Potential role of epicardial adipose tissue in the pathogenesis of calcific aortic stenosis| JOURNAL OF GERONTOLOGY AND GERIATRICS

Abstract

Aortic stenosis (AS) is the most common valvular heart disease in industrialized countries, with a prevalence
that increases with age, and represents an important cause of morbidity, hospitalization and death in the elderly population.
It is widely recognized that AS is a progressive and active process that leads to calcific degeneration of the
aortic valve, involving complex and multifactorial pathological mechanisms, and including triggering factors
which lead to inflammation. In the last decades, several pieces of evidence have suggested a pathogenetic
role of the epicardial adipose tissue (EAT), the cardiac visceral fat depot, in the development and progression of
AS. EAT contributes to the inflammatory burden of AS through the secretion of numerous pro-inflammatory and
pro-atherogenic cytokines. Therefore, this review aims to explore the potential role of EAT in the pathogenesis
of AS and the potential therapeutic perspectives to slower AS progression.

CALCIFIC AORTIC STENOSIS IN THE ELDERLY

Aortic stenosis (AS) is the most common valvular heart disease in industrialized countries, with a prevalence that increases with age. Therefore, a significant increase in prevalence is expected considering aging of the global population, thus making this disease a huge health and socio-economic burden ^1-3.

Given the demographic changes leading to an increase of older people in industrialized countries, the number of patients affected by degenerative AS will dramatically rise in the next decades. In this regard, it has been estimated that, in the European countries, the number of subjects with symptomatic severe AS will increase from 1.3 million in 2025 to 2.1 million in 2050. AS is associated with frequent hospitalizations, functional decline even in the absence of reduction of myocardial contractility ⁴, and severe prognosis (average survival rate after symptom onset 50% at two years and 20% at five years) ^5-9.

ACTIVE PATHOPHYSIOLOGICAL MECHANISMS INVOLVED IN AS (FIG. 1)

In adults, especially in patients over 70 years, calcific degeneration represents the main mechanism involved in the development of AS. Several pieces of evidence support the concept that the pathophysiology of AS shares many features with vascular atherosclerosis and is associated with traditional atherosclerotic risk factors such as age, hypercholesterolemia, smoking, hypertension, diabetes and obesity ^{10 11}. For decades, valve calcification has been considered as an inevitable consequence of ageing; nowadays, it is widely recognized that AS is a progressive and active process, involving multifactorial pathological mechanisms, ranging from an initial calcification and focal thickening leaflet with preserved valvular function, to valvular aortic sclerosis up to the end-stage with obstruction of the left ventricular outflow due to severe calcification and immobilization of the valvular leaflets.

The active mechanisms involved in the calcific degeneration of the aortic valve are particularly complex and include triggering factors which lead to inflammation. In this regard, mechanical stresses affecting the aortic valve during the cardiac cycle may play an important role in damaging the integrity of the leaflet tissue and promoting valve calcification. As with atherosclerosis, increased mechanical stress and reduced shear stress result in damage and dysfunction of the valvular endothelial cells that lose the barrier function against mechanical, metabolic and inflammatory insults.

Endothelial injury allows infiltration of lipid and inflammatory cells into the interstitial valvular tissue. In early aortic valve lesions, there is the presence of low-density lipoprotein (LDLs) and lipoprotein A, also implicated in atherogenesis, which undergo oxidative modifications becoming highly cytotoxic and promoting inflammatory activity and mineralization by secretion of proinflammatory and profibrotic cytokines. Oxidized LDLs stimulate the activation of valve fibroblasts and consequently the formation of a core for calcium deposition.

In stenotic valve, an important increase in oxidative stress due to reduction in expression and activity of antioxidant enzymes was described, associated to a high production of free radicals, such as superoxide and oxygen peroxide, which play an important role in the pathogenesis and progression of AS, promoting the activation of profibrotic and pro-osteogenic signals ¹².

