Epicardial adipose tissue (EAT) represents the true visceral adipose tissue of the heart with which it shares both its embryonic origin as well as blood supply [1]. EAT has unobstructed anatomical contiguity with the myocardium and envelops up to 80% of its surface [2]. Research in the past decade has linked EAT to vast implications in cardiac biology that extend past the mechanical and thermal protection of the heart and coronary arteries. Indeed, epicardial fat provides an energy source for cardiomyocytes, protects them from free fatty acid lipotoxicity and modulates intracellular Ca²⁺ cycling, the electrical and mechanical behavior of heart muscle cells and the myocardial redox state [3]. However, the presence of underlying cardiometabolic conditions, mainly overweight/obesity and diabetes, is a major risk factor leading to EAT expansion and inflammation [4,5]. The subsequent EAT dysfunction is responsible for the shift from a protective phenotype toward a pro-inflammatory, pro-oxidant and pro-fibrotic cardiac micro-environment that contributes to the pathogenesis of cardiometabolic pathologies and their progression toward heart failure with the whole spectrum of the ejection fraction [6]. Nowadays, EAT is regarded as a modifiable risk factor in cardiovascular diseases [7], which can be evaluated with non-invasive imaging techniques [8] and also therapeutically targeted [6].

Statins remain the first-line lipid-lowering treatment in primary and secondary cardiovascular prevention due to their demonstrated long-term benefits in reducing both morbidity and mortality. These drugs primarily decrease low-density lipoprotein cholesterol (LDL-C) levels both by inhibiting 3-hydroxy-3-methylglutarate CoA reductase, a critical component in the cholesterol biosynthesis pathway, and enhancing the expression of the LDL receptor, thereby augmenting LDL-C clearance from the bloodstream [9]. Given the pivotal contribution of LDL-C to the onset of atherosclerosis, the two aforementioned synergistic mechanisms largely account for the observed reductions in major adverse cardiovascular events associated with statin therapy [9]. However, irrespective of the lipid-lowering effect, statins have been unequivocally demonstrated to exert pleiotropic effects, such as improvement in plaque stability, alleviation of endothelial function, reduction in inflammation and thrombosis and, mitigation of oxidative stress [9]. Among these, a highly investigated effect was the diminution of EAT volume, thickness and density, as well as EAT-derived inflammatory mediators [10,11,12].

Perivascular adipose tissue (PVAT) encompasses the fat depots that are adjacent to the vascular tree and is required to maintain the functional status of vasculature. However, when excessive in various vascular disorders, PVAT becomes dysfunctional and its altered secretome impairs both vascular smooth muscle and endothelial cells [13].

The present study was purported to assess the oxidative stress in samples of epicardial and perivascular adipose tissues harvested from patients undergoing elective cardiac surgery and compare ROS production between patients treated or not with statin therapy. A second objective was to investigate whether correlations could be found between the magnitude of oxidative stress and the echocardiographic parameters.

Patients who were chronically treated with statins (atorvastatin or rosuvastatin) exhibited significantly lower levels of reactive oxygen species (ROS) in their epicardial (EPI) and perivascular (PV) adipose tissue compared to those who were not receiving treatment (Figure 1).

Correlation analysis was performed to evaluate a potential relationship between the echocardiographic parameters (LVEF, LAD, RVD, IVS, LVPWT, LVEDD) and the degree of oxidative stress (H₂O₂ measured by FOX assay) of the analyzed samples. A positive correlation was observed between the level of ROS in epicardial and perivascular adipose tissue and the diameter of the right ventricle (r = 0.47, p < 0.05) (Figure 2).

Epicardial and perivascular adipose depots have emerged in the past decades as main modulators of the pathophysiology of both the heart and blood vessels, as well as therapeutic targets [19]. While in the normal heart, EAT exerts protective effects by providing thermogenic and energetic support to the coronary arteries and myocardium and being a source of local anti-inflammatory molecules, in pathological settings, EAT expansion is a major risk factor for cardiovascular diseases, particularly a predictor for coronary artery disease [20,21]. In the presence of multiple risk factors, such as obesity, systemic inflammation, hyperlipidemia and smoking, EAT adipocytes may undergo phenotypic changes and produce a secretome rich in proinflammatory cytokines that promote both atherosclerosis and myocardial fibrosis [5]. EAT plays a distinct pathophysiological role in HF with a reduced ejection fraction (HFrEF), indicating the decreased metabolic reservoir due to the catabolic state, whereas in HF with a preserved ejection fraction (HFpEF), its volume and activity increase, particularly in the presence of metabolic comorbidities [22].

