Effects of aromatase inhibitor therapy on visceral adipose tissue area and cardiometabolic health in postmenopausal women with early and locally advanced breast cancer.

OBJECTIVE: Aromatase inhibitor (AI) therapy provides oncological benefits in postmenopausal women with oestrogen receptor-positive breast cancer. However, AI treatment has been associated with increased cardiovascular risk. In nonbreast cancer populations, experimentally induced low oestrogen states and natural transition to menopause have been associated with increases in visceral adipose tissue (VAT), a known surrogate marker for cardiometabolic risk. Given that AI treatment blocks oestradiol production, we hypothesized that AI treatment would increase VAT. METHODS: We conducted a prospective 12-month cohort study of 52 postmenopausal women newly initiating AI treatment (median age: 64.5 years) and 52 women with breast pathology not requiring endocrine therapy (median age: 63.5 years). VAT area and other body composition parameters were measured at baseline, 6 months and 12 months using dual X-ray absorptiometry. Other risk markers of cardiometabolic health were also assessed. RESULTS: In women initiating AI treatment, there was no statistically significant difference in VAT area after 12 months when compared to controls, with a mean adjusted difference of -5.00 cm2 (-16.9, 6.91), p = .55. Moreover, changes in total fat mass, lean mass, subcutaneous adipose tissue area, hepatic steatosis and measures in endothelial function were also not statistically different between groups after 12 months. Findings were similar after adjustments for activity levels and coronavirus disease 2019 lockdown duration. CONCLUSIONS: These data provide reassurance that over the initial 12 months of AI therapy, AI treatment is not associated with metabolically adverse changes in body composition, hepatic steatosis or vascular reactivity. The impact of extended AI therapy on cardiometabolic health requires further study.

Visceral adipose tissue and risk of COVID-19 susceptibility, hospitalization, and severity: A Mendelian randomization study.

Background: Coronavirus Disease 2019 (COVID-19) has rapidly evolved as a global pandemic. Observational studies found that visceral adipose tissue (VAT) increased the likelihood of worse clinical outcomes in COVID-19 patients. Whereas, whether VAT is causally associated with the susceptibility, hospitalization, or severity of COVID-19 remains unconfirmed. We aimed to investigate the causal associations between VAT and susceptibility, hospitalization, and severity of COVID-19. Methods: We applied a two-sample Mendelian randomization (MR) study to infer causal associations between VAT and COVID-19 outcomes. Single-nucleotide polymorphisms significantly associated with VAT were derived from a large-scale genome-wide association study. The random-effects inverse-variance weighted method was used as the main MR approach, complemented by three other MR methods. Additional sensitivity analyses were also performed. Results: Genetically predicted higher VAT mass was causally associated with higher risks of COVID-19 susceptibility [odds ratios (ORs) = 1.13; 95% confidence interval (CI), 1.09-1.17; P = 4.37 × 10-12], hospitalization (OR = 1.51; 95% CI = 1.38-1.65; P = 4.14 × 10-20), and severity (OR = 1.58; 95% CI = 1.38-1.82; P = 7.34 × 10-11). Conclusion: This study provided genetic evidence that higher VAT mass was causally associated with higher risks of susceptibility, hospitalization, and severity of COVID-19. VAT can be a useful tool for risk assessment in the general population and COVID-19 patients, as well as an important prevention target.

Low muscle mass and high visceral fat mass predict mortality in patients hospitalized with moderate-to-severe COVID-19: a prospective study.