Increased endothelial expression of adhesion molecules such as E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), may allow monocytes and T lymphocytes to penetrate the valvular endothelium and accumulate in areas of inflammation, where monocytes differentiate toward macrophages, and activated T cells release cytokines and growth factors capable of inducing fibrosis and progression of calcification.

Changes in the renin-angiotensin-aldosterone system occurring in AS generate high levels of Angiotensin II, which contributes to the pathogenesis of disease increasing LDL uptake, inflammation, and profibrotic state via the angiotensin II type 1 (AT1) receptor ¹³. Moreover, the inflammatory infiltrate, through the release of mediators, favors the process of angiogenesis with an increase in growth factors and endothelial changes able to promote the progression of fibrosis and calcification.

As the disease progresses, a remodeling of the extracellular matrix promoted by the activation of metalloproteinases and cathepsins occurs, which stimulates the degradation of elastin and the proliferation of fibroblasts with consequent fibrosis, thickening and valvular stiffness up to stenosis. In the most advanced stages of the disease, the presence of cells with osteoblast-like activity and proteins normally present in the bone, such as osteonectin, osteopontin, and osteocalcin has been demonstrated in the valve, suggesting that the calcification process occurs in a similar way to that observed in the bone. The formation of bone tissue at the valvular level would be the consequence of the activation of multiple signaling pathways that lead to the differentiation of fibroblasts into myofibroblasts and osteoblast-like cells, with consequent formation of calcification nodules ¹⁴.

The formation of skeletal bone occurs through the initial deposition of collagen matrix, which provides a basis for progressive calcification. A similar process has been described in the aortic valve.

Several data suggest that inflammation, lipoprotein infiltration, oxidative stress and extracellular matrix remodeling are the main triggers and promoters of the osteogenic processes observed in aortic valve degeneration ¹⁵.

In stenotic aortic valves, an hyperactivation of bone morphogenetic protein (BMP) signaling is observed, with secretion of high levels of bone-forming proteins 2 and 4 from the valvular endothelium, that are implicated in the mechanism of bone mineralization. This process increases further as the impairment of the valve opening progresses ¹⁶.

Several studies demonstrated the presence of osteoblast-like cells and an increase in the gene expression of different osteoblast-specific proteins commonly associated with skeletal bone formation such as osteopontin and bone sialoprotein in the valve ¹⁷.

Concerning the origin of osteoblast-like cells, the most accredited hypothesis calls into question the myofibroblasts present in the valve interstitium, whose osteoblastic differentiation is modulated by numerous molecules and very complex signaling pathways.

Some data suggest that differentiation of resident valvular interstitial cells toward an osteoblast-like phenotype would be mediated by proinflammatory cytokines such as interleukin 1β (IL-1β), IL-6, IL-8, insulin-like growth factor 1, tumor necrosis factor (TNF), transforming growth factor-β (TGF-β), mainly secreted by macrophages. However, in the later stages of the disease, this differentiation seems to be modulated by complex calcified pathways, including the Notch, Wnt/β-catenin, and receptor activator of nuclear factor kappa B/receptor activator of nuclear factor kappa B ligand/osteoprotegerin pathways (RANK/RANKL/OPG) ^18-20.

RANKL is a member of the TNF cytokine family; RANK is a transmembrane protein expressed on osteoclast precursors but also on valvular interstitial cells. In the bone tissue, binding of RANKL to RANK promotes osteoclastic differentiation and maturation, inducing the process of bone resorption and demineralization. By contrast, in the aortic valve, RANKL binds to RANK in valvular interstitial cells, acting as a strong inducer of osteogenic differentiation with subsequent calcium deposition and formation of calcific nodules ²¹.

This pathway is inhibited by osteoprotegerin, a soluble receptor that binds RANKL and prevents its linking to RANK, contrasting both the bone demineralization process and the calcium deposition at the valve level. RANKL acts with pro-osteoblastic effects even against vascular smooth muscle cells through the upregulation of BMP-2 ²².

