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The influence of NAFLD on the risk of atherosclerosis and cardiovascular diseases

The influence of NAFLD on the risk of atherosclerosis and cardiovascular diseases Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed countries and is associated with obesity, dyslipidaemia, diabetes, and metabolic syndrome. Atherosclerosis and cardiovascular diseases are also highly prevalent in this group of patients, due to the presence of shared risk factors. The inci- dences of coronary artery calcification, hypertension, aortic valve sclerosis, diastolic dysfunction, atherosclerotic plaques, and increased carotid intima-media thickness were more common in patients with NAFLD than in those without. The present paper reviews the medical literature concerning the association between NAFLD and cardiovascular events. Key words: non-alcoholic fatty liver disease, ischaemic heart disease, atherosclerosis. Address for correspondence Kamila Wójcik-Cichy, Department of Infectious Diseases and Hepatology, Medical University of Lodz, 1/5 Kniaziewicza St., 91-347 Lodz, Poland, e-mail: camilaw@tlen.pl Introduction ing on age and ethnicity [7]. Types of dyslipidaemia have a significant impact on the prevalence of NAFLD. Non-alcoholic fatty liver disease (NAFLD) is the Mixed hyperlipidaemia is reported in 50% of patients most common chronic liver disease in developed coun- with NAFLD. Isolated hypertriglyceridaemia is report- tries, with a  prevalence ranging from 20% to 30% of ed in 27% of subjects with NAFLD, and hypercholes- the population of Europe. However, experts estimate terolaemia in 17% [8]. An analysis of lipid fractions that NAFLD aeff cts from 25% to 90% of obese pa- in patients with NAFLD revealed a tendency towards tients and 70% of patients with diabetes mellitus [1, 2]. elevated triglyceride levels and low HDL levels in the e hi Th stologic spectrum of NAFLD ranges from simple atherogenic lipid profile [9]. steatosis to nonalcoholic steatohepatitis (NASH) with Insulin resistance contributes to the development of the presence of fibrosis. Simple steatosis tends to be NAFLD. Subclinical inflammation plays also an import- a stable condition, but steatohepatitis may progress to ant role in the pathogenesis of NAFLD. High-sensitivi- liver cirrhosis [3]. Liver failure in the course of NAFLD ty C-reactive protein (Hs-CRP) is elevated in patients is the second most common indication for liver trans- suffering with NAFLD, even in young age; hs-CRP plantation in the USA [4]. may be a  marker of NAFLD [10-12]. Hs-CRP is not NAFLD is diagnosed mostly in patients between associated with severity of NAFLD or NASH [11, 12]. the ages of 40 and 60 years. Although the prevalence Subclinical inflammation also plays the principal role of NAFLD is higher in men, faster progression to cir- in the pathophysiology of atherosclerosis. Hs-CRP is rhosis is noted in women [5]. NAFLD is regarded as a  stronger cardiovascular risk predictor than LDL-C an isolated disease or as a spectrum of metabolic syn- (low-density lipoprotein) [13]. However, many other drome, and is associated with diabetes, obesity, dys- studies have shown that oxidant stress and chronic in- lipidaemia, and hypertension [6]. NAFLD is found in a fl mmation associated with the production of cytokines 30% to 75% of patients with type 2 diabetes, depend- including interleukin (IL) 6, tumour necrosis factor α Clinical and Experimental Hepatology 1/2018 1 Kamila Wójcik-Cichy, Ewa Koślińska-Berkan, Anna Piekarska (TNF-α), pro-coagulant factors, and adipocytokines are diabetes have a 2-4-fold increased risk of cardiovascu- also involved in NAFLD pathogenesis [14, 15]. These lar diseases [23]. Of note, the meta-analysis published risk factors are also strongly related to atherosclerosis. by Ballestri shows that NAFLD is also associated with Patients with NAFLD exhibit a  range of non-tradi- an approximately twofold increased risk of incident of tional risk factors of cardiovascular disease, including metabolic syndrome [24]. Again, Gami et al. in a meta- hyperuricaemia and hypovitamino sis D [16]. In addi- analysis of 37 studies comprising 172,573 patients with tion, shared genetic factors exist between NAFLD and metabolic syndrome, found 1.78-fold higher relative coronary artery heart disease, for instance: gene poly- risk of cardiovascular events in patients with metabolic morphisms of