforts in early detection, risk stratification, and management. This review offers cardiologists a comprehensive overview of MASLD including the epidemiology, diagnostic approaches, and therapeutic options of MASLD while highlighting cardiologists' pivotal role in its multidisciplinary management.

**KEY WORDS:** cardiologists, cardiovascular disease, metabolic dysfunction-associated steatotic liver disease.
ABBREVIATIONS AND ACRONYMS

AHA = American Heart Association

ASCVD = atherosclerotic cardiovascular disease

BMI = body mass index

CV = cardiovascular

CVD = cardiovascular disease

ELF = Enhanced Liver Fibrosis test

FIB-4 = Fibrosis-4 index

GLP-1 = glucagon-like peptide-1

HF = heart failure

MASLD = metabolic dysfunction-associated steatotic liver disease

MASH = metabolic dysfunction-associated steatohepatitis

MetS = metabolic syndrome

MRI = magnetic resonance imaging

NAFLD = nonalcoholic fatty liver disease

NFS = NAFLD Fibrosis Score

NIT = noninvasive test

PCSK9 = proprotein convertase subtilisin/Kexin type 9

PNPLA3 = patatin-like phospholipase domain-containing protein 3

SGLT2 = sodium-glucose cotransporter 2

T2D = type 2 diabetes

TG = triglyceride
TM6SF2 = transmembrane 6 superfamily member 2

TZD = thiazolidinedione

VCTE = vibration-controlled transient elastography

VLDL = very low density lipoprotein
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is one of the fastest-growing causes of chronic liver disease in the United States. Globally, MASLD affects about one-third of the population, with a higher prevalence among male (40%) compared with female (26%) individuals.¹ In the United States, MASLD has now become the leading indication for liver transplantation, reflecting its growing clinical and public health burden. Although traditionally regarded as a liver-specific condition, growing evidence suggests that MASLD is a multisystem disease, linked to a range of extrahepatic conditions such as cardiovascular disease (CVD).² In fact, CVD is the leading cause of mortality in individuals with MASLD.³ A meta-analysis involving 34,043 patients demonstrated a significantly increased risk of both fatal and nonfatal cardiovascular (CV) events among those with MASLD.⁴ Given this substantial burden, the relationship between MASLD and CVD has gained increasing attention within the field of cardiology.

Reflecting this evolving perspective, recent initiatives have emphasized the need for an integrated, multidisciplinary approach to the management of MASLD and related cardiometabolic disorders.⁵ In 2023, the American Heart Association (AHA) introduced the cardiovascular-kidney-metabolic health (CKMH) initiative, which calls for closer collaboration among cardiology, nephrology, and endocrinology to address overlapping pathophysiological processes.⁶ Building on this model, the cardiovascular-renal-hepatic-metabolic (CRHM) framework was developed to further recognize the impact of MASLD and its progression to metabolic dysfunction-associated steatohepatitis (MASH) on cardiometabolic outcomes.⁷ In parallel, there is growing recognition that the liver is not peripheral to CV health, prompting calls for the inclusion of individuals with MASLD in cardio-renal-metabolic clinical trials.⁸
MASLD and CVD share key risk factors and converge on common pathological pathways, such as insulin resistance, chronic inflammation, oxidative stress, and endothelial dysfunction.⁹ Each condition may exacerbate the other’s progression. As a result, MASLD falls well within the scope of contemporary cardiology practice. Cardiologists routinely manage patients with metabolic comorbidities such as diabetes, obesity, and dyslipidemia, all of which are closely tied to MASLD. In addition, cardiologists frequently encounter clinical manifestations of hepatic dysfunction, including heart failure with preserved ejection fraction, atherosclerosis, and arrhythmias. These intersections highlight the need for cardiologists to develop a solid understanding of MASLD to effectively contribute to integrated care within multidisciplinary teams.

In this context, this article presents a comprehensive review of MASLD geared toward the practicing cardiologist. We discuss the disease’s definition, epidemiology, risk factors, diagnostic tools, and therapeutic options, while also summarizing current evidence linking MASLD to a range of CV conditions. In addition, we highlight the key role of cardiologists in multidisciplinary care, with a focus on early detection, risk assessment, and timely intervention to improve outcomes in MASLD.

## UNDERSTANDING MASLD: DEFINITION, PREVALENCE, AND RISK FACTORS
### DEFINING AND DIAGNOSING MASLD

MASLD is the current terminology for the disease previously known as NAFLD. In 2023, a multi-stakeholder global consortium agreed to rename the disease MASLD to better reflect the metabolic drivers of the condition.¹⁰ The term MASLD is used in this review, although some of the relevant literature was developed using the previous criteria and terminology.¹⁰ MASLD is defined by the presence of hepatic steatosis (at least 5%) along with 1 or more metabolic risk factors, including obesity, hypertension, dyslipidemia (either hypertriglyceridemia or low high-density lipoprotein), or type 2 diabetes (T2D). MASLD describes a spectrum of diseases, ranging from metabolic dysfunction-associated steatosis liver (MASL, characterized by hepatic steatosis alone), regarded as the benign form, and the more aggressive form, MASH. MASH is characterized by the presence of steatohepatitis and hepatocellular injury and can be associated with varying degrees of liver fibrosis,¹¹
a key determinant of liver-related outcomes (Central Illustration).

EPIDEMIOLOGY OF MASLD

The global prevalence of MASLD is estimated at 30%, with the highest rates in Latin America (44%), followed by the Middle East and North Africa (37%) and South Asia (34%). In contrast, prevalence rates are slightly lower in North America (31%), East Asia (30%), and Western Europe (25%).<sup>12</sup> In the United States, prevalence ranges from 24% to 32%,<sup>3,13</sup> with Mexican American individuals showing the highest rates (21.2%), followed by non-Hispanic White individuals (12.5%) and non-Hispanic Black individuals (11.6%).<sup>14</sup> However, these estimates may underrepresent the true burden of disease, as MASLD remains widely underrecognized and underdiagnosed,<sup>15</sup> particularly among African American populations.<sup>16</sup> These racial and ethnic disparities in MASLD prevalence are likely multifactorial, influenced by environmental exposures, socioeconomic conditions, healthcare access, systemic bias, and genetic predisposition.<sup>17</sup> South Asia and the Asia Pacific regions have also seen a marked increase in MASLD prevalence, mirroring rising rates of obesity and diabetes. Although individuals of Asian descent generally have lower body mass index (BMI) than White individuals, they tend to accumulate more visceral fat and exhibit greater insulin resistance at lower BMI thresholds, contributing to a disproportionately high burden of MASLD.<sup>18</sup> A meta-analysis estimated MASLD prevalence among South Asian individuals at approximately 34%,<sup>12</sup> whereas recent observational studies suggest that up to 40% of Asian American individuals may be affected.<sup>19</sup>

The global burden of MASLD is projected to rise substantially, with estimates suggesting that by 2040, global prevalence could approach 55%, and 50% of those affected will develop MASH with significant fibrosis (F ≥ 2).<sup>20</sup> This increase is expected to drive a 168% rise in cases of decompensated cirrhosis and a 137% increase in hepatocellular carcinoma.<sup>21</sup> Despite these alarming trends, only 5 to 10% of individuals with MASLD are aware of their diagnosis, and many lack adequate understanding of the disease and its management.<sup>22</sup> This widespread under-recognition is fueled by the asymptomatic nature of MASLD, the absence of systematic population-level screening, and fragmentation in care delivery. MASLD is currently captured under the International Classification of Diseases codes K76.0 and K75.8<sup>23</sup>; however, these classifications are nonspecific
and do not reflect the updated nomenclature or the underlying metabolic basis of the disease. The
recent proposal for a dedicated International Classification of Diseases, 11th Revision code may
facilitate more accurate identification, enhance clinical recognition, and support better integration of
MASLD into care pathways.²⁴

RISK FACTORS

Metabolic syndrome (MetS) is a key risk factor for MASLD and may include hypertension, hyperglycemia, dyslipidemia, increased waist circumference, and evidence of insulin resistance or T2D.²⁵ Insulin resistance, a hallmark of MetS, is also closely linked to MASLD and plays a critical role in its development and progression.²⁶,²⁷ In addition, sarcopenic obesity also serves as a key risk factor, strongly predicting morbidity and mortality in patients with MASLD.²⁸ Genetic predisposition also influences MASLD susceptibility and severity.⁹,²⁹ Polymorphisms in genes, such as *patatin-like phospholipase domain-containing 3 (PNPLA3)* and *transmembrane 6 superfamily member 2 (TM6SF2)*, have been implicated in disease risk. *PNPLA3* encodes a multifunctional enzyme involved in lipid droplet remodeling and triglyceride metabolism. A common variant in this gene is associated with increased hepatic fat accumulation and a higher risk of progressive liver disease, including cirrhosis and hepatocellular carcinoma. *TM6SF2*, on the other hand, plays a role in hepatic very low-density lipoprotein (VLDL) secretion, and its variants are linked to increased susceptibility to MASH and liver fibrosis.⁹,²⁹ Importantly, a substantial degree of the variation in MASLD prevalence and progression by race and ethnicity has been attributed to the occurrence of unfavorable *PNPLA3 genotypes*, which are highest in individuals of Mexican descent.³⁰,³¹

PATHOPHYSIOLOGICAL MECHANISMS LINKING MASLD AND CVD

In addition to the common lifestyle risk factors, such as unhealthy diet, physical inactivity, and smoking, MASLD and CVD share key pathophysiological mechanisms.⁹ These include complex and interrelated metabolic, inflammatory, and vascular pathways that contribute to the development and progression of both conditions. Although several studies have explored these mechanisms in depth,³²,³³ the following section highlights the key processes that contribute to the heightened CV risk
observed in individuals with MASLD (Figure 1).

Chronic low-grade inflammation, largely driven by adiposity, is a hallmark feature of MASLD and also plays a key role in the development of CV complications.⁹,³⁴ This inflammation extends beyond the liver, leading to the systemic release of proinflammatory cytokines, particularly tumor necrosis factor-alpha and interleukin-6.⁹ Tumor necrosis factor-alpha activates the nuclear factor kappa B pathway, leading to the expression of downstream inflammatory mediators. It also recruits monocytes and facilitates their transformation into foam cells, a key event in atherogenesis.³⁵ Concurrently, interleukin-6 stimulates hepatic synthesis of acute-phase proteins such as C-reactive protein and serum amyloid A, further intensifying systemic inflammation and vascular injury.³⁶⁻³⁸ Together, these cytokine-driven pathways create a pro-atherogenic environment conducive to plaque development and instability.³⁴,³⁹

This inflammatory milieu is closely intertwined with oxidative stress. In individuals with MASLD, impaired methionine metabolism and reduced homocysteine clearance lead to elevated homocysteine levels, which exhaust intracellular glutathione and generate reactive oxygen species.⁴⁰ These reactive oxygen species diminish nitric oxide bioavailability, disrupt endothelial signaling, and facilitate vasoconstriction and platelet activation, culminating in endothelial dysfunction and progression of atherosclerosis.⁴¹⁻⁴³

Endothelial dysfunction, arising from the interplay between inflammation and oxidative stress, serves as a critical interface between hepatic injury and vascular impairment.⁴⁴ Under physiological conditions, the endothelium maintains vascular tone and homeostasis through nitric oxide-mediated mechanisms.⁴⁵ In MASLD, this equilibrium is disrupted by increased oxidative stress and elevated levels of asymmetric dimethylarginine, an endogenous inhibitor of endothelial nitric oxide synthase.⁴⁶ This results in reduced vasodilation, increased vascular resistance, and elevated blood pressure.⁴⁶ In addition, endothelin-1, a potent vasoconstrictor, is upregulated in MASLD in response to oxidative and inflammatory stimuli, further contributing to vascular remodeling and endothelial injury.⁴⁷

Lipid metabolism is also disrupted in MASLD. Under normal conditions, the liver maintains lipid homeostasis through de novo lipogenesis, lipid oxidation, and lipoprotein metabolism.⁴⁸ In
MASLD, hepatic dysfunction leads to atherogenic dyslipidemia, characterized by elevated plasma triglycerides (TGs); VLDL; intermediate-density lipoproteins; an increased proportion of small, dense low-density lipoprotein particles, and reduced high-density lipoprotein cholesterol.³⁴ These lipid abnormalities, especially when compounded by T2D and MetS, are evinced to play a considerable role in promoting vascular inflammation and atherosclerotic plaque formation, thereby contributing to elevated CVD risk.³²,⁴⁹

In insulin resistance, peripheral tissues become less responsive to insulin, leading to increased hepatic glucose production, impaired peripheral glucose uptake, and enhanced lipolysis.⁵⁰ These metabolic disturbances elevate circulating levels of free fatty acid, which accumulate in the liver as TGs, driving the development of hepatic steatosis.⁵¹ Insulin resistance also impairs the liver's capacity to export lipids via VLDL, further exacerbating hepatic lipid retention and promoting disease progression from simple steatosis to steatohepatitis, fibrosis, and ultimately cirrhosis.⁵² In parallel, hyperinsulinemia over activates the phosphoinositide 3-kinase/protein kinase B signaling pathway, which amplifies atherogenic processes and contributes to the increased CVD risk observed in individuals with MASLD.⁵³

Ectopic fat deposition further reinforces the connection between MASLD and CVD. When the liver's capacity to store fat is overwhelmed, due to insulin resistance, high fat intake, or underlying genetic factors, TGs begin to accumulate not only within the liver, worsening steatosis, but also in non-adipose tissues such as the myocardium, skeletal muscle, and pancreas.⁹,⁵⁴ This is particularly detrimental to the heart, where lipid accumulation in the myocardium and surrounding vasculature induces lipotoxic effects, characterized by oxidative stress, mitochondrial dysfunction, and inflammation.⁵⁵ These pathological changes drive structural and functional remodeling of the heart, increasing susceptibility to ischemic injury and ultimately contributing to the onset of heart failure (HF), cardiac arrhythmias, and other adverse CV outcomes.⁵⁶,⁵⁷

Gut dysbiosis, an imbalance in the intestinal microbiota, is another important factor linking hepatic and CV pathology.⁹ By disrupting the gut–liver axis, gut dysbiosis increases intestinal permeability, allowing bacterial endotoxins to translocate into the bloodstream, and trigger both hepatic and systemic inflammation.⁵⁸ This inflammatory response exacerbates metabolic dysfunction
and promotes the progression of both liver disease and CVD. Microbial metabolism of dietary
components such as choline and L-carnitine generates trimethylamine, which is converted in the liver
to trimethylamine N-oxide, a pro-atherogenic metabolite implicated in endothelial injury and
increased risk of myocardial infarction and stroke.⁵⁹,⁶⁰

Variants in the *PNPLA3* gene, such as rs738409, are also associated with increased hepatic
fat accumulation and progression to advanced liver disease.⁶¹,⁶² Although the direct effect of
PNPLA3 variants on CVD risk remains unclear, they may contribute indirectly by promoting a
proatherogenic lipid profile.⁶³ Similarly, variants in the *TM6SF2* gene also affect MASLD
progression.⁶⁴ Specifically, the TM6SF2 E167K variant is linked to more severe liver disease but
paradoxically correlates with lower circulating lipid levels, potentially providing some protection
against CV complications.⁶⁵