VISCERAL FAT AND OBESITY AS RISK FACTORS FOR AS

It is now recognized that the process of calcific aortic valve degeneration shares many mechanisms with atherosclerosis including risk factors, such as obesity. Importantly, the increase in visceral fat is associated with the incidence of cardiovascular events both in general and in AS populations ²³.

In recent decades, a significant increase in the prevalence of overweight or obese subjects, often with type 2 diabetes or with metabolic alterations associated with insulin resistance has been observed: we are talking about “the metabolic syndrome”. In this regard, the visceral abdominal fat, through the production of inflammatory cytokines, is strongly associated with the development of insulin resistance ²⁴ and diabetes mellitus, and with an increased risk of cardiovascular outcomes. Pathogenetic factors underlying the complications related to visceral obesity include a pro-atherogenic alteration of the lipid profile with a reduction of high-density lipoproteins and an increase in small, low-density lipoprotein particles. Moreover, another important characteristic is represented by the chronic inflammatory state with large production of pro-inflammatory cytokines ²⁵.

Therefore, central obesity contributes to the definition of the metabolic syndrome, which is an important cardiovascular risk factor associated with the progression of coronary artery disease, but it is also highly related to the development and progression of calcific aortic degeneration. Indeed, several studies have shown the importance of abdominal visceral adipose tissue in the development of aortic valve calcification.

The Multi-Ethnic Study of Atherosclerosis (MESA) showed a significant association between the metabolic syndrome and the incidence of aortic valve calcification ²⁶.

Oikawa et al. highlighted the relationship between the abdominal visceral adiposity and the presence of aortic valve calcification, thus supporting the role of visceral adipose tissue as an independent risk factor for this valve disease ²⁷.

The ASTRONOMER (Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin) study showed a significant association between the metabolic syndrome and the progression of aortic valve calcification ²⁸.

There is a growing body of evidence that the involvement of visceral adipose tissue in the pathogenesis of AS implies inflammatory and oxidative stress processes, through the production of inflammatory cytokines and reactive oxygen species (ROS). Reis et al. described an increased expression of TNF-α, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and plasminogen activator inhibitor-1 in the adipose tissue of obese mice. Similarly, they reported an increase in oxidative stress with greater ROS production and increase in NADPH oxidase activity in obese humans ²⁹.

Other Authors evaluated the association between global (estimated with the Body Max Index) and regional adiposity and valve calcification and mortality for all cardiovascular causes in a cohort of symptomatic elderly patients with severe AS, referred to transcatheter aortic valve replacement (TAVR). Paradoxically, in this population a low BMI was associated with aortic valve calcification and higher incidence of death. Accordingly, the amount of visceral adipose tissue was inversely associated with the aortic valve calcification mass score.

This paradox would be, at least in part, explained by the progressive reduction of the fat mass observed with aging, that must be ascribed to the increase of catabolic processes up to the development of sarcopenia and cachexia ^{30 31}. Therefore, in elderly obese patients with heart disease, the favorable prognosis could be linked to the greater metabolic reserve that allows to better tolerate the catabolic stress with respect to non-obese patients ³².

ASSOCIATION BETWEEN CARDIAC VISCERAL FAT AND AS

Several studies explored whether the epicardial adipose tissue (EAT), the cardiac visceral fat depot, could contribute to the inflammatory burden of AS.

Parisi et al. enrolled 95 patients with severe calcific AS, who underwent cardiac surgery for aortic valve replacement. In these patients, EAT thickness was assessed by echocardiography, and systemic and local inflammatory profiles were analyzed measuring the levels of 27 cytokines both in plasma and in the EAT secretome. EAT thickness was significantly higher in patients with AS than in the control group. Plasma levels of inflammatory mediators were almost similar in AS patients and controls. Noteworthy, the EAT secretome of patients with increased EAT thickness showed higher levels of inflammatory mediators. Furthermore, the thickness of EAT significantly correlated with the levels of different pro-inflammatory and pro-atherogenic cytokines, such as IL-6, TNF-α, MCP-1, IL-1β, so that the greater the thickness of EAT, the greater the secretion of these mediators. These data support the hypothesis of a pro-inflammatory activation of EAT in patients with AS, and of EAT involvement in aortic valve calcific degeneration ³³.