adiponectin-encoding gene (ADIPOQ), syndrome compared to healthy subjects [25]. In another leptin receptor (LEPR), apolipoprotein C3 (APOC3), meta-analysis that incorporated 16 observational stud- peroxisome proliferator-activated receptors (PPAR), ste- ies with 34,043 patients with NAFLD, the authors con- rol regulatory element binding proteins (SREBP), trans- cluded that the presence of NAFLD conferred an OR of membrane 6 superfamily member 2 (TM6SF2), micro- 1.64 for fatal and non-fatal incidence of cardiovascular somal triglyceride transfer protein (MTTP), TNF-α, and events, and the risk appeared to increase with greater manganese superoxide dismutase (MnSOD) [17]. severity of NAFLD [26]. A large number of studies con- firm the relationship between NAFLD and incidence of Association between cardiovascular risk cardiovascular events and death (Table 1). and NAFLD NAFLD and coronary artery disease e in Th dividuals with NAFLD had a  higher risk of 10-year cardiovascular events than healthy individu- An increasing number of studies suggest the presence als. In subjects with and without NAFLD, the mean of a  relationship between NAFLD and coronary artery respective cardiovascular risks according to Framing- heart disease [34, 35]. It is estimated that cancers and ham scoring were 16.0% and 12.7% in men and 6.7% cardiovascular disease are the leading causes of death in and 4.6%, in women [18]. patients with NAFLD [36]. NAFLD is observed in 51% A  meta-analysis of 34 studies (164,494 partici- of patients with mild and insignificant coronary stenosis pants) published between 1965 and 2015 indicates an and in as much as 100% of patients with three ae ff cted increased risk of cardiovascular disease in NAFLD pa- coronary arteries [37]. Perera et al. note the presence of tients, although the prevalence of NAFLD was not asso- NAFLD in 46.7% of patients with acute coronary syn- ciated with mortality from cardiovascular events in this drome [38]. Patients with NAFLD show a  significantly group. The results of this study suggest that NAFLD was higher prevalence of calcified and non-calcified coronary an independent risk factor for the incidence of cardio- plaques than healthy subjects, independent of the inci- vascular events [19]. However, Hamaguchi et al. report dence of metabolic syndrome [39]. Again, the coronary that NAFLD is strongly related to metabolic syndrome. flow reserve (CFR), measured as the maximum increase Because it is important to note that it is extremely dif- in blood flow through the coronary arteries above the ficult to separate the components of metabolic syn- normal resting volume, is significantly lower in patients drome in statistical analysis, Hamaguchi et al. suggest with NAFLD than in healthy subjects [40]. that high cardiovascular risk in patients with NAFLD is not a  consequence of liver disease but of metabolic NAFLD and arrhythmias syndrome [20]. NAFLD is associated with an increased risk of the Association between NAFLD, incidence of arrhythmias, especially the atrial fibril- type 2 diabetes, and cardiovascular risk lation or ventricular tachyarrhythmias typically ob- served in the course of left ventricular diastolic dys- NAFLD is hepatic manifestation of metabolic syn- function [41]. drome and may predict the development of type 2 dia- betes independently of obesity and age [21]. Insulin NAFLD and hypertension resistance is a  key pathogenic factor for NAFLD and type 2 diabetes. The presence of NAFLD increases two- Hypertension is diagnosed in about 50% of patients fold the risk of developing type 2 diabetes over a median period of five years [21]. Ekstedt et al . found that 78% with NAFLD [42]. Hypertension predisposes to the of patients with NAFLD develop type 2 diabetes or im- development of left ventricular hypertrophy and in- paired glucose tolerance [22]. Patients with NAFLD and creases the risk of plaque rupture. 