Risk of cardiovascular, cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease

Table 1 Main cross-sectional study examining the association of non-alcoholic fatty liver disease with the presence and severity of clinical coronary heart disease, ordered by year

Ref.	Study characteristics	NAFLD diagnosis	CHD diagnosis	Main findings
Lin et al[31], 2005	2088 male workers undergoing an annual health examination screening; NAFLD in 29.5%	US	Patient history, ECG	NAFLD associated with higher prevalence of CHD, independently of obesity and other traditional CVD risk factors. The odds for CHD increased progressively with ultrasonographic severity of NAFLD
Targher et al[32], 2007	2839 type 2 diabetic outpatients; NAFLD in 69.5%	US	Patient history, review of patient records, ECG, doppler ultrasound of carotid and lower limb arteries	NAFLD associated with higher prevalence of coronary, cerebrovascular and peripheral vascular disease than their counterparts without NAFLD, independently of traditional CVD risk factors, hemoglobin A1c, medication use and MetS features
Arslan et al[33], 2007	92 consecutive Turkish patients admitted with ACS; NAFLD in 70%	US	CAG (elective)	NAFLD was an independent predictor of CHD (> 50% stenosis of ≥ 1 major coronary artery) after adjustment for traditional CVD risk factors and MetS features
Mirbagheri et al[34], 2007	317 Iranian patients admitted for either ACS, angina or suspected CHD; NAFLD in 54%	US	CAG (elective)	NAFLD was an independent predictor of "clinically relevant" CHD (> 30% stenosis of ≥ 1 major coronary artery) after adjustment for CVD risk factors and MetS features
Alper et al[35], 2008	80 Turkish patients with MS (stable or unstable angina, prognostic reasons); NAFLD in 54%	US	CAG (acute and elective)	NAFLD was the only independent predictor of severe CHD (> 70% stenosis of ≥ 1 major coronary artery) after adjustment for established CVD risk factors and MetS features
Akabame et al[36], 2008	298 consecutive Japanese patients with suspected CHD; NAFLD in 20%	CT	CT (elective)	NAFLD was independently associated with remodeling lesions or lipid core of coronary plaques but not with calcified coronary plaques or stenosis
Açikel et al[37], 2009	355 consecutive Turkish patients admitted for ACS or CHD suspicion; NAFLD in 60%	US	CAG (acute and elective)	NAFLD was an independent predictor of CHD (> 50% stenosis of ≥ 1 major coronary artery) after adjustment for conventional CVD risk factors
Assy et al[38], 2010	29 Israeli patients with low or intermediate risk of CHD and NAFLD and 32 healthy controls matched for age and sex	CT	CT (elective)	NAFLD was associated with greater prevalence of calcified and non-calcified coronary plaques, independently of the MetS and plasma C-reactive protein
Targher et al[39], 2010	250 type 1 diabetic patients; NAFLD in 44.4%	US	Patient history, chart review, ECG, doppler ultrasound of carotid and lower limb arteries	NAFLD was associated with higher prevalence of coronary, cerebrovascular and peripheral vascular disease than their counterparts without NAFLD, independently of traditional CVD risk factors, medication use, hemoglobin A1c, and albuminuria
Sun et al[40], 2011	542 hospitalized Chinese patients with high suspicion of CHD; NAFLD in 46%	CT	CAG (elective)	NAFLD was associated with greater severity of CHD, independently of traditional CVD risk factors
Wong et al[41] 2011	612 Chinese patients with suspicion of CHD; NAFLD in 58%	US	CAG (elective)	NAFLD was associated with CHD, independently of established CVD risk factors and MetS features
Domanski et al[42], 2012	377 patients with NAFLD (retrospective chart review); 219 of these patients had NASH	Biopsy	History of CVD (stroke, unstable angina, myocardial infarction, congestive heart failure, or need for coronary revascularization)	No increased prevalence of CVD in NASH patients compared with those with non-NASH fatty liver
Agaç et al[43], 2013	80 Turkish patients with ACS; NAFLD in 81%	US	CAG (acute)	NAFLD was independently associated with a greater severity of CHD (by Syntax score)
Boddi et al[44], 2013	95 consecutive non-diabetic Italian patients admitted for ACS; NAFLD in 87%	US	CAG (acute)	Presence and severity of NAFLD was independently associated with a three-fold higher risk of multi-vessel CHD
Inci et al[45], 2013	136 consecutive Turkish patients with CHD (stable angina or positive stress test results)	US	CAG (elective)	NAFLD was associated with greater severity of CHD, independently of traditional CVD risk factors

