Studies have shown that NAFLD strongly associates with increased levels of inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and C-reactive protein (CRP) [19]. In addition, these cytokines are elevated in patients with primary hypertension [20].

Liver is an innate immune organ and the continuing production of metabolites, in this case triglycerides that accumulates in hepatocytes, leads to excessive inflammatory cytokines release, that promotes hepatic steatosis and fibrosis [13,21].

Other mechanisms that are involved in the activation of systemic inflammation are increased release of very-low-density lipoproteins (VLDL) from the overloaded triglyceride hepatocytes that stimulates Toll-like receptors (TLRs) and increased levels of hepatokines (fetuin A and retinol-binding protein 4) [22,23].

The innate immune components and TLRs are playing important roles in the induction and sustenance of hypertension.

Another mechanism that is involved in the development of hypertension is inflammation-induced activation of the renine-angiotensin system (RAS). TNF-α and IL-6 are responsible for the regulation of RAS components, especially angiotensinogen production in the liver and kidney, promoting angiotensin-related hypertension.

Moreover, various clinical evidence has demonstrated the correlation between NAFLD and chronic kidney disease, which is also a cause of hypertension.

In conclusion, these studies contribute to the theory that inflammation that appears in NAFLD is a cause of hypertension that accompanies this affliction [24].

The mechanisms that are behind insulin resistance (IR) and hypertension are the activation of sympathetic nervous system and the renal sodium retention [25]. IR in NAFLD might be caused by a variety of factors, such as: hepatokines secretion, cytokines, and farnesoid X receptors (FXR).

Hepatokines originate from the fatty liver. They are able, through VLDL to alter the fatty acids metabolism. Moreover, they induce inflammation and insulin resistance in other cell types [26]. IR itself, is also responsible for the development of NAFLD [27]. Insulin is responsible for vasodilatation through nitric oxide (NO) production, and in reverse, IR stimulates vasoconstriction, leading also to hypertension.

FXR are identified as a bile acid activated nuclear receptors. They control lipid metabolism by regulating the synthesis, conjugation and transport of the bile acids. In NAFLD, their number is increased and they contribute to the suppression of hepatic FXR-mediated metabolic signaling, which further promotes IR [28].

All of the above considered, it can be stated that IR is, as most, a part of the mechanisms that induce hypertension in NAFLD patients, as it is one of the causes that leads to fatty liver disease.

Asymmetric dimethylarginine (ADMA) is a recently discovered marker of endothelial dysfunction and atherosclerosis. It is generated by breaking down the proteins that were post-translationally methylated at an arginine residue [29]. ADMA is endogenously responsible for the inhibition of nitric oxide synthase (NOS), therefore causing the inhibition of vasodilatation. It has been observed that ADMA levels are significantly higher in patients with NAFLD (liver being the main site of elimination), even without traditional cardiovascular risk factors [29]. In addition, there is evidence that ADMA associates with endothelial dysfunction in patients with hypertension [30]. Several studies have shown that circulating ADMA is increased in subjects with histological-proven NAFLD: one study had only male subjects enrolled, with no morbid obesity, type 2 diabetes mellitus (T2DM), or hypertension, and another one showed that ADMA levels are higher in insulin resistance states [31] and that plasma ADMA levels are decreasing as a response to insulin sensitivity improvement [29,32]. Although several studies have demonstrated the correlation between vasoconstriction, ADMA and NAFLD, further investigation still needs to be done given the heterogeneity of the current studies.

Arterial stiffness results as a consequence of the complex interaction between stable and dynamic effects in cellular and structural components of the vascular wall [33]. The resistance and compliancy of the arteries are determined by two main structural components: elastin and collagen. Their quantity is kept stable by the interplay between production and degradation. Disruption of this balance, stimulated by an inflammatory context, might lead to reduced quantities of normal elastin and overproduction of altered collagen, therefore leading to increased arterial stiffness [34]. One theory that comes into the support of arterial stiffness and NAFLD is inflamed visceral adipose tissue. In this case, NASH might be responsible for releasing inflammatory, pro-thrombotic and oxidative-stress substances and NAFLD interferes with insulin resistance and atherogenic dyslipidemia [35,36,37].

