Cardiovascular Complications of Chronic Liver Disease

Abstract

Chronic liver disease is an increasingly prevalent and heterogeneous syndrome with important consequences to cardiovascular function. As the global burden of chronic liver disease and cirrhosis continue to rise, cardiovascular disease has emerged as a major driver of overall morbidity and mortality in affected patients. Despite the growing recognition of the intersectionality between hepatology and cardiology care clinically, cardiovascular disease risk among patients with liver disease is underrecognized. This State-of-the-Art Review summarizes the current understanding of the bidirectional interactions between the liver and the cardiovascular system. Shared mechanisms—including inflammation, endothelial injury, and neurohormonal overactivation—that contribute to the development of adverse myocardial remodeling, atherosclerotic cardiovascular disease, heart failure, arrhythmias, pulmonary vascular syndromes, and cirrhosis-associated cardiovascular syndromes, are reviewed. A specific focus is placed on metabolic dysfunction-associated steatotic liver disease (MASLD), which is the most common form of chronic liver disease, while highlighting the distinct cardiovascular manifestations associated with other types of chronic liver disease. These include alcohol-associated liver disease and infiltrative diseases that affect the liver and heart with cardiovascular implications across the spectrum from early stages of liver disease through cirrhosis. We discuss practical approaches to detecting liver disease, including the assessment of liver fibrosis noninvasively in individuals at risk. Once chronic liver disease is detected, we discuss the approach to assessing cardiovascular risk through cardiac imaging, biomarkers, and cardiac functional testing. Management considerations for commonly encountered cardiovascular conditions and a critical appraisal of the evolving evidence supporting cardiometabolic therapies in patients with chronic liver disease are discussed to underscore potential cardiovascular and liver benefits. Critical evidence gaps and future research priorities are identified, including the development and evaluation of liver-informed cardiovascular risk models, incorporation of cardiovascular endpoints into liver disease trials, and implementation of integrated cardio-hepato-metabolic care pathways. Improved recognition of chronic liver disease and related cardiovascular disease risk represents a major opportunity to facilitate earlier disease detection, enhance risk stratification, and improve outcomes across the spectrum of chronic liver disease.

CENTRAL FIGURE:

Liver–Heart Interactions in Chronic Liver Disease: Mechanisms, Clinical Phenotypes, and Integrated Cardiovascular Care

Chronic liver disease, including steatotic liver disease, toxic, infectious, inflammatory, vascular, and genetic etiologies and systemic disorders affecting both the liver and heart, influences cardiovascular disease through shared metabolic, inflammatory, hemodynamic, and neurohormonal pathways.

Introduction

Chronic liver disease encompasses a heterogeneous group of disorders including metabolic, toxic, infectious, inflammatory, vascular and genetic etiologies that are increasingly recognized to co-occur with cardiovascular disease (CVD). Chronic liver disease exists along a spectrum of progressive hepatic injury ranging from no fibrosis (stage 0) to clinically significant fibrosis (fibrosis stage ≥2), advanced fibrosis (stage 3), and cirrhosis (stage 4), which may lead to portal hypertension, hepatic dysfunction, and clinical decompensation. Despite distinct hepatic etiologies, many chronic liver diseases share common pathways including systemic inflammation, endothelial dysfunction, and myocardial remodeling, which contribute to adverse cardiovascular outcomes.¹ CVD is now a major determinant of morbidity and mortality across the spectrum of chronic liver disease, and management of CVD should be recognized as a central focus of patients with chronic liver disease.²

Among the various causes of chronic liver disease, steatotic liver disease has emerged as the most prevalent worldwide and accounts for an increasing proportion of advanced fibrosis and cirrhosis.³ Steatotic liver disease is characterized by excessive hepatic fat accumulation and includes metabolic dysfunction-associated steatotic liver disease (MASLD; formerly nonalcoholic fatty liver disease [NAFLD]), alcohol-associated liver disease (ALD), metabolic dysfunction and alcohol-related liver disease (MetALD; steatotic liver disease with coexistence of metabolic risk factors and alcohol consumption above MASLD thresholds but below levels diagnostic of ALD), and other less common causes of hepatic steatosis.^4,5 Steatotic liver disease is closely linked to obesity, type 2 diabetes, chronic kidney disease (CKD), and other cardiometabolic disorders that substantially influence cardiovascular risk.⁶ Although MASLD has been the most extensively studied in relation to cardiovascular outcomes, growing evidence suggests that cardiovascular risk extends across the spectrum of chronic liver disease.²

Cardiovascular risk in chronic liver disease is likely underestimated by contemporary risk prediction tools, including the Predicting Risk of CVD EVENTs (PREVENT) equations, because these models were not developed or intended for populations with chronic liver disease.⁷ Moreover, advanced-stage chronic liver disease, particularly cirrhosis, is associated with unique hemodynamic, neurohormonal and inflammatory adaptations that give rise to distinct cardiovascular pathophenotypes, including cirrhotic cardiomyopathy (CCM), high-output heart failure (HoHF), and portopulmonary hypertension.^8,9 These syndromes carry important implications for diagnosis, risk stratification, procedural evaluation, and management (Central Figure).

Taken together, chronic liver disease influences cardiovascular health through both shared cardiometabolic risk factors and liver-specific pathophysiologic mechanisms. These complex interactions highlight the need for an integrated cardio–hepato–metabolic approach to patient care. Here, we provide a contemporary framework for understanding the epidemiology, pathophysiology, clinical phenotypes, and practical approaches to diagnosis and management of CVD across the liver disease spectrum.

Epidemiology of Chronic Liver Disease and Associated Cardiovascular Risk

Chronic liver disease is increasingly prevalent worldwide and encountered frequently in CVD patients. The pooled global prevalence of steatotic liver disease is 37.5%, with MASLD accounting for most cases (pooled global prevalence 33.6%).³ In contrast, MetALD and ALD affect approximately 4.1% and 2.2% of the global population, respectively. The prevalence of steatotic liver disease exceeds 70% among individuals with type 2 diabetes and those with overweight or obesity, underscoring its close association with cardiometabolic disease.^3,10

Indeed, MASLD has emerged as a central component of the cardiovascular–kidney–metabolic continuum because of its strong association with obesity, insulin resistance, type 2 diabetes, and CKD.^11,12 Metabolic dysfunction-associated steatohepatitis (MASH; previously termed nonalcoholic steatohepatitis [NASH]) represents the progressive inflammatory form of MASLD, characterized by hepatocellular injury (ballooning) and inflammation that promote fibrogenesis, and can lead to liver fibrosis and ultimately cirrhosis. In MASLD, CVD is the leading cause of death,¹³ and regression of MASLD is associated with lower cardiovascular risk.¹⁴ Beyond liver-related complications, steatotic liver diseases are associated with increased risks of a broad spectrum of cardiovascular conditions, including coronary artery disease (CAD), heart failure (HF), atrial fibrillation (AF), stroke, and cardiovascular mortality.^15–17 Comparative studies of MASLD, MetALD, and ALD have generally reported similar rates of major adverse cardiovascular events (MACE), although some cohorts suggest modest variation according to the relative contributions of metabolic dysfunction and alcohol use.^15–17 However, despite these consistent associations, current evidence remains insufficient to establish MASLD as an independent causal cardiovascular risk factor. Available data have methodological limitations, including residual confounding, incomplete adjustment for established cardiovascular risk factors, small sample sizes, and potential selection bias.¹⁸

Independent of liver disease etiology, increasing liver disease severity and fibroinflammatory activity appear to be important determinants of cardiovascular risk. The burden of advanced liver disease in the general population is substantial, with a recent systematic review and meta-analysis of predominantly cross-sectional population-based studies estimating pooled global prevalences of advanced fibrosis (stage 3) and cirrhosis (stage 4) at 3.3% and 1.3%, respectively.¹⁹ Individuals with more advanced fibrosis have a two-fold greater incidence of CVD compared with those without fibrosis.²⁰ In patients with MASH, clinically significant fibrosis (stage ≥2) is associated with a 2.5-fold increase in risk of MACE²¹ and 1.5-fold increase in all-cause mortality compared to no fibrosis (stage 0).²² Collectively, these findings suggest that liver fibrosis severity provides prognostic information beyond liver-related outcomes alone.