ACS: Acute coronary syndrome; NAFLD: Non-alcoholic fatty liver disease; CAG: Coronary angiography; CT: Computed tomography; CVD: Cardiovascular disease; ECG: Electrocardiogram; MetS: Metabolic syndrome; NASH: Non-alcoholic steatohepatitis; US: Ultrasonography.

Table 2 Main prospective studies relating non-alcoholic fatty liver disease to increased risk of incident coronary heart disease or cardiovascular events, ordered by methodology used for the diagnosis of non-alcoholic fatty liver disease

Ref.	Study characteristics	Years of follow-up	NAFLD diagnosis	Study outcomes	Main findings
Fraser et al[47], 2007	Meta-analysis of 10 population-based cohort studies	7.3	Liver enzymes	Fatal and non-fatal CVD events	Elevated serum GGT level was associated with increased incidence of CVD events, independently of alcohol intake and traditional CVD risk factors
Schindhelm et al[48], 2007	Population-based cohort, n = 1439 subjects (Hoorn Study)	10.0	Liver enzymes	Fatal and non-fatal CHD events	Elevated serum ALT level was associated with CHD events, independently of the MetS and traditional CVD risk factors
Goessling et al[49], 2008	Community-based cohort, n = 2812 (Framingham Offspring Heart Study)	20.0	Liver enzymes	Fatal and non-fatal CVD events	Elevated serum ALT level was not associated with CVD events at multivariate analyses
Dunn et al[50], 2008	Population-based cohort, n = 7574 (NHANES-III)	8.7	Liver enzymes	All-cause and cause- specific mortality	Increased all-cause and CVD mortality rates in NAFLD but only in 45-54 year age group, independently of conventional CVD risk factors and C-reactive protein
Ong et al[51], 2008	Population-based cohort, n = 11285 subjects (NHANES-III)	8.7	Liver enzymes	All-cause and cause- specific mortality	Increased rates of all-cause, CVD and liver-related mortality in NAFLD. Liver disease was the third leading cause of death among persons with NAFLD after CVD and cancer-related mortality
Ruhl et al[52], 2009	Population-based cohort, n = 14950 (NHANES-III)	8.8	Liver enzymes	All-cause and cause- specific mortality	Elevated serum GGT level was associated with mortality from all causes, liver disease but not from CVD causes. Serum ALT level was associated only with liver disease mortality
Yun et al[53], 2009	Community-based cohort, n = 37085 (Health Promotion Center)	5.0	Liver enzymes	CVD or diabetes-related mortality	Elevated serum ALT level was independently associated with increased CVD or diabetes-related mortality
Calori et al[54], 2011	Community based-cohort, n = 2074 (Cremona study)	15.0	FLI index	All-cause and cause- specific mortality	FLI was independently associated with all-cause, hepatic, cancer and CVD mortality. When HOMA-insulin resistance was included in multivariate analyses, FLI retained its statistical association with hepatic-related mortality but not with all-cause, CVD and cancer-related mortality
Lerchbaum et al[55], 2013	Consecutive sample of patients, n = 3270 subjects routinely referred to coronary angiography	7.7	FLI index	All-cause and cause- specific mortality	High FLI was independently associated with increased all-cause, CVD, non-cardiovascular and cancer mortality
Jepsen et al[56], 2003	Population-based cohort, n = 1804 with hospital diagnosis of NAFLD (Danish national registry of patients)	16.0	US	All-cause and cause- specific mortality	Increased rates of all-cause, CVD and liver-related mortality in NAFLD, independently of sex, diabetes, and cirrhosis at baseline
Targher et al[57], 2007	Outpatient cohort, n = 2103 type 2 diabetic subjects (Valpolicella Heart Diabetes Study)	6.5	US	Fatal and non-fatal CVD	Increased rates of fatal and non-fatal CVD events in NAFLD, independently of age, sex, body mass index, smoking, diabetes duration, hemoglobin A1c, LDL-cholesterol, MetS features, medication use
Soler Rodriguez et al[58], 2007	Community-based cohort, n = 1637 healthy Japanese	5.0	US	Non-fatal CVD events	Increased rates of non-fatal CVD events in NAFLD, independently of age, sex, body mass index, alcohol intake, smoking, LDL-cholesterol, MetS features