Several studies, most of them with cross-sectional designs [38,39,40,41] confirmed the connection between increased arterial stiffness and NAFLD, independently of any additional cardio-metabolic predisposing factors. The weaknesses of these studies were their designs, that allow only mere correlations to be made and that the mainly diagnostic method used for NAFLD was ultrasonography. Ozturk et al. used biopsy for the diagnosis of NAFLD. They concluded that independently of MetS, NAFLD is responsible for increasing the risk of atherosclerosis and impaired function of the endothelium in adult male subjects [42].

In resume, the possible biological mechanisms that link NAFLD to increased arterial stiffness remain still unknown, but they possibly involve adipokines imbalance and chronic low-grade inflammation [33,43].

Oxidative stress reflects a disparity between the availability of reactive oxygen species (ROS) and cellular antioxidant system. This imbalance leads to the alteration of the cell functions and eventually cellular death [44]. These ROS are produced by the body due to normal intracellular metabolism and have physiological roles at low concentration, but, in high concentration, they can damage deoxyribonucleic acid (DNA) [45]. NAFLD has been suggested to be linked to oxidative stress [13,46].

One major source of oxidative stress is represented by homocysteine and the liver is a major metabolic organ for this. Alterations of the homocysteine metabolism involves impaired re-methylation to methionine and reduced trans sulphuration to cysteine. Therefore, intrahepatic vascular resistance is increased due to impaired NO formation, as homocysteine reduces NO release from sinusoidal endothelial cells and also causes hepatic stellate cell contraction [47]. Moreover, the production of ROS in NAFLD is responsible for the oxidation of low-density lipoproteins (LDL), which induces the transformation of the macrophages into foam cells. This is the first step of the atherosclerotic lesion development [48].

All these particularities described above suggest that oxidative stress is in charge for both increased intrahepatic resistance and atherosclerosis. In addition, clinical evidence has shown that elevated homocysteine levels are associated with hypertension [49].

Axenic animal models have long been used to assess the repercussions that the absence of gut microbiota have.

Regarding NAFLD, it has been observed that the absenteeism of intestinal flora in mice leads to the gathering of active constituent ligands/androstane receptor (CAR), bile acids, bilirubin, and steroid hormones, which lead to alteration of hepatic xenobiotic metabolism, which could favor the development of NAFLD [50]. The mechanisms that are involved in the correlation between gut microbiota and NAFLD are changes in the quantity of energy absorbed from food, changes in the permeability of the intestine, and alterations of the expression of the genes involved in the lipogenesis. In addition, choline and bile acid metabolic signaling pathways are involved mechanisms, along with the production of ethanol in the intestine and interactions with the innate immunity [51].

On the other hand, gut microbiota and, specifically, dysbiosis has an important role in hypertension development [13]. Regarding the effect that dysbiosis has on hypertension, the following mechanisms are involved: inflammation, vasodilatation, and short-chain fatty acids. Intestinal dysbiosis regulates the differentiation and maturation of immune cells, therefore being implied in the systemic inflammatory state [52].

Vasodilatation is a mechanism that protects against hypertension. It seems to be caused by short-chain fatty acids in the presence of specific gut microbes, a process which is mediated through G-coupled protein receptors. The intestinal flora of the patients suffering from prehypertension and hypertension had a larger amount of Prevotella, a type of enteric bacteria, whereas the intestinal flora of controls individuals contained mostly bacteria from the genus Bacteroidetes [52].

So, it can be assumed that there is a correlation between hypertension, NAFLD, and gut dysbiosis.

Although there are consistent data that prove the link between hypertension and NAFLD, genetics research is limited regarding this association [13]. Family studies demonstrate that first degree relatives of the NAFLD patients have a much higher risk of developing the disease than the general population, and same familial distribution has long been proved for primary hypertension [53].

Adiponectin (ADIPOQ) gene (which encodes adiponectin) polymorphisms have been indicated to be the link between hypertension and NAFLD [54]. Adiponectin is a hormone derived from adipocytes. It has an important role in modulating lipid and glucose metabolism [55].