DIFFERENTIAL DIAGNOSIS FOR MASLD

MASLD is the most common cause of hepatic steatosis; however, several other conditions can mimic
its clinical and histological features. Alcohol-associated liver disease and MASLD in combination
with alcohol-associated liver disease (MetALD) are chronic liver diseases that also can present with a
spectrum of histological findings similar to MASLD and in addition share overlapping metabolic risk
factors. ¹⁰ Drug-induced liver injury caused by long-term use of amiodarone also can lead to histologic
alterations resembling steatohepatitis. ⁶⁶ Although mild abnormalities in liver function tests are
frequently observed in these patients, only a subset of patients develop significant hepatic
inflammation or fibrosis. ⁶⁷ Similarly, hepatitis C virus infection, particularly genotype 3, also induces
steatosis by directly disrupting lipid metabolism⁶⁸; however, the steatosis seen in hepatitis C virus is
typically mild and diffusely distributed, differing in pattern and severity from that of MASLD. ⁶⁸
Wilson disease, an autosomal recessive disorder caused by mutations in the *ATP7B* gene, results in
copper accumulation in the liver. ⁶⁹ This disrupts mitochondrial function and impairs fatty acid β-
oxidation, resulting in hepatic injury that resembles MASH or presents as chronic hepatitis due to
necrosis. ⁶⁹ In addition, iron overload syndromes, particularly hereditary hemochromatosis resulting
from HFE mutations, can also contribute to hepatic steatosis. ⁷⁰ Although MASLD is typically
associated with mild iron deposition involving both hepatocytes and Kupffer cells, hereditary hemochromatosis is characterized by marked iron accumulation, predominantly in hepatocytes.⁷¹

Elevated ferritin levels, whether due to underlying HFE variants or as a nonspecific acute-phase reactant, are common in MASLD but require careful interpretation, as HFE mutations have been implicated not only in promoting hepatic iron overload but also in causing more severe liver injury in individuals with MASLD.⁷¹,⁷²

## ASSESSING THE ROLE OF MASLD IN CARDIOVASCULAR DISEASE: INDEPENDENT RISK FACTOR OR SHARED COMORBIDITY?

MASLD has been associated with an increased risk of CVD; however, whether this increased risk is truly independent or largely driven by shared cardiometabolic risk factors remains uncertain.⁷³⁻¹⁰¹

Several large observational studies have suggested that MASLD is independently associated with increased CV risk, even after adjusting for age, sex, adiposity, diabetes, and other traditional risk factors. For instance, a meta-analysis by Mantovani et al,⁷⁶ which included 36 longitudinal studies involving >5.8 million individuals and nearly 100,000 CVD events, reported that MASLD was associated with a significantly increased risk of fatal or nonfatal CV events (adjusted hazard ratio [aHR]: 1.31; 95% CI: 1.31–1.61) following maximal covariate adjustment. In addition, other studies have found that MASLD remains independently associated with coronary artery calcification, valvular heart disease, and HF, even after accounting for conventional CV risk factors.⁷³,⁹³,⁹⁹

However, it is important to note that some studies reporting positive associations did not adequately adjust for key confounders such as obesity and T2D, raising concerns about residual confounding. These limitations, along with potential publication bias and heterogeneity in analytic rigor across studies, suggest that the strength of the MASLD and CVD association may be overstated in parts of the existing literature.⁹⁴,⁹⁸

Adding to this complexity, several well-conducted studies have found no significant association between MASLD and CVD outcomes once comprehensive adjustments for cardiometabolic risk factors were applied. For instance, a cohort study using data from primary care databases reported that the association between MASLD and myocardial infarction or stroke became
non-significant after full adjustment for metabolic risk factors.⁷⁸ Similarly, another cohort study
found no association between MASLD and the risk of hospitalization for ischemic heart disease or
stroke after adjusting for BMI, diabetes, and hypertension.⁷⁷ These discrepancies underscore the need
for cautious interpretation of existing data and highlight the importance of rigorously adjusted,
prospective studies to determine whether MASLD confers an independent CV risk or merely reflects
underlying metabolic dysfunction. **Table 1** summarizes key studies, prioritizing large-scale data with
worldwide representation and reporting the extent of covariate adjustment.

MASLD REMAINS ABSENT FROM THE NEW AHA CARDIOVASCULAR RISK CALCULATOR

The AHA recently introduced the PREVENT (Predicting Risk of Cardiovascular Disease Events) calculator, which builds on the pooled cohort equation framework to estimate both 10- and 30-year risks of atherosclerotic cardiovascular disease (ASCVD) and HF. Compared with older models, PREVENT incorporates a broader range of cardiometabolic variables, including BMI and kidney function (eg, estimated glomerular filtration rate), allowing for more comprehensive CV risk stratification.¹⁰² However, PREVENT like all currently available CV risk tools does not account for MASLD.

The absence of MASLD from current risk prediction models likely stems from several
practical and methodological limitations. First, MASLD was not systematically characterized in the
derivation cohorts used to develop tools such as the pooled cohort equation and PREVENT
calculators, restricting their ability to account for liver-related contributions to CV risk.¹⁰³ Second,
although noninvasive tests (NITs) such as Fibrosis-4 index (FIB-4) and the NAFLD Fibrosis Score
(NFS) are available, they were originally developed for other liver conditions, such as hepatitis C,
and demonstrate variable diagnostic accuracy when applied to MASLD. Last, many NITs have
limited ability to distinguish between stages of fibrosis or to track changes in disease activity over
time, and their performance may vary by age, sex, and ethnicity.¹⁰⁴

Addressing this gap will require the development of CV risk prediction models that explicitly
incorporate MASLD-related variables. Incorporating liver-directed imaging, such as evaluating
hepatic steatosis or fibrosis during coronary calcium scoring, may further enhance risk assessment.

Emerging technologies, including artificial intelligence-driven algorithms applied to electronic medical records, also could help identify relevant liver-related patterns to inform model development.

In addition, inflammatory biomarkers like high-sensitivity C-reactive protein, which has been shown to be a strong and independent predictor of adverse CV events,¹⁰⁵ may improve model accuracy.

Large, prospective studies across diverse populations are needed to enable the integration of MASLD into CV risk prediction frameworks.

## CLINICAL APPROACH TO MASLD DETECTION IN CARDIOLOGY: SCREENING AND DIAGNOSTICS

Diagnosing MASLD is often challenging in clinical practice, as 40% to 50% of patients may have normal liver enzyme levels and may progress to fibrosis without showing warning signs or symptoms.¹⁰⁶,¹⁰⁷ This silent progression underscores the importance of early identification, particularly in cardiology, where many patients have overlapping risk factors such as obesity, T2D, dyslipidemia, or other features of MetS. According to the American Association for the Study of Liver Diseases (AASLD), patients with incidental hepatic steatosis and at least 1 metabolic risk factor should undergo noninvasive fibrosis assessment to guide further management, including consideration of hepatology referral.²⁹ Although AASLD does not recommend population-wide screening, other societies, such as the American College of Endocrinology, support targeted screening of high-risk individuals.²⁹

The initial detection of hepatic steatosis is typically performed using imaging modalities such as liver-dedicated ultrasound, computed tomography, or magnetic resonance imaging (MRI) (Figure 2). Ultrasound is widely available, non-invasive, and inexpensive but has limited sensitivity for detecting mild steatosis and does not assess fibrosis.¹⁰⁸ Computed tomography scan may incidentally reveal liver fat during investigations for chest pain or cancer staging but involves radiation exposure and lacks sufficient diagnostic sensitivity.¹⁰⁹ MRI provides the most accurate quantification of hepatic fat, capable of detecting steatosis at levels as low as 5%.¹⁷ Multiparametric MRI techniques, such as LiverMultiScan, enable simultaneous assessment of hepatic fat, disease activity, and fibrosis with
high reproducibility.<sup>110</sup> LiverMultiScan generates corrected T1 maps of the liver, with correction for iron using parallel T2* mapping (T2* is an MRI parameter sensitive to tissue iron content), to estimate extracellular expansion linked to inflammation and fibrosis, while also quantifying hepatic fat.<sup>111,112</sup> Current guidelines recognize LiverMultiScan as a suitable noninvasive imaging modality in MASLD<sup>111,112</sup>; however, the high cost and limited availability restrict the routine use of MRI in cardiovascular care. Other imaging technologies, such as acoustic radiation force impulse elastography, provide additional diagnostic value for assessing liver fibrosis but are not routinely used in cardiology settings.<sup>113</sup> Although imaging modalities discussed previously are helpful in confirming steatosis, they rarely change CV management. Therefore, cardiologists should focus on evaluating fibrosis risk, which is a more relevant predictor of liver-related outcomes, CV, and overall mortality.<sup>114</sup>

To address this, noninvasive fibrosis scoring tools such as the FIB-4 index, the NFS and aspartate aminotransferase-to-platelet ratio index offer practical options for risk stratification in cardiology practice.<sup>112, 115</sup> These tools are based on routinely available laboratory data and can be easily integrated into existing clinical workflows. Among them, FIB-4 is the most widely validated and is endorsed by multiple guidelines as the preferred first-line tool for fibrosis assessment.<sup>116</sup> It is simple, cost-free, and can be embedded within electronic medical record systems to allow automated calculations and alerts when thresholds are exceeded. Importantly, FIB-4 not only helps identify patients with advanced fibrosis but also correlates with liver-related morbidity, CV events, and all-cause mortality.<sup>117,118</sup>

Current recommendations suggest that a FIB-4 score <1.3 indicates a low risk of advanced fibrosis and that such patients can be monitored with repeat testing every 2 to 3 years in low-risk individuals or every 1 to 2 years in those with higher risk.<sup>112,115, 119-121</sup> In contrast, a score >2.67 suggests a high probability of advanced fibrosis and warrants referral to hepatology.<sup>112,115, 119-121</sup> For those with an indeterminate FIB-4 score (1.3-2.67), second-line risk stratification is recommended.<sup>121</sup> This may include vibration-controlled transient elastography (VCTE), such as FibroScan, which is approved by the U.S. Food and Drug Administration (FDA) and increasingly available in cardiometabolic centers, or the Enhanced Liver Fibrosis (ELF) test, a proprietary serum
biomarker panel.¹¹⁶ Both methods enhance diagnostic precision and can be selected based on availability and institutional protocols. In cases in which cardiologists are not familiar or comfortable with ordering these diagnostic tests, they should consider referring such patients to hepatology.

If second-line testing suggests a low risk of fibrosis (VCTE <8.0 kPa or ELF <7.7), continued surveillance is generally appropriate. In contrast, patients with intermediate or high-risk scores (VCTE ≥8.0 kPa or ELF ≥7.7) should be referred for comprehensive evaluation to a hepatologist,¹¹⁶ where further assessment may include advanced imaging such as magnetic resonance elastography or multiparametric MRI techniques like LiverMultiScan, which enable simultaneous evaluation of steatosis and fibrosis with reproducible accuracy.¹¹⁰ In selected cases, or when results from noninvasive tests are discordant and diagnostic uncertainty remains, liver biopsy may still be required to confirm the diagnosis and accurately stage fibrosis.¹⁰³ As these procedures are typically performed under the supervision of a hepatologist, referral to a liver specialist is strongly recommended.

When interpreting fibrosis scores and making referral decisions, it is important to consider individual patient factors that may influence the accuracy of NITs. For instance, age significantly affects the performance of FIB-4. In adults aged 65 years or older, FIB-4 specificity declines, leading to a higher likelihood of false-positive results.¹²² To reduce unnecessary referrals in this population, a higher cutoff value (> 2.0) is recommended. Conversely, in individuals younger than 35 years, FIB-4 tends to underperform, and alternative methods of fibrosis assessment may be more appropriate.¹²³ In pediatric patients, neither FIB-4 nor NFS is validated. Current guidelines instead recommend using serum aminotransferase levels as the initial tool for evaluating liver health in children and adolescents.¹¹² In addition, VCTE is approved by the FDA for use in children and can be used to assess liver stiffness in pediatric patients.²⁹

In summary, for cardiologists, incorporating simple and validated tools such as FIB-4 into routine practice provides a low-cost, effective strategy to identify patients with MASLD who may be at increased risk for adverse hepatic and CV outcomes. This approach promotes more comprehensive cardiometabolic risk assessment and facilitates timely referral to hepatology when
appropriate. **Figure 3** presents a practical, stepwise algorithm that cardiologists can follow when screening and evaluating patients with suspected MASLD in clinical settings.

## MANAGEMENT OF MASLD AND CARDIOMETABOLIC RISK FACTORS

With the approval of the first drug for MASH, resmetirom, there is hope that further pharmacologic therapies may follow. However, weight loss through lifestyle modifications such as healthy diet, exercise or combination remain the mainstay treatments (Figure 4).¹²⁴ **Supplemental Table 1** summarizes key findings from studies on MASLD/MASH management, and **Supplemental Table 2** summarizes ongoing clinical trials.

## LIFESTYLE INTERVENTIONS

### Exercise

Exercise plays a central role in MASLD management by promoting weight loss and improving cardiometabolic health. A 5% weight loss can decrease liver fat by approximately 30% and improve metabolic parameters, whereas 7% to 10% weight loss is typically needed to reduce hepatic inflammation, and ≥10% may be required for fibrosis regression.¹²⁴ These thresholds can vary by baseline weight, with women potentially requiring greater weight loss than men to achieve similar histologic improvements.¹²⁵ In one clinical trial involving 31 patients with biopsy-proven MASH, participants randomized to a combination of diet, exercise, and behavioral interventions showed greater weight loss and significant reductions in nonalcoholic steatohepatitis (NASH) histologic activity scores over 48 weeks.¹²⁶

The optimal intensity required to maximize these benefits remains unclear.¹²⁷⁻¹²⁹ Both moderate and vigorous activity have been found equally effective in reducing intrahepatic triglyceride content among patients with MASLD and central obesity.¹²⁸ Similarly, both aerobic and resistance training have been shown to reduce hepatic fat.¹²⁴,¹²⁹ However, resistance training, in particular, enhances cardiometabolic health by promoting favorable changes in body composition, resulting in an anti-inflammatory and anti-atherogenic profile.¹³⁰⁻¹³¹

Combining moderate physical activity with dietary intervention has been shown to
significantly reduce visceral adipose tissue and hepatic fat, even in the absence of substantial weight
loss.<sup>132-134</sup> Although these findings are encouraging, evidence from large randomized controlled trials
specifically evaluating the histological impact of exercise on MASH remains limited. Current
European practice guidelines recommend 150 to 200 minutes per week of moderate-intensity aerobic
exercise across 3 to 5 sessions, combined with resistance training to support musculoskeletal health
and reduce metabolic risk.<sup>123</sup> These recommendations are consistent with broader public health
guidelines, which suggest 75 to 150 minutes of vigorous-intensity or 150 to 300 minutes of
moderate-intensity activity per week, along with at least 2 sessions of muscle-strengthening
exercises.<sup>135,136</sup>

Diet

Dietary recommendations for managing MASLD and CVD prevention suggest modifying the macronutrient composition to resemble the Mediterranean diet pattern. This entails adhering to a vegetable-based diet that primarily consists of whole grains for carbohydrates, plant oils (olive oil) for fat, and nuts and legumes for proteins.¹³⁷ There is ambiguity regarding the direct role of a high-fructose diet on MASLD pathogenesis; patients should be recommended to avoid fructose-rich beverages and meals until conclusive findings are available.¹³⁸ It is also advised that alcohol consumption be limited to 30 g for men and 20 g for women.¹³⁹ In patients with MASH with fibrosis ≥F2, complete abstinence from alcohol is recommended to prevent hepatocellular carcinoma development and progression of liver disease.¹⁴⁰ Emerging studies suggest that even low-to-moderate alcohol use may be associated with increased fibrosis progression in the early stage of MASLD.¹⁴¹ Last, smoking cessation is also recommended in these patients, considering that it is an established CV risk factor and may promote progression of MASLD.⁹

PHARMACOLOGICAL INTERVENTIONS

Direct therapies

The FDA has conditionally approved resmetirom, a liver-selective thyroid hormone receptor-β agonist, for the treatment of MASH in patients with moderate to advanced fibrosis (stage 2 to 3).<sup>142</sup> This decision was based on the results of the phase 3 MAESTRO clinical program.<sup>143</sup> The phase 3
MAESTRO-NASH (A Phase 3 Study to Evaluate the Efficacy and Safety of MGL-3196 [Resmetirom] in Patients With NASH and Fibrosis) trial included 966 obese people with biopsy-confirmed MASH and found that both the 80-mg and 100-mg dosages of resmetirom outperformed placebo in resolving MASH and improving fibrosis by at least 1 stage at week 52.¹⁴³ Resmetirom also reduced hepatic fat content, which leads to an improvement in liver damage indicators.¹⁴³ Because MASLD is a multisystem disease, combining resmetirom with other potentially hepatoprotective medicines, such as incretin receptor agonists, may minimize the cardio-metabolic risk associated with MASLD/MASH and serve as a potential treatment for this disease.¹⁴² An ongoing clinical trial (MAESTRO-NASH OUTCOMES [A Phase 3 Study to Evaluate the Effect of Resmetirom on Clinical Outcomes in Patients With Well-compensated NASH Cirrhosis; NCT05500222) is evaluating the safety and efficacy of resmetirom in patients with compensated cirrhosis due to MASH.