Other studies investigated and confirmed the association between EAT and AS development. A retrospective study determined the EAT thickness in 400 patients with and without AS, concluding that the EAT thickness was significantly associated with severe AS, independently of traditional risk factors ³⁴.

A recent study evaluated the prognostic value of EAT volume (assessed by pre-procedural multi-detector computed tomography) in 503 patients with severe AS undergoing TAVR. The volume of EAT was significantly correlated with mortality after TAVR, resulting independently associated with all-cause mortality at 1, 2 and 3 years. Therefore, the pre-interventional assessment of EAT volume was proposed by these authors as an important prognostic factor for risk stratification of TAVR candidate patients ³⁵.

Importantly, EAT could also contribute to unfavorable cardiac remodeling in response to the presence of aortic valve disease. AS determines an increase in post-load and leads to a chronic pressure overload of the left ventricle, resulting in concentric hypertrophy. This response is initially an adaptive phenomenon that allows the heart to overcome the obstacle represented by valve stenosis while maintaining adequate cardiac output even under stress. However, as for other compensatory mechanisms, it becomes a maladaptive phenomenon over time and evolves towards diastolic dysfunction, finally leading to heart failure ³⁶. Numerous pieces of evidence support the role of EAT in promoting myocardial hypertrophy ³⁷. The presence of increased EAT mass in AS could enhance the hypertrophic stimuli induced by chronic pressure overload and contribute to negative cardiac remodeling.

Coisne et al. recently analyzed the specific association between EAT and ventricular remodeling assessed by a comprehensive transthoracic echocardiography (TTE) in patients suffering from severe AS and normal left ventricular ejection fraction. In these patients, the Authors showed that the EAT thickness was significantly and independently associated with the hypertrophic response estimated by indexed left ventricular mass and with a more pathological remodeling pattern. The intense metabolic and pro-inflammatory activity of EAT could account for this association. The causative mechanism explaining the association between EAT pro-inflammatory activity and cardiac damage was demonstrated in rodent models and in vitro cardiomyocyte cultures ³⁸.

Overall, these data confirm, at least in part, the previous hypothesis of Iacobellis et al. and of other Authors, who analyzed the relationship between EAT and left ventricle morphology in healthy subjects with different degrees of obesity, and established an association between increased EAT volume and increased left ventricular mass ³⁷, and heart failure ^{39 40}.

THERAPEUTIC PERSPECTIVES

AS is the result of a very complex active process that involves several cell lines, in particular myofibroblasts and valvular interstitial cells, which undergo osteoblastic transformation and promote the formation of calcification nodules and bone deposition at the valve level. These events involve different signaling pathways which could be considered as potential therapeutic targets to control the development and progression of the disease.

Considering the pathophysiological similarities with atherosclerosis, especially in the early stages of the disease, it was hypothesized that statins might be beneficial to slow the progression of AS.

Studies in hypercholesterolemic animal models showed that atorvastatin is able to counteract the deposition of lipids and the oxidative stress that is observed in the early stages of degenerative calcified aortic disease ⁴¹.

A prospective open label study by Moura et al., showed a positive effect of statin therapy, proving that rosuvastatin treatment in AS patients, by lowering serum LDL, slowed the hemodynamic progression of disease ⁴².

The possible beneficial effects of this drug class would not be exclusively ascribed to the reduction of cholesterol biosynthesis and therefore of C-LDL levels, but also to pleiotropic effects. In fact, several activities of statin therapy have been described: wall effect on endothelial cells and vascular smooth muscle cells, inhibitory effect on migration and proliferation of these cells, with consequent anti-inflammatory and antithrombotic properties ⁴³.