Another gene that was investigated was angiotensin receptor type 1 (AGTR1). In a recent prospective cohort study, the gain-of function A1166C (rs5186) variant in the AGTR1 gene represented a strong predictor for incident NAFLD and associated hypertension. In addition, polymorphism in AGTR1 may influence the risk of liver fibrosis in NAFLD [56].

Regarding the epigenetic changes, they are responsible for the interaction with inherited risk factors and, therefore, determine the susceptibility of NAFLD, hypertension, and cardiovascular disease [57,58].

Although promising research data show a clear link between hypertension and NAFLD, considering genetics and epigenetics, many data are still missing and more detailed investigations should be carried out.

This theory is supported by various studies demonstrating that the higher the liver fat content is the lesser the hepatic insulin sensitivity is.

Kotronen et al. carried out a study where T2DM patients were examined. They concluded that insulin resistance in patients with increased liver fat is due to diminished insulin clearance. Sixty-eight patients with T2DM were compared to a control group containing non-diabetic subjects. Liver steatosis was determined by proton magnetic resonance spectroscopy. The clearance and action of insulin was assessed by the infusion of (3-3H) glucose and by the euglycemic insulin clamp technique. In addition, MRI was used in order to determine the body composition. The results confirmed that type 2 diabetic patients had higher liver fat (54%) and lower insulin clearance (24%) than nondiabetic subjects. In addition, their insulin levels were higher (34 mU/L vs. 25 mU/L) [64].

Jun N-terminal kinases (JNKs) are kinases involved in the survival and differentiation of the cells. They belong to the mitogen-activated protein kinase (MAPK) superfamily [65]. JNKs are involved in insulin resistance and have important roles regarding the β-cells of the pancreas. Those roles are concerning their secretory function and survival. They are activated by inflammatory cytokines. It has been found that insulin resistance is associated with the formation of autophagosomes in pancreatic β-cells [66]. The main mechanisms that are proposed to be responsible for the alteration of the insulin signaling molecules are post-transcriptional modifications. Various kinases are able to phosphorylate the substrate of the insulin receptor. This phosphorylation is responsible for the inhibition of this receptor [67]. TNF- α is a proinflammatory cytokine effector that is over-expressed in obese patients. It can activate JNKs and, therefore, mediate IR by inhibiting insulin signaling in the liver [68].

On the other hand, chronic high concentrations of glucose and leptin induce the secretion of IL-1β from the pancreatic islet, that can also possibly promote β-cell malfunction and death. This mechanism is also mediated by the JNK pathway. Therefore, the inhibition of JNK might protect the pancreatic β-cells from the outcomes that high levels of leptin and glucose have in diabetic patients.

Another reason that leads to insulin resistance is chronic oxidative stress. This mechanism is linked to JNKs that can mediate the consequences that stress has on insulin resistance. This mediation is due to the inhibition of the phosphorylation of insulin receptor substrate 1 (IRS-1). In addition, free fatty acids are able to activate, via JNKs, autophagy in pancreatic β-cells.

Studies have shown that adipokines (cytokines secreted by the adipocytes) are increased in NAFLD patients.

Yilmaz et al. investigated the patients with histological confirmed NAFLD regarding the relationship between the thickness of epicardial fat (EFT), adipokines related to epicardial fat, and coronary flow reserve (CFR). Fifty-four subjects with NAFLD (26 males and 28 females) and 56 control subjects (27 males and 29 females) were analyzed. NAFLD was evaluated by endoscopic ultrasound-guided biopsies. CFR and EFT were assessed by transthoracic cardiac ultrasonography. In addition, enzyme-linked immunosorbent assay (ELISA) was used in order to measure serum levels of vaspin and chemerin. The results proved that CFR was notably lower and EFT significantly higher in subjects with fatty liver disease than in controls. In addition, patients with NAFLD had serum levels of chemerin and vaspin significantly increased compared to controls [69].

