Liver stiffness as a cornerstone in heart disease risk assessment

Metabolic dysfunction‐associated steatotic liver disease (MASLD) typically presents with hepatic fibrosis in advanced disease, resulting in increased liver stiffness. A subset of patients further develops liver cirrhosis and hepatocellular carcinoma. Cardiovascular disease is a common comorbidity in patients with MASLD and its prevalence is increasing in parallel. Recent evidence suggests that especially liver stiffness, whether or not existing against a background of MASLD, is associated with heart diseases. We conducted a narrative review on the role of liver stiffness in the prediction of highly prevalent heart diseases including heart failure, cardiac arrhythmias (in particular atrial fibrillation), coronary heart disease, and aortic valve sclerosis. Research papers were retrieved from major scientific databases (PubMed, Web of Science) until September 2023 using ‘liver stiffness’ and ‘liver fibrosis’ as keywords along with the latter cardiac conditions. Increased liver stiffness, determined by vibration‐controlled transient elastography or hepatic fibrosis as predicted by biomarker panels, are associated with a variety of cardiovascular diseases, including heart failure, atrial fibrillation, and coronary heart disease. Elevated liver stiffness in patients with metabolic liver disease should lead to considerations of cardiac workup including N‐terminal pro–B‐type natriuretic peptide/B‐type natriuretic peptide determination, electrocardiography, and coronary computed tomography angiography. In addition, patients with MASLD would benefit from heart disease case‐finding strategies in which liver stiffness measurements can play a key role. In conclusion, increased liver stiffness should be a trigger to consider a cardiac workup in metabolically compromised patients.


| INTRODUC TI ON
Non-alcoholic fatty liver disease (NAFLD) is an increasing health problem affecting up to one-third of the world's population. 1 Recently, the nomenclature of NAFLD was changed to metabolic dysfunction-associated steatotic liver disease (MASLD), in which liver steatosis should be present in combination with at least one cardiometabolic condition, including impaired glucose regulation, overweight, hypertension, hypertriglyceridemia, or dyslipidaemia, underscoring the importance of cardiovascular disease (CVD) in these patients. 2Of note, approximately, 99% of patients with NAFLD also meet the MASLD criteria, suggesting that existing literature on NAFLD can be taken under the novel MASLD nomenclature. 3To avoid confusion in terminology and to promote uniformity in future research, the MASLD nomenclature is used throughout this article.
MASLD encompasses a spectrum of slowly progressing disease stages including hepatic steatosis, inflammatory metabolic dysfunction-associated steatohepatitis (MASH) with or without fibrosis, and cirrhosis potentially resulting in hepatocellular carcinoma. 4The economic burden of MASH is high with especially the late-stage disease patients being responsible for accumulating healthcare costs. 5Multiple factors have been proposed to be at the interface between MASLD and heart disease development including adipose-derived and diabetes-related factors, intestine-derived factors, thrombogenic molecules, and pro-inflammatory and oxidative stress-related components. 6Within the MASLD spectrum, liver fibrosis severity and especially the presence of cirrhosis are the most potent determinants of disease-specific mortality. 7,8Current guidelines recommend screening for advanced fibrosis in high-risk groups for MASLD using non-invasive tests (NITs). 9Among the NITs, vibration-controlled transient elastography (VCTE) and the blood-based Fibrosis-4 (FIB-4) index are the most widely used.
VCTE directly assesses liver stiffness and multiple studies have described the correlation with hepatic fibrosis, [10][11][12] while the FIB-4 index is based on age, aspartate aminotransferase, alanine aminotransferase, and platelet count. 9,13e presence of MASLD and advanced fibrosis increase the risk of CVD, while CVD is a primary cause of death in patients with MASLD. 14,15As a result, the management of MASLD requires a multidisciplinary approach including hepatologists, primary care providers, diabetologists, dieticians, and cardiologists. 16creasing evidence suggests that MASLD is a contributor to the onset and/or progression of CVD, 17 including heart failure (HF), 18 coronary heart disease (CHD), 19 atherosclerosis, 20 and arrhythmias. 213][24][25] Furthermore, subclinical portal hypertension can occur in non-cirrhotic MASLD, which can impair renal vasoregulation. 26,27[31][32][33] Of note, increased liver stiffness does not solely result from liver disease-related fibrogenesis but also from increased central venous pressure and congestive hepatopathy. 34,35Consequently, measuring liver stiffness could be a convenient tool for counteracting cardiovascular sequelae through active surveillance and case finding in metabolically compromised patients. 30,36is Review summarizes the evidence for the relation between increased liver stiffness in patients with cardiometabolic risk factors and MASLD and the incidence, prevalence, and prognosis of related heart diseases.Finally, we propose considerations for cardiac workup based on finding elevated liver stiffness using NITs.
