Interplay between cardiometabolic risk factors in metabolic dysfunction-associated steatotic liver disease: Clinical evidence on cardiovascular disease

Table 4 Representative clinical studies on the association between metabolic dysfunction-associated steatotic liver disease and cardiovascular disease

Ref.	Country, year	Type of study	Population, diagnostic method	Main outcomes
Subclinical atherosclerosis and arterial stiffness
Kim et al[193]	South Korea, 2012	Cross-sectional study	4023 subjects (ultrasonography)	CAC scores were associated with a higher prevalence of MASLD (OR = 1.84, 95%CI: 1.61-2.10). CAC scores were significantly associated with MASLD (OR = 1.28, 95%CI: 1.04-1.59) independent of visceral adiposity
Huang et al[196]	China, 2012	Cross-sectional study	8632 participants (ultrasonography)	MASLD had remarkably higher CIMT and ba-PWV compared to the control group (0.594 ± 0.105 mm vs 0.578 ± 0.109 mm and 1665 ± 424 cm/second vs 1558 ± 430 cm/second)
Targher et al[173]	Italy, 2016	Meta-analysis	16 studies; 34043 adult individuals (imaging or histology)	MASLD had a higher risk of fatal and/or non-fatal CVD events (OR = 1.64, 95%CI: 1.26-2.13). Severe MASLD had more development of fatal and non-fatal CVD events (OR = 2.58, 95%CI: 1.78-3.75)
Zhou et al[194]	China, 2018	Systematic review and meta-analysis)	26 studies; 85395 participants (ultrasonography, computed tomography, or biopsy)	MASLD was independently associated with subclinical atherosclerosis (OR = 1.60, 95%CI: 1.45-1.78). MASLD also increased the risk of carotid artery intima-media thickness/plaques, arterial stiffness, CAC, and endothelial dysfunction with OR and 95%CIs of 1.74 (1.47-2.06), 1.56 (1.24-1.96), 1.40 (1.22-1.60), and 3.73 (0.99-14.09), respectively
Wong et al[195]	Singapore, 2018	Meta-analysis	64 studies; 172385 participants (ultrasonography, liver biopsy, CT, MRS, or FLI)	MASLD was associated with increased CIMT (OR 2.00, 95%CI: 1.56-2.56). MASLD was also associated with any coronary calcification (OR = 1.21, 95%CI: 1.12-1.32) and the development/progression of CAC (OR = 1.26, 95%CI: 1.04-1.52)
Liu et al[199]	United States, 2012	Cross-sectional study	2884 participants (CT)	Liver attenuation was inversely associated with CAC in data adjusted for age and sex (OR = 0.84, 95%CI: 0.7-0.9). Fatty liver was associated with CAC independent of abdominal VAT or BMI in African Americans
Guo et al[202]	China, 2017	Cross-sectional study	8571 patients	The prevalence of carotid (56.5% vs 44.5%) and lower limb plaque (56.2% vs 48.7%) and carotid (11.2% vs 6.8%) and lower limb stenosis (15.1% vs 10.3%) were significantly higher in diabetic patients with MASLD compared to those without it (P < 0.001)
Lee et al[206]	South Korea, 2018	Cross-sectional study	5121 individuals (ultrasonography)	Atherosclerotic plaque (OR = 1.18, 95%CI: 1.03-1.35) and non-calcified plaque (OR = 1.27, 95%CI: 1.08-1.48) were significantly higher in MASLD. There was a significant association of FLI ≥ 30 with non-calcified plaque (OR = 1.37, 95%CI: 1.14-1.65) and NFS ≥ -1.455 with non-calcified plaque (OR = 1.20, 95%CI: 1.08-1.42)
Park et al[208]	South Korea, 2019	Retrospective cohort	488 subjects (FibroScan)	CAP ≥ 222 dB/m was independently associated with the presence of coronary plaques (OR = 1.624, 95%CI: 1.047-2.518). CAP ≥ 222 dB/m was significantly associated with non-calcified plaque (OR = 3.528, 95%CI: 1.463-8.511)