Some examples of adipokines are leptin, adiponectin, resistin, and TNF-α. Because adipokines are involved in insulin resistance and inflammation, they might also be involved in NAFLD pathogenesis. TNF-α intercedes with insulin signaling and has also proinflammatory action. It has a major role in the apoptotic and proinflammatory responses to endotoxin [70]. Adiponectin is a protein that has completely opposite effects to TNF-α and also suppresses its secretion [71]. Regarding the lipidic metabolism, adiponectin has anti-lipogenic effects and reduces fat deposition. These effects are due to the inhibition of hepatic gluconeogenesis and also to the suppression of lipogenesis [72]. It has been shown that patients with NAFLD have hypoadiponectinemia, which is linked to CAD and diminished glucose tolerance in non-diabetic individuals [73,74].

The factors that are proposed to be responsible for oxidative stress are hyperinsulinemia, bacterial overgrowth, hepatic iron, and lipid peroxidation [75].

Bacterial overgrowth might increase the hepatic oxidative stress by increasing the endogenous manufacturing of ethanol. Moreover, other mechanisms that may be involved in this process are the activation of inflammatory cytokines and macrophages [76].

It has been shown that patients that undergo chronic peritoneal dialysis only develop hepatic steatosis when insulin is infused to the peritoneal fluid dialysis [77,78]. This effect might be due to the ability of insulin to generate oxidative stress [79]. Another explanation is that insulin has the ability to up-regulate the lipogenic protein, sterol regulatory element-binding protein (SREBP) [80]. On the other hand, recent studies show that insulin might also be involved in apoptosis. This process might be due to insulin’s capacity to cause stress to endoplasmic reticulum, which leads to unfolding protein response [81].

Regarding iron’s prooxidant role, its contribution is still unclear. The only data that comes into the support for its oxidant role suggests that almost 30% of the NAFLD patients have elevated ferritin [82,83,84]. In addition, it has been reported that phlebotomy improves hepatic histology in patients with NAFLD [85]. Further investigations still need to be carried out regarding iron’s role in NAFLD.

The starting point of oxidative stress within the liver in patients with fatty liver disease are the free fatty acids (FFAs). Elevated FFAs act as ligands for peroxisome proliferator-activated receptor, which is in charge of the up-regulating of FFAs oxidation. This process take place in mitochondria, microsomes, and peroxisomes. FFAs oxidation results in hydrogen peroxide, superoxide, and lipid peroxides that generate oxidative stress and consequent lipid peroxidation [86].

Apoptosis is a mechanism that has multiple pathophysiologic causes and takes part in the development of liver injury and steatosis [75]. It affects hepatocytes and natural killer T cells. The causes of apoptosis in NAFLD are increased TNF, hyperinsulinemia, and oxidative stress. TNF serum levels are higher in patients with NAFLD and obesity. It is responsible for increased mitochondrial permeability, impaired mitochondrial respiration, and depleted mitochondrial cytochrome, all mechanisms leading to apoptosis [87,88].

As it was discussed before, hyperinsulinemia is another mechanism responsible for apoptosis. This effect might be due to insulin’s capacity to generate oxidative stress or up-regulate the lipogenic protein, SREBP [79,80]. On the other hand, hyperinsulinemia might also have direct effects on fibrogenesis by increasing the activity of connective tissue growth factor, mainly if hyperglycemia is present [89].

Regarding oxidative stress, malondialdyde (MDA) and hydroxynonenal (HNE) are two of the byproducts. They are able to attract neutrophils, to act as stimulants for hepatic stellate cells and to increase the number of receptors for cytokines and transforming growth factor-β (TGF-β) in macrophages [90]. Oxidative stress can also stimulate the discharge of TNF from the hepatic cells, lipocytes, and macrophages [90]. Hepatic stellate cells have the capacity to engulf the apoptotic bodies, a process that might stimulate their fibrogenic process [91]. Another mechanism that is responsible for hepatocyte deaths is ROS-induced fatty acid synthase (FAS) ligand [92,93].