Relevant scientific literature was retrieved from major scientific databases (PubMed, Web of Science) using 'liver stiffness', 'liver fibrosis' and the respective heart diseases as keywords until September 2023.

| Chronic heart failure
MASLD has been found to increase the risk for incident HF by 1.5 times independent of common cardiovascular risk factors. 18nsidering the poor prognosis of HF, 37 it is important to retrieve the driving force behind MASLD that promotes its onset.A handful of studies investigated if increased liver stiffness determined by NITs, whether or not accompanied by evident hepatic steatosis, could be related to the increasing incidence and poor prognosis of HF.
Liver stiffness determined by VCTE has been evaluated in the Rotterdam study, a large cohort study in the Netherlands, for its possible association with mortality in elderly patients with HF.The

Key points
• Metabolic dysfunction-associated steatotic liver disease (MASLD) and heart diseases are tightly interrelated.
• MASLD typically presents with hepatic fibrosis in advanced disease resulting in elevated liver stiffness.
Venous hepatic congestion is also a source of liver stiffness.
• Increased liver stiffness relates to heart failure, atrial fibrillation, and coronary heart disease.
• Non-invasive tests for liver fibrosis can aid the multidisciplinary management of MASLD patients.
• Elevated liver stiffness should be a cue to consider a cardiac workup.
authors reported that increased liver stiffness measurement (LSM) (≥8.0 kPa) was solely a poor prognostic factor for mortality in patients with HF (hazard ratio (HR): 2.48, 95% confidence interval (CI): 1.15-5.35),and not in those without HF (HR: 1.07, 95% CI: 0.70-1.64), 38indicating the relevance of measuring liver stiffness in this population and providing a basis for liver VCTE in the risk assessment for HF (Figure 1).VCTE has been employed in other smaller studies with inpatients that substantiate the role of liver stiffening in the course of HF.In a prospective study consisting of 171 hospitalized participants and a median follow-up of 203 days, VCTE of the liver was performed before discharge with subsequent stratification of the study participants liver stiffness tertiles with cut-offs of 4.7 and 6.9 kPa.Patients in the high liver stiffness category had an HR of 3.57 (95% CI: 1.93-6.83)for mortality and HF rehospitalization when compared with the lower LSM tertiles, which remained significant in different multivariable models.Here, it was also demonstrated that increased liver stiffness (>6.9 kPa) was associated with a higher New York Heart Association (NYHA) functional class, jugular venous distention, tricuspid regurgitation, and a large inferior vena cava diameter in patients with HF compared with the lower tertiles.VCTE-determined liver stiffness thus reflects right-sided filling pressure and liver congestion and is predictive for shorter-term mortality in HF in this population. 39In a similar setup with 53 hospitalized patients with HF and a follow-up of 24 months, an HR of 4.81 (95% CI: 1.69-13.7)was found for the composite endpoint of death and rehospitalization because of HF for patients in the high liver stiffness group. 40Yet, it is unclear whether the increased liver stiffness was due to incomplete recompensation or pre-existing liver disease.
Similar results were obtained when using the FIB-4 index as a surrogate for liver fibrosis/stiffness.In a study with 1058 HF inpatients, the FIB-4 index was used to group the study population in tertiles with FIB-4 index <1.72,FIB-4 index ≥1.72 and F<3.01, and FIB-4 index ≥3.01.After a mean follow-up period of 1047 days, the FIB-4 index was found to associate with increased all-cause mortality in a stepwise manner, suggesting that the presence of hepatic fibrosis in HF underlies a worse outcome. 41In terms of cardiovascular outcomes, NAFLD fibrosis score (NFS) quartiles predicted cardiovascular events (deaths due to progressive HF, myocardial infarction, stroke, sudden cardiac death, and rehospitalization due to worsening of HF) in 516 patients with chronic HF and a median follow-up of 464 days (HR: 1.126, 95% CI: 1.014-1.250),suggesting a prominent role of liver fibrosis and CVD progression. 42nce increased liver stiffness could arise from architectural remodelling in the liver because of venous congestion, 34 it would be relevant to investigate if liver stiffness specifically caused by MASLD also contributes to a worse outcome in patients with HF instead of being part of a slowly-progressing liver disease.When comparing patients having HF and MASLD-fibrosis as determined by a fatty liver index (FLI) ≥ 60, and a BARD score ≥2, to patients fulfilling the same criteria with a BARD score <2, an HR for all-cause mortality of 1.597 (95% CI: 1.001-2.548)was found, 43 indicating that hepatic fibrosis can be at the basis of a worse prognosis in patients with both MASLD and HF.In addition, advanced hepatic fibrosis (BARD ≥ 2) in patients with MASLD was also predictive of increased incident HF (HR: 1.116, 95% CI: 1.037-1.201).Nevertheless, whether hepatic fibrogenesis occurred solely through advancing liver disease or long-lasting venous congestion, remains a point of discussion.