Besides inflammation, oxidative stress is another mechanism contributing to HF pathogenesis and progression. Here, we have assessed the magnitude of oxidative stress in patients with HFmrEF treated or not with statins. In their pioneering study, Salgado-Somoza et al. reported back to 2010 an increased mRNA levels for several proteins related to oxidative stress, e.g., glutathione S-transferase P, protein disulfide isomerase and phosphoglycerate mutase 1 (but not catalase) in EAT compared to the subcutaneous adipose tissue (SAT) harvested from patients undergoing cardiac surgery [23]. In another study that compared EAT with SAT, the p53 mRNA level was up-regulated and increased after ex vivo adrenergic stimulation, mainly in EAT harvested from patients with HF [24]. An elevation of p53 in white AT promotes apoptosis, senescence, chronic inflammation and oxidative stress [25].

Importantly, there is a bidirectional cross-talk between cardiomyocyte and EAT, with adipokines such as adiponectin or leptin affecting the heart’s function, and the heart influencing EAT biology through various signaling pathways [26]. For instance, an elevated ROS activates signaling pathways that stimulate epicardial adipocytes to secrete adiponectin with the subsequent inhibition of NADPH oxidase in cardiomyocytes, thereby restoring myocardial redox balance. More recently, Naryzhnaya et al. reported an increased ROS production in EAT adipocytes isolated from explants harvested from prediabetic and diabetic patients undergoing a coronary artery bypass. The ROS level in adipocytes was directly correlated with postprandial glycemia and inversely correlated with serum adiponectin [27]. Sacks et al. reported that at least one of the reasons for EAT producing more ROS than SAT is because of the higher mRNA expression (over three-fold) of gp91^phox and p47^phox, NADPH components [28].

In a recent study, Chen et al. investigated the effects of EAT-derived leptin on myocardium in an experimental model of metabolic syndrome with diastolic dysfunction in rats, and also explored the underlying molecular mechanisms in H9C2 rat cardiomyoblasts exposed to either leptin or an EAT-conditioned medium. The authors reported that the EAT-derived leptin (but not serum leptin) elicited myocardial injury via the activation of the PKC/NADPH oxidase/ROS pathway, which was responsible for two cooperative pathomechanisms: mitochondrial oxidative stress with subsequent apoptosis and inflammation by promoting activator protein 1 nuclear translocation. Interestingly, the increased generation of NADP oxidase-derived ROS was the consequence of leptin-promoted interaction between p-p47^phox and gp91^phox in H9C2 cardiomyocytes [29].

Statins serve as the cornerstone therapy in primary and secondary cardiovascular and metabolic disease prevention and treatment due to their pleiotropic effects that extend far beyond the lipid-lowering action [12,30].

In a pioneering retrospective study conducted in patients subjected to a percutaneous coronary intervention, Park et al. showed that the thickness of EAT decreased to a greater extent in patients treated with atorvastatin compared to those treated with the simvastatin–ezetimibe combination [31].

More recently, Parisi et al. demonstrated that atorvastatin therapy was strongly associated between a decreased accumulation of EAT in patients with aortic stenosis subjected to cardiac surgery. Moreover, in vitro incubation with statin elicited a direct anti-inflammatory effect on EAT that was significantly higher compared to its effect on SAT [11]. A possible explanation could be the peculiar EAT structure (adipocytes with a smaller size and an important vascular supply), leading to an improved penetration of lipophilic statin at its level [32]. The efficacy of atorvastatin in diminishing EAT size was reported to be superior to that of either pravastatin or simvastatin [33].

EAT accumulation was associated with the persistence of atrial fibrillation or its recurrence after ablation [34,35]. In an elegant study, Natsui et al. comprehensively assessed the association between the EAT profile and the occurrence of postoperative atrial fibrillation (POAF) in patients who underwent cardiovascular surgery. They reported that the onset of POAF negatively correlated with the EAT adipocyte size and positively with TNF-α expression. Similarly, the mitochondrial respiratory capacity also showed a negative correlation with the size of EAT adipocytes and a positive one with adiponectin secretion [36].

Here, we have reported an increased ROS production of EAT and PVAT samples harvested from patients with HFmrEF with and without diabetes treated with two statins, atorvastatin or rosuvastatin. We have to acknowledge as limitations of this study the fact that we neither assessed the level of inflammatory cytokine (as the anti-inflammatory effect of statins may be responsible for lower oxidative stress) nor provided mechanistic evidence regarding the ROS sources in the adipose tissues harvested from these patients. Also, in the statin-treated group, there was a higher number of males compared to females; thus, the sex differences in ROS production could not be analyzed.

Statin therapy is associated with reduced oxidative stress in both epicardial and perivascular adipose tissue. The generation of reactive oxygen species from cardiac adipose tissues may play a role in the right ventricle enlargement. However, larger studies are required to assess whether the decrease in oxidative stress related to the long-term statin treatment represents a direct effect or indirect consequence of their anti-inflammatory effect.