Introduction: The severity of coronavirus disease 2019 (COVID-19) has been positively correlated with several comorbidities. The primary outcome of the study was to assess the relationship between the mortality and severity of COVID-19 and obesity classes according to BMI, visceral adipose tissue (VAT) area, s.c. adipose tissue area, muscle area (MA), and leptin levels. Methods: In this prospective cohort study, 200 patients hospitalized with moderate-to-severe COVID-19 underwent an unenhanced CT of the thorax and laboratory tests, and leptin levels between June and August 2020 were obtained. Results: Our study included 200 patients (male 52%; mean age: 62 (49-74) years; obesity (BMI > 30): 51.5%)). Fifty-eight patients (23.5%) were admitted to the intensive care unit and 29 (14.5%) died. In multivariate logistic regression (corrected for leptin, sex, age, and serum biomarkers) and receiver operating characteristic curve analyses, high VAT > 150 cm2 (odds ratio (OR): 6.15; P < 0.002), MA < 92 cm2 (OR: 7.94; P < 0.005), and VAT/MA ratio > 2 (OR: 13.9; P < 0.0001) were independent risk factors for mortality. Indeed, the Kaplan-Meier curves showed that patients with MA < 92 cm2 and without obesity (BMI < 30) had a lower survival rate (hazard ratio between 3.89 and 9.66; P < 0.0006) than the other groups. Leptin levels were not related to mortality and severity. Conclusion: This prospective study reports data on the largest number of hospitalized severe COVID-19 patients and pinpoints VAT area and MA calculated by CT as predictors of COVID-19 mortality.

Impact of visceral fat on the prognosis of coronavirus disease 2019: an observational cohort study.

BACKGROUND: Clarification of the risk factors for coronavirus disease 2019 (COVID-19) severity is strongly warranted for global health. Recent studies have indicated that elevated body mass index (BMI) is associated with unfavorable progression of COVID-19. This is assumed to be due to excessive deposition of visceral adipose tissue (VAT); however, the evidence investigating the association between intra-abdominal fat and COVID-19 prognosis is sparse. We therefore investigated whether measuring the amount of intra-abdominal fat is useful to predict the prognosis of COVID-19. METHODS: The present study enrolled 53 consecutive cases of COVID-19 patients aged ≥ 20 years with chest computed tomography (CT) scans. The VAT area, total adipose tissue (TAT) area, and VAT/TAT ratio were estimated using axial CT images at the level of the upper pole of the right kidney. Severe COVID-19 was defined as death or acute respiratory failure demanding oxygen at ≥ 6 L per minute, a high-flow nasal cannula, or mechanical ventilation. The association of VAT/TAT with the incidence of progression to a severe state was estimated as a hazard ratio (HR) using Cox regression analysis. To compare the prediction ability for COVID-19 disease progression between BMI and VAT/TAT, the area under the receiver operating characteristic curve (AUC) of each was assessed. RESULTS: A total of 15 cases (28.3% of the whole study subjects) progressed to severe stages. The incidence of developing severe COVID-19 increased significantly with VAT/TAT (HR per 1% increase = 1.040 (95% CI 1.008-1.074), P = 0.01). After adjustment for potential confounders, the positive association of VAT/TAT with COVID-19 aggravation remained significant (multivariable-adjusted HR = 1.055 (95% CI 1.000-1.112) per 1% increase, P = 0.049). The predictive ability of VAT/TAT for COVID-19 becoming severe was significantly better than that of BMI (AUC of 0.73 for VAT/TAT and 0.50 for BMI; P = 0.0495 for the difference). CONCLUSIONS: A higher ratio of VAT/TAT was an independent risk factor for disease progression among COVID-19 patients. VAT/TAT was superior to BMI in predicting COVID-19 morbidity. COVID-19 patients with high VAT/TAT levels should be carefully observed as high-risk individuals for morbidity and mortality.

Association of body composition parameters measured on CT with risk of hospitalization in patients with Covid-19.

PURPOSE: To assess prognostic value of body composition parameters measured at CT to predict risk of hospitalization in patients with COVID-19 infection. METHODS: 177 patients with SARS-CoV-2 infection and with abdominopelvic CT were included in this retrospective IRB approved two-institution study. Patients were stratified based on disease severity as outpatients (no hospital admission) and patients who were hospitalized (inpatients). Two readers blinded to the clinical outcome segmented axial CT images at the L3 vertebral body level for visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), muscle adipose tissue (MAT), muscle mass (MM). VAT to total adipose tissue ratio (VAT/TAT), MAT/MM ratio, and muscle index (MI) at L3 were computed. These measures, along with detailed clinical risk factors, were compared in patients stratified by severity. Various logistic regression clinical and clinical + imaging models were compared to discriminate inpatients from outpatients. RESULTS: There were 76 outpatients (43%) and 101 inpatients. Male gender (p = 0.013), age (p = 0.0003), hypertension (p = 0.0003), diabetes (p = 0.0001), history of cardiac disease (p = 0.007), VAT/TAT (p < 0.0001), and MAT/MM (p < 0.0001), but not BMI, were associated with hospitalization. A clinical model (age, gender, BMI) had AUC of 0.70. Addition of VAT/TAT to the clinical model improved the AUC to 0.73. Optimal model that included gender, BMI, race (Black), MI, VAT/TAT, as well as interaction between gender and VAT/TAT and gender and MAT/MM demonstrated the highest AUC of 0.83. CONCLUSION: MAT/MM and VAT/TAT provides important prognostic information in predicting patients with COVID-19 who are likely to require hospitalization.