Since most studies investigating the role of MASLD and liver stiffness in HF describe the HF syndrome as one continuum, it is difficult to understand their pathophysiological links.A meta-analysis covering 280 645 individuals reported an OR of 2.02 (95% CI: 1.47-2.79)to have diastolic dysfunction when suffering from MASLD, suggesting a potent role of metabolic liver disease in HF with preserved ejection fraction (HFpEF). 44In addition, a study indicating that left ventricular diastolic dysfunction is even more prevalent in advanced MASLD. 45In recent years, it became indeed clear that patients with MASLD are especially at an increased risk for developing HFpEF compared with HF with reduced ejection fraction (HFrEF) (HR HFpEF: 1.24, 95% CI: 1.14-1.34;HR HFrEF: 1.09, 95% CI: 0.98-1.2). 46 Therefore, studies evaluating liver stiffness in cohorts consisting only of HFpEF patients are of importance to gain insights into the liver-heart axis at the basis of this phenomenon.
A study covering 1423 patients with HFpEF showed a prevalence of advanced fibrosis in 37.57% determined by the NFS (>0.675) and 8.02% determined by the FIB-4 index (>3.25),indicating a high prevalence of liver fibrosis in these patients. 47Another study with 116 HFpEF patients reported that an increase in FIB-4 index was associated with right ventricular dysfunction and 2.202-fold (95% CI 1.110;4.368)risk to develop major adverse cardiovascular events (FIB-4 index ≥3.11vs. <3.11),which substantiates the previous finding. 48Remarkably, when comparing HFpEF to HFmrEF and HFrEF, the FIB-4 index (<1.3,1.3-2.67,>2.67)only predicted total cardiovascular events in HFpEF (HR: 1.09, 95% CI: 1.03-1.15). 49 a prospective observational study with 492 hospitalized patients suffering from HFpEF, it was found that the NFS predicted all-cause mortality when comparing the fourth to first quartile (HR: 2.784, 95% CI: 1.343-5.775)while hepatic fibrosis was also associated with increased central venous pressure and circulating markers of systemic fibrosis among which procollagen type III peptide, type IV collagen 7S, and hyaluronic acid.Therefore, collagen turnover with associated fibrogenesis could be the link between MASLD and HFpEF, 50 which has been raised by others as well. 41This mechanistic basis of HFpEF exacerbation in patients with MASLD could explain the concurrence of advanced HFpEF and fibrosis in MASLD, as shown in a prospective study including 181 patients. 51e association between increased liver stiffness whether or not accompanied by MASLD, with incident HF and associated mortality is clear.Yet, it remains unclear whether hepatic inflammation and fibrosis in MASLD effectively contribute to cardiac remodelling in the course of HF.Sparse data are available to substantiate this interaction, although one prospective study including 92 MASLD patients undergoing two-dimensional transthoracic echocardiography implemented with speckle-tracking echocardiography analysis and VCTE of their liver, elegantly showed that increased liver stiffness (≥5.5 kPa) can identify those patients with subclinical myocardial dysfunction. 52

| Acute heart failure
Elderly patients with MASLD admitted for acute HF showed to be especially at risk for mortality when having MASLD-fibrosis (determined using ultrasonography, FIB-4 index, and aspartate aminotransferase (AST) to platelet ratio index (APRI)), suggesting a role to also measure liver stiffness in the context of acute HF. 53 The predictive role of the FIB-4 index for mortality in acute HF was investigated in 1854 patients and seemed to be limited to patients with HFpEF (HR per SD: 1.069, 95% CI: 1.047-1.092)and HFmrEF (HR per SD: 1.036, 95% CI: 1.002-1.072),and not of use in HFrEF (HR per SD: 1.005, 95% CI: 0.997-1.012). 54t, if MASLD-related fibrosis apart from fluid overload potently contributes to the exacerbation of acute HF remains to be clarified, especially considering that VCTE-determined liver stiffness was found to decrease along with N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels during hospitalization in patients with acute decompensated HF. 55 This has been substantiated in a study including 877 patients hospitalized for acute HF that separated the cohort based on the reduction of FIB-4 index during hospitalization (low (<1.0%, n = 293), middle (1.0%-27.4%,n = 292), and high (>27.4%,n = 292) reduction of FIB-index).The authors showed that patients from the low (HR: 2.16, 95% CI: 1.41-3.32,p < .001)and middle (HR: 1.70, 95% CI: 1.10-2.63)group were at an increased risk to die from all causes or to get rehospitalized because of HF within 180 days compared with patients from the high reduction in FIB-4 index group. 