Importantly, noninvasive markers of fibroinflammatory liver activity and fibrosis may also provide cardiovascular risk stratification. In a UK Biobank analysis including 33,616 participants undergoing magnetic resonance imaging (MRI)-based liver phenotyping, elevated iron-corrected T1 values—a marker of fibroinflammatory liver disease—were associated with a 14%, 19%, and 27% increase in risk of major cardiovascular events, cardiovascular hospitalization, and all-cause mortality, respectively, at a median follow-up time of 2.5 years.² Similarly, elevated Fibrosis-4 score ≥ 2.67 is associated with a 2.3-fold increase in cardiovascular mortality compared with scores <2.67.^23–25 These findings suggest that noninvasive markers of liver injury and fibrosis may help identify individuals at heightened cardiovascular risk and further support the concept that liver disease severity is closely linked to cardiovascular outcomes.

Pathophysiologic Interplay between Liver Disease and CVD

Shared Metabolic and Inflammatory Pathways Linking Liver Disease and CVD

Despite differences in etiology, chronic liver diseases converge on several common pathophysiologic mechanisms that contribute to cardiovascular injury (Figure 1). Many of these mechanisms, including systemic inflammation, insulin resistance, oxidant stress, endothelial dysfunction, lipotoxicity, and neurohormonal overactivation, are systemic processes that affect both the liver and cardiovascular system.^11,26,27 As liver disease progresses, hepatic dysfunction may further exacerbate these pathways and contribute directly to cardiovascular injury. Collectively, these processes promote systemic vascular dysfunction and atherosclerosis while contributing to left ventricular remodeling, myocardial fibrosis, and HF phenotypes; in some patients, pulmonary vascular and right ventricular abnormalities may also occur.^11,26

Figure 1. Shared Pathophysiology of Chronic Liver Disease and Cardiovascular Disease.

The figure illustrates the mechanistic pathways linking the full spectrum of chronic liver disease (CLD) and cardiovascular disease, organized into two distinct phenotypes separated by a dashed divider.

Upper panel (Pre-Cirrhotic CLD): The left column depicts the pre-cirrhotic liver disease spectrum, which includes infectious, inflammatory, vascular, genetic, metabolic, infiltrative and toxic etiologies. As the most common cause of CLD, steatotic liver disease encompasses metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and metabolic and alcohol-related liver disease (MetALD), which may progress to steatohepatitis, including metabolic dysfunction-associated steatohepatitis (MASH) or alcohol-associated hepatitis (AH).

Shared pathophysiologic mechanisms linking pre-cirrhotic steatotic liver disease to cardiovascular disease include systemic inflammation (driven by interleukin-6 [IL-6], C-reactive protein [CRP], and tumor necrosis factor-alpha [TNF-α]), insulin resistance and lipotoxicity, atherogenic dyslipidemia (elevated triglycerides [TG] and low-density lipoprotein [LDL], reduced high-density lipoprotein [HDL]), endothelial dysfunction and oxidant stress, expansion of epicardial adipose tissue (EAT), and gut-liver axis disruption with microbial translocation. These mechanisms promote distinct cardiovascular phenotypes: atherosclerosis and coronary artery disease (CAD), heart failure with preserved ejection fraction (HFpEF) — predominantly associated with MASLD and MetALD — heart failure with reduced ejection fraction (HFrEF) and dilated cardiomyopathy — predominantly associated with ALD via ethanol and acetaldehyde cardiotoxicity — and atrial fibrillation.

Lower panel (Cirrhosis): Cirrhosis induces a distinct hemodynamic and neurohormonal phenotype. Increased intrahepatic vascular resistance leads to portal hypertension and, paradoxically, splanchnic vasodilation with decreased effective arterial blood volume, compounded by endotoxemia from gut barrier dysfunction. These changes trigger neurohormonal activation via the renin–angiotensin–aldosterone system (RAAS), sympathetic nervous system (SNS), and antidiuretic hormone (ADH), as well as autonomic dysfunction with β-adrenergic desensitization, bile acid toxicity (cholecardia), and impaired cardiomyocyte calcium (Ca²⁺) signaling and remodeling. The resulting hyperdynamic circulation with reduced systemic vascular resistance (SVR) and volume expansion drives myocardial stress and cirrhotic cardiomyopathy (CCM). Cardiovascular manifestations include CCM, high-output heart failure, pulmonary vascular disease, and functional tricuspid regurgitation.

Abbreviations: ADH, antidiuretic hormone; AH, alcohol-associated hepatitis; ALD, alcohol-associated liver disease; CAD, coronary artery disease; Ca²⁺, calcium; CCM, cirrhotic cardiomyopathy; CLD, chronic liver disease; CRP, C-reactive protein; EAT, epicardial adipose tissue; HDL, high-density lipoprotein; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HPS, hepatopulmonary syndrome, IL-6, interleukin-6; LDL, low-density lipoprotein; MASLD, metabolic dysfunction-associated steatotic liver disease; MetALD, metabolic and alcohol-related liver disease; PoPH, portopulmonary hypertension; RAAS, renin–angiotensin–aldosterone system; SNS, sympathetic nervous system; SVR, systemic vascular resistance; TG, triglycerides; TNF-α, tumor necrosis factor-alpha.

Created in BioRender. Park, S. (2026) https://BioRender.com/3fgzguv

Lipotoxicity, oxidant stress and inflammation.

In MASLD, chronic low-grade systemic inflammation is driven by visceral adiposity and gut dysbiosis, leading to increased circulating proinflammatory mediators (e.g., interleukin-6, C-reactive protein) that contribute to both hepatic and cardiovascular injury. Lipotoxicity resulting from excess free fatty acid flux and accumulation of toxic lipid intermediates in hepatic and myocardial tissues further amplifies these pathways. The metabolites promote oxidant stress, mitochondrial dysfunction, and inflammation, contributing to myocardial fibrosis and adverse cardiac remodeling.^26,28 In contrast, inflammation in ALD is driven largely by disruption of the gut-liver axis as a consequence of alcohol-induced alterations in the microbiome and intestinal barrier that increase microbial translocation and hepatic inflammation.²⁹ In MetALD, metabolic and alcohol-related inflammatory pathways may synergistically promote endothelial dysfunction, atherosclerosis, and myocardial fibrosis.²⁷

Insulin resistance.

Insulin resistance is a central pathogenic mechanism linking liver disease and cardiovascular dysfunction. By promoting adipose tissue lipolysis and hepatic de novo lipogenesis, insulin resistance leads to accumulation of toxic lipid intermediates including ceramides and diacylglycerols, within hepatic and cardiac tissues.²⁶ These metabolites induce oxidant stress, mitochondrial dysfunction, and apoptosis, contributing to hepatocellular and myocardial injury.³⁰

Atherogenesis.

Steatotic liver disease is also associated with atherogenic dyslipidemia, characterized by elevated triglycerides, very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL) as well as decreased high-density lipoprotein (HDL) levels.³¹ In MASH, smaller LDL particle size and increased LDL particle concentration reflect an greater atherogenic lipoprotein profile.³² These abnormalities promote endothelial dysfunction, plaque formation, and accelerated atherosclerosis, contributing to the increased risk of coronary artery disease observed in steatotic liver disease.

Direct effects of alcohol on cardio-hepatic function.

Beyond these shared metabolic pathways, disease-specific factors may further influence cardiovascular risk and cardiac remodeling. Although vascular dysfunction is common across steatotic liver diseases, alcohol can independently cause both hepatic and direct myocardial injury.^33,34 Ethanol and acetaldehyde promote myocardial dysfunction and adverse ventricular remodeling through direct cardiotoxic effects, and alcohol-related cardiomyopathy may occur even in the absence of cirrhosis.^33,34 In MetALD, alcohol-related cardiotoxicity may further exacerbate metabolic injury.^27,35 Alcohol also worsens insulin resistance, adipose tissue dysfunction, and dyslipidemia, amplifying systemic inflammation and oxidant stress.^27,35 However, advanced ALD may further compound cardiovascular dysfunction through cirrhosis-associated hemodynamic and neurohormonal alternations. Together, these mechanisms may help explain why ALD is more strongly associated with dilated cardiomyopathy and heart failure with reduced ejection fraction (HFrEF).³⁶

Paracrine signaling.