Lazo et al[59], 2011	Population-based cohort, n = 11371 (NHANES-III)	14.5	US	All-cause and cause-specific mortality	NAFLD was not associated with increased all-cause and cause-specific (CVD, cancer and liver) mortality
Stepanova et al[60], 2012	Population-based cohort, n = 11613 (NHANES-III)	14.2	US	All-cause and cause-specific mortality	NAFLD was associated with increased prevalence of CVD, after adjusting for established CVD risk factors, but not with increased CVD mortality
Zhou et al[61], 2012	Community-based cohort study, n = 3543 adult men and women	4.0	US	All-cause and CVD mortality	Increased rates of all-cause and CVD mortality in NAFLD
Younossi et al[62], 2013	Population-based cohort, n = 1448 with NAFLD (NHANES-III)	14.2	US	All-cause and cause- specific mortality	NAFLD was independently associated with increased all-cause, CVD and liver-related mortality only among NAFLD patients with the MetS
Haring et al[63], 2009	Population-based cohort, n = 4160 German subjects (Study of Health in Pomerania)	7.2	US and liver enzymes	All-cause and CVD mortality	Elevated serum GGT level was independently associated with increased all-cause and CVD mortality in men
Kim et al[64], 2013	Population-based cohort, n = 1154 (NHANES-III)	14.5	US and advanced fibrosis score systems	All-cause and cause- specific mortality	NAFLD was not associated with increased all-cause mortality. However, NAFLD with advanced hepatic fibrosis (defined by NAFLD fibrosis score, APRI index or Fib-4) was independently associated with risk of all-cause mortality, of which the majority of deaths were due to CVD
Treeprasertsuk et al[65], 2012	Community-based cohort, n = 309 patients with NAFLD	11.5	US and CT	Fatal and non-fatal CHD	NAFLD patients had a higher 10-year CHD risk by FRS than the general population of the same age and sex. Almost identical number of FRS-predicted and actual new CHD events
Matteoni et al[66], 1999	Patient-based cohort, n = 132 NAFLD	18.0	Histology	All-cause and cause-specific mortality	Increasing liver-related mortality with the severity of NAFLD histology (according to four different histological subtypes). All-cause mortality and other causes of mortality were not significantly different across histological subtypes
Dam-Larsen et al[67], 2004	Patient-based cohort (Danish national registry of patients), n = 109 subjects with non-alcoholic SS	16.7	Histology	All-cause and cause-specific mortality	All-cause and cause-specific mortality did not significantly differ between patients with non-alcoholic SS and the general population
Adams et al[68], 2005	Community-based cohort, n = 420 patients with NAFLD	7.6	US/CT and histology	All-cause and cause-specific mortality	Increased rate of age- and sex-adjusted all-cause mortality in NAFLD than in the general population with CHD being the second cause of death
Ekstedt et al[69], 2006	Patient-based cohort, n = 129 consecutive patients with NAFLD and elevated serum liver enzymes (55% NASH)	13.7	Histology	All-cause and cause-specific mortality	Increased rates of CVD and liver-related mortality in patients with NASH, but not in those with SS, compared with in the reference population
Rafiq et al[70], 2009	Patient-based cohort, n = 173 patients with NAFLD (41.6% NASH)	13.0	Histology	All-cause and cause-specific mortality	CHD was the first cause of death in NAFLD cohort with no difference between NASH and non-NASH. Liver-related mortality, but not all-cause mortality, was higher in NASH vs non-NASH. No comparison was provided with the general population
Söderberg et al[71], 2010	Patient-based cohort, n = 118 patients with NAFLD and elevated serum liver enzymes (43% NASH)	24.0	Histology	All-cause and cause-specific mortality	Increased mortality rates of CVD, malignancy and liver disease in patients with NASH, but not in those with SS, compared with the matched general population