56erefore, the determination of liver stiffness using NITs in acute HF could predict short-term prognosis 53,54,56,57 and can help inform about adequate venous decongestion prior to discharge. 58,59| C ARDIAC ARRHY THMIA S Most evidence linking MASLD to cardiac arrhythmias is present for atrial fibrillation (AF), although associations exist as well for ventricular arrhythmias and cardiac conduction defects. 21tabolic dysfunction-associated steatotic liver disease has been related to an increased risk of incident AF in a prospective cohort study consisting of 400 patients with type 2 diabetes (T2D) who were followed over a period of 10 years (odds ratio (OR): 6.38, 95% CI: 1.7-24.2). 60 The association between incident AF and MASLD was later confirmed in other studies, among which one based on a large primary care database in Germany, reporting an HR of 1.15 (95% CI: 1.04-1.26)when having MASLD 23 and another one based on a large Korean sample reporting an HR of 1.55 (95% CI: 1.19-2.03)for the fourth versus first quartile of the FLI, 61 resulting in an absolute risk increase of about 1.3 (95% CI: 0.5-2.1)per 1000 person-years. 62Although it is fair to conclude from these reports that MASLD impacts incident AF, the individual roles of hepatic steatosis and fibrosis were not taken into account.In addition, the association between MASLD and HF can impact its association with AF as well. 63tably, the relation between hepatic steatosis and incident AF has been investigated over a period of 12 years in 2122 participants of the Framingham Heart Study.Here, hepatic steatosis was determined using computed tomography (CT) with a liver phantom cut-off of 0.33.After adjusting for age, sex, BMI, and a set of well-established cardiovascular risk factors, no significant association was found between the presence of hepatic steatosis and incident AF (HR: 0.96, 95% CI: 0.64-1.45). 64This finding was confirmed in the Rotterdam study covering 5825 participants of which 35.7% had hepatic steatosis determined by abdominal ultrasound (HR for incident AF: 0.88, 95% CI: 0.59-1.33).On cross-sectional analysis, liver steatosis was neither associated with prevalent AF (OR: 0.80, 95% CI: 0.62-1.03), in contrast to liver stiffness determined by VCTE (OR: 1.09 per 1.0 kPa, 95% CI: 1.03-1.16).Remarkably, the association between increased liver stiffness and prevalent AF was only persistent in the absence of hepatic steatosis (OR: 1.18 per kPa, 95% CI: 1.08-1.29), 65which points to the value of referring patients with isolated increased liver stiffness for electrocardiography.Nonetheless, the authors justly stated that the exact origin and pathophysiological basis of the observed increased liver stiffness in these patients remain elusive.These data confirm an earlier smaller study with elderly people, showing that liver stiffness is significantly higher in individuals with existing AF (VCTE stiffness with AF: 9.3 kPa; without AF: 6.3 kPa, p = .018).Conspicuously, when ranking the VCTE-based liver stiffness value based on i. having no MASLD or AF, ii.MASLD but no AF, iii MASLD and AF and iv.no MASLD with AF, the highest liver stiffness was observed among those having both MASLD and AF (p = .019). 66Although the study was limited in the number of participants (n = 73), it points to the possible relevance of defining VCTEbased cut-offs for liver stiffness in cardiovascular risk assessment in specific populations.Yet, as AF is also a driving factor in HF, it is important to adjust for it which was not done in the former study. 63 terms of laboratory-based NITs, the FIB-4 index (in categories <1.30, 1.3-2.67,>2.67) showed to associate with the risk of AF in patients with MASLD (adjusted OR: 2.255, 95% CI: 1.744-2.915). 67mited data are available for the association between liver stiffness and other cardiac arrhythmias.
A retrospective study with 751 patients suffering from T2D who were discharged from the hospital investigated if MASLD (determined by abdominal ultrasound), and accompanying advanced fibrosis (evidenced by a FIB-4 index >2.67),were associated with prevalent heart block, defined as at least one block among first-degree atrio-ventricular block, second-degree block, third-degree block, left bundle branch block, right bundle branch block, left anterior hemi-block or left posterior hemi-block.The authors found a three-fold increased risk for prevalent heart block in patients with MASLD after adjusting for confounders (OR: 3.04, 95% CI: 1.81-5.10).Furthermore, MASLD patients with a FIB-4 index being indicative of advanced fibrosis (FIB-4 > 2.67) had a significantly higher prevalence of heart blocks compared with patients with a lower FIB-4 index, 68 suggesting an exacerbating role for hepatic fibrosis in patients with MASLD.