VanWagner et al[210]	United States, 2014	Cross-sectional study	2424 participants (CT)	MASLD was associated with CAC (OR = 1.33, 95%CI: 1.001-1.82) and AAC (OR = 1.74, 95%CI: 1.29-2.35). However, these associations were attenuated after adjustment for VAT (CAC OR = 1.05, 95%CI: 0.74-1.48; AAC OR = 1.20, 95%CI: 0.86-1.67)
Cerebrovascular disease and stroke
Wang et al[213]	China, 2022	Meta-analysis	18 studies; 17031672 participants (ultrasonography, CT, MRI, or FLI)	MASLD was associated with a mildly increased risk of stroke (OR = 1.18, 95%CI: 1.08-1.30)
Chen et al[215]	China, 2023	Large prospective cohort study	325129 participants years (FLI)	MASLD was significantly associated with myocardial infarction (HR = 1.35, 95%CI: 1.29-1.41) or stroke (HR = 1.26, 95%CI: 1.18-1.33)
Tang et al[216]	Singapore, 2022	Meta-analysis	30 studies; 7951 patients (biopsy, ultrasonography, CT)	In individuals with MASLD, the incidence of stroke was 5.04% (95%CI: 2.74%-9.09%)
Mahfood Haddad et al[174]	United States, 2017	Systematic review and meta-analysis	6 studies; 25837 patients (elevated transaminases without imaging confirmation)	MASLD had a significantly higher risk of CVE compared to controls (RR = 1.77, 95%CI: 1.26-2.48), while clinical CAD (RR = 2.26, 95%CI: 1.04-4.92) and ischemic stroke (RR = 2.09, 95%CI: 1.46-2.98) were also increased
Alon et al[273]	Italy, 2022	Systematic review and meta-analysis	3254 records; 20 studies (ultrasonography, CT, ICD codes, FLI)	MASLD was associated with an increased risk of MI (OR = 1.66, 95%CI: 1.39-1.99, 95%PI: 0.84-3.30), IS (OR = 1.41, 95%CI: 1.29-1.55, 95%PI: 1.03-1.93), AF (OR = 1.27, 95%CI: 1.18-1.37, 95%PI: 1.07-1.52), and HF (OR = 1.62, 95%CI: 1.43-1.84, 95%PI: 1.04-2.51)
Coronary artery disease and myocardial infarction
Lu et al[223]	China, 2022	Retrospective cross-sectional study	1346 patients (ultrasonography)	The FIB-4 score and NFS were independently associated with CAD. The AST to platelet ratio index was not a significant factor for CAD
Namakchian et al[224]	Iran, 2023	Prospective study	1664 patients (ultrasonography)	FIB-4 score independently correlates with CAD in patients with MASLD
Gastaldelli et al[225]	Italy, 2009	Prospective, observational, cohort study	1307 subjects; 19 centers in 14 European countries (FLI)	FLI was associated with increased CHD risk (r = 0.48)
Wong et al[230]	China, 2011	Prospective cohort study	612 patients (ultrasonography)	After adjusting for demographic and metabolic factors, MASLD (OR = 2.31, 95%CI: 1.46-3.64) remained independently associated with CAD
Toh et al[231]	Singapore, 2022	Meta-analysis	38 articles; 67070 patients (ultrasonography or CT)	The prevalence of CHD was higher in patients with moderate to severe steatosis (37.5%, 95%CI: 15.0%-67.2%) than in those with mild steatosis (29.6%, 95%CI: 13.1%-54.0%)
Emre et al[234]	Turkey, 2015	Prospective cohort study	186 patients (ultrasonography)	Patients with an MASLD score ≥ 3 were more likely to have absent myocardial perfusion (MBG 0/1, 37% vs 12%), absent STR (27% vs 9%), and a higher in-hospital MACE rate (31% vs 8%)