AST: Alanine aminotransferase; CHD; Coronary heart disease; CT: Computed tomography; US: Ultrasonography; FLI: Fatty liver index; FRS: Framingham risk score; GGT: Gamma-glutamyltransferase; HOMA: Homeostasis model assessment; MetS: Metabolic syndrome; NASH: Non-alcoholic steatohepatitis; SS: Simple steatosis; CVD: Cardiovascular.

Table 3 Cardiac imaging studies relating -non-alcoholic fatty liver disease to structural and arrhythmogenic cardiac complications

	Ref.	Study characteristics	NAFLD diagnosis	Study measures	Main findings
Abnormalities in myocardial metabolism	Lautamaki et al[28], 2006	55 consecutive type 2 diabetic adults with known CHD	1H-MRS	Cardiac PET using [15O]-water and [18F]-2-fluoro-2-deoxy-D-glucose	Decreased coronary functional capacity and myocardial glucose uptake in NAFLD. These abnormalities were worse in those with higher intra-hepatic fat content
	Perseghin et al[7], 2008	Case-control: 21 nondiabetic, nonobese, normotensive, young men with NAFLD and 21 age- and BMI-matched male controls	1H-MRS	Cardiac 31P-MRS and MRI	Impaired LV energy metabolism in NAFLD, independently of age, BMI, blood pressure, lipids, fasting glucose. LV mass and function were not different between the groups
	Rijzewijk et al[74], 2008	Case-control: 38 uncomplicated type 2 diabetic men without CHD and 28 age, sex- and BMI-matched healthy controls	1H-MRS	Cardiac 1H-MRS and MRI	Myocardial fat content, which was much higher in diabetics than in control subjects, was positively associated with intra-hepatic fat content in both groups. Myocardial steatosis was a strong predictor of LV diastolic dysfunction
	Rijzewijk et al[75], 2010	61 uncomplicated type 2 diabetic men without CHD (32 of whom with high intra-hepatic triglyceride content)	1H-MRS	Cardiac MRI, 31P-MRS and cardiac PET using [15O]-water, [11C]-palmitate, and [18F]-2-fluoro-2-deoxy-D-glucose	Decreased myocardial perfusion, glucose uptake and impaired LV energy metabolism in NAFLD. Cardiac fatty acid metabolism, LV mass and function were not different between the two groups
Cardiac structure and function in adults	Goland et al[76], 2006	Case-control: 38 non-diabetic, normotensive NAFLD patients and 25 age- and sex-matched healthy controls	US and biopsy (29% of cases)	Echocardiography with TDI	Increased LV mass and increased prevalence of diastolic dysfunction in NAFLD. Reduced E’ wave only independent parameter associated with NAFLD on multivariate analysis
	Fallo et al[77], 2009	Case-control: newly-diagnosed untreated hypertensive patients (non-obese, non-diabetic): 48 NAFLD vs 38 controls	US	Echocardiography	Increased prevalence of diastolic dysfunction in NAFLD (according to its severity on ultrasound). LV mass was not different between the groups. Diastolic dysfunction and insulin resistance were independently associated with NAFLD
	Fotbolcu et al[78], 2010	Case-control: 35 nondiabetic, normotensive NAFLD patients and 30 age- and sex-matched healthy controls	US	Echocardiography with TDI	Increased LV mass and early impairment in systolic and diastolic function in NAFLD (no adjustment for potential confounders was made)
	Mantovani et al[79], 2011	116 consecutive older patients with hypertension and type 2 diabetes (53% of whom had NAFLD) without history of CHD and hepatic diseases	US	Echocardiography	Increased prevalence of LV hypertrophy in NAFLD. NAFLD was associated with LV hypertrophy independently of age, sex, BMI, systolic blood pressure, kidney function parameters and other diabetes-related variables
	Bonapace et al[8], 2012	50 consecutive type 2 diabetic patients without CHD and hepatic diseases (32 patients had NAFLD)	US	Echocardiography with TDI (speckle tracking analyses)	Impairment in LV diastolic function (including global longitudinal diastolic strain) in NAFLD, independently of age, sex, BMI, hypertension and other diabetes-related variables. These abnormalities were worse in those with severe NAFLD on ultrasonography. No differences in LV mass and systolic function between the groups