In a large cross-sectional study with 31 116 individuals from the general population, it was observed that MASLD severity, by means of ultrasonographic criteria (i.e.increased parenchymal brightness compared with the right renal cortex and the ability to visualize portal venule walls 69 ), was associated with a higher risk for heart rate-corrected QT (QTc) prolongation, going up to an extension of 12.13 ms in QTc interval, 70 implying also a role for MASLD in ventricular arrhythmias.Later, liver stiffness determined by VCTE in patients with chronic liver disease, most of them having MASLD or chronic viral hepatitis, appeared to be a predictor for QTc prolongation (spearman's correlation coefficient ρ = 0.137 with p = .011)while hepatic steatosis determined by the controlled attenuation parameter (CAP) did not (spearman's correlation coefficient ρ = 0.019 with p = .718).Although these results support the role of liver stiffening in QT prolongation, they must be interpreted with caution to draw conclusions regarding specific liver diseases because of the heterogeneous study population. 71

| CORONARY HE ART DIS E A S E
MASLD is a well-known contributor to progressive coronary artery atherosclerosis 72,73 and consequently associates with an increased incidence of myocardial infarction (adjusted HR: 1.54, 95% CI: 1.11-2.14). 74In terms of NITs and early effects of MASLD on CHD, the FLI predicts both clinical and subclinical atherosclerosis. 75 a study with 120 patients having symptoms of CHD, hepatic steatosis and fibrosis were determined using ultrasonography and shear stress elastography, respectively, while making the definite diagnosis of CHD with coronary angiography or CT angiography.
Although the study made use of different techniques to objectivate the presence of CHD and was of cross-sectional nature, the authors found an association between the degree of liver stiffness and the presence of CHD (β = 1.404 with p < .001). 76The predictivity of liver stiffness for CHD was later substantiated in another cross-sectional study including 105 patients with MASLD, determined by magnetic resonance imaging proton density fat fraction (MRI-PDFF) of at least 5% while liver stiffness was measured using magnetic resonance elastography (MRE).Here, it was found that liver stiffness is an independent predictor of coronary artery calcification (coronary artery calcification score >0) determined using cardiac CT (OR: 2.16, 95% CI: 1.29-4.09). 77Furthermore, a study including 142 MASLD patients reported that LSM by VCTE was as well independently associated with the coronary artery calcification score (β = 0.311, p = .001). 78Similar results were obtained in a smaller study with 49 MASLD patients using both VCTE and a non-invasive biomarker panel (NFS). 79In addition, multiple liver fibrosis scores including the FIB-4 index and NFS, showed to correlate with coronary artery calcification progression and severity 80,81 and cardiovascular risk scores (among which the Framingham risk score) in patients with MASLD. 82,83In the general population, the FIB-4 index predicted the onset of ischemic heart disease in individuals with liver steatosis determined by ultrasonography with a follow-up of 10 years (HR: 1.42, 95% CI: 1.13-1.77)allowing to take early preventive measures in primary care. 84Altogether, these data indicate that liver stiffness determination using VCTE or blood-based NITs suggestive of hepatic fibrosis should be implemented for cardiovascular risk assessment in patients with MASLD.
However, there exist also some conflicting data on the contribution or predictive value of liver stiffness in CHD from a well-designed prospective cohort study of 576 patients who underwent coronary angiography and liver VCTE.Here, MASLD was diagnosed based on a CAP of at least 234 dB/m, and advanced fibrosis as a LSM of at least 7.9 kPa.Patients with clinically relevant coronary artery stenosis, implying a reduction of at least 75% of the luminal diameter, had moderately but significantly higher median CAP values (273 ± 61 vs. 260 ± 66 dB/m; p = .038),while MASLD was also more prevalent in this group compared with patients without or with a lower coronary artery stenosis grade (75.0% vs. 63.1%,p = .0068).To differentiate MASLD-related hepatic fibrosis from other causes of liver stiffening, patients with congestive hepatopathy and other causes of increased liver stiffness were excluded from the analysis of MASLD-specific fibrosis.Based on a well-defined subset of 392 patients, the authors found no significantly higher prevalence of MASLD-related advanced fibrosis among patients with CHD with a luminal reduction of at least 75% compared with less-affected subjects (10.7% vs. 12.5%, p = .60). 85Since the stringent criteria for CHD in this study might have overridden the modifying effect of liver stiffness in the early course of the disease, one might question whether the presence of MASLD-related liver stiffness could effectively contribute to increased mortality in these patients.Indeed, although increased liver stiffness appears to associate with the development and progression of CHD, its effect on mortality in patients living with CHD was found to be insignificant in the Rotterdam study (HR: 1.43, 95% CI: 0.58-3.49for liver stiffness ≥8 kPa determined by VCTE), although a trend towards an increased risk of mortality could be observed. 38markably, patients suspected of MASLD with a FIB-4 index ≥2.67 that underwent percutaneous coronary intervention (PCI) within 24 h after the onset of acute myocardial infarction had a 3.45fold (95% CI: 1.07-11.00)higher chance for rehospitalization because of HF within 13 months, compared with patients with a FIB-4 index <2.67). 86These results suggest a prognostic role of liver stiffness in patients with advanced CHD undergoing PCI but await confirmation given the wide confidence interval and lack of adjustment for sex, age, and cardiovascular risk factors.Overall, liver stiffness whether or not resulting from MASLD seems to especially contribute to the early phases of CHD while its role in more advanced disease is less clear.