## Cardiometabolic therapies

### Lipid lowering agents.

Dyslipidemia is a key contributor to the development of both MASLD and CVD, and statins remain the most effective and commonly prescribed lipid-lowering agents.¹⁴⁴ Beyond their lipid-lowering properties, statins offer additional benefits through anti-inflammatory, antioxidant, antifibrotic, and plaque-stabilizing effects,¹⁴⁵ which may improve both liver and CV health in individuals with MASLD. In a cohort of nearly 8,000 patients with MASLD, statin use was linked to lower risks of all-cause mortality, liver-related events, and liver stiffness progression.¹⁴⁶ Other studies have shown that moderate- and high-intensity statins may slow fibrosis progression and reduce the risk of hepatocellular carcinoma.¹⁴⁷⁻¹⁴⁹ Despite this, statins remain underused in MASLD due to concerns about hepatotoxicity. The 2018 AHA/American College of Cardiology Cholesterol Guidelines, however, affirm that statins are safe for patients with elevated ASCVD risk and chronic, stable liver disease such as MASLD.¹⁵⁰ Mild transaminase elevations may occur but are usually transient and resolve with dose adjustment or switching agents. Severe liver injury is rare, and routine liver enzyme monitoring has not been shown to reduce this risk.¹⁵⁰ These outdated safety concerns may lead to missed opportunities for improving outcomes in a high-risk population that stands to benefit
significantly from statin therapy.

Ezetimibe, is also safe and effective for reducing CV risk in patients with MASLD.<sup>151</sup>

However, its benefits for liver-specific outcomes remain uncertain, and its use beyond CV indications is still speculative.<sup>152,153</sup> A trial involving patients with MASH found no significant improvements in liver fat content or aminotransferase levels with ezetimibe.<sup>154</sup>

Elevated levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) may also contribute to the progression of MASLD<sup>155</sup>; however, the effects of PCSK9 inhibitors on liver-related outcomes remain uncertain. In a retrospective study, 8 of 11 patients with confirmed MASLD achieved complete radiologic resolution after treatment with PCSK9 monoclonal antibodies. The study also reported reductions in alanine aminotransferase and aspartate aminotransferase levels.<sup>156</sup> Beyond liver-related effects, clinical trials also have shown that PCSK9 monoclonal antibody therapy significantly reduces the risk of recurrent CV events in patients with established ASCVD who are already on statin therapy.<sup>157,158</sup> MASLD should not be considered a contraindication to PCSK9 inhibitor therapy for CV risk reduction.

### Anti-hyperglycemic agents.

Glucagon-like peptide-1 (GLP-1) agonists have shown beneficial effects on both hepatic and CV endpoints in patients with MASLD.<sup>159</sup> In the LEAN (Liraglutide Efficacy and Action in Non-alcoholic Steatohepatitis) study, a greater proportion of patients in the liraglutide group showed improvement in MASH histology compared with those receiving placebo (39% vs 9%), whereas worsening of fibrosis was more common in the placebo group (36% vs 9%).<sup>160</sup> Further supporting these findings, a clinical trial evaluated tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and GLP-1 receptors in patients with biopsy-proven MASH and moderate to severe fibrosis.<sup>161</sup> After 52 weeks of treatment, tirzepatide demonstrated greater efficacy than placebo in achieving MASH resolution without worsening fibrosis. In another study, survodutide, a dual glucagon and GLP-1 receptor agonist, was also associated with improvement in MASH compared with placebo, again without fibrosis progression.<sup>162</sup> Most recently, results from the ESSENCE (The Effect of Semaglutide in Subjects with Non-cirrhotic Non-alcoholic Steatohepatitis) trial were published. In this trial, 1,197
patients with biopsy-confirmed MASH and stage 2 or 3 fibrosis were randomized in a 2:1 ratio to receive once-weekly subcutaneous semaglutide or placebo. At week 72, semaglutide was associated with a higher rate of steatohepatitis resolution without worsening fibrosis (62.9% vs 34.2%; P<0.001), as well as a higher rate of fibrosis improvement without worsening of steatohepatitis (36.8% vs 22.4%; P<0.001).¹⁶³

Thiazolidinediones (TZDs) are another therapeutic option for patients with MASLD and T2D.¹³⁷ As selective peroxisome proliferator-activated receptor gamma (PPARγ) agonists, TZDs enhance insulin sensitivity in adipose tissue, liver, and muscle. In a randomized trial of 101 patients with prediabetes or T2D and biopsy-confirmed MASH, pioglitazone significantly improved liver histology.¹⁶⁴ The primary outcome, a ≥2-point reduction in the NAFLD activity score in at least 2 histologic categories without worsening of fibrosis was achieved in a significantly greater proportion of patients receiving pioglitazone compared with placebo (P < 0.001). Treatment also resulted in significant improvements in metabolic parameters, including insulin sensitivity, hepatic triglyceride content, and glycemic control (all P < 0.05), with effects sustained for over 18 months. Despite these benefits, the use of TZDs is limited by adverse effects, most notably weight gain primarily due to fluid retention. This may be mitigated through combination therapy with and sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have diuretic and cardioprotective properties. However, with the advent of newer cardiometabolic agents offering comparable or superior efficacy and more favorable safety profiles, the role of TZDs in MASLD management requires further evaluation.

Patients with MASLD and co-existing T2D also may be treated with metformin and SGLT2 inhibitors. These medications reduce the amount of ectopic fat, ameliorate its inflammation, and inhibit its secretion of adipokines.¹⁶⁵ A cohort study involving 80,178 patients showed that SGLT2 inhibitors may be preferable to other oral antidiabetic medications for promoting MASLD regression and improving composite liver-related outcomes.¹⁶⁶

## 2.3) Antihypertensive agents

In MASLD, treatment with angiotensin-converting enzyme and angiotensin receptor blockers has been linked with possibly reduced risks of mortality, major adverse liver outcomes, and major adverse cardiovascular events.¹⁶⁷ These agents may also improve liver enzymes, such as alanine
aminotransferase, although consistent benefits on steatohepatitis or fibrosis have not been demonstrated.¹⁶⁸ The ongoing RELIEF-NAFLD (Role of Lisinopril in Preventing the Progression of Non-Alcoholic Fatty Liver Disease) trial is examining whether lisinopril can slow fibrosis progression by tracking changes in PRO-C3, a serum fibrosis marker, over 24 weeks in patients with advanced fibrosis (**Supplemental Table 2**). Other antihypertensives, including mineralocorticoid receptor antagonists and calcium channel blockers, have shown encouraging effects on liver histology in preclinical models, but clinical evidence in MASLD remains limited. Overall, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in MASLD should be guided by established cardiovascular indications, with any hepatic benefits considered secondary until more definitive evidence becomes available.

## Other agents

Acetylsalicylic acid might also exert antifibrotic effects in MASLD. Data from a prospective cohort study involving 361 patients with MASLD reported that daily administration of acetylsalicylic acid was correlated with reduced histologic severity of MASLD and MASH, as well as a decreased risk of progression to advanced fibrosis over time.¹⁶⁹ The greatest benefit was observed in patients who had been using acetylsalicylic acid for 4 years or longer. Data from another trial involving 80 patients with MASLD corroborated these findings, concluding that daily administration of aspirin for 6 months was associated with a reduction in liver fat content.¹⁷⁰

## Surgery

Patients with MASLD may choose bariatric surgery as a final option when lifestyle modifications and optimal management of comorbidities fail to adequately reduce disease burden and cardiometabolic risk.¹⁷¹,¹⁷² A retrospective cohort study reported that, among patients with MASH and obesity, bariatric surgery was associated with a significantly lower risk of major adverse liver outcomes and CV events compared with nonsurgical treatment.¹⁷³ In a clinical trial involving 288 participants with biopsy-confirmed MASH, patients either received lifestyle modification plus best medical care (n = 96), Roux-en-Y gastric bypass (n = 96), or sleeve gastrectomy (n = 96).¹⁷⁴ At 1-year follow-up, histological resolution of MASH without worsening fibrosis was significantly higher in both the
Roux-en-Y gastric bypass and sleeve gastrectomy groups compared to the lifestyle modification group (P <0.0001). Specifically, the probability of MASH resolution was 3.6 times greater in the gastric bypass group and in the sleeve gastrectomy group compared with the lifestyle modification group (P < 0.001 for both).<sup>174</sup> Taken together, these findings suggest that bariatric surgery may not only improve histological features of MASH and reduce the risk of disease progression, including cirrhosis, but also confer CV benefit in patients with MASLD and obesity.

## THE ROLE OF CARDIOLOGISTS IN MULTIDISCIPLINARY CARE OF MASLD

Given the multisystem nature of MASLD and its association with CVD, a holistic, multidisciplinary framework is essential to address shared risk factors and effectively slow disease progression.<sup>175,176</sup> Evidence already supports the effectiveness of multidisciplinary care for MASLD. In an observational study of patients with poorly controlled T2DM, a team-based approach led to significant improvements in both liver-related and cardiometabolic outcomes, as well as demonstrated cost-effectiveness.<sup>177</sup> Although cardiologists were not included in that model, their involvement represents a logical and necessary progression. Cardiologists routinely care for patients with obesity, T2D, and dyslipidemia, the central components of MetS and common comorbidities of MASLD. Hence, there is a compelling opportunity to incorporate liver fibrosis screening into routine CV practice. The FIB-4 index, a simple and non-invasive first-line tool, can help identify individuals at risk for advanced fibrosis. Patients with elevated scores indicative of advanced fibrosis should be referred by cardiologists to hepatologists, whereas those with intermediate-risk scores may undergo second-line evaluation using tests such as VCTE or the ELF panel to further assess fibrosis severity. If second-line testing suggests significant fibrosis, referral to a liver specialist is warranted for a comprehensive diagnostic workup and targeted management. In cases in which cardiologists are not familiar or comfortable with arranging these diagnostic tests (VCTE or ELF), they should consider referring patients directly to hepatology. Following referral, patients may undergo more advanced evaluation, including magnetic resonance elastography, liver biopsy, or multiparametric MRI approaches such as LiverMultiScan. In parallel, cardiologists can assess CV risk using tools such as the PREVENT
calculator, enabling coordinated, organ-specific evaluations that support a more integrated approach
to managing patients with overlapping metabolic risk factors.

Beyond screening and referral, the cardiology therapeutic arsenal offers additional opportunities to influence liver outcomes. Guideline-directed medical therapies commonly used for CVD management, including GLP-1 receptor agonists, SGLT2 inhibitors, and statins, not only improve CV health but have also demonstrated beneficial effects on hepatic steatosis, inflammation, and fibrosis. In addition to pharmacologic therapy, lifestyle interventions such as dietary modification and regular physical activity have been shown to improve both liver and CV outcomes. By prescribing these therapies and promoting evidence-based lifestyle changes, cardiologists can contribute meaningfully to both CV and hepatic disease modification, reinforcing the value of a multisystem, patient-centered approach to cardiometabolic care (Figure 5).

This integrated model is not only clinically useful but also a pragmatic solution to a growing burden of MASLD. With only approximately 7,300 hepatologists practicing in the United States,¹⁷⁸ a significant workforce gap limits patient access to specialized liver care. By empowering cardiologists to screen for, risk-stratify, and initiate management of MASLD, we can expand access to care, enhance clinical efficiency, and ultimately advance the delivery of high-quality, coordinated management for this high-risk patient population.

CONCLUSIONS

MASLD is a multisystem disease closely linked to CV risk, requiring timely screening and intervention to reduce morbidity and mortality. This review highlights the opportunity to integrate MASLD screening and treatment into CV care. Cardiologists, given their routine management of metabolic risk factors, are well positioned to identify at-risk patients using noninvasive tools and initiate therapies that benefit both liver and heart health. Involving cardiologists in MASLD care can improve early detection, streamline management, and support a more coordinated, patient-centered approach.
REFERENCES

1. Teng ML, Ng CH, Huang DQ, et al. Global incidence and prevalence of nonalcoholic fatty liver disease. *Clin Mol Hepatol*. 2023;29:S32-S42.

2. Jiang F, Wang L, Ying H, et al. Multisystem health comorbidity networks of metabolic dysfunction-associated steatotic liver disease. *Med*. 2024;5:1413-1423.e3.

3. Duell PB, Welty FK, Miller M, et al. Nonalcoholic Fatty Liver Disease and Cardiovascular Risk: A Scientific Statement From the American Heart Association. *Arterioscler Thromb Vasc Biol*. 2022;42:e168-e185.

4. Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. *N Engl J Med*. 2010;363:1341-1350.

5. Sperling LS, Mechanick JI, Neeland IJ, et al. The CardioMetabolic Health Alliance: Working Toward a New Care Model for the Metabolic Syndrome. *J Am Coll Cardiol*. 2015;66:1050-1067.

6. Ndumele CE, Rangaswami J, Chow SL, et al. Cardiovascular-Kidney-Metabolic Health: A Presidential Advisory From the American Heart Association. *Circulation*. 2023;148:1606-1635.

7. Theodorakis N, Nikolaou M. From Cardiovascular-Kidney-Metabolic Syndrome to Cardiovascular-Renal-Hepatic-Metabolic Syndrome: Proposing an Expanded Framework. *Biomolecules*. 2025;15:213.

8. Zannad F, Sanyal AJ, Butler J, Miller V, Harrison SA. Integrating liver endpoints in clinical trials of cardiovascular and kidney disease. *Nat Med*. 2024;30:2423-2431.

9. Zheng H, Sechi LA, Navarese EP, Casu G, Vidili G. Metabolic dysfunction- associated steatotic liver disease and cardiovascular risk: a comprehensive review. *Cardiovasc Diabetol*. 2024;23:346.

10. Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. *Hepatology*. 2023;78:1966-1986.

11. Hagström H, Shang Y, Hegmar H, Nasr P. Natural history and progression of
metabolic dysfunction-associated steatotic liver disease. *Lancet Gastroenterol Hepatol.* 2024;9:944-956.

12. Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. *Hepatology*. 2023;77:1335-1347.

13. Paik JM, Hobbs K, Gupta A, Alkalbani RJ, Reyes MA, Younossi ZM. Prevalence of MASLD, Met-ALD, and ALD and Associated Fibrosis Among US Adults: Insights From NHANES 2017 to 2023. *J Clin Gastroenterol*. 2025; 10-97.

14. Schneider AL, Lazo M, Selvin E, Clark JM. Racial differences in nonalcoholic fatty liver disease in the U.S. population. *Obesity (Silver Spring)*. 2014;22:292-299.

15. Williams CD, Stengel J, Asike MI, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. *Gastroenterology*. 2011;140:124-131.

16. Caldwell SH, Harris DM, Patrie JT, Hespenheide EE. Is NASH underdiagnosed among African Americans?. *Am J Gastroenterol*. 2002;97:1496-1500.

17. Díaz LA, Lazarus JV, Fuentes-López E, et al. Disparities in steatosis prevalence in the United States by Race or Ethnicity according to the 2023 criteria. *Commun Med (Lond)*. 2024;4:219.

18. Latif S, Ahsan T. Prevalence of Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD) in Persons with Obesity and Type 2 Diabetes Mellitus: A Cross-sectional Study. *Euroasian J Hepatogastroenterol*. 2024;14:129-133.

19. Truong E, Yeo YH, Cook-Wiens G, et al. Nonalcoholic fatty liver disease prevalence and severity in Asian Americans from the national health and nutrition examination surveys 2017-2018. *Hepatol Commun*. 2022;6:2253-2261.