2 Clinical and Experimental Hepatology 1/2018 NAFLD and cardiovascular diseases Table 1. Selected observational studies exploring the risk of cardiovascular disease in patients with non-alcoholic fatty liver disease (NAFLD) Authors, year Study population Follow-up NAFLD Main findings [ref.] length diagnosis Söderberg et al., Retrospective cohort of 118 Swedish patients 24 years Histology Patients with NASH, but not those with simple steatosis, 2010 [27] with NAFLD and raised serum liver enzymes had twofold higher rate of cardiovascular disease than the matched general population. Ekstedt et al., Retrospective cohort of 229 Swedish patients 26.4 ± 5.6 Histology Patients with NAFLD have increased overall mortality 2015 [28] with biopsy-proven NAFLD years (HR 1.29, 95%CI: 1.04-1.59), with a high risk of death from cardiovascular diseases (HR 1.55, 95% CI: 1.11-2.15) and liver-related disease. Stage of fibrosis rather than presence of NASH predicted both overall and disease specific mortality. Fracanzani et al., Prospective case-control study of 125 Italian 10 years Histology NAFLD was independently associated with incident 2016 [29] patients with NAFLD and 250 age-matched and non-fatal coronary heart disease (HR 1.99, and sex-matched control individuals without ultrasound 95% CI: 1.01-3.91). known liver diseases Targher et al., Prospective cohort of 2103 Italian individuals 6.5 years Ultrasound NAFLD was independently associated with increased 2007 [30] with type 2 diabetes without baseline viral risk of fatal and non-fatal cardiovascular disease events hepatitis and cardiovascular disease (HR 1.87, 95% CI: 1.2-2.6). Wong et al., 612 consecutive Chinese patients undergoing 6 years Ultrasound Patients with NAFLD, compared to those without, 2016 [31] coronary angiograms without knowing were more likely to have > 50% stenosis in one or liver disease more coronary arteries. NAFLD was not significantly associated with fatal and non-fatal cardiovascular disease events. Treeprasertsuk et al., Community-based cohort of 309 US patients 11.5 ± 4.1 Ultrasound Patients with NAFLD have a higher 10-year 2012 [32] with NAFLD years and computer cardiovascular disease risk than general population tomography of the same age and sex. Zeb et al., 2016 Prospective cohort study of 4119 US adult 7.6 years Computer NAFLD was independently associated with incident [33] participants who were free of cardiovascular tomography of coronary heart disease events (HR 1.42, disease and known liver disease at baseline 95% CI: 1.00-2.03). (The Multi-Ethnic Study of Atherosclerosis) creased arterial stiffness results from the degeneration NAFLD and atherosclerosis of the extracellular matrix of elastic arteries, apoptosis of endothelial cells, and diffusion of macromolecules into e g Th reater intima-media thickness (IMT) of carotid the arterial wall [50]. e Th decrease in vascular suscepti- arteries represents a  marker of endothelial dysfunction, bility leads to an increase in cardiac aer ft load output and and subclinical atherosclerosis was found in patients with insufficient coronary flow [51]. NAFLD [43]. NAFLD is associated with a high coronary artery calcification score, irrespective of the presence of NAFLD and ischaemic stroke traditional cardiovascular risk factors and metabolic syn- drome [44]. Lower flow-mediated dilation (FMD)-indi- NAFLD was found in 42.7% of ischaemic stroke cated endothelial dysfunction is found in patients with patients and 22.7% of controls in a  population from NAFLD and is associated with an elevated risk of acute Iran. It is estimated that the risk of ischaemic stroke in coronary syndrome and ischaemic stroke [45, 46]. NAFLD sufferers is 1.68-times higher than in the gen- Increased arterial stiffness, as a  marker of cardi- eral population and is associated with the incidence of ac hyper trophy and early atherosclerotic changes, was traditional cardiovascular risk factors [52]. reported in patients with NAFLD [47]. Brachial-ankle pulse wave velocity is used as a simple index of assessing NAFLD and left ventricular systolic arte rial stiffness [48]. Lee et al . reported elevated bra- and diastolic dysfunction chial-ankle pulse wave velocity in patients with NAFLD, independent of conventional cardiovascular risk factors Morphological and functional changes in cardiac and the presence of metabolic syndrome [49]. The in- myocytes are observed in cases of NAFLD [53]. Myo- Clinical and Experimental Hepatology 1/2018 3 Kamila Wójcik-Cichy, Ewa Koślińska-Berkan, Anna Piekarska cardial steatosis is a well-known predictor of diastolic liver tests [70]. We could explain an excellent protec- heart failure [54]. Diastolic dysfunction is three times tion of statin treatment against cardiovascular risk in more common in patients with NAFLD than in the NAFLD patients not only with reduction of fat accu- general population, especially left ventricular relax- mulation in atheromatous plaques but also