Koh et al[236]	Singapore, 2025	Retrospective observational cohort	5702 patients (HSI)	Non-obesity MASLD had the highest risk of heart failure (P = 0.034), cardiogenic shock (P < 0.001), and all-cause long-term mortality (P = 0.019). The non-obesity MASLD (HR = 1.400, 95%CI: 1.077-1.820, P = 0.012) and obesity MASLD phenotypes (HR = 1.222, 95%CI: 1.005-1.485, P = 0.044) were independently associated with long-term all-cause mortality
Sinn et al[237]	South Korea, 2020	Retrospective cohort analysis	111492 adults over 40 years old (ultrasonography)	Myocardial infarction had an incidence rate of 0.3 cases per 1000 person-years. The age-, sex-, and year-of-visit-adjusted HR for incident myocardial infarction comparing participants with MASLD with those without it was 2.14 (95%CI: 1.59-2.89)
Alexander et al[238]	England, 2019	Matched cohort study	120795 adults (method not reported)	After adjustment for age and smoking, the pooled HR for AMI was 1.17 (95%CI: 1.05-1.30)
Heart failure and structural heart changes
Houghton et al[220]	England, 2019	Cross-sectional study	96 sedentary patients (MRS)	Diastolic variability and systolic variability [LF/HF-SBP (n/1); 2.3 (1.7) vs 3.4 (1.5), P < 0.01] were impaired in patients with MASLD when compared to controls
Targher et al[240]	Italy, 2021	Observational study	356 individuals (ultrasonography)	Individuals with T2D and MASLD (OR = 4.29, 95%CI: 1.90-10.6) and individuals with MASLD alone (OR = 3.41, 95%CI: 1.59-7.29) had an increased risk of having cardiac sympathetic/parasympathetic imbalance
Roderburg et al[243]	Germany, 2023	Retrospective cohort study	173966 patients (method not reported)	MASLD was significantly associated with a subsequent diagnosis of HF (HR = 1.34, 95%CI: 1.28-1.39)
Wu et al[245]	China, 2024	Prospective cohort	96576 participants (ultrasonography)	MASLD was associated with a higher risk of HF (HR = 1.45, 95%CI: 1.31-1.63). In women, MASLD was associated with an 84% increased risk of HF (HR = 1.84, 95%CI: 1.43-2.37), while in men, the risk was 36% (HR = 1.36, 95%CI: 1.20-1.53)
Li et al[247]	China, 2022	A meta-analysis of observational studies	6 cohort studies; 10979967 participants (CT, FLI, biopsy)	In the unadjusted model, MASLD had a greater risk of incident HF (HR = 1.47, 95%CI: 1.25-1.75, I2 = 99%), compared with those without MASLD
Mantovani et al[122]	Italy, 2015	Cross-sectional study	222 patients (ultrasonography)	Patients with MASLD had a remarkably greater prevalence of mild and/or moderate LVDD compared with those without MASLD (71% vs 33%, P < 0.001)
Jung et al[248]	South Korea, 2017	Cross-sectional study	20821 participants (ultrasonography)	The mild and moderate-to-severe MASLD had higher OR for abnormal LV relaxation (mild group 1.29, 95%CI: 1.15-1.46; moderate-to-severe group 1.95, 95%CI: 1.61-2.35) and increased relative wall thickness (> 0.42; mild group 1.26, 95%CI: 1.05-1.52; moderate-to-severe group 1.46, 95%CI: 1.08-1.95)
Fallo et al[249]	Italy, 2009	Observational cross-sectional study	86 patients (ultrasonography)	Patients with MASLD had a similar prevalence of LVH compared to patients without MASLD but a higher prevalence of diastolic dysfunction (62.5% vs 21.1%, P < 0.001), as defined by E/A ratio < 1 and an E-wave deceleration time > 220 ms