Emerging evidence suggests that epicardial adipose tissue (EAT), a metabolically active fat depot that expands with increasing liver fibrosis,³⁷ may represent an important mechanistic link between liver and cardiac dysfunction.^11,38 EAT has been associated with atherosclerosis, arrhythmogenesis, and myocardial remodeling through local pro-inflammatory paracrine signaling,^11,38 while adipokine imbalance and myocardial lipid infiltration may further contribute to impaired cardiac relaxation and electrophysiological remodeling.³⁸ Hepatokines and bile acid signaling have also been implicated in liver-heart crosstalk, although their contribution to cardiovascular risk remains uncertain.^39–42

Unique Considerations for Cardiac Dysfunction in Cirrhosis

Cirrhosis may contribute to a distinct cardiovascular phenotype because of profound hemodynamic, inflammatory, and neurohormonal alterations that affect cardiac structure and function.⁴³ As hepatic fibrosis progresses, a decrease in intrahepatic nitric oxide bioavailability promotes sinusoidal vasoconstriction and increases intrahepatic vascular resistance, leading to portal hypertension. Paradoxically, increased systemic nitric oxide synthesis, particularly in the splanchnic circulation, drives splanchnic vasodilation.⁴⁴ These processes lower systemic vascular resistance (SVR) and create a hyperdynamic circulation.⁴⁴ To compensate for low effective arterial blood volume, overactivation of the renin-angiotensin-aldosterone system, sympathetic nervous system, and antidiuretic hormone release promotes sodium and water retention, volume expansion, and further circulatory dysfunction. This cascade leads to secondary hyperaldosteronism, which promotes myocardial fibrosis and hypertrophy, contributing primarily to left ventricular remodeling and diastolic dysfunction. Cirrhosis also promotes myocardial and vascular dysfunction^45,46 via gut barrier alteration, bacterial translocation, and endotoxemia that amplifies a distributive circulatory phenotype and self-perpetuates further extrahepatic organ injury.⁴⁴

Cholecardia.

Disrupted enterohepatic circulation leads to bile acid accumulation, or “cholecardia,” which impairs cardiomyocyte fatty acid utilization through suppression of fatty acid oxidation pathways. However, excess bile acids are cardiotoxic and modulate myocardial structural and electrophysiologic abnormalities.⁴⁷ In a cholestatic biliary fibrosis model (3,5-diethoxycarbonyl-1,4-dihydrocollidine-fed mice), bile acid accumulation was associated with cardiac hypertrophy and prolonged QTc.⁴⁷ Similarly, in a genetic bile acid-overload model (farnesoid X receptor [FXR] and small heterodimer partner [SHP] double-knowout mice), elevated bile acid levels impaired myocardial fatty acid oxidation through downregulation of proliferator-activated receptor-γ coactivator 1α, a key regulator of fatty acid metabolism.⁴⁸ In humans, elevated conjugated bile acid correlates with increased left atrial volume index and abnormal (>30%) ventricular extracellular volume fraction (ECV), features that are often encountered clinically as myocardial edema and diffuse myocardialfibrosis.^47,49 Notably, bile acid sequestration with cholestyramine reversed cardiac dysfunction in the FXR/SHP double-knockout model, supporting a causal role for bile acid accumulation;,⁴⁸ however the therapeutic efficacy of this approach in humans remains unclear.⁴⁷

Cirrhotic cardiomyopathy.

Together, these hemodynamic, inflammatory, and metabolic changes modulated by excess bile acid accumulation due to hepatic impairment can contribute to cirrhotic cardiomyopathy (CCM), which is a condition characterized by systolic or diastolic dysfunction in the absence of an alternative cause (e.g., obstructive coronary artery disease, etc.).⁸ Pathogenetic mechanisms underlying CCM also include autonomic dysfunction, alterations in cardiomyocyte membrane content, β-adrenergic receptor desensitization, impaired calcium handling, and circulating vasoactive and inflammatory mediators.⁵⁰

CVD Phenotypes Across the Chronic Liver Disease Spectrum

The pathophysiologic mechanisms described above manifest clinically as distinct cardiovascular pathophenotypes that vary according to liver disease etiology and stage, including cardiomyopathy, HF, accelerated atherosclerosis, arrhythmias, pulmonary vascular complications, and valvular heart disease (Table 1).

Table 1.

Cardiovascular Disease Phenotypes and Clinical Implications across the Spectrum of Chronic Liver Disease

Cardiovascular disease phenotype	Chronic liver disease context	Pathophysiologic link	Clinical/diagnostic features	Cardiology implications
ASCVD	MASLD/MASH*, MetALD, ALD; risk rises with fibrosis	Insulin resistance, inflammation, endothelial dysfunction, oxidant stress, dyslipidemia	↑ CAC, ↑ IMT, atherogenic lipid profile	Optimize ASCVD risk factors; interpret MASLD/fibrosis as cardiometabolic risk markers
HFpEF-predominant phenotype	MASLD/MASH, MetALD; especially with T2D or obesity	Myocardial steatosis, EAT, microvascular dysfunction, myocardial fibrosis	Exertional dyspnea, elevated filling pressures, diastolic dysfunction, preserved EF	Consider MASLD in HFpEF with cardiometabolic disease; prioritize weight/metabolic therapy, GLP-1RA and SGLT2i when indicated
Alcohol-related cardiomyopathy / HFrEF	ALD; MetALD with harmful alcohol use	Ethanol/acetaldehyde cardiotoxicity, oxidant stress, mitochondrial injury	Dilated cardiomyopathy, reduced EF, AF, hypertension	Screen for alcohol use; alcohol reduction/abstinence is central
Cirrhotic cardiomyopathy +	Cirrhosis of any etiology	Autonomic dysfunction, β-adrenergic desensitization, inflammation, impaired cardiac reserve	Often silent at rest; diastolic dysfunction; abnormal GLS or systolic dysfunction	Important before TIPS, surgery, or LT; do not rely on resting LVEF alone
High-output HF / hyperdynamic circulation	Advanced cirrhosis, portal hypertension	Splanchnic vasodilation, ↓ SVR, neurohormonal activation, volume expansion	High cardiac output/index, low SVR, wide pulse pressure, edema, elevated filling pressures	Standard HF algorithms may not apply; assess volume, kidney function, and hemodynamics
Arrhythmias	MASLD, MetALD, ALD, cirrhosis	Atrial remodeling, autonomic dysfunction, inflammation, electrolyte disturbances	AF, supraventricular arrhythmias, QT prolongation; ventricular arrhythmias less common	Assess alcohol use, electrolytes, QT drugs, renal function, and bleeding risk when selecting rhythm/rate control and anticoagulation strategies
Hepatopulmonary syndrome	Portal hypertension, cirrhosis	Intrapulmonary vasodilation, right-to-left shunt, V/Q mismatch, NO signaling	Dyspnea, hypoxemia, platypnea/orthodeoxia, ↑ A–a gradient, late bubbles on saline echo	Consider in unexplained hypoxemia or dyspnea in cirrhosis; affects LT priority and perioperative risk
Portopulmonary hypertension	Portal hypertension/cirrhosis	Pulmonary vascular remodeling, ↑ PVR, shear stress, vasoactive dysregulation	Dyspnea, fatigue, syncope, RV strain; screen with TTE; confirm by RHC	Critical for LT candidacy; requires PH-directed and multidisciplinary management
Functional TR / right-sided congestion	Cirrhosis, congestive hepatopathy, right-sided HF	Volume expansion, RV/RA dilation, venous hypertension, hepatic congestion	TR murmur, ↑ JVP/RAP, IVC/hepatic vein dilation, abnormal hepatic vein flow	Evaluate liver function in moderate-to-severe TR; optimize volume; consider hepatic risk before valve intervention
Congestive hepatopathy	Right-sided HF, severe TR, constriction, Fontan circulation	Chronic hepatic venous congestion and reduced perfusion	Hepatomegaly, RUQ fullness, cholestatic liver test pattern, elevated liver stiffness	Distinguish congestion from primary liver disease; stiffness may overestimate fibrosis risk
Iron-overload cardiomyopathy	Hereditary hemochromatosis or secondary iron overload	Iron deposition with oxidant stress, myocardial and hepatic injury	Restrictive/dilated cardiomyopathy, conduction disease, arrhythmias, liver fibrosis/cirrhosis	Early recognition; treat iron overload with phlebotomy or chelation as appropriate
Amyloid cardiomyopathy	AL or ATTR amyloidosis	Misfolded protein deposition in myocardium; hepatic involvement may occur; congestion can worsen liver injury	HFpEF, increased wall thickness, conduction disease, low-voltage ECG, ↑ NT-proBNP	Evaluate amyloidosis red flags in HFpEF with liver abnormalities or congestion
Cardiac sarcoidosis	Sarcoidosis my involved heart and/or liver	Granulomatous inflammation affecting conduction system, myocardium, and liver	AV block, ventricular arrhythmias, inflammatory cardiomyopathy; hepatic fibrosis/portal HTN in some	Monitor conduction disease and ventricular arrhythmias; immunosuppression may be indicated