20. Le MH, Yeo YH, Zou B, et al. Forecasted 2040 global prevalence of nonalcoholic fatty liver disease using hierarchical bayesian approach. *Clin Mol Hepatol*. 2022;28:841-850.

21. Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. *Hepatology*. 2018;67:123-133.
22. Le MH, Yeo YH, Cheung R, Wong VW, Nguyen MH. Ethnic influence on nonalcoholic fatty liver disease prevalence and lack of disease awareness in the United States, 2011-2016. *J Intern Med.* 2020;287:711-722.

23. Issa G, Shang Y, Strandberg R, Hagström H, Wester A. Cause-specific mortality in 13,099 patients with metabolic dysfunction-associated steatotic liver disease in Sweden. *J Hepatol.* 2025.

24. Hagström H, Adams LA, Allen AM, et al. The future of International Classification of Diseases coding in steatotic liver disease: An expert panel Delphi consensus statement. *Hepatol Commun.* 2024;8:e0386.

25. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. *Nat Med.* 2018;24:908-922.

26. Huh Y, Cho YJ, Nam GE. Recent Epidemiology and Risk Factors of Nonalcoholic Fatty Liver Disease. *J Obes Metab Syndr.* 2022;31:17-27.

27. Kim HK, Bae SJ, Lee MJ, et al. Association of Visceral Fat Obesity, Sarcopenia, and Myosteatosis with Non-Alcoholic Fatty Liver Disease without Obesity. *Clin Mol Hepatol.* 2023;29:987-1001.

28. Kim D, Wijarnpreecha K, Sandhu KK, Cholankeril G, Ahmed A. Sarcopenia in nonalcoholic fatty liver disease and all-cause and cause-specific mortality in the United States. *Liver Int.* 2021;41:1832-1840.

29. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. *Hepatology.* 2018;67:328-357.

30. Rutledge SM, Soper ER, Ma N, et al. Association of HSD17B13 and PNPLA3 With Liver Enzymes and Fibrosis in Hispanic/Latino Individuals of Diverse Genetic Ancestries. *Clin Gastroenterol Hepatol.* 2023;21:2578-2587.

31. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. *Nat Genet.* 2008;40:1461-1465.

32. 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. *J Am Coll Cardiol.*
2019;73:948-963.

33. Møller S, Kimer N, Hove JD, Barløse M, Gluud LL. Cardiovascular disease and metabolic dysfunction-associated steatotic liver disease: pathophysiology and diagnostic aspects. *Eur J Prev Cardiol.* 2025.

34. Castillo-Núñez Y, Almeda-Valdes P, González-Gálvez G, Arechavaleta-Granell MDR. Metabolic dysfunction-associated steatotic liver disease and atherosclerosis. *Curr Diab Rep.* 2024;24:158-166.

35. Zhu M, Lei L, Zhu Z, et al. Excess TNF-α in the blood activates monocytes with the potential to directly form cholesteryl ester-laden cells. *Acta Biochim Biophys Sin (Shanghai)*. 2015;47:899-907.

36. Rafaqat S, Gluscevic S, Mercantepe F, Rafaqat S, Klisic A. Interleukins: Pathogenesis in Non-Alcoholic Fatty Liver Disease. *Metabolites*. 2024;14:153.

37. Duan Y, Pan X, Luo J, et al. Association of Inflammatory Cytokines With Non-Alcoholic Fatty Liver Disease. *Front Immunol*. 2022;13:880298.

38. Ngwa DN, Pathak A, Agrawal A. IL-6 regulates induction of C-reactive protein gene expression by activating STAT3 isoforms. *Mol Immunol.* 2022;146:50-56.

39. Medina-Leyte DJ, Zepeda-García O, Domínguez-Pérez M, González-Garrido A, Villarreal-Molina T, Jacobo-Albavera L. Endothelial Dysfunction, Inflammation and Coronary Artery Disease: Potential Biomarkers and Promising Therapeutical Approaches. *Int J Mol Sci.* 2021;22:3850.

40. Pacana T, Cazanave S, Verdianelli A, et al. Dysregulated Hepatic Methionine Metabolism Drives Homocysteine Elevation in Diet-Induced Nonalcoholic Fatty Liver Disease. *PLoS One*. 2015;10:e0136822.

41. Pastore A, Alisi A, di Giovamberardino G, et al. Plasma levels of homocysteine and cysteine increased in pediatric NAFLD and strongly correlated with severity of liver damage. *Int J Mol Sci.* 2014;15:21202-21214.

42. Distrutti E, Mencarelli A, Santucci L, et al. The methionine connection: homocysteine and
hydrogen sulfide exert opposite effects on hepatic microcirculation in rats. *Hepatology*.
2008;47:659-667.

43. Batty M, Bennett MR, Yu E. The Role of Oxidative Stress in Atherosclerosis. *Cells*.
2022;11:3843.

44. Vanhoutte PM. Endothelial dysfunction: the first step toward coronary
arteriosclerosis. *Circ J*. 2009;73:595-601.

45. Krüger-Genge A, Blocki A, Franke RP, Jung F. Vascular Endothelial Cell Biology: An
Update. *Int J Mol Sci*. 2019;20:4411.

46. Vairappan B. Endothelial dysfunction in cirrhosis: Role of inflammation and
oxidative stress. *World J Hepatol*. 2015;7:443-459.

47. Gunawardena T, Merinopoulos I, Wickramarachchi U, Vassiliou V, Eccleshall S.
Endothelial Dysfunction and Coronary Vasoreactivity - A Review of the History,
Physiology, Diagnostic Techniques, and Clinical Relevance. *Curr Cardiol Rev.*
2021;17:85-100.

48. Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. *Hepatology*.
2010;52:774-788.

49. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. *Gastroenterology*.
2012;142:711-725.e6.

50. Aedh AI, Alshahrani MS, Huneif MA, Pryme IF, Oruch R. A Glimpse into Milestones of Insulin Resistance and an Updated Review of Its Management. *Nutrients*. 2023;15:921.

51. Zhao J, Wu Y, Rong X, Zheng C, Guo J. Anti-Lipolysis Induced by Insulin in Diverse Pathophysiologic Conditions of Adipose Tissue. *Diabetes Metab Syndr Obes*. 2020;13:1575-1585.

52. Pal SC, Méndez-Sánchez N. Insulin resistance and adipose tissue interactions as the
cornerstone of metabolic (dysfunction)-associated fatty liver disease pathogenesis. *World J Gastroenterol.* 2023;29:3999-4008.

53. Kosmas CE, Bousvarou MD, Kostara CE, Papakonstantinou EJ, Salamou E, Guzman E. Insulin resistance and cardiovascular disease. *J Int Med Res.* 2023;51:3000605231164548.

54. Sakurai Y, Kubota N, Yamauchi T, Kadowaki T. Role of Insulin Resistance in MAFLD. *Int J Mol Sci.* 2021;22:4156.

55. Berardo C, Di Pasqua LG, Cagna M, Richelmi P, Vairetti M, Ferrigno A. Nonalcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: Current Issues and Future Perspectives in Preclinical and Clinical Research. *Int J Mol Sci.* 2020;21:9646.

56. Lim S, Meigs JB. Links between ectopic fat and vascular disease in humans. *Arterioscler Thromb Vasc Biol.* 2014;34:1820-1826.

57. D'Oria R, Genchi VA, Caccioppoli C, et al. Impact of Dysfunctional Adipose Tissue Depots on the Cardiovascular System. *Int J Mol Sci.* 2022;23:14296.

58. Han H, Jiang Y, Wang M, et al. Intestinal dysbiosis in nonalcoholic fatty liver disease (NAFLD): focusing on the gut-liver axis. *Crit Rev Food Sci Nutr.* 2023;63:1689-1706.

59. Zhen J, Zhou Z, He M, et al. The gut microbial metabolite trimethylamine N-oxide and cardiovascular diseases. *Front Endocrinol (Lausanne)*. 2023;14:1085041.

60. Querio G, Antoniotti S, Geddo F, Levi R, Gallo MP. Modulation of Endothelial Function by TMAO, a Gut Microbiota-Derived Metabolite. *Int J Mol Sci.* 2023;24:5806.

61. Cherubini A, Casirati E, Tomasi M, Valenti L. PNPLA3 as a therapeutic target for fatty liver disease: the evidence to date. *Expert Opin Ther Targets*. 2021;25:1033-1043.

62. Shen JH, Li YL, Li D, Wang NN, Jing L, Huang YH. The rs738409 (I148M) variant of the PNPLA3 gene and cirrhosis: a meta-analysis. *J Lipid Res.* 2015;56:167-175.

63. Luukkonen PK, Qadri S, Lehtimäki TE, et al. The PNPLA3-I148M Variant Confers an Antiatherogenic Lipid Profile in Insulin-resistant Patients. *J Clin Endocrinol Metab.*
2021;106:e300-e315.

64. Huang G, Wallace DF, Powell EE, Rahman T, Clark PJ, Subramaniam VN. Gene Variants Implicated in Steatotic Liver Disease: Opportunities for Diagnostics and Therapeutics. *Biomedicines*. 2023;11:2809.

65. Dongiovanni P, Petta S, Maglio C, et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. *Hepatology*. 2015;61:506-514.

66. Lewis JH, Zimmerman HJ. Drug-induced liver disease. *Med Clin North Am.* 1989;73:775-792.

67. Kneeman JM, Misdraji J, Corey KE. Secondary causes of nonalcoholic fatty liver disease. *Therap Adv Gastroenterol*. 2012;5:199-207.

68. Brown AJ. Viral hepatitis and fatty liver disease: how an unwelcome guest makes pâté of the host. *Biochem J*. 2008;416:e15-e17.

69. Burkhead JL, Gray LW, Lutsenko S. Systems biology approach to Wilson's disease. *Biometals*. 2011;24:455-466.

70. Crawford DHG, Ross DGF, Jaskowski LA, et al. Iron depletion attenuates steatosis in a mouse model of non-alcoholic fatty liver disease: Role of iron-dependent pathways. *Biochim Biophys Acta Mol Basis Dis*. 2021;1867:166142.

71. Aigner E, Datz C. Iron perturbations in human non-alcoholic fatty liver disease (NAFLD): clinical relevance and molecular mechanisms. 2008: 213-220.

72. Yeh MM, Brunt EM. Pathology of fatty liver: differential diagnosis of non-alcoholic fatty liver disease. *DiagnostiC histopathology*. 2008;14:586-597.

73. Sung KC, Yoo TK, Lee MY, Byrne CD, Zheng MH, Targher G. Comparative Associations of Nonalcoholic Fatty Liver Disease and Metabolic Dysfunction-Associated Fatty Liver Disease With Coronary Artery Calcification: A Cross-Sectional and Longitudinal Cohort Study. *Arterioscler Thromb Vasc Biol*. 2023;43:482-491.
74. Ma W, Wu W, Wen W, et al. Association of NAFLD with cardiovascular disease and all-cause mortality: a large-scale prospective cohort study based on UK Biobank. *Ther Adv Chronic Dis.* 2022;13:20406223221122478.

75. Shang Y, Nasr P, Widman L, Hagström H. Risk of cardiovascular disease and loss in life expectancy in NAFLD. *Hepatology*. 2022;76:1495-1505.

76. Mantovani A, Csermely A, Petracca G, et al. Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis. *Lancet Gastroenterol Hepatol.* 2021;6:903-913.

77. Chang Y, Cho J, Cho YK, et al. Alcoholic and Nonalcoholic Fatty Liver Disease and Incident Hospitalization for Liver and Cardiovascular Diseases. *Clin Gastroenterol Hepatol.* 2020;18:205-215.e7.

78. Alexander M, Loomis AK, van der Lei J, 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. *BMJ*. 2019;367:j5367.

79. Allen AM, Therneau TM, Mara KC, et al. Women With Nonalcoholic Fatty Liver Disease Lose Protection Against Cardiovascular Disease: A Longitudinal Cohort Study. *Am J Gastroenterol*. 2019;114:1764-1771.

80. Hwang YC, Ahn HY, Park SW, Park CY. Nonalcoholic Fatty Liver Disease Associates With Increased Overall Mortality and Death From Cancer, Cardiovascular Disease, and Liver Disease in Women but Not Men. *Clin Gastroenterol Hepatol.* 2018;16:1131-1137.e5.

81. Zou Y, Li X, Wang C, et al. Association between non-alcoholic fatty liver disease and peripheral artery disease in patients with type 2 diabetes. *Intern Med J.* 2017;47:1147-1153.

82. Sinn DH, Cho SJ, Gu S, et al. Persistent Nonalcoholic Fatty Liver Disease Increases Risk for Carotid Atherosclerosis. *Gastroenterology*. 2016;151:481-488.e1.

83. Lazo M, Hernández R, Bonekamp S, et al. Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study. *BMJ*. 2011;343:d6891.

84. Simon TG, Ebrahimi F, Roelstraete B, Hagström H, Sundström J, Ludvigsson JF. Incident cardiac arrhythmias associated with metabolic dysfunction-associated steatotic
liver disease: a nationwide histology cohort study. *Cardiovasc Diabetol*. 2023;22:343.

85. Cai X, Zheng S, Liu Y, Zhang Y, Lu J, Huang Y. Nonalcoholic fatty liver disease is associated with increased risk of atrial fibrillation. *Liver Int*. 2020;40:1594-1600.

86. Mantovani A, Dauriz M, Sandri D, et al. Association between non-alcoholic fatty liver disease and risk of atrial fibrillation in adult individuals: An updated meta-analysis. *Liver Int*. 2019;39:758-769.

87. Hung CS, Tseng PH, Tu CH, et al. Nonalcoholic Fatty Liver Disease Is Associated With QT Prolongation in the General Population. *J Am Heart Assoc*. 2015;4:e001820.

88. Yong JN, Ng CH, Lee CW, et al. Non-alcoholic fatty liver disease association with structural heart, systolic and diastolic dysfunction: a meta-analysis. *Hepatol Int*. 2022;16:269-281.

89. VanWagner LB, Wilcox JE, Colangelo LA, et al. Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: A population-based study. *Hepatology*. 2015;62:773-783.

90. JY, Park SK, Ryoo JH, et al. Effect of non-alcoholic fatty liver disease on left ventricular diastolic function and geometry in the Korean general population. *Hepatol Res*. 2017;47:522-532.

91. Hao QY, Zeng YH, Lin Y, et al. Observational and genetic association of non-alcoholic fatty liver disease and calcific aortic valve disease. *Front Endocrinol (Lausanne)*. 2024;15:1421642.

92. Mantovani A, Pernigo M, Bergamini C, et al. Heart valve calcification in patients with type 2 diabetes and nonalcoholic fatty liver disease. *Metabolism*. 2015;64:879-887.

93. Bonapace S, Valbusa F, Bertolini L, et al. Nonalcoholic fatty liver disease is associated with aortic valve sclerosis in patients with type 2 diabetes mellitus. *PLoS One*. 2014;9:e88371.

94. Li G, Peng Y, Chen Z, Li H, Liu D, Ye X. Bidirectional Association between Hypertension and NAFLD: A Systematic Review and Meta-Analysis of Observational Studies. *Int J Endocrinol*. 2022;2022:8463640.
95. Bonnet F, Gastaldelli A, Pihan-Le Bars F, et al. Gamma-glutamyltransferase, fatty liver index and hepatic insulin resistance are associated with incident hypertension in two longitudinal studies. *J Hypertens*. 2017;35:493-500.

96. Ryoo JH, Suh YJ, Shin HC, Cho YK, Choi JM, Park SK. Clinical association between non-alcoholic fatty liver disease and the development of hypertension. *J Gastroenterol Hepatol*. 2014;29:1926-1931.

97. Lau K, Lorbeer R, Haring R, et al. The association between fatty liver disease and blood pressure in a population-based prospective longitudinal study. *J Hypertens*. 2010;28:1829-1835.