Chiu et al[251]	United States, 2020	Cross-sectional study	2356 Framingham Heart Study participants (CT)	MASLD was associated with LV mass (β = 1.45, 95%CI: 0.01-2.88), LV wall thickness (β = 0.01, 95%CI: 0.00-0.02), mass volume ratio (β = 0.02, 95%CI: 0.01-0.03), mitral peak velocity (E) (β = 0.83, 95%CI: 0.31-1.36) and LV filling pressure (E/e’ ratio) (β = 0.16, 95%CI: 0.09-0.23); and inversely associated with global systolic longitudinal strain (β = 0.20, 95%CI: 0.07-0.33), diastolic annular velocity (e’) (β = -0.12, 95%CI: -0.22 to -0.03), and E/A ratio (β = -0.01, 95%CI: -0.02 to -0.00)
VanWagner et al[253]	United States, 2020	Large population-based prospective study	1827 participants (CT)	MASLD had higher LV mass, relative wall thickness, incident LV hypertrophy, and abnormal LV geometry vs non-MASLD (P < 0.02). MASLD had impaired LV relaxation (E/A ratio 1.1 vs 1.2), higher LV filling pressures (E/e’ ratio 7.9 vs 7.2), worse longitudinal strain (-13.9% vs -15.3%), and lower LV ejection fraction (58.9% vs 60.2%, P < 0.01)
VanWagner et al[254]	United States, 2015	Cross-sectional analysis	2713 participants (CT)	MASLD had lower early diastolic relaxation (e’) velocity (10.8 ± 2.6 cm/second vs 11.9 ± 2.8 cm/second), higher LV filling pressure (E/e’ ratio: 7.7 ± 2.6 vs 7.0 ± 2.3), and worse absolute GLS (14.2% ± 2.4% vs 15.2% ± 2.4%) than non-MASLD (P < 0.0001 for all)
Arrhythmias and conduction disorders
Cai et al[261]	China, 2020	Meta-analysis of cohort studies	6 studies; 614673 participants (ultrasonography, CT, FLI)	MASLD was associated with an increased risk of AF (RR = 1.65, 95%CI: 1.23-2.20, I2 = 63.0%). After adjustment for multiple cardiometabolic risk factors, the association was still higher than that in non-MASLD (RR = 1.19, 95%CI: 1.04-1.31, I2 = 54.0%)
Donnellan et al[262]	United States, 2020	Retrospective cohort study	267 patients (ultrasonography, CT, MRI)	MASLD was independently associated with increased rates of arrhythmia recurrence (HR = 3.01, 95%CI: 1.98-4.68, P < 0.0001)
Mantovani et al[263]	Italy, 2016	Retrospective, cross-sectional design	330 patients (ultrasonography)	MASLD was associated with a 35-fold increased risk of ventricular arrhythmias (OR = 3.47, 95%CI: 1.65-7.30)
Targher et al[264]	Italy, 2013	Prospective study	400 patients (ultrasonography)	MASLD was associated with an increased risk of incident AF (OR = 4.49, 95%CI: 1.6-12.9)
Käräjämäki et al[265]	Finland, 2015	Prospective study	958 subjects (ultrasonography)	MASLD was an independent predictor of AF (adjusted OR = 1.88, 95%CI: 1.03-3.45)
Mantovani et al[272]	Italy, 2025	Systematic review and meta-analysis)	16 retrospective cohort studies; approximately 19.5 million participants (liver biopsy, imaging techniques, blood-based scores)	MASLD was significantly associated with an increased risk of developing incident AF (HR = 1.20, 95%CI: 1.10-1.32, I2 = 92%). This risk did not appear to further increase with the severity of liver fibrosis (n = 3 studies, HR = 1.22, 95%CI: 1.18-1.26, I2 = 10%)
Roh et al[274]	South Korea, 2020	Cross-sectional analysis	334280 healthy individuals (FLI)	AF was significantly higher in subjects with higher FLIs. Adjusted HRs indicated that a higher FLI was independently associated with an increased risk for AF (HR between Q4 and Q1 = 1.35, 95%CI: 1.11-1.63)
Targher et al[277]	Italy, 2013	Cross-sectional analysis	702 patients with T2D (ultrasonography)	MASLD was associated with an increased risk of prevalent AF (OR = 3.04, 95%CI: 1.54-6.02)