	Hallsworth et al[80], 2013	Case-control: 19 non-diabetic, overweight adults with NAFLD and 19 age-, sex- and BMI-matched healthy controls	1H-MRS	Cardiac MRI and 31P-MRS	Early impairment in systolic and diastolic function in NAFLD. Myocardial energy metabolism and LV mass were not altered in NAFLD
Cardiac structure and function in children or adolescents	Alp et al[81], 2013	Case-control: 400 obese children (93 with NAFLD) and 150 age- and sex-matched healthy controls	US	Echocardiography with TDI	Increased LV mass and early impairment in systolic and diastolic function in obese children with NAFLD independently of traditional cardiac risk factors. These abnormalities were worse in those with severe NAFLD on ultrasonography
	Singh et al[82], 2013	Case-control: 14 lean adolescents, 15 obese adolescents without NAFLD and 15 obese adolescents with NAFLD	1H-MRS	Echocardiography with TDI (speckle tracking analyses)	Decreased rates of LV global longitudinal systolic strain and early diastolic strain in obese adolescents with NAFLD independently of traditional cardiac risk factors. LV mass was not different between the groups
	Sert et al[83], 2013	Case-control: 108 obese adolescents and 68 healthy controls	US	Echocardiography with TDI (speckle tracking analyses)	Increased LV mass and impaired diastolic function and altered global systolic and diastolic myocardial performance in obese adolescents with NAFLD
	Pacifico et al[84], 2013	Case-control: 108 obese children (54 with NAFLD) and 18 lean healthy controls	MRI and biopsy (in 41 obese children)	Echocardiography with TDI	Early impairment in systolic and diastolic function in obese children with NAFLD independently of traditional cardiac risk factors. These abnormalities were more severe in those with NASH
Risk of atrial fibrillation	Sinner et al[87], 2013	Community-based cohort of 3744 adult individuals free of clinical HF (from the Framingham Heart Study original and Offspring cohorts)	Liver enzymes	Incidence of AF over up 10 yr of follow-up	Mildly elevated serum transaminases were associated with increased incidence of AF, independently of age, sex, BMI, systolic blood pressure, electrocardiographic PR interval, anti-hypertensive treatment, smoking, diabetes, valvular heart disease, alcohol consumption
	Targher et al[9], 2013	Hospital-based sample of 702 patients with type 2 diabetes without a history of hepatic diseases, or excessive alcohol intake (73% of them had NAFLD)	US	Prevalence of persistent or permanent AF	Increased prevalence of AF in those with NAFLD, independently of age, sex, systolic blood pressure, hemoglobin A1c, estimated glomerular filtration rate, total cholesterol, electrocardiographic left ventricular hypertrophy, chronic obstructive pulmonary disease, and prior history of heart failure, valvular heart disease or hyperthyroidism
	Targher et al[10], 2013	Random sample of 400 type 2 diabetic outpatients free from AF, moderate-to-severe heart valve disease and known causes of chronic liver diseases at baseline (70% of them had NAFLD)	US	Incidence of AF over 10 yr of follow-up	Increased incidence of AF in those with NAFLD, independently of age, sex, prior history of HF, BMI, systolic blood pressure, anti-hypertensive treatment, electrocardiographic LV hypertrophy, PR interval

BMI: Body mass index; CHD: Coronary heart disease; LV: Left ventricular; MRI: Magnetic resonance imaging; MRS: Magnetic resonance spectroscopy; TDI: Tissue doppler imaging; US: Ultrasonography; E’: Mitral annular tissue doppler early diastolic velocity; NAFLD: Non-alcoholic fatty liver disease; AF: Atrial fibrillation; HF: Heart failure.