with reduc- ation correlating with NAFLD Activity Score (NAS) tion of subclinical inflammation and with decrease of [55, 56]. Trovato et al. reported a higher left ventricu- pro-coagulant factors production in the cardiovascu- lar system, especially in coronary arteries [71]. Statin lar mass index in patients with NAFLD [57]. In these patients, there is a significantly greater left ventricular hepatotoxicity is minimal in patients with elevated liv- filling pressure (E/e’ ratio: mitral filling velocity [E]/ er tests [70]. Study published by Ruscica et al. showed early diastolic mitral annular velocity [E/e’] ratio) [55]. that liver fat accumulation is associated with increased However, NAFLD patients with obesity, hypertension, circulating PCSK9 (proprotein convertase subtilisin/ kexin type 9) [72]. PCSK9 inhibitors have significant or diabetes also display impaired left ventricular sys- tolic function [58]. cardiovascular benefit in high-risk patients, but the ef- NAFLD patients tend to demonstrate the presence fect of PCSK9 inhibition on liver fat accumulation and of epicardial adipose tissue [59], which acts as a source liver fibrosis is still unknown [73]. The cardiovascular of pro-inflammatory cytokines and increases the risk benefit of other promising NAFLD treatment options must also be studied in the future. of cardiovascular diseases [60]. In addition, NAFLD is strongly associated with an increased risk of aortic valve Patients with NAFLD possess a  high risk of devel- sclerosis, which is an independent indicator of athero- oping acute or chronic cardiovascular diseases with shared pathogenic factors. Therefore, it is necessary to sclerosis [61]. Aortic stenosis is the most common val- vular heart disease and increases the risk of cardiovas- estimate the cardiovascular risk in patients with NAFLD and to determine the potential benefits of early cardio- cular death [62]. vascular prevention strategies. Histological severity of NAFLD Disclosure and incidence of cardiovascular diseases Authors report no conflict of interest. Byrne et al. reported a  correlation between the risk for cardiovascular mortality and the progression References of NAFLD [63]. Many studies found the stage of liv- er fibrosis and steatosis in NAFLD to be related to 1. Bellentani S, Scaglioni F, Marino M, et al. Epidemiology of the incidence of cardiovascular diseases [64]. Targher non-alcoholic fatty liver disease. Dig Dis 2010; 28: 155-161. 2. Scorletti E, Calder PC, Byrne CD. 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The influence of NAFLD on the risk of atherosclerosis and cardiovascular diseases

Wójcik-Cichy, Kamila; Koślińska-Berkan, Ewa; Piekarska, Anna
Clinical and Experimental Hepatology , Volume 4 (1) – Jan 20, 2018
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Copyright: © 2018 Clinical and Experimental Hepatology
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Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed countries and is associated with obesity, dyslipidaemia, diabetes, and metabolic syndrome. Atherosclerosis and cardiovascular diseases are also highly prevalent in this group of patients, due to the presence of shared risk factors. The inci- dences of coronary artery calcification, hypertension, aortic valve sclerosis, diastolic dysfunction, atherosclerotic plaques, and increased carotid intima-media thickness were more common in patients with NAFLD than in those without. The present paper reviews the medical literature concerning the association between NAFLD and cardiovascular events. Key words: non-alcoholic fatty liver disease, ischaemic heart disease, atherosclerosis. Address for correspondence Kamila Wójcik-Cichy, Department of Infectious Diseases and Hepatology, Medical University of Lodz, 1/5 Kniaziewicza St., 91-347 Lodz, Poland, e-mail: camilaw@tlen.pl Introduction ing on age and ethnicity [7]. Types of dyslipidaemia have a significant impact on the prevalence of NAFLD. Non-alcoholic fatty liver disease (NAFLD) is the Mixed hyperlipidaemia is reported in 50% of patients most common chronic liver disease in developed coun- with NAFLD. Isolated hypertriglyceridaemia is report- tries, with a  prevalence ranging from 20% to 30% of ed in 27% of subjects with NAFLD, and hypercholes- the population of Europe. However, experts estimate terolaemia in 17% [8]. An analysis of lipid fractions that NAFLD aeff cts from 25% to 90% of obese pa- in