98. Roderburg C, Krieg S, Krieg A, et al. Non-Alcoholic Fatty Liver Disease (NAFLD) and risk of new-onset heart failure: a retrospective analysis of 173,966 patients. *Clin Res Cardiol*. 2023;112:1446-1453.

99. 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;71:1867-1875.

100. Fudim M, Zhong L, Patel KV, et al. Nonalcoholic Fatty Liver Disease and Risk of Heart Failure Among Medicare Beneficiaries. *J Am Heart Assoc*. 2021;10:e021654.

101. Roh JH, Park JH, Lee H, et al. Higher fatty liver index is associated with increased risk of new onset heart failure in healthy adults: a nationwide population-based study in Korea. *BMC Cardiovasc Disord*. 2020;20:204.

102. Larkin H. What to Know About PREVENT, the AHA's New Cardiovascular Disease Risk Calculator. *JAMA*. 2024;331:277-279.

103. Chew NWS, Mehta A, Goh RSJ, et al. Cardiovascular-Liver-Metabolic Health: Recommendations in Screening, Diagnosis, and Management of Metabolic Dysfunction-Associated Steatotic Liver Disease in Cardiovascular Disease via Modified Delphi Approach. *Circulation*. 2025;151:98-119.

104. Noureddin M, Mena E, Vuppalanchi R, et al. Increased accuracy in identifying NAFLD with advanced fibrosis and cirrhosis: independent validation of the Agile 3+ and 4 scores.
105. Avan A, Tavakoly Sany SB, Ghayour-Mobarhan M, Rahimi HR, Tajfard M, Ferns G. Serum C-reactive protein in the prediction of cardiovascular diseases: Overview of the latest clinical studies and public health practice. *J Cell Physiol.* 2018;233:8508-8525.

106. van Son KC, Te Nijenhuis-Noort LC, Boone SC, et al. Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in a middle-aged population with overweight and normal liver enzymes, and diagnostic accuracy of noninvasive proxies. *Medicine* (Baltimore). 2024;103:e34934.

107. Portillo-Sanchez P, Bril F, Maximos M, et al. High Prevalence of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes Mellitus and Normal Plasma Aminotransferase Levels. *J Clin Endocrinol Metab.* 2015;100:2231-2238.

108. Li Q, Dhyani M, Grajo JR, Sirlin C, Samir AE. Current status of imaging in nonalcoholic fatty liver disease. *World J Hepatol.* 2018;10:530-542.

109. Pirmoazen AM, Khurana A, El Kaffas A, Kamaya A. Quantitative ultrasound approaches for diagnosis and monitoring hepatic steatosis in nonalcoholic fatty liver disease. *Theranostics*. 2020;10:4277-4289.

110. McDonald N, Eddowes PJ, Hodson J, et al. Multiparametric magnetic resonance imaging for quantitation of liver disease: a two-centre cross-sectional observational study. *Sci Rep.* 2018;8:9189.

111. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). *Obes Facts*. 2024;17:374-444.

112. Cusi K, Isaacs S, Barb D, et al. American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: Co-Sponsored by the American Association for the Study of Liver Diseases (AASLD). *Endocr Pract.* 2022;28:528-562.
113. Kang YW, Baek YH, Lee JH, et al. Assessing the utility of acoustic radiation force impulse in the evaluation of non-alcoholic fatty liver disease with severe obesity or steatosis. Diagnostics. 2024;14(11):1083.

114. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. *Gastroenterology*. 2015;149:389-97.e10.

115. Kanwal F, Shubrook JH, Adams LA, et al. Clinical Care Pathway for the Risk Stratification and Management of Patients With Nonalcoholic Fatty Liver Disease. *Gastroenterology*. 2021;161:1657-1669.

116. Allen AM, Charlton M, Cusi K, et al. Guideline-based management of metabolic dysfunction-associated steatotic liver disease in the primary care setting. *Postgrad Med*. 2024;136:229-245.

117. Unalp-Arida A, Ruhl CE. Liver fibrosis scores predict liver disease mortality in the United States population. *Hepatology*. 2017;66:84-95.

118. Lee J, Vali Y, Boursier J, et al. Prognostic accuracy of FIB-4, NAFLD fibrosis score and APRI for NAFLD-related events: A systematic review. *Liver Int*. 2021;41:261-270.

119. Long MT, Noureddin M, Lim JK. AGA Clinical Practice Update: Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Lean Individuals: Expert Review. *Gastroenterology*. 2022;163:764-774.e1.

120. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. *Hepatology*. 2023;77:1797-1835.

121. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update. *J Hepatol*. 2021;75:659-689.

122. McPherson S, Hardy T, Dufour JF, et al. Age as a Confounding Factor for the Accurate Non-Invasive Diagnosis of Advanced NAFLD Fibrosis. *Am J Gastroenterol*. 2017;112:740-751.
123. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the Management of Non-Alcoholic Fatty Liver Disease. *Obes Facts*. 2016;9:65-90.

124. Stefan N, Häring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. *Lancet Diabetes Endocrinol*. 2019;7:313-324.

125. Singh DK, Sakhuja P, Malhotra V, Gondal R, Sarin SK. Independent predictors of steatohepatitis and fibrosis in Asian Indian patients with non-alcoholic steatohepatitis. *Dig Dis Sci*. 2008;53:1967-1976.

126. Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. *Hepatology*. 2010;51:121-129.

127. Stine JG, Schreibman IR, Faust AJ, et al. NASHFit: A randomized controlled trial of an exercise training program to reduce clotting risk in patients with NASH. *Hepatology*. 2022;76:172-185.

128. Zhang HJ, He J, Pan LL, et al. Effects of Moderate and Vigorous Exercise on Nonalcoholic Fatty Liver Disease: A Randomized Clinical Trial. *JAMA Intern Med*. 2016;176:1074-1082.

129. Bacchi E, Negri C, Targher G, et al. Both resistance training and aerobic training reduce hepatic fat content in type 2 diabetic subjects with nonalcoholic fatty liver disease (the RAED2 Randomized Trial). *Hepatology*. 2013;58:1287-1295.

130. Lechner K, McKenzie AL, Kränkel N, et al. High-Risk Atherosclerosis and Metabolic Phenotype: The Roles of Ectopic Adiposity, Atherogenic Dyslipidemia, and Inflammation. *Metab Syndr Relat Disord*. 2020;18:176-185.

131. Fiuza-Luces C, Santos-Lozano A, Joyner M, et al. Exercise benefits in cardiovascular disease: beyond attenuation of traditional risk factors. *Nat Rev Cardiol*. 2018;15:731-743.

132. Gepner Y, Shelef I, Schwarzfuchs D, et al. Effect of Distinct Lifestyle Interventions on Mobilization of Fat Storage Pools: CENTRAL Magnetic Resonance Imaging Randomized
Controlled Trial. Circulation. 2018;137:1143-1157.

133. Oh S, So R, Shida T, et al. High-Intensity Aerobic Exercise Improves Both Hepatic Fat Content and Stiffness in Sedentary Obese Men with Nonalcoholic Fatty Liver Disease. *Sci Rep*. 2017;7:43029.

134. Sung KC, Ryu S, Lee JY, Kim JY, Wild SH, Byrne CD. Effect of exercise on the development of new fatty liver and the resolution of existing fatty liver. *J Hepatol*. 2016;65:791-797.

135. Piercy KL, Troiano RP, Ballard RM, et al. The Physical Activity Guidelines for Americans. JAMA. 2018;320:2020-2028.

136. Fletcher GF, Landolfo C, Niebauer J, Ozemek C, Arena R, Lavie CJ. Promoting Physical Activity and Exercise: JACC Health Promotion Series. *J Am Coll Cardiol*. 2018;72:1622-1639.

137. Niederseer D, Wernly B, Aigner E, Stickel F, Datz C. NAFLD and Cardiovascular Diseases: Epidemiological, Mechanistic and Therapeutic Considerations. *J Clin Med*. 2021;10:467.

138. Barrera F, George J. The role of diet and nutritional intervention for the management of patients with NAFLD. *Clin Liver Dis*. 2014;18:91-112.

139. Liangpunsakul S, Chalasani N. What should we recommend to our patients with NAFLD regarding alcohol use?. *Am J Gastroenterol*. 2012;107:976-978.

140. Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. *Hepatology*. 2010;51:1972-1978.

141. Marti-Aguado D, Calleja JL, Vilar-Gomez E, et al. Low-to-moderate alcohol consumption is associated with increased fibrosis in individuals with metabolic dysfunction-associated steatotic liver disease. *J Hepatol*. 2024;81:930-940.

142. Petta S, Targher G, Romeo S, et al. The first MASH drug therapy on the horizon: Current perspectives of resmetirom. *Liver Int*. 2024;44:1526-1536.
143. Harrison SA, Bedossa P, Guy CD, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. *N Engl J Med.* 2024;390:497-509.

144. Pastori D, Polimeni L, Baratta F, Pani A, Del Ben M, Angelico F. The efficacy and safety of statins for the treatment of non-alcoholic fatty liver disease. *Dig Liver Dis.* 2015;47:4-11.

145. Oesterle A, Laufs U, Liao JK. Pleiotropic Effects of Statins on the Cardiovascular System. *Circ Res.* 2017;120:229-243.

146. Zhou XD, Kim SU, Yip TC, et al. Long-term liver-related outcomes and liver stiffness progression of statin usage in steatotic liver disease. *Gut.* 2024;73:1883-1892.

147. Schreiner AD, Zhang J, Petz CA, et al. Statin prescriptions and progression of advanced fibrosis risk in primary care patients with MASLD. *BMJ Open Gastroenterol.* 2024;11:e001404.

148. Tarar ZI, Farooq U, Inayat F, et al. Statins decrease the risk of hepatocellular carcinoma in metabolic dysfunction-associated steatotic liver disease: A systematic review and meta-analysis. *World J Exp Med.* 2024;14:98543.

149. Ayada I, van Kleef LA, Zhang H, et al. Dissecting the multifaceted impact of statin use on fatty liver disease: a multidimensional study. *EBioMedicine*. 2023;87:104392.

150. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. *J Am Coll Cardiol.* 2019;73:e285-e350.

151. Averna M. The effect of ezetimibe on NAFLD. Atheroscler Suppl. 2015;17:27-34.

152. Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. *Eur Heart J.* 2020;41:255-323.

153. Takeshita Y, Takamura T, Honda M, et al. The effects of ezetimibe on non-alcoholic fatty
liver disease and glucose metabolism: a randomised controlled trial. *Diabetologia*.
2014;57:878-890.

154. Loomba R, Sirlin CB, Ang B, et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). *Hepatology*.
2015;61:1239-1250.

155. Theocharidou E, Papademetriou M, Reklou A, Sachinidis A, Boutari C, Giouleme O. The Role of PCSK9 in the Pathogenesis of Non-alcoholic Fatty Liver Disease and the Effect of PCSK9 Inhibitors. *Curr Pharm Des*. 2018;24:3654-3657.

156. Shafiq M, Walmann T, Nutalapati V, Gibson C, Zafar Y. Effects of proprotein convertase subtilisin/kexin type-9 inhibitors on fatty liver. *World J Hepatol*.
2020;12:1258-1266.

157. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. *N Engl J Med*. 2017;376:1713-1722.

158. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. *N Engl J Med*. 2018;379:2097-2107.

159. Newsome P, Francque S, Harrison S, et al. Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. *Aliment Pharmacol Ther*. 2019;50:193-203.

160. Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. *Lancet*. 2016;387:679-690.

161. Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. *N Engl J Med*. 2024;391:299-310.

162. Sanyal AJ, Bedossa P, Fraessdorf M, et al. A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. *N Engl J Med*. 2024;391:311-319.

163. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 Trial of Semaglutide in Metabolic
Dysfunction-Associated Steatohepatitis. *N Engl J Med.* 2025;392:2089-2099.

164. Cusi K, Orsak B, Bril F, et al. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. *Ann Intern Med.* 2016;165:305-315.

165. Packer M. Epicardial Adipose Tissue May Mediate Deleterious Effects of Obesity and Inflammation on the Myocardium. *J Am Coll Cardiol.* 2018;71:2360-2372.

166. Jang H, Kim Y, Lee DH, et al. Outcomes of Various Classes of Oral Antidiabetic Drugs on Nonalcoholic Fatty Liver Disease. *JAMA Intern Med.* 2024;184:375-383.

167. Ng WH, Yeo YH, Kim H, et al. Renin-angiotensin-aldosterone system inhibitor use improves clinical outcomes in patients with metabolic dysfunction-associated steatotic liver diseases: Target trial emulation using real-world data. *Hepatology*. 2025;10-97.

168. Li Y, Xu H, Wu W, et al. Clinical application of angiotensin receptor blockers in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis. *Oncotarget*. 2018;9:24155-24167.

169. Simon TG, Henson J, Osganian S, et al. Daily Aspirin Use Associated With Reduced Risk For Fibrosis Progression In Patients With Nonalcoholic Fatty Liver Disease. *Clin Gastroenterol Hepatol.* 2019;17:2776-2784.e4.

170. Simon TG, Wilechansky RM, Stoyanova S, et al. Aspirin for Metabolic Dysfunction-Associated Steatotic Liver Disease Without Cirrhosis: A Randomized Clinical Trial. *JAMA*. 2024;331:920-929.

171. Laursen TL, Hagemann CA, Wei C, et al. Bariatric surgery in patients with non-alcoholic fatty liver disease - from pathophysiology to clinical effects. *World J Hepatol.* 2019;11:138-149.

172. Garg H, Aggarwal S, Shalimar, et al. Utility of transient elastography (fibroscan) and impact of bariatric surgery on nonalcoholic fatty liver disease (NAFLD) in morbidly obese patients. *Surg Obes Relat Dis.* 2018;14:81-91.

173. Aminian A, Al-Kurd A, Wilson R, et al. Association of Bariatric Surgery With Major
Adverse Liver and Cardiovascular Outcomes in Patients With Biopsy-Proven Nonalcoholic
Steatohepatitis. JAMA. 2021;326:2031-2042.

174. Verrastro O, Panunzi S, Castagneto-Gissey L, et al. Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial. Lancet. 2023;401:1786-1797.

175. Byrne CD, Targher G. NAFLD: a multisystem disease. *J Hepatol*. 2015;62:S47-S64.

176. Sebastiani G, Raggi P, Guaraldi G. Integrating the Care of Metabolic Dysfunction-associated Steatotic Liver Disease Into Cardiac Rehabilitation: A Multisystem Approach. *Can J Cardiol*. 2025.

177. Moolla A, Motohashi K, Marjot T, et al. A multidisciplinary approach to the management of NAFLD is associated with improvement in markers of liver and cardio-metabolic health. *Frontline Gastroenterol*. 2019;10:337-346.

178. Russo MW, Fix OK, Koteish AA, et al. Modeling the Hepatology Workforce in the United States: A Predicted Critical Shortage. *Hepatology*. 2020;72:1444-1454.
## Figure Legends

**Figure 1. Pathophysiological Mechanisms Linking MASLD and CVD.** This figure highlights the key pathophysiological mechanisms through which MASLD is associated with CVD. Major shared or contributing pathways include dysregulated lipid metabolism, endothelial dysfunction, oxidative stress, obesity-driven inflammation, insulin resistance, gut dysbiosis, ectopic fat accumulation, and genetic predisposition. Each segment outlines specific mediators or biomarkers implicated in the interaction between MASLD and CVD. A red upward arrow indicates an increase and a downward arrow indicates a decrease. CRP = C-reactive protein; CVD = cardiovascular disease; HDL = high-density lipoprotein; IDL = intermediate-density lipoprotein; IL-6 = interleukin-6; LDL = low-density lipoprotein; MASLD = metabolic dysfunction-associated steatotic liver disease; NF-κB = nuclear factor kappa B; PNPLA3 = patatin-like phospholipase domain-containing 3; TG = triglyceride; TNF = tumor necrosis factor; VLDL = very low density lipoprotein.

