Epicardial adipose tissue volume and CT-attenuation as prognostic factors for pulmonary embolism and mortality in critically ill patients affected by COVID-19

Our study shows that in COVID-19 intubated critically ill, subjects with a higher amount of EAT are at higher risk of pulmonary embolism in ICU.

EAT volume, and not EAT density, was associated with increased mortality in our population of critically ill COVID-19 subjects, but after adjustment for potential confounders this relationship was no longer significant.

Previous studies showed that the abdominal visceral fat area, as evaluated by CT, is associated with unfavorable health outcomes and mortality in COVID-19 subjects [2, 8].

Our finding is partially in line with the previous reports from Mehta et al. and Grodecki et al. [1, 10]. and this is not surprising considering that SARS-CoV-2 enters into cells using the ACE2 receptor, which is highly expressed in EAT and other visceral adipose depots [22]. However, when age was included with comorbidities in the final model it was the only significant predictor of mortality.

The role of EAT density as a risk factor for severe COVID-19 is under debate. Lower VAT density, as evaluated with CT, is associated with higher adipocyte weight and diameter and consequent adipose tissue inflammation [23, 24]. In a post-hoc analysis, Conte et al. showed that in a population of subjects admitted to San Raffaele University Hospital emergency department EAT attenuation was predictive of critical illness, while EAT volume was not [25]. Similarly, Iacobellis et al., in a sample of 41 patients admitted for COVID-19, showed that patients with severe and critical COVID-19 had significantly greater EAT attenuation as compared to subjects with mild and moderate COVID-19 [9].

However important differences with those studies should be noted and could partially justify discrepancies. In fact, our population was limited only to critically ill subjects in ICU and not unselected COVID-19 positive subjects admitted to the emergency department. Conte et al. found that EAT attenuation was significantly, although weakly, related with systemic inflammation as evaluated by CRP. On the contrary, in our population, IL-6 was not related to EAT density, whilst a relation with EAT volume was observed, partially explaining higher mortality observed in the highest EAT volume tertile. This is in line with Abrishami et al., who, in a population of 100 subjects, observed an association between EAT volume, CRP and more severe COVID-19 course in obese subjects [26]. Moreover, according to with previous reports [27], we found that EAT density was inversely related to age, which partially explains the lack of association with mortality observed in our population.

Even after adjustment for potential confounders, subjects in the highest tertile of EAT volume showed a 4 times increased risk of pulmonary embolism. 13 subjects out of 46 in the highest tertile of EAT volume presented pulmonary embolism, corresponding to 28.2% and an association between the quantity of this adipose depot and increased thromboembolic risk can be hypothesized. This percentage decreased to 21.7% and 6.5% in subjects in the second and first tertile, respectively. A study by Mazzocolli et al. [7]. carried out on 77 patients showed that patients with a higher amount of EAT had an increased risk of developing idiopathic deep vein thrombosis compared to controls.

In our population, we observed higher IL-6 in subjects in the highest tertile of EAT volume. EAT should be considered to all effects as intrathoracic VAT [28]. Similar to abdominal visceral adipose tissue, EAT produces high amounts of inflammatory cytokines which, in patients affected by COVID-19, can determine an increased prothrombotic risk and facilitate the onset of pulmonary embolism.

The increased expression of Angiotensin-converting enzyme 2 (ACE2) observed in VAT, including EAT, make this extrapulmonary depot a susceptible point for SARS-CoV-2 infection within lung tissue.

COVID-19 is commonly complicated by coagulopathy, disseminated intravascular coagulation and pulmonary embolism associated with a severe inflammatory state [29] leading to higher mortality. Likewise, obesity is highly related with a hypercoagulopathy status.

VAT depots, including EAT, are characterized by systemic oxidative stress, leading to the loss of the antithrombotic properties of the endothelium, increased platelet activation and decreased fibrinolysis [30]. Viral infection and proinflammatory cytokines production from VAT depots synergistically contribute to vascular endothelium, platelets and other circulating vascular cells stimulation, thereby promoting the upregulation of procoagulant factors and adhesion molecules and concomitant downregulation of anticoagulant regulatory proteins, increased thrombin generation and enhanced platelet activation [31].

We found that subjects with low EAT density were at higher risk of pulmonary embolism. This finding can be explained by the fact that CT measured AT density is related to adipocyte hypertrophy and hyperplasia following excess lipid accumulation. Increased adipocytes weight and size is in fact associated with higher inflammation, increased cardiometabolic and prothrombotic risk.

Moreover EAT is anatomically close to the pulmonary artery and may potentially enable the diffusion of proinflammatory cytokines into pulmonary circulation with paracrine and vasocrine consequences on lung tissue and circulation [32]. We can therefore hypothesize that EAT may act as an important SARS-CoV-2 reservoir [3] and promote local viral shedding in the thoracic region, thereby facilitating pulmonary damage and also pulmonary embolism [33], and resulting in an additional increase of mortality in subjects with severe COVID-19.

Some limitations need to be mentioned. Firstly, this is a single-center observational prospective study with relatively small number of subjects and we used arbitrary categorization in tertiles that leads to a loss of power when examining predictor-outcome associations. Therefore, the threshold that we obtained dividing the study sample by tertiles cannot be generalized to other populations. Secondly, patients were treated with different protocols, influencing mortality rates. Thirdly, the study sample size precludes meaningful exploration of the association of wasting with specific disease entities and comorbidities. Finally, our analysis was limited to the population in which pulmonary embolism was clinically suspected and CT was performed on the basis of either worsening hypoxia or acute cor pulmonale, which may have resulted in selection bias.

As the SARS-CoV-2 may continue to spread worldwide, clinicians should identify subjects at higher risk for unfavorable health outcomes. Our results cannot be generalized and must be considered with caution, but if confirmed in wider populations, moderately to severely ill hospitalized COVID-19 patients with high EAT volume and lower EAT density could benefit from prophylactic or therapeutic heparin [34]. Moreover, considering that multiple studies of post-discharge patients with COVID-19 show incidences of symptomatic venous thromboembolism ranging from

below 1% to 2.5%, extended short-term thrombophylaxis beyond hospitalization should also be considered in high-risk population [35].

The use of easily available EAT parameters in critically ill subjects undergoing standard thoracic CT could help to identify, monitor and treat subjects carefully at higher pulmonary embolism and mortality risk, in order to prevent serious life-threatening consequences and the increase of related hospital costs.

In conclusion, EAT volume, and not EAT density, was associated with mortality in subjects admitted to the ICU for severe COVID-19, independently of general obesity, but when age was included in the model the relationship was no longer significant.

Subjects in the highest tertile of EAT volume and in the lowest tertile of EAT density showed respectively a 4- and 3.6-times increased risk of pulmonary embolism after adjustment for potential confounders.

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