patients with NAFLD revealed a tendency towards tients and 70% of patients with diabetes mellitus [1, 2]. elevated triglyceride levels and low HDL levels in the e hi Th stologic spectrum of NAFLD ranges from simple atherogenic lipid profile [9]. steatosis to nonalcoholic steatohepatitis (NASH) with Insulin resistance contributes to the development of the presence of fibrosis. Simple steatosis tends to be NAFLD. Subclinical inflammation plays also an import- a stable condition, but steatohepatitis may progress to ant role in the pathogenesis of NAFLD. High-sensitivi- liver cirrhosis [3]. Liver failure in the course of NAFLD ty C-reactive protein (Hs-CRP) is elevated in patients is the second most common indication for liver trans- suffering with NAFLD, even in young age; hs-CRP plantation in the USA [4]. may be a  marker of NAFLD [10-12]. Hs-CRP is not NAFLD is diagnosed mostly in patients between associated with severity of NAFLD or NASH [11, 12]. the ages of 40 and 60 years. Although the prevalence Subclinical inflammation also plays the principal role of NAFLD is higher in men, faster progression to cir- in the pathophysiology of atherosclerosis. Hs-CRP is rhosis is noted in women [5]. NAFLD is regarded as a  stronger cardiovascular risk predictor than LDL-C an isolated disease or as a spectrum of metabolic syn- (low-density lipoprotein) [13]. However, many other drome, and is associated with diabetes, obesity, dys- studies have shown that oxidant stress and chronic in- lipidaemia, and hypertension [6]. NAFLD is found in a fl mmation associated with the production of cytokines 30% to 75% of patients with type 2 diabetes, depend- including interleukin (IL) 6, tumour necrosis factor α Clinical and Experimental Hepatology 1/2018 1 Kamila Wójcik-Cichy, Ewa Koślińska-Berkan, Anna Piekarska (TNF-α), pro-coagulant factors, and adipocytokines are diabetes have a 2-4-fold increased risk of cardiovascu- also involved in NAFLD pathogenesis [14, 15]. These lar diseases [23]. Of note, the meta-analysis published risk factors are also strongly related to atherosclerosis. by Ballestri shows that NAFLD is also associated with Patients with NAFLD exhibit a  range of non-tradi- an approximately twofold increased risk of incident of tional risk factors of cardiovascular disease, including metabolic syndrome [24]. Again, Gami et al. in a meta- hyperuricaemia and hypovitamino sis D [16]. In addi- analysis of 37 studies comprising 172,573 patients with tion, shared genetic factors exist between NAFLD and metabolic syndrome, found 1.78-fold higher relative coronary artery heart disease, for instance: gene poly- risk of cardiovascular events in patients with metabolic morphisms of adiponectin-encoding gene (ADIPOQ), syndrome compared to healthy subjects [25]. In another leptin receptor (LEPR), apolipoprotein C3 (APOC3), meta-analysis that incorporated 16 observational stud- peroxisome proliferator-activated receptors (PPAR), ste- ies with 34,043 patients with NAFLD, the authors con- rol regulatory element binding proteins (SREBP), trans- cluded that the presence of NAFLD conferred an OR of membrane 6 superfamily member 2 (TM6SF2), micro- 1.64 for fatal and non-fatal incidence of cardiovascular somal triglyceride transfer protein (MTTP), TNF-α, and events, and the risk appeared to increase with greater manganese superoxide dismutase (MnSOD) [17]. severity of NAFLD [26]. A large number of studies con- firm the relationship between NAFLD and incidence of Association between cardiovascular risk cardiovascular events and death (Table 1). and NAFLD NAFLD and coronary artery disease e in Th dividuals with NAFLD had a  higher risk of 10-year cardiovascular events than healthy individu- An increasing number of studies suggest the presence als. In subjects with and without NAFLD, the mean of a  relationship between NAFLD and coronary artery respective cardiovascular risks according to Framing- heart disease [34, 35]. It is estimated that cancers and ham scoring were 16.0% and 12.7% in men and 6.7% cardiovascular disease are the leading causes of death in and 4.6%, in women [18]. patients with NAFLD [36]. NAFLD is observed in 51% A  meta-analysis of 34 studies (164,494 partici- of patients with mild and insignificant coronary stenosis pants) published between 1965 and 2015 indicates an and in as much as 100% of patients with three ae ff cted increased risk of cardiovascular disease in NAFLD