^*Strongest data to support association in MASLD/MASH

⁺Diagnostic criteria according to the 2020 CCM: Systolic dysfunction - LVEF (≤ 50%) or diminished absolute GLS (<18%); Diastolic dysfunction – ≥3 of septal e’ < 7cm/s, septal E/e’ ≥15, LAVI >34 mL/m², TR maximal velocity >2.8m/s

Abbreviations: A–a, alveolar–arterial; AF, atrial fibrillation; AL, amyloid light-chain; ALD, alcohol-related liver disease; ASCVD, atherosclerotic cardiovascular disease; ATTR, transthyretin amyloidosis; AV, atrioventricular; CAC, coronary artery calcium; CCM, cirrhotic cardiomyopathy; ECG, electrocardiogram; EAT, epicardial adipose tissue; EF, ejection fraction; GLP-1RA, glucagon-like peptide-1 receptor agonist; GLS, global longitudinal strain; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HTN, hypertension; IMT, intima-media thickness; IVC, inferior vena cava; JVP, jugular venous pressure; LT, liver transplantation; LVEF, left ventricular ejection fraction; MASLD, metabolic dysfunction-associated steatotic liver disease; MASH, metabolic dysfunction-associated steatohepatitis; MetALD, metabolic dysfunction and alcohol-related liver disease; NO, nitric oxide; NT-proBNP, N-terminal pro–B-type natriuretic peptide; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RA, right atrial; RAP, right atrial pressure; RHC, right-heart catheterization; RUQ, right upper quadrant; RV, right ventricular; SGLT2i, sodium–glucose cotransporter-2 inhibitor; SVR, systemic vascular resistance; T2D, type 2 diabetes; TIPS, transjugular intrahepatic portosystemic shunt; TR, tricuspid regurgitation; TTE, transthoracic echocardiography; V/Q, ventilation/perfusion.

Cardiomyopathy and HF.

The predominant HF phenotype varies according to etiology and severity of liver disease, reflecting distinct pathophysiologic patterns. MASLD is most closely associated with HFpEF through shared pathways of obesity and cardiometabolic risks. In addition, systemic disorders such as iron overload, amyloidosis, and sarcoidosis may directly involve both the myocardium and liver, producing cardiomyopathic phenotypes that should be considered when cardiac dysfunction and liver abnormalities coexist (Table 1).

Advanced cirrhosis represents a distinct cardiovascular state characterized by systemic vasodilation, reduced SVR, and hyperdynamic circulation, which may progress to HoHF and/or CCM.⁸ Diastolic dysfunction, the hallmark abnormality of CCM, is present in nearly one-third of patients with cirrhosis.⁸ CCM is defined by impaired systolic function (LVEF ≤50% or absolute global longitudinal strain <18%) and/or diastolic dysfunction in the absence of primary cardiac disease.⁵¹ Its reported prevalence ranges from 20–45%,⁵² although estimates vary according to the diagnostic criteria used.⁵³ While resting systolic function is often preserved, impaired cardiac reserve may become apparent only during physiologic stress, predisposing patients to adverse hepatic and cardiovascular outcomes following TIPS placement, acute-on-chronic liver failure, hepatorenal syndrome, and liver transplantation.^8,47,51 Despite increasing recognition of CCM, important uncertainties remain regarding its natural history, reversibility, and optimal management.

Atherosclerotic CVD (ASCVD).

The ASCVD phenotype in chronic liver disease is most evident in steatotic liver disease, where insulin resistance, atherogenic dyslipidemia, systemic inflammation, oxidant stress, and endothelial dysfunction converge to promote vascular injury and accelerated atherosclerosis. This manifests with high prevalence of subclinical markers of atherosclerosis, including increased coronary artery calcification, carotid intima-media thickness, and arterial stiffness.^26,39

Among steatotic liver disease subtypes, the strongest epidemiologic evidence linking liver disease and ASCVD exists for MASLD. For example, a recent meta-analysis demonstrated that individuals with MASLD had a 26% higher risk of myocardial infarction than those without MASLD.⁵⁴ However, whether hepatic steatosis directly contributes to atherosclerosis remains uncertain. Mendelian randomization studies suggest that genetically determined liver fat is not associated with an increased risk of ASCVD, raising the possibility that the observed relationship is driven primarily by shared cardiometabolic risk factors rather than liver fat itself.⁵⁵ Although another Mendelian randomization study supports a potential causal relationship between MASLD and arterial stiffness, a causal association between MASLD and coronary artery disease has not been established.⁵⁶

Arrhythmias.

Arrhythmia risk in chronic liver disease reflects overlapping pathophysiologic substrates that differ by liver disease subtype: cardiometabolic and inflammatory atrial remodeling in MASLD, direct alcohol-related myocardial and electrophysiologic toxicity in ALD, and autonomic dysfunction, metabolic derangements, and impaired cardiac reserve in cirrhosis.¹¹ In a nationwide cohort study, patients with biopsy-confirmed MASLD had a 30% higher risk of incident arrhythmias than matched controls without MASLD, including AF, ventricular arrhythmias/cardiac arrest, bradyarrhythmias, and other supraventricular arrhythmias.⁵⁷ In ALD, alcohol-related atrial fibrosis, left atrial enlargement, electrical remodeling, autonomic imbalance, and electrolyte disturbances may further explain the higher burden of AF observed in ALD.^34,58

A large nationwide study of over 2.4 million individuals with type 2 diabetes found that the risk of incident AF increased across steatotic liver disease categories. Compared with individuals without steatotic liver disease, MASLD was associated with a modestly increased risk of AF (HR 1.10, 95% CI 1.08–1.11), whereas the risk was higher in MetALD, defined by alcohol consumption of 20–50 g/day in women and 30–60 g/day in men (aHR 1.26, 95% CI 1.22–1.29), and highest in ALD defined by alcohol consumption >50g/day in women and 60g/day in men (aHR 1.48, 95% CI 1.41–1.55).⁵⁹

Cirrhosis is associated with increased arrhythmia risk independent of liver disease etiology.⁹ Patients with cirrhosis are most susceptible to atrial tachyarrhythmias, particularly AF, with reported prevalences ranging from 6.6–14.2%.⁵⁸ In contrast, ventricular tachyarrhythmias are uncommon but may occur in advanced disease, often in association with QT prolongation and metabolic derangements.⁶⁰ Bradyarhythmias and conduction abnormalities are rare and typically reflect advanced systemic illness or medication effects rather than primary electrical disease.

Pulmonary Vascular Syndromes.