**Figure 2. The Diagnostic Approaches Employed in MASLD.** A visual summary of diagnostic methods that can be used for MASLD diagnosis. Green check marks represent advantages of the diagnostic method and red downward arrows indicate its disadvantages. ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; CT = computed tomography; FIB-4 = fibrosis-4 index; MASH = metabolic dysfunction-associated steatohepatitis; MRE = magnetic resonance elastography; MRI = magnetic resonance imaging; NAFLD = nonalcoholic fatty liver disease; NFS = NAFLD fibrosis score; US = ultrasound; VCTE = vibration-controlled transient elastography; other abbreviation as in Figure 1.

**Figure 3. Clinical Approach to MASLD Detection in Cardiology.** A stepwise clinical algorithm for detecting MASLD among cardiology patients at high risk is outlined. The initial screening uses the FIB-4 to assess fibrosis risk, followed by second-line noninvasive tests like LSM or the ELF score to stratify risk and guide follow-up or referral. ELF = Enhanced Liver Fibrosis test; FIB-4 = fibrosis-4 index; LSM = liver stiffness measurement; other abbreviation as in Figure 1.

**Figure 4. Management Strategies for Patients with MASLD.** Illustrated are the key lifestyle and pharmacologic strategies that can be used for treating these patients. CV = cardiovascular; ACEI =
angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; DASH = Dietary Approaches to Stop Hypertension; FDA = U.S. Food and Drug Administration; GLP-1 RA = glucagon-like peptide-1 receptor agonist; PCSK9i = proprotein convertase subtilisin/kexin type 9 inhibitor; SGLT2i = sodium-glucose cotransporter-2 inhibitor; T2DM = type 2 diabetes mellitus; TZD = thiazolidinedione; other abbreviations as in Figures 1 and 2.

**Figure 5. Role of Cardiologists in the Multidisciplinary Care of MASLD.** This summary box outlines the key actions cardiologists should take in caring for patients with MASLD. These include screening high-risk individuals, using noninvasive tools for fibrosis assessment, referring to hepatology as needed, monitoring low-risk patients, evaluating CV risk, prescribing evidence-based pharmacotherapy, and promoting lifestyle modifications. CV = cardiovascular; ELF = enhanced liver fibrosis; FIB-4 = fibrosis-4 index; GLP-1 RA = glucagon-like peptide-1 receptor agonist; MASLD = metabolic dysfunction-associated steatotic liver disease; SGLT-2 = sodium-glucose cotransporter 2; T2DM = type 2 diabetes mellitus; VCTE = vibration-controlled transient elastography.

**Central Illustration. Metabolic Dysfunction-Associated Steatotic Liver Disease and Cardiovascular Disease-A Guide for Cardiologists.** The multisystem nature of MASLD, its progression from hepatic steatosis to cirrhosis, and the key mechanisms linking MASLD to CVD are depicted. Current approaches to diagnosis, risk stratification, and management relevant to cardiometabolic care are summarized. ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; ASCVD = atherosclerotic cardiovascular disease; CT = computed tomography; CVD = cardiovascular disease; CV = cardiovascular; FDA = U.S. Food and Drug Administration; FIB-4 = fibrosis-4 index; GLP-1 = glucagon-like peptide-1; MASLD = metabolic dysfunction-associated steatotic liver disease; MRE = magnetic resonance elastography; MRI = magnetic resonance imaging; NFS = NAFLD fibrosis score; PREVENT = Predicting Risk of Cardiovascular Disease Events; SCORE2-SCORE2OP = Systematic Coronary Risk Evaluation 2-Systematic Coronary Risk Evaluation 2-Older Persons; SGLT2i = sodium-glucose cotransporter 2 inhibitor; VCTE = vibration-controlled transient elastography.
<table><caption>Table 1: Summary of Studies Investigating the Association Between MASLD/MASH and CVD.</caption><thead><tr><th>Author, Year</th><th>Study Design</th><th>Study Settings</th><th>Patient Population</th><th>Sample Size (n)</th><th>MASLD Diagnosis</th><th>Objectives</th><th>Covariates Adjusted</th><th>Outcomes</th><th>Effect Size (RR, OR, HR, MD), 95% CI</th></tr></thead><tbody><tr><td colspan="10">Atherosclerotic Disease</td></tr><tr><td rowspan="2">Sung et al. 2023 (73)</td><td rowspan="2">Cross-sectional and longitudinal cohort Study</td><td rowspan="2">South Korea</td><td rowspan="2">Participants who underwent health examinations for the assessment of fatty liver and CAC</td><td rowspan="2">162,180 (Cross-sectional study) 34,233 (Longitudinal cohort study)</td><td rowspan="2">US or CT</td><td rowspan="2">To examine associations between MASLD and the risk of having or developing CAC</td><td rowspan="2">Age, sex, education level, smoking history, exercise, LDL, prior history of CAD, and use of lipid-lowering medications</td><td>Association between MASLD and presence of CAC (cross-sectional analysis)</td><td>aOR: 1.34 (1.29 to 1.39) P &lt; 0.05</td></tr><tr><td>Association between MASLD and incident CAC (longitudinal analysis)</td><td>aHR: 1.68 (1.43 to 1.99) P &lt; 0.05</td></tr><tr><td rowspan="2">Ma et al. 2022 (74)</td><td rowspan="2">Prospective cohort study</td><td rowspan="2">United Kingdom</td><td rowspan="2">Adults aged 40–69 years, free of baseline CVD and chronic liver disease</td><td rowspan="2">215,245</td><td rowspan="2">FLI</td><td rowspan="2">To investigate the link between MASLD and adverse CVD outcomes</td><td rowspan="2">Age, sex, ethnicity, smoking status, TC, diabetes, and HTN</td><td>Association between MASLD and AMI mortality</td><td>aHR: 1.58 (1.19–2.11) P&lt;0.01</td></tr><tr><td>Association between MASLD and stroke mortality</td><td>aHR: 1.18 (0.85–1.64) P= 0.32</td></tr><tr><td rowspan="2">Shang et al. 2022 (75)</td><td rowspan="2">Retrospective cohort study</td><td rowspan="2">Sweden</td><td rowspan="2">Adults ≥18 years with MASLD and cardiometabolic risk factors</td><td rowspan="2">106, 336</td><td rowspan="2">ICD-9/10 codes</td><td rowspan="2">To assess the association between MASLD and CV outcomes compared with the general population</td><td rowspan="2">Matched for age, sex, municipality, and HTN; adjusted for T2DM, dyslipidemia, obesity, and COPD</td><td>Association between MASLD and fatal CVD events</td><td>aHR:1.20 (0.98–1.42) P&gt;0.05</td></tr><tr><td>Association between MASLD and nonfatal CVD events</td><td>aHR: 3.71 (3.29 to 4.17) P &lt; 0.05</td></tr><tr><td>Mantovani et al. 2021 (76)</td><td>Meta-analysis</td><td>Asia, Europe, the United States, and Egypt</td><td>Adults (≥18 years) with and without MASLD, excluding those with significant alcohol consumption or other causes of liver disease</td><td>5,802,226</td><td>Imaging, ICD-9/10 codes, or liver biopsy</td><td>To assess the long-term risk of fatal and nonfatal CVD events associated with MASLD</td><td>Age, sex, smoking status, adiposity measures, SBP, or HTN status, lipid profile, and glycemic status (preexisting diabetes, FBG, or HbA1c levels)</td><td>Association between MASLD and risk of fatal or nonfatal CVD events</td><td>aHR: 1.31 (1.31 to 1.61) P &lt; 0.05</td></tr></tbody></table>
<table><tr><td>Chang et al, 2020 (77)</td><td>Prospective cohort study</td><td>South Korea</td><td>Individuals with and without MASLD, excluding those with other causes of liver disease</td><td>218,030</td><td>US</td><td>To assess the risk of CVD hospitalization in patients with MASLD</td><td>Age, sex, BMI, smoking, physical activity, educational level, total calorie intake, family history of CVD, diabetes, HTN, LDL, medications, plasma high sensitivity CRP, HOMA-IR</td><td>Association between MASLD and CVD hospitalization for ischemic heart disease or ischemic stroke</td><td>aHR: 1.05 (0.89 to 1.23) P > 0.05</td></tr><tr><td>Alexander et al, 2019 (78)</td><td>Retrospective cohort study</td><td>Italy, Spain, and the Netherlands</td><td>Adults with MASLD/MASH from 4 European primary care databases</td><td>120,795</td><td>ICD/Read/ICPC codes</td><td>To assess the risk of incident AMI and stroke in people with MASLD, compared with matched controls</td><td>Age, sex, smoking, T2DM, SBP, TC, statin use, and HTN</td><td>Risk of incident AMI in patients with MASLD<br>Risk of incident stroke in patients with MASLD</td><td>aHR: 1.01 (0.91 to 1.12) P = 0.12<br>aHR: 1.04 (0.99 to 1.09) P = 0.92</td></tr><tr><td>Allen et al, 2019 (79)</td><td>Retrospective cohort study</td><td>United States</td><td>Adults diagnosed with MASLD</td><td>19,078</td><td>ICD-9 codes</td><td>To examine whether female sex remains a protective factor against CVD in MASLD</td><td>Age, sex, county</td><td>To assess the association between MASLD and CV events in women</td><td>aHR: 0.90 (0.74 to 1.08) P = 0.25</td></tr><tr><td>Hwang et al, 2018 (80)</td><td>Prospective cohort study</td><td>South Korea</td><td>Adults aged 20-94 years undergoing health screening, with cardiometabolic risk factor assessment</td><td>318,224</td><td>US</td><td>To assess the link between MASLD and CVD mortality in men and women</td><td>Age, sex, BMI, smoking status, alcohol consumption, physical activity, diabetes, HTN, hypercholesterolemia</td><td>Association between MASLD and CVD mortality in men<br>Association between MASLD and CVD mortality in women</td><td>aHR: 1.09 (0.82 to 1.44) P = 0.56<br>aHR: 1.63 (1.00 to 2.66) P = 0.05</td></tr><tr><td>Zou et al, 2017 (81)</td><td>Cross-sectional study</td><td>China</td><td>Patients aged ≥40 years with T2DM</td><td>2,646</td><td>US</td><td>To explore the association between MASLD and PAD in patients with T2DM</td><td>Age, gender, education, smoking status, use of insulin or oral antidiabetic medication, BMI, FPG, SBP, TG, and TC</td><td>Association between MASLD and PAD</td><td>aOR: 1.49 (1.12 to 2.00) P = 0.009</td></tr><tr><td>Sinn et al, 2016 (82)</td><td>Retrospective cohort study</td><td>South Korea</td><td>Males with abdominal and carotid US performed at least 1 year apart</td><td>8,020</td><td>US</td><td>This study assessed the longitudinal association between MASLD and the onset of SCA</td><td>Age, smoking, alcohol consumption, BMI, weight change, SBP, use of antihypertensive and lipid-lowering medications, FPG, use of hypoglycemic medications, LDL, HDL, TG</td><td>Risk of SCA in MASLD</td><td>aHR: 0.91 (0.80 to 1.03) P = 0.12</td></tr></table>
<table><tbody><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>level</td><td>Risk of SCA in patients with high FIB-4 score</td><td>aHR: 1.43 (1.19 to 1.70)<br/>P &lt; 0.001</td></tr><tr><td rowspan="2">Lazo et al,<br/>2011 (83)</td><td rowspan="2">Prospective<br/>cohort study</td><td rowspan="2">United<br/>States</td><td rowspan="2">Adults aged 20-74<br/>years with<br/>cardiometabolic risk<br/>factors</td><td rowspan="2">11,371</td><td rowspan="2">US</td><td rowspan="2">To evaluate the link<br/>between MASLD/MASH<br/>and CVD mortality</td><td rowspan="2">Age, sex, BMI, ethnicity,<br/>education, smoking status,<br/>alcohol consumption, physical<br/>activity, HTN, dyslipidemia,<br/>T2DM</td><td>Association between<br/>MASLD and CVD mortality</td><td>aHR: 0.86 (0.67 to 1.12)<br/>P &gt; 0.05</td></tr><tr><td>Association between MASH<br/>and CVD mortality</td><td>aHR: 0.59 (0.29 to 1.20)<br/>P &gt; 0.05</td></tr><tr><td colspan="10"><b>Cardiac arrhythmias</b></td></tr><tr><td>Simon et al,<br/>2023 (84)</td><td>Retrospective<br/>cohort<br/>study</td><td>Sweden</td><td>Adults ≥18 years in<br/>with liver biopsy-<br/>confirmed MASLD</td><td>63,062</td><td>Liver biopsy</td><td>To examine the incidence<br/>of cardiac arrhythmias<br/>according to the presence<br/>and histological severity<br/>of MASLD</td><td>Age, sex, calendar year,<br/>county, diabetes, obesity,<br/>HTN, dyslipidemia, CKD, a<br/>family history of early CVD,<br/>education, hospitalizations,<br/>and alcohol use</td><td>Association between<br/>MASLD and incident cardiac<br/>arrhythmias</td><td>aHR: 1.30 (1.22 to 1.38)<br/>P &lt; 0.05</td></tr><tr><td>Cai et al,<br/>2020 (85)</td><td>Meta-analysis</td><td>Korea,<br/>Germany,<br/>the<br/>United<br/>States,<br/>and Italy</td><td>Adult patients (≥18<br/>years) diagnosed with<br/>MASLD and<br/>having cardiometabolic<br/>risk factors</td><td>614,673</td><td>FLI, CT, and<br/>ICD-10 code</td><td>To examine the<br/>association of MASLD<br/>with the risks of AF</td><td>Age, gender, smoking, BMI or<br/>obesity, HTN, BP or<br/>antihypertensive treatment,<br/>FPG, HbA1c or T2DM, and<br/>serum cholesterol or<br/>hypercholesterolemia</td><td>Association between<br/>MASLD and AF risk</td><td>aRR: 1.19 (1.04 to 1.31)<br/>P = 0.001</td></tr><tr><td>Mantovani et<br/>al, 2019 (86)</td><td>Meta-analysis</td><td>Europe,<br/>Asia, the<br/>United<br/>States</td><td>Adult patients (≥18<br/>years) diagnosed with<br/>MASLD and<br/>having cardiometabolic<br/>risk factors</td><td>364,919</td><td>FLI, CT, US,<br/>and<br/>ICD-9 code</td><td>To examine the<br/>association between<br/>MASLD<br/>and the risk of prevalent<br/>AF</td><td>Age, sex, BMI, HTN, T2DM,<br/>dyslipidemia, and smoking</td><td>Association between<br/>MASLD and prevalent AF</td><td>aOR: 2.07 (1.38 to 3.10)<br/>P &lt; 0.05</td></tr><tr><td>Hung et al,<br/>2015 (87)</td><td>Cross-<br/>sectional study</td><td>Taiwan</td><td>Adults ≥20 years<br/>attending routine health<br/>checkups</td><td>31,116</td><td>US</td><td>To investigate the<br/>association between<br/>MASLD and QT<br/>prolongation among the<br/>general population with<br/>or without diabetes</td><td>Age, sex, diabetes, HTN,<br/>cholesterol, HDL, TGs, AST,<br/>BMI, LV hypertrophy, a<br/>history of CAD, hypokalemia,<br/>eGFR, CRP, and smoking</td><td>Association between severe<br/>MASLD and QTC<br/>prolongation (≥440 ms) in<br/>men, Bazett's criteria</td><td>aOR: 1.87 (1.51 to 2.31)<br/>P &lt; 0.001</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Association between severe<br/>MASLD and QTC<br/>prolongation (≥440 ms) in<br/>women, Bazett's criteria</td><td>aOR: 2.28 (1.89 to 2.74)<br/>P &lt; 0.001</td></tr></tbody></table>