pa- coronary arteries [37]. Perera et al. note the presence of tients, although the prevalence of NAFLD was not asso- NAFLD in 46.7% of patients with acute coronary syn- ciated with mortality from cardiovascular events in this drome [38]. Patients with NAFLD show a  significantly group. The results of this study suggest that NAFLD was higher prevalence of calcified and non-calcified coronary an independent risk factor for the incidence of cardio- plaques than healthy subjects, independent of the inci- vascular events [19]. However, Hamaguchi et al. report dence of metabolic syndrome [39]. Again, the coronary that NAFLD is strongly related to metabolic syndrome. flow reserve (CFR), measured as the maximum increase Because it is important to note that it is extremely dif- in blood flow through the coronary arteries above the ficult to separate the components of metabolic syn- normal resting volume, is significantly lower in patients drome in statistical analysis, Hamaguchi et al. suggest with NAFLD than in healthy subjects [40]. that high cardiovascular risk in patients with NAFLD is not a  consequence of liver disease but of metabolic NAFLD and arrhythmias syndrome [20]. NAFLD is associated with an increased risk of the Association between NAFLD, incidence of arrhythmias, especially the atrial fibril- type 2 diabetes, and cardiovascular risk lation or ventricular tachyarrhythmias typically ob- served in the course of left ventricular diastolic dys- NAFLD is hepatic manifestation of metabolic syn- function [41]. drome and may predict the development of type 2 dia- betes independently of obesity and age [21]. Insulin NAFLD and hypertension resistance is a  key pathogenic factor for NAFLD and type 2 diabetes. The presence of NAFLD increases two- Hypertension is diagnosed in about 50% of patients fold the risk of developing type 2 diabetes over a median period of five years [21]. Ekstedt et al . found that 78% with NAFLD [42]. Hypertension predisposes to the of patients with NAFLD develop type 2 diabetes or im- development of left ventricular hypertrophy and in- paired glucose tolerance [22]. Patients with NAFLD and creases the risk of plaque rupture. 2 Clinical and Experimental Hepatology 1/2018 NAFLD and cardiovascular diseases Table 1. Selected observational studies exploring the risk of cardiovascular disease in patients with non-alcoholic fatty liver disease (NAFLD) Authors, year Study population Follow-up NAFLD Main findings [ref.] length diagnosis Söderberg et al., Retrospective cohort of 118 Swedish patients 24 years Histology Patients with NASH, but not those with simple steatosis, 2010 [27] with NAFLD and raised serum liver enzymes had twofold higher rate of cardiovascular disease than the matched general population. Ekstedt et al., Retrospective cohort of 229 Swedish patients 26.4 ± 5.6 Histology Patients with NAFLD have increased overall mortality 2015 [28] with biopsy-proven NAFLD years (HR 1.29, 95%CI: 1.04-1.59), with a high risk of death from cardiovascular diseases (HR 1.55, 95% CI: 1.11-2.15) and liver-related disease. Stage of fibrosis rather than presence of NASH predicted both overall and disease specific mortality. Fracanzani et al., Prospective case-control study of 125 Italian 10 years Histology NAFLD was independently associated with incident 2016 [29] patients with NAFLD and 250 age-matched and non-fatal coronary heart disease (HR 1.99, and sex-matched control individuals without ultrasound 95% CI: 1.01-3.91). known liver diseases Targher et al., Prospective cohort of 2103 Italian individuals 6.5 years Ultrasound NAFLD was independently associated with increased 2007 [30] with type 2 diabetes without baseline viral risk of fatal and non-fatal cardiovascular disease events hepatitis and cardiovascular disease (HR 1.87, 95% CI: 1.2-2.6). Wong et al., 612 consecutive Chinese patients undergoing 6 years Ultrasound Patients with NAFLD, compared to those without, 2016 [31] coronary angiograms without knowing were more likely to have > 50% stenosis in one or liver disease more coronary arteries. NAFLD was not significantly associated with fatal and non-fatal cardiovascular disease events. Treeprasertsuk et al., Community-based cohort of 309 US patients 11.5 ± 4.1 Ultrasound Patients with NAFLD have a higher 10-year 2012 [32] with NAFLD years and computer cardiovascular disease risk than general population tomography of the same age and sex. Zeb et al., 