Anti-inflammatory effects of statins were also reported on visceral fat depots, and starting from this assumption, recent studies have been conducted to evaluate their potential effects also on EAT, which represents a potential new target for drugs, given its significant involvement in the development and progression of heart disease ⁴⁴.

A recent study conducted by Parisi et al. has explored, in vivo and in vitro, the effects of statin therapy on EAT accumulation and inflammatory activity, enrolling 193 patients with severe calcific AS taking and not taking statins. In order to evaluate the association between statin therapy and EAT inflammation, EAT biopsies were performed and the corresponding secretomes were analyzed to explore the concentration of different cytokines. In addition, ithe EAT and subcutaneous adipose tissue (SCAT) biopsies from patients not assuming statins were treated in vitro with atorvastatin to verify whether this statin might directly affect EAT inflammatory profile. The results of this study showed a significant association between statin therapy, EAT thickness and levels of cytokines secreted from this tissue. In fact, statin therapy was associated with a reduction of EAT thickness and a parallel attenuation of its inflammatory profile. Furthermore, the in vitro studies showed a direct and selective anti-inflammatory effect of atorvastatin on EAT but not on SCAT. These results support the unique role of EAT in cardiac diseases and suggest EAT as a potential new therapeutic target for statin therapy ⁴⁵.

If it is true that EAT might be involved in the pathogenesis of AS through its pro-inflammatory activities, we should expect that therapies able to modulate the EAT inflammatory profile, such as statin therapy, could positively affect the progression of AS. In contrast to the preliminary results reported by the open label study of Moura et al, three randomized controlled trials, SALTIRE, ASTRONOMER, and SEAS trials, utilizing atorvastatin, rosuvastatin, and simvastatin plus ezetimibe respectively in patients with mild to moderate AS, failed to demonstrate a beneficial effect of statin therapy in halting or slowing AS progression despite the significant reduction in serum LDL cholesterol concentrations ^46-48. A plausible explanation for this failure could be referred to the timing of therapy, which probably should be started in the early stages of the disease in order to significantly affect its progression. In fact, whether in the initial phase of the disease, inflammation and lipid deposition are the predominant pathophysiological mechanisms, in later stages, the propagation phase of the disease is characterized by self-perpetuating the process of formation, and the deposition of calcium and valve degeneration that cannot be affected by statins. Future long-term controlled trials conducted on patients with less advanced AS are needed to examine and establish the effect of statin therapy in this disease and explore whether this effect could be reconducted to an influence on EAT activity.

As for statin therapy, other therapeutic strategies were proven in AS patients targeting several signaling pathways potentially contributing to the inflammatory activity described in the valve in the early stage of the disease. In this regard, renin-angiotensin system, oxidative stress, RANK-RANK ligand pathway and peroxisome proliferator-activated receptors were all recognized as potentially involved in the pathological processes leading to AS. Intriguingly, the same pathways were shown to contribute to the shift of EAT toward a pro-inflammatory and pro-atherogenic phenotype. Unfortunately, studies exploring these pathways as potential therapeutic targets in AS failed to demonstrate a favorable effect ⁴⁹.

Figures and tables

Figure 1.Mechanisms involved in the pathogenesis of calcific aortic stenosis. Differentiation of resident valvular interstitial cells to an osteoblast-like phenotype is mediated by proinflammatory cytokines such as interleukin 1β (IL-1β), IL-6, IL-8, insulin- like growth factor 1, tumor necrosis factor (TNF-a), transforming growth factor β (TGF-β), mainly secreted by circulating macrophages and activated T lymphocytes penetrating the endothelium of aortic valve leaftlets. EAT could contribute to this mechanism through the secretion of pro-inflammatory cytokines reaching the aortic valve interstitium via paracrine and vasocrine pathways.

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