Cardiomyopathy
<table><tbody><tr><td>Mantovani et al, 2015 (92)</td><td>Cross-sectional study</td><td>Italy</td><td>T2DM outpatients without a history of HF, valvular heart conditions, or liver diseases</td><td>247</td><td>US</td><td>To determine the association between MASLD and valvular calcification in diabetic patients</td><td>Age, sex, WC, smoking history, HbA1c, LDL, eGFR, DBP, use of hypoglycemic, lipid-lowering, and antihypertensive drugs</td><td>Association between MASLD and valvular calcification (AVS and/or MAC)</td><td>aOR: 2.70 (1.23 to 7.38) P &lt; 0.01</td></tr><tr><td rowspan="2">Bonapace et al, 2014 (93)</td><td rowspan="2">Cross-sectional study</td><td rowspan="2">Italy</td><td rowspan="2">T2DM patients free from ischemic heart disease, valvular heart conditions, liver disorders, or excessive alcohol use</td><td rowspan="2">180</td><td rowspan="2">US</td><td rowspan="2">To investigate the association between MASLD and AVS in patients with T2DM</td><td rowspan="2">Age, sex, BMI, smoking status, daily alcohol consumption, HTN, dyslipidemia, duration of diabetes, diabetes treatment, HbA1c, and eGFR</td><td>Association between MASLD and MAC</td><td>aOR: 3.01 (1.12 to 7.99) P = 0.026</td></tr><tr><td>Association between MASLD and AVS</td><td>aOR: 2.65 (1.07 to 6.31) P = 0.035</td></tr><tr><td colspan="11" style="text-align: left; font-weight: bold;">Hypertension</td></tr><tr><td>Li et al, 2022 (94)</td><td>Meta-analysis</td><td>Asia, Europe, and the United States</td><td>Participants aged ≥18 years with cardiometabolic risk factors</td><td>86,342</td><td>US, CT, and surrogate scores (FLI, hepatic steatosis index, and comprehensive MASLD score)</td><td>To examine the association between MASLD and HTN</td><td>Age and sex</td><td>Association between MASLD and the incidence of HTN</td><td>aHR: 1.55 (1.29 to 1.87) P &lt; 0.01</td></tr><tr><td>Bonnet et al, 2017 (95)</td><td>Prospective cohort study</td><td>France</td><td>Adults aged 30–65 years without baseline HTN</td><td>2,565</td><td>FLI</td><td>To evaluate whether the FLI predicts incident HTN in normotensive individuals</td><td>Age, sex, smoking, FPG, alcohol intake, and HOMA-IR</td><td>Association between FLI and incident HTN</td><td>aOR: 1.44 (1.20 to 1.74) P = 0.0001</td></tr><tr><td>Ryoo et al, 2014 (96)</td><td>Prospective cohort study</td><td>South Korea</td><td>Participants free of CVD and liver disease, undergoing routine health checkups</td><td>22,090</td><td>US</td><td>To investigate the association between MASLD and the development of HTN</td><td>Age, BMI, TG, serum creatinine, liver enzymes, recent smoking status, regular exercise, and T2DM</td><td>Association between severe to moderate MASLD and incident HTN</td><td>aHR: 1.14 (1.00 to 1.30) P &gt; 0.05</td></tr><tr><td>Lau et al, 2010 (97)</td><td>Prospective longitudinal cohort study</td><td>Germany</td><td>Patients aged 20–79 years with cardiometabolic risk factors</td><td>3,191</td><td>US</td><td>To examine the relationship between FLD and BP, including HTN</td><td>Age, sex, WC, BMI, T2DM, mean daily alcohol consumption, and the use of antihypertensive medication</td><td>Association between HTN and US+ with increased ALT at follow-up</td><td>aOR: 3.1 (1.70 to 5.80) P &lt; 0.05</td></tr></tbody></table>
<table><thead><tr><th colspan="11">Heart failure</th></tr></thead><tbody><tr><td rowspan="2">Roderburg et al, 2023 (98)</td><td rowspan="2">Retrospective cohort study</td><td rowspan="2">Germany</td><td rowspan="2">Participants ≥18 years with cardiometabolic risk factors</td><td rowspan="2">173,966</td><td rowspan="2">ICD-10 codes</td><td rowspan="2">To examine the association between MASLD and incident HF, adjusting for established HF risk factors</td><td>CKD</td><td rowspan="2">Association between MASLD and incident HF</td><td>aHR: 1.29 (1.24 to 1.34)<br/>P &lt; 0.001</td></tr><tr><td>Antihypertensive and statin therapy</td><td>aHR: 1.41 (1.36 to 1.47)<br/>P &lt; 0.001</td></tr><tr><td rowspan="2">Simon et al, 2022 (99)</td><td rowspan="2">Retrospective cohort study</td><td rowspan="2">Sweden</td><td rowspan="2">Adults aged ≥18 with no underlying cause of liver disease and free from CVD</td><td rowspan="2">56,939</td><td rowspan="2">Liver biopsy</td><td rowspan="2">To investigate the relationship between the severity of biopsy-confirmed MASLD and the incidence of major adverse CV events (CHF)</td><td>Age, sex, year, county of residence, education, diabetes, obesity, HTN, dyslipidemia, CKD, family history of CVD, and alcohol use disorder</td><td>Association between MASLD and CHF</td><td>aHR: 1.75 (1.63 to 1.87)<br/>P &lt; 0.05</td></tr><tr><td>Association between MASH without fibrosis and CHF</td><td>aHR: 1.60 (1.31 to 1.96)<br/>P &lt; 0.05</td></tr><tr><td rowspan="2">Fudim et al, 2021 (100)</td><td rowspan="2">Retrospective cohort study</td><td rowspan="2">United States</td><td rowspan="2">Medicare beneficiaries with no known history of HF</td><td rowspan="2">870,535</td><td rowspan="2">ICD-9 codes</td><td rowspan="2">To evaluate the relationship between MASLD and the risk of developing HF, including HFpEF and HFrEF</td><td>Age, sex, race, region, HTN, diabetes, obesity, AMI, AF, CKD, and VD</td><td>Risk of overall HF in MASLD</td><td>aHR: 1.23 (1.18 to 1.29)<br/>P &lt; 0.001</td></tr><tr><td>Risk of HFpEF in MASLD</td><td>aHR: 1.24 (1.14 to 1.34)<br/>P &lt; 0.001</td></tr><tr><td rowspan="2">Roh et al, 2020 (101)</td><td rowspan="2">Retrospective cohort study</td><td rowspan="2">South Korea</td><td rowspan="2">Adults aged ≥20 with no history of HF and comorbid conditions</td><td rowspan="2">308,578</td><td rowspan="2">FLI</td><td rowspan="2">To assess the relationship between FLI and the risk of new onset HF</td><td>Age, sex, smoking, alcohol consumption, physical activity, SBP, DBP, and cholesterol</td><td>Association between FLI (12.6-31.0) and new-onset HF</td><td>aHR: 1.31 (1.147 to 1.504)<br/>P &lt; 0.001</td></tr><tr><td>Association between FLI (&gt;31.0) and new-onset HF</td><td>aHR: 1.71 (1.489 to 1.964)<br/>P &lt; 0.001</td></tr></tbody></table>
AF = atrial fibrillation; aHR = adjusted hazard ratio; ALT = alanine aminotransferase; AMI = acute myocardial infarction; aOR = adjusted odds ratio; aRR = adjusted relative risk; AST = aspartate aminotransferase;

AVS = aortic valve sclerosis; BMI = body mass index; BP = blood pressure; CAC = coronary artery calcification; CAD = coronary artery disease; CHF = congestive heart failure; CI = confidence interval; CKD = chronic

kidney disease; COPD = chronic obstructive pulmonary disease; CRP = C-reactive protein; CT = computed tomography; CV = cardiovascular; CVD = cardiovascular disease; DBP = diastolic blood pressure; ECG = electrocardiogram; eGFR = estimated

glomerular filtration rate; FBG = fasting blood glucose; FIB-4 = Fibrosis-4 index; FLD = fatty liver disease; FLI = fatty liver index; FPG = fasting plasma glucose; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; HF = heart failure; HFpEF = heart

failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; HOMA-IR = homeostasis model assessment of insulin resistance; HTN = hypertension; ICD = International Classification of Diseases; ICPC = International

Classification of Primary Care; LDL = low-density lipoprotein; LV = left ventricle; LVEF = left ventricular ejection fraction; LVM = left ventricular mass; LVMI = left ventricular mass index; MAC = mitral annular calcification; MASLD = metabolic

dysfunction-associated steatotic liver disease; MASH = metabolic dysfunction-associated steatohepatitis; MD = mean difference; MRI = magnetic resonance imaging; PAD = peripheral arterial disease; QTc = corrected QT interval; SBP = systolic blood

pressure; SCA = subclinical atherosclerosis; T2DM = type 2 diabetes mellitus; TC = total cholesterol; TG = triglyceride; US = ultrasound; US+ = ultrasound positive; VD = valvular disease; WC = waist circumference.
Supplemental Material

**Supplemental Table 1:** Summary of Key Clinical Studies on MASLD/MASH Management
(Pages 2-7).

**Supplemental Table 2:** Ongoing Clinical Trials Investigating MASLD/MASH Therapies
(Page 8).
<table><caption>**Supplemental Table 1:** Summary of Key Clinical Studies on MASLD/MASH Management.</caption><thead><tr><th>Study</th><th>Study Design</th><th>Patient Population</th><th>Sample Size (n)</th><th>Age, years</th><th>MASLD/MASH diagnosis</th><th>Treatment Arms</th><th>Outcomes Assessed</th><th>Findings</th></tr></thead><tbody><tr><td colspan="9">Lifestyle Intervention</td></tr><tr><td rowspan="4">Stine et al. 2022 (127)</td><td rowspan="4">RCT</td><td rowspan="4">Patients with MASH and CV risk factors such as diabetes, HTN, and hyperlipidemia</td><td rowspan="4">28</td><td rowspan="4">48.9</td><td rowspan="4">Liver biopsy</td><td rowspan="4">Exercise Training vs. Standard Care</td><td>Change in liver fat, %</td><td>-4.7 vs. 1.2<br>p=0.011</td></tr><tr><td>Change in AST, U/L</td><td>-0.9 vs. 0.3<br>p=0.21</td></tr><tr><td>Change in ALT, U/L</td><td>-2.2 vs. -1.3<br>p=0.62</td></tr><tr><td>Change in IHTG content (%)</td><td>3.5% (5.6% to -1.3%)<br>p = 0.002</td></tr><tr><td rowspan="4">Zhang et al. 2016 (128)</td><td rowspan="4">RCT</td><td rowspan="4">Patients with central obesity and MASLD</td><td rowspan="4">220</td><td rowspan="4">53.9</td><td rowspan="4">Proton magnetic resonance spectroscopy</td><td rowspan="2">Moderate Exercise vs. Control</td><td>Change in weight, kg</td><td>-2.61 vs. -1.11<br>p&lt;0.001</td></tr><tr><td>Change in AST, U/L</td><td>0.8 vs. 0.3<br>p=0.63</td></tr><tr><td rowspan="2">Vigorous to moderate exercise vs. Control</td><td>Change in ALT, U/L</td><td>-2.7 vs. -1.3<br>p=0.45</td></tr><tr><td>Change in weight, kg</td><td>-3.19 vs. -1.11<br>p&lt;0.001</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Change in IHTG content (%)</td><td>3.8% (-6.0% to -1.7%)<br>p &lt; 0.001</td></tr></tbody></table>
<table><tr><td rowspan="4">Bacchi et al. 2013 (129)</td><td rowspan="4">RCT</td><td rowspan="4">Patients had HbA1c of 6.5%-9.0% and BMI of 24-36 kg/m² and used only oral hypoglycemics for diabetes management</td><td rowspan="4">31</td><td rowspan="4">55.8</td><td rowspan="4">MRI</td><td rowspan="4">Aerobic Training vs. Resistance Training</td><td>Change in BMI, kg/m2</td><td>-0.70 vs. -0.55<br/>p=0.55</td></tr><tr><td>Reduction in hepatic fat content, %</td><td>-32.8% vs. -25.9%<br/>p&gt;0.05</td></tr><tr><td>Change in ALT, U/L</td><td>0.38 vs. -5.33<br/>p=0.449</td></tr><tr><td>Change in AST, U/L</td><td>0.15 vs. -1<br/>p=0.970</td></tr><tr><td rowspan="3">Promrat et al. 2010 (126)</td><td rowspan="3">RCT</td><td rowspan="3">Individuals with elevated ALT (&gt;41 U/L) or AST (&gt;34 U/L), BMI 25-40 kg/m², and no other liver disease except MASH</td><td rowspan="3">31</td><td rowspan="3">48.2</td><td rowspan="3">Liver biopsy</td><td rowspan="3">Lifestyle Modification vs. Control</td><td>Mean change in weight, kg</td><td>-8.7 vs. -0.5<br/>p=0.005</td></tr><tr><td>Change in the overall disease activity of NASH</td><td>-2.4 vs. -1.4<br/>p=0.05</td></tr><tr><td>Patients with a ≥ 3-point reduction in overall NASH activity score</td><td>11 vs. 2<br/>p=0.04</td></tr></table>