2016 Prospective cohort study of 4119 US adult 7.6 years Computer NAFLD was independently associated with incident [33] participants who were free of cardiovascular tomography of coronary heart disease events (HR 1.42, disease and known liver disease at baseline 95% CI: 1.00-2.03). (The Multi-Ethnic Study of Atherosclerosis) creased arterial stiffness results from the degeneration NAFLD and atherosclerosis of the extracellular matrix of elastic arteries, apoptosis of endothelial cells, and diffusion of macromolecules into e g Th reater intima-media thickness (IMT) of carotid the arterial wall [50]. e Th decrease in vascular suscepti- arteries represents a  marker of endothelial dysfunction, bility leads to an increase in cardiac aer ft load output and and subclinical atherosclerosis was found in patients with insufficient coronary flow [51]. NAFLD [43]. NAFLD is associated with a high coronary artery calcification score, irrespective of the presence of NAFLD and ischaemic stroke traditional cardiovascular risk factors and metabolic syn- drome [44]. Lower flow-mediated dilation (FMD)-indi- NAFLD was found in 42.7% of ischaemic stroke cated endothelial dysfunction is found in patients with patients and 22.7% of controls in a  population from NAFLD and is associated with an elevated risk of acute Iran. It is estimated that the risk of ischaemic stroke in coronary syndrome and ischaemic stroke [45, 46]. NAFLD sufferers is 1.68-times higher than in the gen- Increased arterial stiffness, as a  marker of cardi- eral population and is associated with the incidence of ac hyper trophy and early atherosclerotic changes, was traditional cardiovascular risk factors [52]. reported in patients with NAFLD [47]. Brachial-ankle pulse wave velocity is used as a simple index of assessing NAFLD and left ventricular systolic arte rial stiffness [48]. Lee et al . reported elevated bra- and diastolic dysfunction chial-ankle pulse wave velocity in patients with NAFLD, independent of conventional cardiovascular risk factors Morphological and functional changes in cardiac and the presence of metabolic syndrome [49]. The in- myocytes are observed in cases of NAFLD [53]. Myo- Clinical and Experimental Hepatology 1/2018 3 Kamila Wójcik-Cichy, Ewa Koślińska-Berkan, Anna Piekarska cardial steatosis is a well-known predictor of diastolic liver tests [70]. We could explain an excellent protec- heart failure [54]. Diastolic dysfunction is three times tion of statin treatment against cardiovascular risk in more common in patients with NAFLD than in the NAFLD patients not only with reduction of fat accu- general population, especially left ventricular relax- mulation in atheromatous plaques but also with reduc- ation correlating with NAFLD Activity Score (NAS) tion of subclinical inflammation and with decrease of [55, 56]. Trovato et al. reported a higher left ventricu- pro-coagulant factors production in the cardiovascu- lar system, especially in coronary arteries [71]. Statin lar mass index in patients with NAFLD [57]. In these patients, there is a significantly greater left ventricular hepatotoxicity is minimal in patients with elevated liv- filling pressure (E/e’ ratio: mitral filling velocity [E]/ er tests [70]. Study published by Ruscica et al. showed early diastolic mitral annular velocity [E/e’] ratio) [55]. that liver fat accumulation is associated with increased However, NAFLD patients with obesity, hypertension, circulating PCSK9 (proprotein convertase subtilisin/ kexin type 9) [72]. PCSK9 inhibitors have significant or diabetes also display impaired left ventricular sys- tolic function [58]. cardiovascular benefit in high-risk patients, but the ef- NAFLD patients tend to demonstrate the presence fect of PCSK9 inhibition on liver fat accumulation and of epicardial adipose tissue [59], which acts as a source liver fibrosis is still unknown [73]. The cardiovascular of pro-inflammatory cytokines and increases the risk benefit of other promising NAFLD treatment options must also be studied in the future. of cardiovascular diseases [60]. In addition, NAFLD is strongly associated with an increased risk of aortic valve Patients with NAFLD possess a  high risk of devel- sclerosis, which is an independent indicator of athero- oping acute or chronic cardiovascular diseases with shared pathogenic factors. Therefore, it is necessary to sclerosis [61]. 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