In conclusion, there is a direct connection between NAFLD and CAD. Despite the fact that the pathophysiologic mechanisms behind this correlation still need further investigation, it is clear that a multidisciplinary approach of these patients must be taken into consideration.

In the OPERA (Oulu Project Elucidating Risk of Atherosclerosis) prospective study, 958 hypertensive subjects and control subjects of the same age and sex were arbitrarily selected from the national registries in 1990s, and the association between atrial fibrillation (AF) and NAFLD was determined. NAFLD was diagnosed by sonography and AF was tracked in the National Registers. The aim of this research was to evaluate the capacity of NAFLD to predict AF. The subjects included in this study were followed-up for 16.3 years. The authors concluded that NAFLD was an independent predictor of AF [94]. Another prospective study carried out by Giovanni et al. followed 400 patients with T2DM over 10 years. The subjects had no AF to start with. They also found out that NAFLD is related to a higher incidence of AF [95].

Recent data have suggested that type 2 diabetes patients with NAFLD have a higher chance of heart rate-corrected QT (QTc) interval prolongation. QT prolongation is a known risk factor for ventricular arrhythmias and sudden cardiac death.

Hung et al. carried out a cross-sectional study that included 31,116 participants. QTc interval was derived from Bazett’s formula and from electrocardiography. Ultrasonography was used to diagnose and classify NAFLD. NAFLD was staged as severe, moderate, mild, or none. The analyses found that mild, moderate, and severe NAFLD were associated with increased QTc interval compared to no NAFLD. The conclusions were that NAFLD was indeed associated with an increased risk of prolonged QTc interval among general population, independently of the presence of diabetes [96].

Another study carried out by Mantovani et al. has retrospectively evaluated 330 patients with T2DM and no end-stage renal disease, preexisting atrial fibrillation, or known liver diseases. The patients undergone 24-h Holter monitoring between 2013 and 2015. NAFLD was diagnosed by ultrasonography. Their study concluded that NAFLD was linked to a higher risk of prevalent ventricular arrhythmias in subjects with T2DM [97].

Matovani et al. carried out a retrospective study assessing whether there is any association connecting fatty liver disease and heart blocks. Seven hundred and fifty-one patients with T2DM were examined during 2007–2014. Atrioventricular blocks were assessed by electrocardiogram and NAFLD was diagnosed by ultrasonography. The study concluded that patients with fatty liver disease had a much higher risk of persistent heart block than those without NAFLD [98].

Currently, it is difficult to ignore the possibility that similar risk factors might be the cause behind cardiac arrhythmias and NAFLD. Obesity is generally associated with NAFLD and AF development [99,100]. On the other hand, both obesity and NAFLD are strongly associated with the accumulation of fat in the epicardium. Epicardial fat is linked to an increased mass of the left ventricle and diastolic dysfunction, the latter being associated with the promotion of AF [101]. Recent studies link NAFLD and diastolic dysfunction. The mechanisms behind this association might be extensive toxic results, mediated through adiponectin, insulin, and inflammation or indirect effects of hypertension or diabetes [102].

On the other hand, NAFLD is also associated with autonomic nervous system dysfunction and so is epicardial fat, dysfunction that is a risk factor for AF [103,104].

Regarding systemic inflammation, there are studies revealing that AF is as most a cause of systemic inflammation as it is a consequence [105], and, as it was discussed before, NAFLD is also associated with systemic inflammation. Moreover, hypoadiponectinemia, a usual finding in NAFLD is also related to AF [106]. This might explain how obesity and inflammation seem to play an important part in the relationship between NAFLD and AF. Taking all this information into consideration, we are still unable to differentiate if NAFLD is a cause of AF without the association of metabolic syndrome or if AF can itself contribute to the progression of NAFLD. Therefore, further studies are still needed in order to evaluate the real contribution of NAFLD to AF. Figure 1 presents the way that NAFLD and obesity increase the risk of developing hypertension.