Pharmacotherapy

<table><tr><td rowspan="3">Ng et al. 2025 (167)</td><td rowspan="3">Retrospective cohort study</td><td rowspan="3">Adults (≥21 years) with MASLD receiving ACEi/ARBs and calcium channel blockers</td><td rowspan="3">14,476</td><td rowspan="3">53.4</td><td rowspan="3">ICD-10 codes</td><td rowspan="3">ACEi/ARBs vs Calcium channel blockers</td><td>Major adverse liver outcomes</td><td>HR: 0.70 (0.61 to 0.80)<br/>p&lt;0.05</td></tr><tr><td>Major adverse cardiac events</td><td>HR: 0.82 (0.76 to 0.90)<br/>p&lt;0.05</td></tr><tr><td>Mortality</td><td>HR: 0.59 (0.51 to 0.68)<br/>p&lt;0.05</td></tr><tr><td>Sanyal et al. 2025 (163)</td><td>RCT</td><td>Adults (≥18 years) with biopsy-confirmed steatohepatitis, fibrosis stage 2-3 (NASH CRN), and NAS ≥4</td><td>1,197</td><td>55.9</td><td>Liver biopsy</td><td>Semaglutide 2.4 mg vs. placebo</td><td>Number of patients with resolution of steatohepatitis without worsening of fibrosis</td><td>62.9% vs. 34.3%<br/>p&lt;0.001</td></tr></table>
<table><tr><td></td><td></td><td></td><td></td><td></td><td></td><td>Number of patients with a reduction in liver fibrosis without worsening of steatohepatitis</td><td>36.8% vs.22.4% p&lt;0.001</td></tr><tr><td rowspan="3">Zhou et al. 2024 (146)</td><td rowspan="3">Prospective cohort Study</td><td rowspan="3">Patients aged ≥18 years with MASLD diagnosed by liver histology (steatosis in ≥5% of hepatocytes) or imaging methods</td><td rowspan="3">7,988</td><td rowspan="3">53</td><td rowspan="3">US, CT, MRI, or CAP</td><td rowspan="3">Statin users vs. non-users</td><td>All-cause mortality</td><td>aHR: 0.233 (0.127 to 0.426) p&lt;0.05</td></tr><tr><td>Liver-related clinical events</td><td>aHR: 0.380 (0.268 to 0.539) p&lt;0.05</td></tr><tr><td>Liver stiffness progression rates</td><td>aHR: 0.450 (0.342 to 0.592) p&lt;0.05</td></tr><tr><td rowspan="2">Simon et al. 2024 (170)</td><td rowspan="2">RCT</td><td rowspan="2">Patients with biopsy-confirmed steatotic liver disease or documented steatosis through appropriate imaging techniques</td><td rowspan="2">80</td><td rowspan="2">48</td><td rowspan="2">Liver biopsy or imaging techniques</td><td rowspan="2">Aspirin vs. Placebo</td><td>Absolute change in hepatic fat % by MRS</td><td>MD: -10.2 (-27.7 to -2.6) p=0.009</td></tr><tr><td>Liver stiffness by VCTE, kPA</td><td>MD: -2.8 (-4.0 to -1.5) p&lt;0.001</td></tr><tr><td>Schreiner et al. 2024 (147)</td><td>Retrospective cohort study</td><td>Patients with MASLD were identified by ICD-9/10 codes or imaging evidence of hepatic steatosis</td><td>1,238</td><td>53.7</td><td>ICD-9/10 codes or radiographic imaging</td><td>Statin users vs. non-users</td><td>Risk of progressing to a FIB-4≥2.67.</td><td>HR: 0.60 (0.45 to 0.80) p&lt;0.05</td></tr><tr><td rowspan="4">Harrison et al. 2024 (143)</td><td rowspan="4">RCT</td><td rowspan="4">Patients with biopsy-confirmed MASH and a fibrosis stage of F1B, F2, or F3</td><td rowspan="4">966</td><td rowspan="4">56.7</td><td rowspan="4">VCTE or liver biopsy</td><td>Resmetirom 80 mg vs. Placebo</td><td>Difference in MASH resolution with no worsening of fibrosis</td><td>16.4 (11.0 to 21.8) p&lt;0.001</td></tr><tr><td>Resmetirom 100 mg vs. Placebo</td><td>Difference in fibrosis improvement by ≥1 stage with no worsening of NAS</td><td>10.2 (4.8 to 15.7) p&lt;0.001</td></tr><tr><td>Resmetirom 80 mg vs. Placebo</td><td>Difference in MASH resolution with no worsening of fibrosis</td><td>20.7 (15.3 to 26.2) p&lt;0.001</td></tr><tr><td>Resmetirom 100 mg vs. Placebo</td><td>Difference in fibrosis improvement by ≥1 stage with no worsening of NAS</td><td>11.8 (6.4 to 17.2) p&lt;0.001</td></tr></table>
<table><tr><td>Ayada et al. 2022 (149)</td><td>Cohort Study (Rotterdam Study)</td><td>Patients with MASLD and CV risk factors such as diabetes and HTN</td><td>4,576</td><td>70.5</td><td>US</td><td>Statin user vs. Non-Statin user</td><td>Association between statin use and MASLD</td><td>aOR: 0.72 (0.60 to 0.86) p&lt;0.001</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Association between statin use and liver fibrosis</td><td>aOR:0.54 (0.36 to 0.82) p=0.004</td></tr><tr><td rowspan="3">Simon et al. 2019 (169)</td><td rowspan="3">Prospective cohort study</td><td rowspan="3">Patients with biopsy-confirmed MASLD and no alcohol consumption or alternative etiologies of liver disease</td><td rowspan="3">361</td><td rowspan="3">54.05</td><td rowspan="3">Liver biopsy</td><td rowspan="3">Daily aspirin user vs. Non-aspirin user</td><td>Association between daily aspirin use and definite MASH</td><td>aOR: 0.68 (0.37 to 0.89) p&lt;0.05</td></tr><tr><td>Association between daily aspirin use and fibrosis</td><td>aOR: 0.54 (0.31 to 0.82) p&lt;0.05</td></tr><tr><td>Association between daily aspirin use and advanced fibrosis stage 3-4</td><td>aOR: 0.46 (0.22 to 0.89) p&lt;0.05</td></tr><tr><td rowspan="2">Cusi et al. 2016 (164)</td><td rowspan="2">RCT</td><td rowspan="2">Patients with prediabetes or T2DM and biopsy-proven MASH</td><td rowspan="2">101</td><td rowspan="2">50.5</td><td rowspan="2">Liver biopsy</td><td rowspan="2">Pioglitazone vs. placebo</td><td>Number of patients ≥2-point reduction in NAS without worsening of fibrosis</td><td>58% vs.17% p&lt;0.001</td></tr><tr><td>Number of patients with resolution of MASH</td><td>51% vs 19% p&lt;0.001</td></tr><tr><td rowspan="4">Li et al. 2017 (168)</td><td rowspan="4">Meta-analysis</td><td rowspan="4">Patients with MASLD/MASH who are receiving treatment with ARBs</td><td rowspan="4">525</td><td rowspan="4">-</td><td rowspan="4">-</td><td rowspan="2">All patients treated with ARBs</td><td>Change in fibrosis score</td><td>MD: 0.47 (0.17 to 0.76) p=0.002</td></tr><tr><td>Change in NAS</td><td>MD: 1.12 (0.54 to 1.71) p=0.0002</td></tr><tr><td rowspan="2">ARBs vs. Control</td><td>Change in fibrosis score</td><td>MD: 0.10 (-0.58 to 0.78) p=0.77</td></tr><tr><td>Change in NAS</td><td>MD: -0.25 (-1.05 to 0.55) p=0.53</td></tr></table>
<table><tbody><tr><td rowspan="3">Loomba et al. 2015 (154)</td><td rowspan="3">RCT</td><td rowspan="3">Adults aged ≥18 years with elevated ALT (≥19 U/L for women and ≥30 U/L for men) and hepatic steatosis ≥5% as determined by MRI-PDFF</td><td rowspan="3">50</td><td rowspan="3">49.25</td><td rowspan="3">Liver biopsy</td><td rowspan="3">Ezetimibe vs. Control</td><td>Difference in AST, IU/L</td><td>1.0, p=0.600</td></tr><tr><td>Difference in ALT, IU/L</td><td>2.0, p=0.670</td></tr><tr><td>Difference in liver fat reduction, %</td><td>-1.3, p=0.48</td></tr><tr><td rowspan="4">Takeshita et al. 2014 (153)</td><td rowspan="4">RCT</td><td rowspan="4">Patients with MASLD and CV risk factors</td><td rowspan="4">31</td><td rowspan="4">52.7</td><td rowspan="4">Liver biopsy</td><td rowspan="4">Ezetimibe vs. Control</td><td>Change in ALT, µkat/l</td><td>-3.9 vs. 0.1 p=0.723</td></tr><tr><td>Change in AST, µkat/l</td><td>-8.1 vs. -1.0 p=0.365</td></tr><tr><td>Change in steatosis</td><td>-0.25 vs. -0.25 p=0.989</td></tr><tr><td>Change in total cholesterol, mmol/l</td><td>-0.49 vs. 0.06 p=0.037</td></tr></tbody></table>

Surgical Intervention

<table><tbody><tr><td rowspan="4">Verrastro et al. 2023 (174)</td><td rowspan="4">RCT</td><td rowspan="4">Participants aged 25–70 years with obesity, with or without T2DM, with histologically confirmed MASH</td><td rowspan="4">288</td><td rowspan="4">47.4</td><td rowspan="4">NAFLD fibrosis score and liver biopsy</td><td rowspan="2">Roux-en-Y gastric bypass vs. lifestyle modification</td><td>Number of patients with histological resolution of MASH without worsening of fibrosis</td><td>56% vs. 16% p&lt;0.0001</td></tr><tr><td>Probability of MASH resolution</td><td>RR: 3.60 (2.19 to 5.92) p&lt;0.0001</td></tr><tr><td rowspan="2">Sleeve gastrectomy vs. lifestyle modification</td><td>Number of patients with histological resolution of MASH without worsening of fibrosis</td><td>57% vs. 16% p&lt;0.0001</td></tr><tr><td>Probability of MASH resolution</td><td>RR: 3.67 (2.23 to 6.02) p&lt;0.0001</td></tr></tbody></table>
<table><tr><td rowspan="3">Aminian et al. 2021 (173)</td><td rowspan="3">Retrospective cohort study</td><td rowspan="3">Patients with obesity and a confirmed histological diagnosis of MASH</td><td rowspan="3">1,158</td><td rowspan="3">49.8<sup>a</sup></td><td rowspan="3">Liver biopsy</td><td rowspan="3">Bariatric Surgery vs. Control</td><td>Reduction in mean body weight, %</td><td>MD: 17.7 (16.7 to 18.7) p&lt;0.001</td></tr><tr><td>Major adverse liver outcomes</td><td>aHR:0.12 (0.02 to 0.63) p=0.01</td></tr><tr><td>Major adverse cardiovascular events</td><td>aHR:0.30 (0.12 to 0.72) p=0.007</td></tr><tr><td rowspan="2">Garg et al. 2018 (172)</td><td rowspan="2">Prospective cohort study</td><td rowspan="2">Patients undergoing bariatric surgery with BMI &gt;40 kg/m<sup>2</sup> or &gt;35kg/m<sup>2</sup> with associated co-morbidities</td><td rowspan="2">124</td><td rowspan="2">39.3</td><td rowspan="2">Liver biopsy</td><td rowspan="2">All patients underwent bariatric surgery</td><td>Weight at 12 months vs. baseline, kg</td><td>79.2 vs. 112.3 p&lt;0.001</td></tr><tr><td>Liver stiffness at 12 months vs. baseline, kPa</td><td>6.0 vs. 8.6 p=0.003</td></tr></table>

Notes: <sup>a</sup>, Median Value; ACEi, Angiotensin-Converting Enzyme inhibitor; aHR, Adjusted Hazard Ratio; ALT, Alanine Aminotransferase; aOR, Adjusted Odds Ratio; ARBs, Angiotensin II Receptor Blockers; AST, Aspartate Aminotransferase; BMI, Body Mass Index; CAP, Controlled Attenuation Parameter; CT, Computed Tomography; CV, Cardiovascular; FIB-4, Fibrosis-4 Index; HbA1c, Hemoglobin A1c; HTN, Hypertension; ICD-9/10, International Classification of Diseases, 9th/10th Revision; IHTG, Intrahepatic Triglyceride; MASH, Metabolic Dysfunction-Associated Steatohepatitis; MASLD, Metabolic Dysfunction-Associated Steatotic Liver Disease; MD, Mean Difference; MRI, Magnetic Resonance Imaging; MRI-PDFF, Magnetic Resonance Imaging Proton Density Fat Fraction; MRS, Magnetic Resonance Spectroscopy; NASH CRN, Nonalcoholic Steatohepatitis Clinical Research Network; NAFLD, Non-Alcoholic Fatty Liver Disease; NAS, NAFLD Activity Score; RCT, Randomized Controlled Trial; RR, Relative Risk; T2DM, Type 2 Diabetes Mellitus; US, Ultrasound; VCTE, Vibration-Controlled Transient Elastography.
<table><caption>**Supplemental Table 2:** Ongoing Clinical Trials Investigating MASLD/MASH Therapies.</caption><thead><tr><td>Trial name</td><td>Phase</td><td>Patient Population</td><td>Sample Size (n)</td><td>Diagnosis of MASLD/MASH</td><td>Treatment Arms</td><td>Key Outcomes</td></tr></thead><tbody><tr><td>MAESTRO-NASH-OUTCOMES (NCT05500222)</td><td>3</td><td>Adults (age >18 years) with well-compensated cirrhosis (Child-Pugh class A) due to MASH</td><td>700</td><td>Biopsy</td><td>Resmitirom 80 mg vs. Placebo</td><td>Composite of liver/CV mortality, transplant, hepatic decompensation (ascites, encephalopathy, variceal bleed), or MELD progression</td></tr><tr><td>NATiV3 (NCT04849728)</td><td>3</td><td>Patients aged ≥18 years with histological evidence of MASH and fibrosis classified as stage 2 or 3</td><td>1000</td><td>Biopsy</td><td>Lanifibranor 800 mg vs. 1200 mg vs. Placebo</td><td>Resolution of MASH and improvement of fibrosis</td></tr><tr><td rowspan="2">MAESTRO - NAFLD-OLE (NCT04951219)</td><td rowspan="2">3</td><td rowspan="2">Patients ≥ 18 years with histological evidence of MASH, fibrosis of stage 1B, 2 or 3</td><td rowspan="2">1000</td><td rowspan="2">Biopsy</td><td rowspan="2">Resmetirom 40 mg vs. 80mg vs. 100 mg</td><td>Percent change in hepatic fat fraction by MRI-PDFF at 16 weeks</td></tr><tr><td>Percent change in hepatic fat fraction by MRI-PDFF at 52 weeks</td></tr><tr><td rowspan="3">AIM2 (NCT04501406)</td><td rowspan="3">2</td><td rowspan="3">Patients aged 21 to 75 years with a diagnosis of T2DM</td><td rowspan="3">166</td><td rowspan="3">Biopsy</td><td rowspan="3">Pioglitazone 15 mg vs. Placebo</td><td>Proportion of patients with ≥2 points improvement in NAS without an increase in fibrosis stage</td></tr><tr><td>Resolution of MASH without worsening of liver fibrosis</td></tr><tr><td>Improvement in fibrosis</td></tr><tr><td rowspan="3">RELIEF-NAFLD (NCT04550481)</td><td rowspan="3">2</td><td rowspan="3">Patients ≥18 years with histological evidence of MASH or with MASH diagnosed by imaging criteria</td><td rowspan="3">45</td><td rowspan="3">Biopsy or body imaging (US, CT, MRI)</td><td rowspan="3">Lisinopril</td><td>Change in steatosis via transient elastography</td></tr><tr><td>Change in liver stiffness via magnetic resonance elastography</td></tr><tr><td>Change in fibrosis scores</td></tr><tr><td>STAT-NASH (NCT04679376)</td><td>2</td><td>Patients aged 18-70 years with histological evidence of MASH, fibrosis stage 2 or higher, and with a NAS of ≥ 4</td><td>70</td><td>Biopsy</td><td>Atorvastatin 40 mg vs. Placebo</td><td>Improvement of MASH with no worsening in fibrosis or improvement in fibrosis without worsening MASH</td></tr></tbody></table>

Notes: CT, computed tomography; CV, cardiovascular; MASLD, metabolic dysfunction-associated steatotic liver disease; MASH, metabolic dysfunction-associated steatotic hepatitis; MELD, Model for End-Stage Liver Disease; MRI, magnetic resonance imaging; MRI-PDFF, magnetic resonance imaging-proton density fat fraction; NAS, NAFLD activity score; T2DM, type 2 diabetes mellitus; US, ultrasound
<figure><img src="image_3.png" /><figcaption>Figure 1: Pathophysiological Mechanisms Linking MASLD and CVD.</figcaption></figure>
<figure><img src="image_4.png" /><figcaption>Figure 2: The diagnostic approaches employed in MASLD.</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>Figure 3: Clinical Approach to MASLD Detection in Cardiology.</figcaption></figure>
<figure><img src="image_6.png" /><figcaption>Figure 4: Management Strategies for Patients with MASLD.</figcaption></figure>

Management Strategies for Patients with MASLD
<figure><img src="image_7.png" /><figcaption>Figure 5: Role of Cardiologists in the Multidisciplinary Care of MASLD.</figcaption></figure>
MASLD: A Multisystem Disease

<figure><img src="image_8.png" /></figure>

Prevalence and Disease Progression

<figure><img src="image_9.png" /></figure>

Shared Pathophysiology Mechanisms Linking MASLD and CVD

<figure><img src="image_10.png" /></figure>

Diagnosis

Assessment of Steatosis

<figure><img src="image_11.png" /></figure>

MRI

<figure><img src="image_12.png" /></figure>

Ultrasound

<figure><img src="image_13.png" /></figure>

CT Scan

Assessment of Fibrosis

<figure><img src="image_14.png" /></figure>

VCTE and
MRE

<figure><img src="image_15.png" /></figure>

NFS and
FIB-4

<figure><img src="image_16.png" /></figure>

Liver
Biopsy

CV Risk Stratification

Risk Assessment Tools

<figure><img src="image_17.png" /></figure>

Framingham Risk Score

Pooled Equation Cohort

SCORE2-SCORE2OP

PREVENT Calculator

ASCVD Risk Score

Management

Pharmacological

<figure><img src="image_18.png" /></figure>

FDA approved:
Resmetirom

<figure><img src="image_19.png" /></figure>

Statins and
ACEi/ARBs (if CV
indications are
present)

<figure><img src="image_20.png" /></figure>

SGLT2i and
GLP-1 analogs

Non-pharmacological

<figure><img src="image_21.png" /></figure>

Healthy Diet

<figure><img src="image_22.png" /></figure>

Exercise

<figure><img src="image_23.png" /></figure>

Bariatric
Surgery