Mantovani et al[278]	Italy, 2019	Meta-analysis	9 cross-sectional and longitudinal studies; 364919 individuals (ultrasonography, biopsy, FLI)	5 cross-sectional studies showed that MASLD was associated with an increased risk of prevalent AF (OR = 2.07, 95%CI: 1.38-3.10, I2 = 54.7%) 4 longitudinal studies showed that MASLD was independently associated with a 10-year increased risk of incident AF only in T2D patients (n = 1 study; HR = 4.96, 95%CI: 1.42-17.28)
Targher et al[281]	Italy, 2014	Cross-sectional analysis	400 outpatients with T2D (ultrasonography)	MASLD was associated with an increased QTc interval (OR = 2.16, 95%CI: 1.4-3.4). Adjusted OR = 2.26, 95%CI: 1.4-3.7
Hung et al[282]	Taiwan, 2015	Cross-sectional analysis	31116 participants (ultrasonography)	Mild, moderate, and severe MASLD were associated with an increased risk for QTc prolongation (OR = 1.11, 95%CI: 1.01-1.21; OR = 1.61, 95%CI: 1.36-1.9; and OR = 1.31, 95%CI: 1.16-2.24), respectively, in women, and (OR = 1.11, 95%CI: 1.01-1.21; OR = 1.39, 95%CI: 1.22-1.59; and OR = 1.87, 95%CI: 1.16-2.24), respectively, in men
Mantovani et al[283]	Italy, 2017	Single-center, retrospective design	751 patients with T2D (ultrasonography)	Patients with MASLD had a remarkably higher prevalence of any persistent heart block than those without MASLD (31.3% vs 16.7%, P < 0.001). MASLD was associated with an increased risk of prevalent heart block (adjusted OR = 3.04, 95%CI: 1.81-5.10)
Peripheral artery disease
Song et al[285]	China, 2023	Prospective cohort study	6833 participants (ultrasonography)	MASLD was associated with a higher risk of the presence of PAD (adjusted OR = 1.30, 95%CI: 1.19-1.42). MASLD at baseline was associated with a higher risk of incident PAD (adjusted HR = 1.67, 95%CI: 1.17-2.38)
Ciardullo et al[288]	Italy, 2022	Cross-sectional complex survey	3094 participants aged 40 years or older (FLI)	PAD was associated with a higher risk of all-cause (1.8, 95%CI: 1.4-2.4) and cardiovascular mortality (HR = 2.5, 95%CI: 1.5-4.3) after adjustment

CT: Computed tomography; MRI: Magnetic resonance imaging; MRS: Magnetic resonance spectroscopy; FLI: Fatty liver index; ICD: International statistical classification of diseases; T2D: Type 2 diabetes; HSI: Hepatic steatosis index; CAC: Coronary artery calcification; MASLD: Metabolic dysfunction-associated steatotic liver disease; OR: Odds ratio; CI: Confidence interval; CIMT: Carotid intima-media thickness; ba-PWV: Brachial-ankle pulse wave velocity; CVD: Cardiovascular disease; VAT: Visceral adipose tissue; BMI: Body mass index; NFS: Non-alcoholic fatty liver disease fibrosis score; CAP: Controlled attenuation parameter; AAC: Abdominal aortic calcification; HR: Hazard ratio; CVE: Cardiovascular events; RR: Relative risk; PI: Prediction interval; MI: Myocardial infarction; IS: Ischemic stroke; HF: Heart failure; AF: Atrial fibrillation; FIB-4: Fibrosis-4; CAD: Coronary artery disease; AST: Aspartate aminotransferase; CHD: Coronary heart disease; MBG: Myocardial blush grade; STR: ST-segment resolution; MACE: Major adverse cardiovascular events; AMI: Acute myocardial infarction; LF: Low frequency; HF: High frequency; SBP: Systolic blood pressure; LV: Left ventricular; LVDD: Left ventricular diastolic dysfunction; LVH: Left ventricular hypertrophy; GLS: Global longitudinal strain; QTc: Heart rate-corrected QT; PAD: Peripheral artery disease.