Portal hypertension can give rise to two distinct pulmonary vascular pathophenotypes with different hemodynamic consequences: Hepatopulmonary syndrome (HPS), characterized by intrapulmonary vasodilation and right-to-left shunting, and portopulmonary hypertension (PoPH), characterized by pulmonary arteriolar remodeling, increased pulmonary vascular resistance, and right ventricular strain.^61,62 HPS prevalence is 4–47%,⁶¹ while PoPH affects 5–6% of patients with cirrhosis.⁶³ Both conditions are associated with substantial morbidity and mortality and have important implications for procedural risk and liver transplantation candidacy. HPS and PoPH are not mutually exclusive and may coexist or develop sequentially.⁶⁴ Recognizing both conditions is critical to avoid misattributing symptoms such as dyspnea, hypoxemia, or right heart dysfunction to primary cardiac disease rather than underlying liver disease.

HPS is driven by VEGF-mediated angiogenesis, nitric oxide overproduction and macrophage recruitment, which result in ventilation-perfusion mismatch, diffusion limitation, and right-to-left shunting.^62,65 Clinically, HPS may present with platypnea and orthodeoxia, although these findings are not universal.⁶¹ Diagnosis is based on arterial blood gas demonstrating elevated A-a gradient, agitated saline echocardiography (“bubble study”) demonstrating intrapulmonary shunting, and, when needed, 99mTc-MAA lung perfusion scanning.⁶²

PoPH is thought to result from hyperdynamic circulation-related increases in shear stress on the pulmonary vasculature, promoting pulmonary arterial endothelial and smooth muscle cell proliferation and dysregulated vasoactive signaling.⁶² Clinically, PoPH presents with exertional dyspnea, fatigue, chest pain, syncope, and signs of right heart strain including a loud P2, right ventricular heave, and tricuspid regurgitation (TR) murmur.⁶² Although transthoracic echocardiography is used for initial screening,⁶⁴ right-heart catheterization is required for a definitive diagnosis.⁶² Cardiopulmonary hemodynamics, particularly cardiac index, are strongly associated with mortality in cirrhosis and PoPH.⁶⁶ PoPH has important clinical implications and may affect liver transplantation candidacy. Management should involve referral to centers with expertise in both pulmonary hypertension and liver transplantation, as optimization of pulmonary hemodynamics may improve transplant eligibility and post-transplant outcomes in selected patients.⁶⁷

Valvular Heart Disease.

Valvular disease in chronic liver disease is most often a secondary hemodynamic phenotype rather than primary valve pathology. In cirrhosis, volume expansion, hyperdynamic circulation, pulmonary vascular disease, and right-sided chamber dilation may contribute to secondary functional TR.⁶⁸ Conversely, severe TR and right-sided HF can cause hepatic venous congestion and worsen liver injury. Because moderate-to-severe TR may reflect or aggravate hepatic damage, liver function should be carefully evaluated before transcatheter tricuspid valve replacement.

Integrated Cardiovascular and Liver Risk Assessment

Liver disease is often unrecognized because it is frequently asymptomatic until advanced stages. As both hepatic disease and CVD risk increase with liver fibrosis severity, early identification of clinically significant liver fibrosis (stage ≥2) represents an important opportunity to integrate cardiovascular and liver disease management.⁶⁹ Moreover, patients with MASH and fibrosis stage 2 or 3 are the primary target population for currently approved MASH-directed therapies. Because abdominal ultrasound has limited sensitivity for detecting mild steatosis, fibrosis risk stratification without liver imaging is reasonable in patients with a high pretest probability of MASLD (e.g., those with type 2 diabetes, ≥2 metabolic risk factors, or elevated aminotransferases).^12,70 Likewise, hepatic steatosis incidentally detected on imaging should trigger prompt fibrosis risk stratification (Figure 2).⁷⁰

Figure 2: Diagnosis & Risk Stratification Across the Liver Disease Continuum.

Clinical workflow begins with FIB-4 screening for patients with hepatic steatosis, elevated aminotransferases, type 2 diabetes, or ≥2 metabolic risk factors. Patients scoring ≥1.3 (≥2.0 if age ≥65) should be referred for second line testing with elastography or ELF. Cardiovascular optimization targets a BP of ≤130/80 mmHg and 7–10% weight loss via Mediterranean diet and weight-directed therapies. Standard risk scores (PCE, FRS, PREVENT) often underperform in CLD. In patients with cirrhosis needing perioperative risk stratification, diagnostic precision for subclinical CVD is enhanced through CCTA and comprehensive TTE (including bubble studies and strain imaging). The VOCAL-PENN score may be used to estimate risk for hepatic decompensation and mortality. Post-liver transplant surveillance focuses on managing immunosuppression-induced metabolic syndrome and monitoring for persistent cirrhotic cardiomyopathy (CCM).

Abbreviations: AUDIT, Alcohol Use Disorders Identification Test; AUDIT-C, Alcohol Use Disorders Identification Test-Consumption; CAD, coronary artery disease; CAD-LT, CAD in liver transplantation; CAR-OLT, cardiovascular risk in orthotopic liver transplantation; CCM, cirrhotic cardiomyopathy; CCTA, coronary CT angiography; CLD, chronic liver disease; CV, cardiovascular; ELF, enhanced liver fibrosis test; FIB-4, fibrosis-4 index; FRS, Framingham Risk Score; GLS, global longitudinal strain; HPS, hepatopulmonary syndrome; LT, liver transplant; LVEF, left ventricle ejection fraction; MACE, major adverse cardiac events; MASLD, metabolic dysfunction-associated steatotic liver disease; NPV, negative predictive value; PCE, Pooled Cohort Equations; Peth, Phosphatidylethanol; PREVENT, Predicting Risk of cardiovascular disease EVENTs; RAP, right atrial pressure; SLD, steatotic liver disease; T2D, type 2 diabetes; TIPS, transjugular intrahepatic portosystemic shunt; TTE, transthoracic echocardiogram.

Created in BioRender. Park, S. (2026) https://BioRender.com/vsvq0fc

Assessment of liver fibrosis.

The AHA/ACC/ADA/ASN guideline on CKM syndrome recommends fibrosis risk stratification using the fibrosis-4 (FIB-4) index in selected at-risk groups: every 1 to 2 years for individuals with CKM syndrome and type 2 diabetes or ≥2 cardiometabolic risk factors, and every 2 to 3 years for adults with CKM stage 1 due to prediabetes.¹² The AASLD and AGA also recommend FIB-4 use in patients with elevated aminotransferases presumed secondary to MASLD or incidentally detected hepatic steatosis.^70,71 FIB-4 index is inexpensive, widely available and calculated from age, AST, ALT, and platelet count. Patients with elevated FIB-4 (adults <65 years, ≥1.3; ≥65 years ≥2.0) are at higher risk of having stage 3–4 hepatic fibrosis and, thus, they should undergo second-line risk assessment with elastography or enhanced liver fibrosis (ELF) testing.^70,71 Fibrosis severity provides prognostic information for both liver-related and cardiovascular outcomes.^72,73

Cardiovascular Risk Prediction in Chronic Liver Disease.

Older cardiovascular risk scores, such as Framingham Risk Score and the Pooled Cohort Equations (PCE) do not fully capture cardiovascular risk in individuals with chronic liver disease.⁷ Although the PCE appears to perform reasonably well for prediction of fatal CVD,⁷⁴ it may underestimate risk in women and in patients with moderate-to-severe hepatic steatosis.⁷⁵ The most contemporary cardiovascular risk score, the PREVENT equations, was developed from a broad general population. Although PREVENT has recently been evaluated in patients with MASLD, its performance was modest, highlighting the need for liver disease-specific cardiovascular risk stratification tools.⁷⁶

Emerging evidence suggests that liver fibrosis severity may provide incremental cardiovascular prognostic information. Liver fibrosis markers are independently associated with MACE, HF, and mortality.^72,73 Furthermore, incorporation of liver-specific biomarkers into cardiovascular risk assessment models has been shown to improve prediction of myocardial infarction and stroke compared with the PCEs, the older risk models.⁷⁷ Whether liver disease should be considered a cardiovascular risk enhancer, incorporated into existing prevention frameworks or integrated into liver-specific cardiovascular risk models remains an important unanswered question.

