Analysis of probable lipotoxic damage and myocardial fibrosis in epicardial obesity

Introduction

Obesity is a chronic disease and leads to the development of numerous complications, which often require an interdisciplinary scientific treatment approach [1]. Obesity is associated with numerous metabolic disorders, including insulin resistance development, increased blood pressure, dyslipidemia, oxidative stress, systemic inflammation, and sympathetic nervous system activation. These disorders affect the morphology and structure of the heart and ultimately its function [2]. The neurohumoral factors controlling these metabolic disorders are produced in white adipose tissues (both subcutaneous and visceral). However, due to the characteristics of innervation, blood supply, and local receptor activities, visceral adipose tissue is accountable for the bulk of specific neurohormones released into the bloodstream [3]. In general, obesity is characterized by chronic inflammation and increased expression and release of proinflammatory neurohumoral factors, including adipokines such as leptin and adiponectin, and proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1 and IL-6 [4]. Proinflammatory cytokines produced by adipose tissue contribute to both local and systemic proinflammatory responses [5]. The excess adipose tissue in ectopic local fat depots, which include epicardial adipose tissue (EAT), is a source of surplus free fatty acids (FFA), pro-inflammatory cytokines, and adipokines, including leptin, resistin, visfatin, galectin, and omentin [6–10]. However, increased epicardial adipose tissue is associated with a decrease in the synthesis of adiponectin, and this can trigger complex pathophysiological mechanisms resulting in the development of myocardial fibrosis [6–10]. In addition, there is a strong correlation between obesity and leptin resistance (LR), and this results in the development of metabolic syndrome, and, ultimately, the progression of cardiovascular complications. At the core of LR is LR in the hypothalamus and a decrease in the number of leptin receptors [11]. In particular, there is a well-established relationship between obesity and chronic heart failure (CHF) development [12–14]. During obesity, CHF develops as a result of metabolic disorders of the myocardium, and they occur due to visceral obesity [2]. Studies have shown that elevated levels of IL-6, IL-2, and TNF-α are associated with CHF and left ventricle (LV) subclinical dysfunction [3]. Upregulation of these neurohumoral factors contributes to the development of fibrosis and to unfavorable variants of cardiac remodeling [5]. Adipokines play an essential regulatory role in myocardial function and dysfunction given their involvement in myocardial metabolism, myocyte hypertrophy processes, cell death, and extracellular matrix (ECM) structure and composition. A direct regulation of myocardial remodeling components (including matrix metalloproteins (MMPs), tissue metalloproteinase inhibitor, and collagen) by adipokines has been demonstrated in in-vitro and in-vivo studies [6].

The development of myocardial fibrosis in epicardial obesity (EO) is characterized by progressing diastolic dysfunction, which leads to CHF (when the ejection fraction is retained). In real-world clinical practice, diastolic dysfunction is usually detected by echocardiography (ECG) in a rather late stage. Therefore, it is necessary to search for markers to detect myocardial fibrosis at an earlier stage. The purpose of this study was to study the relationship of EO and neurohumoral activity of EAT with the level of markers of fibrosis.