| AORTI C VALVE SCLEROS IS AND S TENOS IS
The association between hepatic steatosis and aortic valve sclerosis has been described already a decade ago.In a cross-sectional analysis of 2212 individuals of the general population with available abdominal ultrasound data, subjects with hepatic steatosis had 33% (95% CI: 6%-66%) higher odds of having aortic valve sclerosis determined by echocardiography, compared with those without evident hepatic steatosis. 87This association was replicated in a study sample of 120 patients with T2D, reporting an OR of 3.04 (95% CI: 1.3-7.3) to have aortic valve sclerosis based on the presence of hepatic steatosis determined by ultrasonography. 88Later, a metaanalysis showed that MASLD patients have an OR of 2.28 (95% CI: 1.21-4.28)to have aortic valve sclerosis. 89The association between MASLD and aortic valve sclerosis seems therefore evident, but the contribution of hepatic fibrosis or liver stiffness was not taken into account in these studies and should be elucidated in future research.
Liver fibrosis has been studied regarding aortic valve sclerosis/ stenosis for its prognostic value related to mortality after transcatheter aortic valve implantation (TAVI).In a study with 538 patients who underwent CT before valve implantation, MASLD was defined as a liver-to-spleen attenuation ratio <1.0 on CT without contrast while hepatic fibrosis was assessed using the NFS.Based on a follow-up period of 47 months, MASLD did not predict all-cause mortality (HR: 1.32, 95 CI: 0.97-1.97),nor did the NFS (HR for NFS < −1.455 vs. >0.676 = 1.54, 95% CI: 0.82-2.91), 90suggesting that the existence of liver fibrosis in MASLD should not withhold patients for undergoing TAVI.In contrast, another study with 480 participants reported that a FIB-4 index with a cut-off value of 1.82 predicts 1-year all-cause mortality in patients receiving a novel aortic valve via TAVI with an HR of 1.75 (95% CI: 1.18-2.59)after adjusting for most relevant confounders.Yet in this study, patients with a FIB-4 index >1.82also had a significantly higher rate of pulmonary hypertension (43.8% vs. 31.8%),right-ventricular systolic dysfunction (29.5% vs. 19.2%),and larger inferior vena cava diameter (1.6 ± 0.6 vs. 1.3 ± 0.6 cm) compared with patients with a FIB-4 index ≤1.82, 91suggesting that the increased liver stiffness and poor prognosis were rather related to the existence of long-term cardiac impairment instead of liver disease.Therefore, the exact role of liver stiffness in the prognosis of patients undergoing TAVI needs to be clarified in future studies.

| DISCUSS ION
NITs to stage MASLD and fibrosis are gaining momentum in the field. 13Among the available NITs, especially VCTE seems to be a convenient tool in daily medical practice since it allows ad hoc determination of liver stiffness.Considering that heart diseases, among which HF, arrhythmias, and CHD are important comorbidities and/ or causes of death in MASLD (Figure 2), 30 it is crucial to identify the cues in routine medical practice that reflect their interplay.Hitherto, most evidence is available for liver stiffness, instead of fatty liver, being at the nexus of liver and heart disease.Therefore, the use of liver VCTE and blood-based NITs suggestive of hepatic fibrosis 92 could assist in guiding cardiovascular risk assessment.As a confounding factor, venous congestion and congestive hepatopathy can increase liver stiffness. 93Accordingly, the finding of increased liver stiffness without a liver disease, could be an indicator of underlying CVD and urge immediate clinical investigations.An argument that corroborates this statement emanates from the often poor prognosis of heart diseases that can underlie increased liver stiffness. 94,95is assertion is largely substantiated by experimental data from well-designed studies covering different cardiac pathologies.For example, VCTE-determined liver stiffness in elderly patients with HF showed to increase the risk for all-cause mortality solely in patients with HF, 38 which indicates that increased liver stiffness should not be regarded as an innocent bystander of a slowly progressing disease in this population.On that basis, elevated liver stiffness determined by VCTE was found to associate with prevalent AF, especially in those without hepatic steatosis. 65Although cardiovascular scoring systems remain useful tools for risk assessment, hepatic fibrosis determined by NITs showed to correlate with cardiovascular risk scores, including the Framingham risk score, 82,83 suggesting that measuring liver stiffness can fulfil a role in the assessment of longterm cardiovascular risks.