Cardiovascular Evaluation in Advanced Liver Disease

Advanced liver disease alters cardiovascular physiology and may complicate interpretation of cardiovascular diagnostic testing. In decompensated cirrhosis, hyperdynamic circulation can mask cardiac dysfunction, while hepatic congestion may interfere with noninvasive liver stiffness assessment.^51,78 Reliance on left ventricular ejection fraction (LVEF) alone may be misleading in the context of high cardiac output because reduced afterload can preserve LVEF despite impaired myocardial reserve.⁸

Accordingly, comprehensive echocardiography, including strain imaging and agitated saline contrast study when indicated (e.g., during evaluation for liver transplantation or when signs or symptoms suggest HPS), plays a central role in evaluating myocardial function, pulmonary hypertension, intracardiac or intrapulmonary shunting, and valvular abnormalities.⁸ Electrocardiography should also be routinely performed to assess for underlying arrhythmias, conduction abnormalities, and QTc prolongation with findings interpreted within the context of liver disease severity, kidney function and metabolic abnormalities.⁷⁹ Serial reassessment with electrocardiography and echocardiography may be appropriate in patients waitlisted for transplantation at time intervals based on disease severity.⁸⁰

Procedural and Transplantation Risk Stratification

Patients undergoing evaluation for liver transplantation require a tailored approach to cardiovascular risk assessment that integrates traditional cardiovascular risk factors, functional capacity, and targeted cardiovascular testing. Coronary CT angiography is the preferred anatomic screening modality for pre-operative risk stratification,⁸¹ while invasive coronary angiography is generally reserved for high-risk individuals or those with abnormal noninvasive findings.⁷⁹ Importantly, procedural bleeding risk in patients with cirrhosis is not well predicted with INR and should not be routinely corrected prior to invasive cardiac procedures; procedural risk for angiography may instead be minimized through radial access, individualized antiplatelet therapy plans, and multidisciplinary planning.⁷⁹

Stress echocardiography has limited sensitivity (~30%) for obstructive coronary artery disease in cirrhosis because chronotropic incompetence may blunt physiologic response to stress.⁷⁹ However, impaired cardiac reserve, defined as <25% augmentation in cardiac output during stress, may identify patients with CCM and predict post-liver transplant cardiovascular events and mortality.⁸² Cardiopulmonary exercise testing also provides prognostic information, with an anaerobic threshold <9 mL/kg/min—well below the 12–14mL/kg/min typically used for cardiac transplantation—associated with increased early post-transplant mortality.^79,83 However, it is often impractical for patients with decompensated cirrhosis due to limited functional capacity.^79,83

The VOCAL-Penn score is a validated perioperative risk assessment tool for patients with cirrhosis undergoing non-transplant surgery and predicts postoperative mortality and hepatic decompensation.⁸⁴ In the transplant setting, the CAD-LT and CAR-OLT scores may further refine peri- and post-transplant cardiovascular risk assessment.^85,86

Finally, procedures such as transjugular intrahepatic portosystemic shunt (TIPS) and liver transplantation impose substantial hemodynamic stress. Cardiac decompensation develops in approximately 9% of patients during the first year following TIPS creation.^87,88 Liver transplantation may similarly unmask previously unrecognized CCM, while post-transplant immunosuppressive therapy may be a contributor of the high observed prevalence of hypertension (63–90%), diabetes (25–40%), obesity (36–41%), and ischemic heart disease (5–15%).^89,90

Management of CVD Risk in Chronic Liver Disease

Lifestyle interventions.

Once hepatic steatosis develops, hypocaloric diet-induced weight loss is the primary intervention.⁹¹ A 5–10% weight reduction improves steatosis and inflammation, while a ≥10% reduction improves insulin sensitivity and promotes histologic regression or stabilization of liver fibrosis.⁷¹ In lean MASLD (BMI < 25 kg/m² or <23 kg/m² for Asians), a modest 3–5% weight loss is sufficient to promote disease remission.⁹² Lifestyle interventions align closely with standard AHA/ACC guideline recommendations for CVD risk reduction: a Mediterranean diet improves hepatic steatosis, fibrosis, and cardiometabolic risk,^71,93 with low-fat diets demonstrating comparable benefits for MASLD.⁷¹ High-fructose intake should be restricted because it promotes metabolic syndrome, insulin resistance, hypertriglyceridemia, and fibrosis.⁹⁴ Higher coffee consumption (≥3 cups daily) has been associated with lower prevalence of MASLD and fibrosis, although these findings may be influenced by residual confounding.⁷¹ Patients with MASLD should meet standard AHA recommendations of at least 150 minutes of moderate-intensity exercise per week⁷¹ and minimize alcohol intake, particularly when fibrosis is present, because of synergistic effects with obesity and diabetes.⁷¹

Pharmacotherapy Considerations.

Patients with liver disease frequently have concomitant cardiovascular, metabolic, and kidney disease. Therefore, cardiometabolic effects of liver-directed therapies and the safety, efficacy, and potential hepatic benefits of standard cardiometabolic medications across the spectrum of chronic liver disease are important to understand (Table 2). Although much of the current evidence is derived from studies in MASLD/MASH, many therapeutic principles are applicable to broader chronic liver disease populations.

Table 2.

Cardiovascular and Hepatic Effects of Established Cardiovascular Therapies

	GLP-1RA GIP-RA	SGLT2 Inhibitors	Statins	RAAS inhibitors (ACE-I, ARB, ARNI)	MRA (e.g., Finerenone)	NSBB (e.g., Carvedilol)
Indication	Obesity, T2D, MASH (F2-F3)	HFrEF, HFpEF, CKD, T2D	ASCVD prevention, Dyslipidemia	HTN, HFrEF, CKD	HFrEF, CKD (stage 3+), Ascites management	HF, Post-MI, HTN, Arrhythmia, Primary & Secondary prevention of variceal bleeding, Compensated ALD disease with CSPH
Mechanism of action	Incretin mimetic; ↓appetite	Glucose-sodium symport block	HMG-CoA Reductase block	Angiotensin-II & RAAS blockade	Selective MR Antagonism	β1/β2 & α1 block
Glycemia	↓↓↓	↓ (Moderate)	Neutral	Neutral	Neutral	Neutral / Mild ↑ risk
Blood pressure	↓ (Moderate)	↓ (Moderate)	Neutral	↓↓↓ (Potent)	↓ (Moderate)	↓↓↓ (Potent)
Weight	↓↓↓ (Dose-dependent)	↓ (Mild/Moderate)	Neutral	Neutral	Neutral	Mild ↑ risk
Lipids	↓ TG, ↑ HDL	Neutral / ↑ LDL (slight)	↓↓↓ LDL	Neutral	Neutral	Neutral
Liver steatosis	↓↓↓ (Class-leading)*	↓ (Moderate)†	↓ (Pleiotropic)†	Neutral / ↓ (Minimal in pre-clinical study)	Minimal (for steatosis prevention)†	Unclear
Liver fibrosis	↓ (MASH resolution)*	Neutral / ↓ (Emerging)†	Mixed	Inconclusive (RCTs underpowered) / ↓ (Anti-fibrotic)†	↓ (Experimental)	↓ (Via ↓ Portal Pressure) (Pre-clinical evidence)
CV outcomes	↓ MACE (Strong)	↓ HF Hospitalization & CV Death	↓ MACE (Strong)	↓ MACE / Mortality	↓ Mortality & Hospitalization; ↓ MACE	↓ Mortality in HFrEF
Hepatic outcomes	↓ Progression to cirrhosis ↓ Hepatic decompensation and HCC in MASLD†	↓ Mortality† ↓ Hepatic decompensation† ↓HRS†; Possible benefit in early decompensated cirrhosis† (↓paracentesis requirement, portal hypertensive complications)	↓ Risk of infection & all-cause mortality*† ↓ Portal pressure*†	↓Portal Pressure in early disease*; Potential to slow fibrosis stage transition†	↓ Ascites formation (finerenone - limited evidence in MASLD & cirrhosis)	↓Variceal hemorrhage* ↓Hepatic venous pressure gradient (HVPG)* Prevent hepatic decompensation*
CKD outcomes	↓ GFR loss / UACR	↓↓ ESRD / Dialysis	Neutral	↓↓ Proteinuria	↓↓ UACR / ESRD	Neutral
HFpEF severity	↓ Symptoms (HFpEF)	First-line (All HF)	Neutral	First-line (HFrEF)	First-line (All EF)	First-line (All EF)
Cardiometabolic consideration	Sarcopenia risk: Monitor muscle mass in cirrhosis. Primary agent for MASH resolution.	HF/Cirrhosis Overlap: Useful for congestion; Risk of hypotension, HRS, AKI in advanced liver disease if used with diuretics.	Safe in compensated cirrhosis. Hydrophilic statins (Pravastatin/Rosuvastatin) preferred in post-LT patients on immunosuppressant. Avoid simvastatin at doses >20mg/day in ALD (MELD > 12 or CTP C/D) to prevent rhabdomyolysis. Resmetirom can increase statin concentration.	Stop if SBP < 90mmHg. Avoid in advanced/decompensated cirrhosis. Potent anti-inflammatory effects in CKM.	Finerenone ↓ hyperkalemia risk vs spironolactone; ↓ fibrosis. Spironolactone limited by hyperkalemia & endocrine effects	Carvedilol ↑ insulin sensitivity; May ↓ QTc & arrhythmic risk. Narrow therapeutic window in decompensated cirrhosis (monitor BP, renal function, & volume status). Avoid in refractory ascites, SBP 90mmHg, or hepatorenal physiology