Results

Discussion

Visceral adipose tissue produces a large number of cytokines and adipokines, leading to metabolic and morphological changes. Thus, TNF-α, a widely study cytokine, plays a key role in the pathogenesis and progression of left ventricular remodeling, and its excessive amount leads to myocardial fibrosis and cardiomyocyte apoptosis [4]. It has been shown that TNF-α leads to insulin resistance, which increases the release of FFA [16], the accumulation of which in cardiomyocytes leads to their lipotoxic damage. It has been proved that cytokines as CRPs also play an important role in apoptosis. CRPs stimulate the release of proapoptotic cytokines and inflammatory mediators, which include IL-1 and TNF-α [17]. IL-6, together with TNF-α and IL-1, stimulates the production of proteins in the acute phase of inflammation in the liver and their entry into the general bloodstream. Obesity is associated with an increase in the level of IL-6, whereas weight loss leads to a decrease in its concentration [18]. Here, we studied the effect of leptin on the formation of fibrosis. It has been shown that leptin can cause changes in the ECM, and an increase in its level leads to cardiomyocyte apoptosis and oxidative stress, thereby leading to structural and functional changes in the heart in patients with obesity [19]. It directly stimulates cardiomyocyte hypertrophy and also modulates the fibroblast phenotype by activating the fibrogenic program [20]. The effect of adipokines on the development of myocardial fibrosis has also been studied. The ability of leptin to cause cardiomyocyte apoptosis has been proven in animals. It has been reported that increased cardiomyocyte apoptosis in obese animals compared with that in wild-type mice is due to the changes in leptin signaling (ob/ob and db/db mice), which is associated with greater DNA damage [19]. The local expression of leptin leads to the development of local oxidative stress, in association with macrophages and lymphocytes, induces proinflammatory cytokines, and activates MMP [21]. Endogenous leptin promotes the remodeling of the ECM by increasing the expression of various compounds such as fibronectin and collagen types I and III [19]. Currently, the mechanisms by which adiponectin contributes to the formation of myocardial fibrosis are actively studied. A previous study showed that adiponectin plays an important role in inhibiting collagen synthesis in the heart, and its level negatively correlated with the level of markers of myocardial fibrosis (PICP and PIIINP) [22]. In addition to these neurohumoral factors, numerous profibrotic factors were considered, including, MMP-3, collagen I, TGF-β, VEGFA, and PICP. The MMPs (the synthesis of which is initiated under the influence of TNF-α, interleukins, and CRP) are involved in the degradation of ECM proteins occurs [23]. MMPs actively participate in the processes of remodeling of the ECM, degrading its components such as collagen, elastin, fibronectin, and glycosaminoglycans [24]. As MMPs play a crucial role in the development of fibrosis, it is considered that they are involved in the formation and progression of CHF. TGF-β leads to myocardial fibrosis by activating the differentiation of fibroblasts to myofibroblasts and accelerating the deposition of ECM components. Moreover, it can inhibit the degradation of the ECM by inhibiting MMPs [25]. It has been demonstrated that TGF-β plays a significant role in the pathogenesis of left ventricular remodeling and the development of CHF [18]. VEGFA is the main regulator of angiogenesis and vascular permeability [26]. Recent study results have shown that VEGFA plays an important role in the control of adipose tissue function and systemic energy metabolism by modulating the adipose tissue vasculature [27]. Obesity is associated with angiogenesis, in which VEGFA plays a key role [28]. An increase in the accumulation of collagen in the cardiac interstitium is a sign of cardiac fibrosis. The synthesis of types I and type III collagen considerably increases during cardiac remodeling, regardless of the etiology of fibrosis [29]. The synthesis and degradation of type I collagen can be indirectly assessed using the circulating biomarkers C-terminal propeptide (PICP) and C-terminal telopeptide (CITP), respectively. Data on the metabolism of collagen, as the main protein of the ECM, are limited [30]. Here, we evaluated the relationship of the neurohumoral activity of EAT with the level of fibrosis markers in patients with EO.

Two groups of patients were identified, patients with EO (Group I) and patients without EO (Group II). EO was defined as an increase in the tEAT of ≥7 mm. In both groups I and II, no relationship was observed between metabolic factors or markers of myocardial fibrosis and BMI. This is due to the fact that BMI reflects the degree of general obesity, in which a significant part of the adipose tissue is represented by subcutaneous fat. Unlike visceral neurohumorally active adipose tissue, subcutaneous fat is relatively inert (does not produce pro-inflammatory neurohumoral factors). This may be the reason that an association between BMI obesity with increased cardiovascular risk has not been elucidated [31]. Here, there was no correlation between BMI and tEAT in Groups I and Group II (r = 0.09, p = 0.45 and r = 0.10, p = 0.40, respectively).

Visceral adipose tissue, including EAT, is a source of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-10 [32]. Pro-inflammatory cytokines TNF-α and IL-1, and CRP, can trigger the synthesis of MMPs [23], leading to an increase in other markers of myocardial fibrosis [33, 34], and together these can activate myocardial fibroblasts. Previous studies have shown that dysadipocytosis could lead to the development of myocardial fibrosis and, subsequently, the disruption of heart diastolic function, which occurs as a result of stiffness caused by the fat “shell,” hypertrophy, and myocardial fibrosis, which leads to CHF [31].

In our study, we demonstrated relationships between tEAT and levels of pro-inflammatory cytokines (TNF-α and IL-6), adipokines (leptin and adiponectin), and markers of myocardial fibrosis (MMP-3, TGF-β, and collagen). We also found that patients with EO develop LR and that it is associated with VEGFA, a marker of fibrosis. Previously, EO was demonstrated to be associated with impaired left ventricular diastolic function [31, 35] in lipotoxic damage. Our findings suggest that elevated levels of profibrotic factors in patients with tEAT ≥ 7 mm may be used as markers of preclinical (and therefore early) signs of myocardial fibrosis, before the detection of diastolic dysfunction in ECG.

There are several limitations in the measurement of tEAT by transthoracic ECG. First, we can only partially measure tEAT by transthoracic ECG. In contrast, both tEAT and volume can be measured by cardiac CT and MRI precisely and more accurately than by ECG. Echocardiographic measurements are not as reproducible as cardiac CT and MRI. Another limitation is the relatively weak inter- and intra-observer variability than those in cardiac MRI and CT. The most important limitation is the lack of specific threshold values to predict pathologies. tEAT appears to increase with age, and it could be influenced by sex and ethnicity. Despite these limitations, tEAT measurement by ECG has the advantage of being an easy-to-perform, readily available, repeatable, and low-cost modality without radiation exposure.

Materials and Methods