One should keep in mind the predictive value of liver stiffness in specific populations for estimating short-and long-term risks related to heart disease.Elevated liver stiffness in a population without metabolic or other liver-related risk factors might rather be a consequence of hepatic venous congestion, urging immediate aggressive curative cardiovascular treatment.On the other hand, patients suffering from obesity and T2D are more likely to have MASLD-related advanced fibrosis 96 as their underlying cause of abnormal liver stiffness measurements.As MASLD might lay at the basis of early cardiac remodelling 97 and is a predictive factor for incident HF, 18 liver-directed therapies could be initiated in these types of patients in the context of cardiovascular risk management.Furthermore, variable fibrosis risks exist based on age and sex, and knowledge on these disparities seem essential to select patients for further cardiac investigations.Women of reproductive age are protected from MASLD with a risk reduction of approximately 50% compared with men, while also being protected from fibrosis development in the occasion that MASLD develops. 98,990][101] The sexual dimorphism in cardiometabolic disease is at least partly attributable to the different adipose tissue distribution between women and men, since an elevated BMI in premenopausal women can be based on relatively benign subcutaneous adipose tissue, compared with android visceral adipose tissue in men. 102Consequently, women suffering from the polycystic ovarium syndrome, a reproductive disorder associated with excess androgens, also have a higher prevalence of the metabolic syndrome and MASLD with more severe MASH and advanced fibrosis, [103][104][105] as well as CVD on the long-term. 106In addition, metabolic profiles associated with the risk of advanced liver fibrosis in MASLD differ among age groups, which can influence as well the risk for heart diseases. 107

| CONS IDER ATIONS
Increased liver stiffness can be an indicator to consider a cardiovascular workup in patients with metabolic risk factors.In addition, and as proposed by others, 77 patients with MASLD and elevated liver stiffness should be considered for cardiovascular risk assessment independently of other traditional cardiovascular risk scores.1][112][113] Although F I G U R E 2 Current concepts in the emerging role of MASLD in the landscape of highly prevalent heart diseases.MASLD increases the incidence of CHD and subsequent myocardial infarction.Liver stiffness due to fibrogenesis or venous congestion associates with HF and is a poor prognostic factor.Elevated liver stiffness is associated with prevalent AF.Quality of life is impaired in both MASLD and heart disease.AF, atrial fibrillation; CHD, coronary heart disease; HCC, hepatocellular carcinoma; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; MASH, metabolic dysfunction-associated steatohepatitis.the current NITs are better at ruling out than ruling in hepatic fibrosis and their accuracy can be affected by concurrent T2D, 83,114 their determination would allow for the initiation of referral pathways based on age, sex, comorbidities and physical signs and symptoms of heart disease and could therefore be a convenient tool to initiate a personalized diagnostic path. 16,35,36,115vertheless, these recommendations and cut-offs for liver stiffness in the view of cardiovascular risk assessment are still arbitrary as there is no conclusive data on the utility of such an approach.

| PER S PEC TIVE S AND CON CLUS I ON
Efforts are currently being made in the LiverScreen project covering 30 000 participants from eight European countries to investigate the usefulness and cost-effectiveness of liver stiffness measurement in the general population for identifying subjects with asymptomatic advanced liver disease.Since the study is of prospective nature and also targets CVD in a secondary endpoint, the results could be extrapolated to gain insights in the value of performing liver VCTE in cardiovascular risk assessment in the general population. 116,117though the source of increased liver stiffness is not always obvious and can be the result of a complex interplay between hepatic, cardiac, and systemic factors, hepatic inflammation in MASH could also compromise cardiac health and contribute to the initiation of heart disease. 50,118,119Therefore, one might question whether referral to specialty care for cardiovascular risk assessment based on liver stiffness in MASLD should be rather based on a NIT that can identify patients with MASH, 120,121 independent of evident liver stiffness.
In that perspective, the FibroScan-AST (FAST) score, combining LSM, CAP and AST levels, can non-invasively identify patients at risk of progressive MASH and perhaps even earlier identify patients also at risk for CVD in secondary and tertiary care. 120In the specialized care setting, elevated magnetic resonance-based scores to detect at-risk MASH and advanced fibrosis in individuals with MASLD, of which MRE plus FIB-4 (MEFIB) seems to outperform the magnetic resonance imaging-AST (MAST) and also FAST score, 125 should led to referral for cardiovascular risk management.
Sparse data are available on the mechanisms linking MASLDderived liver stiffness to heart disease that could be targeted using pharmacological therapies.Using bioinformatics, efforts have been made to identify common pathophysiological pathways between MASLD and HFpEF.By comparing transcriptomics data of epicardial adipose tissue of patients suffering from HFpEF with data obtained from liver tissue of MASLD/MASH patients, the authors concluded that bosentan, eldecalcitol, ramipril, and probucol could be possible treatment options to target both diseases. 126Yet, these data await validation and future controlled clinical studies are required to define the most appropriate approach.