↑ denotes increased in human studies; ↓ denotes decreased

^*denotes data supported by randomized control trial

^†denotes data supported by observational study

Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ALD, advanced liver disease; ARB, angiotensin II receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CKM, cardiovascular-kidney-metabolic; CSPH, clinically significant portal hypertension; CTP, Child-Turcotte-Pugh; CV, cardiovascular; ESRD, end-stage renal disease; GFR, glomerular filtration rate; GIP-RA, glucose-dependent insulinotropic polypeptide receptor agonist; GLP-1RA, glucagon-like peptide-1 receptor agonist; HCC, hepatocellular carcinoma; HDL, high-density lipoprotein; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; HRS, hepatorenal syndrome; HTN, hypertension; HVPG, hepatic venous pressure gradient; LDL, low-density lipoprotein; LT, liver transplantation; MACE, major adverse cardiovascular event(s); MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; MI, myocardial infarction; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist; NSBB, non-selective beta-blocker; QTc, corrected QT interval; RAAS, renin-angiotensin-aldosterone system; SBP, systolic blood pressure; SGLT2, sodium-glucose cotransporter 2; T2D, type 2 diabetes; TG, triglycerides; and UACR, urine albumin-to-creatinine ratio.

Glucagon-like peptide 1 (GLP-1).

The GLP-1 and dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonists improve obesity, type 2 diabetes, cardiovascular risk, and steatotic liver disease outcomes. Semaglutide and resmetirom (an oral liver-directed, thyroid hormone receptor β-selective agonist) are FDA-approved therapies for MASH with F2-F3 fibrosis.^95–97 Emerging data suggest GLP-1-based therapies may reduce progression to cirrhosis, hepatic decompensation, and hepatocellular carcinoma, although data in decompensated cirrhosis remain limited.^98,99 Semaglutide is not approved for MASH cirrhosis, but limited data suggest acceptable safety in compensated cirrhosis.^96,100 Given the potential risk of exacerbating sarcopenia in decompensated cirrhosis, insulin remains the preferred agent for glycemic control in this population.⁹⁹ The established cardiovascular benefits of GLP-1–based therapies support their use in appropriately selected patients with chronic liver disease.⁹⁹

Sodium–glucose cotransporter-2 inhibitors (SGLT2i).

This drug class is a foundational therapy for HF, CKD and type 2 diabetes, and may provide hepatic benefits in patients with steatotic liver disease and compensated cirrhosis.^101–104 In liver disease, mechanisms of SGLT2i—including natriuresis, osmotic diuresis, and modulation of RAAS and SNS—may help manage sodium retention and plasma volume expansion, mitigating cardiorenal and hepatorenal complications.¹⁰¹ Observational studies suggest reductions in hepatic decompensation, portal hypertensive complications, and mortality, although prospective trial evidence is needed.^{102,105–108}

HMG-CoA-Reductase Inhibitors (Statins).

Statins are safe in compensated chronic liver disease and should be prescribed according to AHA/ACC Guidelines for the prevention and management of CVD in the absence of decompensated cirrhosis (e.g., ascites, portal hypertensive bleeding, jaundice, or hepatic encephalopathy).^109–112 Although observational studies suggest potential hepatic benefits, evidence for improvements in liver-specific outcomes remains limited.^113–115

In this setting, hydrophilic statins (e.g., pravastatin, rosuvastatin) are often preferred because of fewer drug-drug interactions, particularly among LT recipients receiving immunosuppressive therapy.⁸⁹ Additionally, simvastatin doses exceeding 20 mg/day should generally be avoided in advanced liver disease (e.g., MELD >12 or Child-Pugh C) because of increased risk of myopathy and rhabdomyolysis.¹¹³ A small single-center RCT of atorvastatin in decompensated cirrhosis suggested reductions in cirrhosis-related complications and hepatorenal syndrome, although larger studies are needed to confirm these findings.¹¹⁶ Thus, statins are generally avoided in decompensated cirrhosis but may be considered with close monitoring in selected patients with high cardiovascular risk.⁷¹ Finally, resmetirom increases systemic drug exposure and peak concentration of statins. Hence, statin dose must be adjusted when co-administered with resmetirom to prevent adverse effects such as muscle or liver toxicity.¹¹⁷

Targeting the RAAS pathway.

RAAS inhibitors should be prescribed primarily for established cardiovascular indications in patients with chronic liver disease. In patients with preserved hepatic function, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) should be used for standard cardiovascular indications. Despite preclinical data suggesting potential antifibrotic and metabolic benefits, clinical evidence supporting liver-specific effects remain limited.^118,119 Their use in cirrhosis is more nuanced. In compensated cirrhosis, ACE inhibitors and ARBs may be used cautiously in selected patients, particularly when cardiovascular indications are present.¹²⁰ However, in decompensated cirrhosis, these agents should generally be avoided because underlying systemic vasodilation may predispose patients to hypotension, renal dysfunction, and hepatorenal syndrome.¹²¹ Accordingly, blood pressure, renal function, and electrolytes should be monitored closely when these therapies are prescribed. Although some studies suggest that ACE inhibitors and ARBs may reduce hepatic venous pressure gradient,¹²² current evidence has not demonstrated clear benefits on hepatic decompensation or hepatocellular carcinoma and reported mortality benefits are more likely attributable to their cardiovascular effects.¹²⁰

Mineralocorticoid receptor antagonists (MRAs).

In cirrhosis, spironolactone remains the preferred MRA for the treatment of ascites because it directly counteracts the marked hyperaldosteronism that accompanies portal hypertension, although substantially higher doses are often required than in HF.¹²³ Accordingly, the MRA-to-loop diuretic ratio is approximately 2.5:1 in cirrhosis versus 1:1 to 2:1 in HF.¹²⁴ Close monitoring is required because of the risk of hyperkalemia and endocrine adverse effects.¹²¹ Nonsteroidal MRAs, such as finerenone, provide established cardiorenal benefit in patients with HF, CKD, and diabetes, with lower rates of hormonal adverse effects due to greater receptor selectivity.¹²⁵ Despite limited data in MASLD and cirrhosis population, early studies indicate neutral or modest effects on liver-related parameters.¹²⁶

β adrenergic receptor antagonists.