One study carried out by Lin YK et al. analyzed how adipocytes modulate the electrophysiology of atrial myocytes [15]. They used whole-cell patch clamp in order to record the action potentials and ionic currents in myocytes coming from rabbit left atrium. Myocites were incubated with and without adipocytes belonging to different sites of the body or adipocytes-conditioned supernatant for 2–4 h. Compared to control left atrium myocytes, left atrium myocytes incubated with adipocytes had longer action potentials durations. Left atrium myocytes incubated with adypocites from the epicardium had a more positive resting membrane potential than control left atrium myocytes. However, left atrium myocytes that were incubated with supernatant had longer action potential durations but similar resting membrane potential compared to control myocytes. Moreover, isoproterenol induced a higher incidence of provoked heart beats in left atrium myocytes that were incubated with adipocytes compared to the control group myocytes. All these taken into consideration, they concluded that adipocytes are able to cause arrhythmic heart beats in the myocytes of the left atrium. This might be possible due to adipocytes’ capacity to modulate electrophysiological characteristics and ion currents [107].

Moreover, pro-inflammatory cytokines and protrombotic factors in NAFLD are also linked to increased cardiac structural and arrhythmogenic complications [108].

On the other hand, NAFLD has been shown to be involved in the modifications of the myocardium functions and structure [109]. These modifications may induce fiber discontinuity and circuit re-entry, leading to electrophysiological disturbance [110].

In closing, it might be stated that there is indeed a powerful association between NAFLD and cardiac arrhythmias. Whether the common risk factors of these two entities are the cause or whether NAFLD is itself responsible for cardiac arrhythmias is still poorly investigated and further studies need to be carried on.

Perseghin et al. carried out a study assessing if subjects with fatty liver disease have also modifications regarding the left ventricle (LV). The modifications studied where those concerning the amounts of epicardial fat, the structure, energy metabolism, and function. Forty-two young, non-diabetic men, including 21 with NAFLD and 21 without NAFLD, were investigated. Cardiac MRI, cardiac 31phosphorus-magnetic resonance spectroscopy (31P-MRS) and hepatic 1Hydrogen-MRS (1H-MRS) were used as diagnostic tools. The updated Homeostasis Model Assessment (HOMA-2) computer model was used to determine insulin sensitivity. Systolic and diastolic functions, as well as left ventricular morphology, were not different among the two groups. On the other hand, the authors found out that intrapericardial and extrapericardial adipose tissue was increased in male subjects with fatty liver disease correlated to controls. The phosphocreatine (PCr)/adenosine triphosphate (ATP) ratios is an in vivo marker of myocardial energy metabolism. These ratios were reduced in men with NAFLD. Therefore, they concluded that although the morphological features and systolic and diastolic functions of the LV were normal, the energy metabolism was altered [112].

Despite the studies that show consistent evidence regarding altered heart metabolism, the pathogenic mechanism behind this is ambiguous. Ectopic liver fat accumulation is thought to be due to the increased free fatty acids flux, as it was showed before. Regarding the myocardium, it is known that its main source of energy in the fasting state are FFAs [113]. When the supply of FFAs outreaches the rate of their oxidative disposal, as happens in NAFLD, oxidative stress is induced, with the consequence of increased lipid intermediates and lipotoxicity. Lipotoxicity may be involved in the impairment of energy homeostasis and contractile dysfunction [114]. Other theories that might explain this perturbation, regarding the heart metabolism are the involvement of adipokines and inflammation. Because none of these hypotheses could be confirmed by this study, insulin resistance was thought to also be involved.

Concluding, although strong association between abnormalities in the heart metabolism and NAFLD exists, further studies providing information regarding the pathophysiology still need to be carried out.

In a recent study, Hayrullah et al. assessed the grades of NAFLD and the cardiac functions and associated parameters [115]. Four hundred obese children participated in the study. Ultrasonography was used in order to diagnose NAFLD. Ninety-three children had NAFLD, 307 were in the non-NAFLD group, and these two subgroups were compared to 150 control subjects. In addition, pulsed and tissue Doppler echocardiography were used, and intima-media and epicardial adipose tissue were measured. Fatty liver disease subgroups had increased end-systolic thickness of the interventricular septum and larger left ventricular mass. Moreover, carotid artery intima-media and epicardial adipose tissue thickness were higher in obese children.