Biomarkers for monitoring patients with combined liver and CVD would as well be of practical use.Fetuin-A has been earlier proposed as a biomarker for liver and vascular fibrosis progression F I G U R E 3 Proposed minimal cardiac investigations based on primary care case finding in metabolically compromised patients.Implementation of a simple blood-based non-invasive test in primary care for patients at risk of MASLD-related fibrosis can assist in preventing heart diseases or enable early treatment.AST, aspartate aminotransferase; ALT, alanine aminotransferase; CT, computed tomography; FIB-4, fibrosis-4; LSM, liver stiffness measurement; NT-proBNP, N-terminal pro-B-type natriuretic peptide; VCTE, vibrationcontrolled transient elastography.
in MASLD, 127 and hepatic hypoperfusion and cardiac outcomes in HF, 128 but requires validation for these purposes.Gamma glutamyl transferase has been as well highlighted as a marker of cardiometabolic health, although interpretation of its elevation is highly unspecific and can be the result of multiple other liver-related conditions including cholestatic and alcoholic liver disease. 1291][132] In addition, both entities are typified by impaired quality of life [133][134][135][136][137] along with financial pressure on healthcare systems 138,139 which further emphasizes the need for holistic management of these patients (Figure 2).
In conclusion, determining liver stiffness in the context of a personalized multidisciplinary approach 16,140 comprising 3300 individuals undergoing echocardiography and liver ultrasonography in the setting of a health screening program showed that the prevalence of left ventricular diastolic dysfunction increased along with increasing NAFLD fibrosis grade according to the NFS (30.4% in participants without MASLD, 35.2% in participants with MASLD and low probability of advanced fibrosis (NFS < −1.445), and 57.4% in participants with MASLD and intermediate-high probability of advanced fibrosis (NFS ≥ −1.455), p < .001),F I G U R E 1 Liver stiffness as a cue fo the need for cardiac investigations.Multiple factors, including both liver disease-related and heart disease-related, contribute to stiffening of the liver.Since MASLD, whether or not accompanied by hepatic fibrosis, can contribute to the onset and course of multiple heart diseases, increased liver stiffness is an important sign of a dysregulated liver-heart axis and hence a valuable indicator of the need for cardiac investigations.HFpEF, heart failure with preserved ejection fraction; MASLD, metabolic dysfunction-associated steatotic liver disease; MASH, metabolic dysfunction-associated steatohepatitis.

The FIB- 4
index and LSM by VCTE are currently the most widely used NITs to test for advanced fibrosis and especially have good negative predictive values with a relatively high number of false positives.NITs that combine VCTE-based LSM with routine blood-based laboratory markers, including Agile 3+ and Agile 4 appear to have better positive predictive values to rule in advanced fibrosis and cirrhosis in patients with MASLD, but their use is limited to specialized care centers.
will improve cardiovascular outcomes in patients with metabolic risk factors and MASLD by allowing for preventive strategies or early curative treatments.AUTH O R CO NTR I B UTI O N S Conceptualization: Joost Boeckmans and Jörn M. Schattenberg; Investigation: Joost Boeckmans and JMS; Methodology: Joost Boeckmans and Jörn M Schattenberg; Project administration: Joost Boeckmans and Jörn M. Schattenberg; Supervision: Jörn M. Schattenberg; Writing -original draft: Joost Boeckmans Writingreview & editing: all authors.ACK N O WLE D G E M ENTS Servier Medical Art was used for making figures.Open Access funding enabled and organized by Projekt DEAL.FU N D I N G I N FO R M ATI O N JB receives funding from Colgate-Palmolive -Society of Toxicology, Onderzoeksraad Vrije Universiteit Brussel, and Chair Mireille Aerens for the Development of Alternative Methods.CO N FLI C T O F I NTE R E S T S TATE M E NTJB does not report a conflict of interest.Independent of this review, LS is a full-time employee of Echosens.Independent of this review, CK has served as advisor to TOMTEC Imaging systems, Alnylam, Bristol Myers Squibb and Pfizer.Also, he has received unrestricted grants, paid to institute from Astra Zeneca and Pfizer, and travel grants from TOMTEC Imaging systems.Also, his scientific work has been supported by software and hardware grants from TOMTEC Imaging systems and Medis Imaging.Independent of this review, JMS has acted as consultant to Apollo Endosurgery, Astra Zeneca, Bayer, Boehringer Ingelheim, Gilead Sciences, GSK, Intercept Pharmaceuticals, Ipsen, Inventiva Pharma, Madrigal Pharmaceuticals, MSD, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Siemens Healthineers; has received research Funding from Gilead Sciences, Boehringer Ingelheim, Siemens Healthcare GmbH and Speaker Honorarium from Boehringer Ingelheim, Echosens, MedPublico GmbH, Novo Nordisk, Madrigal Pharmaceuticals.