In patients with cirrhosis, nonselective beta-blockers (NSBBs) reduce portal hypertension through β₁-mediated decreases in cardiac output and β₂-mediated reductions in splanchnic blood flow, making them standard for primary and secondary prevention of variceal bleeding.⁴³ Carvedilol is the preferred NSBB due to its additional α₁-blocking properties, which further decrease portal pressure and improve SVR.¹²⁷ Early initiation of carvedilol is now recommended in patients with compensated advanced chronic liver disease and clinically significant portal hypertension (hepatic venous pressure gradient ≥10mm Hg) to prevent hepatic decompensation, namely ascites.⁴³ Also, NSBBs may shorten QT interval and reduce arrhythmic risk.¹²⁸ However, NSBBs should be avoided in patients with refractory ascites, systolic blood pressure < 90mmHg, or hepatorenal physiology (e.g., up-trending creatinine or down-trending sodium), as excessive beta-blockade can precipitate hypotension, renal dysfunction, or impaired organ perfusion.¹²⁹

Multidisciplinary Cardio-Hepato-Metabolic Care

The growing burden of chronic liver disease, particularly MASLD, necessitates a shift from siloed specialty care to integrated cardio–hepato–metabolic care pathways. Because liver disease and CVD share antecedent risk factors and bidirectional pathways that amplify risk, multidisciplinary collaboration among cardiology, hepatology, primary care, and other subspecialties is essential (Figure 3).¹¹

Figure 3: Integrated Cardio-Hepato-Metabolic Care Pathway for Chronic Liver Disease.

As chronic liver disease is a multisystem disorder, a multidisciplinary care model ensures that Cardiology provides essential cardiovascular risk stratification and cardiovascular disease management and FIB-4 screening to identify and refer patients who are at elevated risk for clinically significant fibrosis (stage ≥2). This framework streamlines the co-management of advanced liver disease and metabolic risk with Hepatology and Endocrinology. Central to this model is the partnership with Primary Care and allied health services, utilizing tailored exercise physiology and nutritional counseling to combat frailty and achieve sustainable lifestyle modification. Collaboration with Behavioral Health and Addiction Medicine is essential to promote alcohol reduction and support sustained abstinence.

Abbreviation: ALD, alcohol-associated liver disease; CBT, cognitive behavioral therapy; CV, cardiovascular; CVD, cardiovascular disease; FIB-4, Fibrosis-4 index; HCC, hepatocellular carcinoma; LT, liver transplant; MASLD, metabolic dysfunction-associated steatotic liver disease; MASH, metabolic dysfunction-associated steatohepatitis; MetALD, metabolic and alcohol-related liver disease

This figure was generated with assistance from ChatGPT (OpenAI, GPT-5.5) and edited by the authors. Created in BioRender. Park, S. (2026) https://BioRender.com/ehbek5s

In cardiology practice routine liver risk assessment should encompass both clinical history and non-invasive screening (e.g., FIB-4), in patients with CKM syndrome and diabetes or ≥2 cardiometabolic risk factors.¹² In parallel, in hepatology practice, incorporation of structured cardiovascular screening to identify HF, arrhythmias, ASCVD, and cirrhosis-specific cardiac syndromes is recommended in MASLD and in patients with chronic liver disease undergoing evaluation for liver transplantation.^71,130 Embedding these assessments into routine care may facilitate earlier detection of high-risk patients and improve longitudinal risk management.¹¹ Furthermore, comprehensive pre- and post-procedural cardiovascular risk assessment and surveillance remain critical for patients undergoing advanced interventions, such as liver transplant or TIPS.^52,131,132

Future Directions & Knowledge Gaps

Major knowledge gaps include whether chronic liver disease should be considered a cardiovascular risk enhancer, optimal strategies for integrated cardiovascular and liver risk prediction, the role of emerging biomarkers, and the cardiovascular impact of liver-directed therapies (Table 3). Future studies should also evaluate multidisciplinary cardio-hepato-metabolic care models and incorporate cardiovascular outcomes into liver disease trials.

Table 3.

Research Gaps and Future Priorities

Research Domain	Current Gap	Future Priorities
Clinical Trial Endpoints	Liver therapies are approved liver-specific histologic endpoints despite CVD being the leading cause of mortality, with limited cardiovascular outcome assessment.	Incorporate cardiovascular outcomes (MACE, HF, stroke) and patient-centered outcomes into CLD trials.
Risk Stratification	No validated integrated cardio-hepatic risk model exists. Cardiac imaging (e.g., global longitudinal strain, diastolic indices, and cardiac MRI) and stress testing lack standardized threshold and prospective validation.	Develop and evaluate integrated cardio-hepatic risk models and standardized cardiovascular screening algorithms.
Biomarker Validation	Emerging biomarkers (e.g., PNPLA3, miR-122, hepatokines, and inflammatory, fibrosis, and lipid markers) require validation for cardiovascular risk prediction and treatment guidance.	Establish the incremental prognostic value and clinical utility of biomarkers for personalized cardiovascular risk assessment.
Therapeutic Evidence	Limited randomized evidence supports cardiometabolic therapies (e.g., SGLT2 inhibitors, GLP-1RAs, statins) in advanced CLD. Optimal management of cirrhotic cardiomyopathy remains uncertain.	Conduct dedicated trials to define cardiometabolic therapy, cirrhotic cardiomyopathy management, and cardiac recovery after liver transplantation.
Integrated Care Models	Standardized multidisciplinary cardio-hepato-metabolic care pathways and surveillance strategies are lacking.	Develop scalable multidisciplinary care models with coordinated screening, risk assessment, and longitudinal follow-up.
AI and Machine Learning	AI-based risk prediction models lack prospective validation across diverse CLD populations.	Prospectively validate AI-assisted risk prediction and implementation in clinical practice.

Abbreviations: AI, artificial intelligence; CLD, chronic liver disease; CVD, cardiovascular disease; GLP-1RA, glucagon-like peptide-1 receptor agonist; HF, heart failure; MACE, major adverse cardiovascular event(s); MRI, magnetic resonance imaging; SGLT2, sodium-glucose cotransporter 2

Conclusion

Chronic liver disease is an important cardiovascular risk modifier that influences the development and management of atherosclerotic disease, heart failure, arrhythmias, and pulmonary vascular complications. Although MASLD now represents the most common form of chronic liver disease worldwide, ALD, MetALD, congestive hepatopathy, and cirrhosis also contribute substantially to cardiovascular morbidity and mortality. Cirrhosis-related cardiovascular alterations warrant individualized cardiac evaluation for TIPS- and transplant- related risk stratification. Conversely, patients with obesity, type 2 diabetes, HFpEF, CKD, and harmful alcohol use are most likely to have previously unrecognized liver disease. Integration of cardiovascular and liver disease screening, risk assessment, and multidisciplinary cardio–hepato–metabolic care represents a major opportunity to improve cardiovascular and liver outcomes.

Abbreviations

ACE

angiotensin-converting enzyme

AF

atrial fibrillation

ALD

alcohol-related liver disease

ARB

angiotensin receptor blocker

ASCVD

atherosclerotic cardiovascular disease

CAD-LT

coronary artery disease in liver transplantation

CAR-OLT

cardiovascular risk in orthotopic liver transplantation

CCM

cirrhotic cardiomyopathy

CKD

chronic kidney disease

CVD

cardiovascular disease

EAT

epicardial adipose tissue

ELF

enhanced liver fibrosis

FIB-4

fibrosis-4 index

GLP-1

glucagon-like peptide-1

HF

heart failure

HFpEF

heart failure with preserved ejection fraction

HFrEF

heart failure with reduced ejection fraction

HoHF

high-output heart failure

HPS

hepatopulmonary syndrome

INR

international normalized ratio

LAVI

left atrial volume index

LT

liver transplantation

LVEF

left ventricular ejection fraction

MACE

major adverse cardiovascular events

MASLD

metabolic dysfunction–associated steatotic liver disease

MASH

metabolic dysfunction–associated steatohepatitis

MRA

mineralocorticoid receptor antagonist

NSBB

nonselective beta-blocker

PCE

Pooled Cohort Equations

PoPH

portopulmonary hypertension

QTc

corrected QT interval

RAAS

renin–angiotensin–aldosterone system

SNS

sympathetic nervous system

SGLT2

sodium–glucose cotransporter-2

SVR

systemic vascular resistance

T2D

type 2 diabetes

TIPS

transjugular intrahepatic portosystemic shunt

TR

tricuspid regurgitation