One pathologic mechanism that might explain these modifications is the eccentric remodeling of the LV as an effect of adaptation to volume overload. Moreover, central fat distribution is associated to higher cardiac output [116].

On the other hand, it is established that insulin resistance increases the chances for LV dysfunction development. Obese patients have increased levels of insulin and altered insulin sensibility, which is also related to NAFLD, as it was discussed before. Elevated insulin levels stimulate the growth of myocytes and interstitial fibrosis, by sodium retention and activation of sympathetic nervous system [117].

A meta-analysis carried out by Borges et al. noted an important relationship between NAFLD and higher left atrium diameter and ratio between left atrial volume and body surface area [118]. The left atrium is responsible for the filling of the left ventricle, and, on the other hand, the left ventricle function influences the left atrium’s function throughout the cardiac cycle [119]. As a consequence of eccentric remodeling of the LV, LV’s filling pressure increases and leads to left atrium dilatation. Therefore, left atrium remodeling occurs and atrial compliance and contractile functions decrease [120].

Bekler et al. studied systolic and diastolic function of the right ventricle and its association with NAFLD [121]. Thirty-two patients had NAFLD diagnosed by ultrasonography, and 22 represented the control group, i.e., had no NAFLD. The function of the right ventricle was assessed using conventional and tissue Doppler echocardiography. Right ventricle global function was evaluated by myocardial performance index (MPI). They concluded that right ventricular diastolic dysfunction correlated with fatty liver disease and the level of fatty changes.

Regarding this association, there are speculations assuming that the promotion of right ventricular diastolic function is due to the excess of lipid accumulation in hepatocytes, that leads to lipid deposition in cardiac myocytes.

Aortic and mitral valves calcification: Several studies have demonstrated that NAFLD associates with calcium deposits of the aorta and mitral valves [122].

Aortic valve sclerosis is associated with a higher incidence of cardiovascular disease mortality. This statement is valid for both diabetic and non-diabetic patients. In addition, the calcium deposits in the mitral valve are associated with adverse cardiovascular disease outcomes [123]. One mechanism that may explain the link between NAFLD and the calcification of aortic and mitral valves is chronic inflammation. It was discussed in the previous paragraphs how the liver produces inflammatory markers. These are believed to contribute to the acceleration of atherosclerosis, as it is demonstrated in histopathological examinations, which show that valve sclerosis is an inflammatory condition mixed with classic atherosclerotic lesions [124,125].

In addition, insulin resistance might be responsible for the association between hepatic steatosis and aortic valve sclerosis. One small cross-sectional study concluded that increased steatosis of the liver is associated with lower insulin clearance, which contributes to insulin resistance in non-diabetic subjects [126]. However, another study carried out by Marcello et al. [127] provided evidence that clinical diabetes mellitus did not substantially affected the results.

Explanations behind diastolic cardiac dysfunction and NAFLD are systemic inflammation, insulin resistance and increased prevalence of metabolic disorders.

Systemic inflammation is mediated by NAFLD, as it was discussed before. Cytokines are able to modify the structural substrate and electrophysiology of the myocardium. Moreover, this pro-inflammatory condition is associated with inflammation in the coronary microvascular endothelium. This is able to increase the LV diastolic stiffness and lead to cardiac failure [128].

Insulin resistance, a common comorbidity among patients with NAFLD and obesity, alters diastolic function. This is possible due to insulin’s ability to regulate the expression of myosin gene [129].

Metabolic disorders, such as hypertension, are risk factors for diastolic cardiac dysfunction and are frequently associated with NAFLD.

Taking all the information above into consideration, it is likely to assume that fatty liver disease is possibly linked to a higher chance of developing congestive heart failure. Several researches that used elevated aminotransferases levels or serum gamma-glutamyl transferase (GGT) as markers of NAFLD have proven that this disorder is strongly connected to heart failure [130,131].

Regarding GGT, the mechanisms that may speculatively be involved in this association are the presence of GGT in atherosclerotic plaques and that elevated GGT levels might be a marker of increased oxidative stress [132].