COVID-19 infection and body weight: A deleterious liaison in a J-curve relationship.

During the course of the COVID-19 pandemic, obesity has been shown to be an independent risk factor for high morbidity and mortality. Obesity confers poor outcomes in younger (<60 years) patients, an age-group considered low-risk for complications, a privilege that is negated by obesity. Findings are consistent, the higher the body mass index (BMI) the worse the outcomes. Ectopic (visceral) obesity also promotes proinflammatory, prothrombotic, and vasoconstrictive states, thus enhancing the deleterious effects of COVID-19 disease. Less, albeit robust, evidence also exists for a higher risk of COVID-19 infection incurred with underweight. Thus, the relationship of COVID-19 and BMI has a J-curve pattern, where patients with both overweight/obesity and underweight are more susceptible to the ailments of COVID-19. The pathophysiology underlying this link is multifactorial, mostly relating to the inflammatory state characterizing obesity, the impaired immune response to infectious agents coupled with increased viral load, the overexpression in adipose tissue of the receptors and proteases for viral entry, an increased sympathetic activity, limited cardiorespiratory reserve, a prothrombotic milieu, and the associated comorbidities. All these issues are herein reviewed, the results of large studies and meta-analyses are tabulated and the pathogenetic mechanisms and the BMI relationship with COVID-19 are pictorially illustrated.

Visceral Adipose Tissue: A New Target Organ in Virus-Induced Type 1 Diabetes.

Type 1 diabetes (T1D) is a proinflammatory pathology that leads to the specific destruction of insulin producing ß-cells and hyperglycaemia. Much of the knowledge about type 1 diabetes (T1D) has focused on mechanisms of disease progression such as adaptive immune cells and the cytokines that control their function, whereas mechanisms linked with the initiation of the disease remain unknown. It has been hypothesized that in addition to genetics, environmental factors play a pivotal role in triggering ß-cell autoimmunity. The BioBreeding Diabetes Resistant (BBDR) and LEW1.WR1 rats have been used to decipher the mechanisms that lead to virus-induced T1D. Both animals develop ß-cell inflammation and hyperglycemia upon infection with the parvovirus Kilham Rat Virus (KRV). Our earlier in vitro and in vivo studies indicated that KRV-induced innate immune upregulation early in the disease course plays a causal role in triggering ß-cell inflammation and destruction. Furthermore, we recently found for the first time that infection with KRV induces inflammation in visceral adipose tissue (VAT) detectable as early as day 1 post-infection prior to insulitis and hyperglycemia. The proinflammatory response in VAT is associated with macrophage recruitment, proinflammatory cytokine and chemokine upregulation, endoplasmic reticulum (ER) and oxidative stress responses, apoptosis, and downregulation of adipokines and molecules that mediate insulin signaling. Downregulation of inflammation suppresses VAT inflammation and T1D development. These observations are strikingly reminiscent of data from obesity and type 2 diabetes (T2D) in which VAT inflammation is believed to play a causal role in disease mechanisms. We propose that VAT inflammation and dysfunction may be linked with the mechanism of T1D progression.

The Obesity Paradox Predicts the Second Wave of COVID-19 to Be Severe in Western Countries.

While COVID-19 infection and mortality rates are soaring in Western countries, Southeast Asian countries have successfully avoided the second wave of the SARS-CoV-2 pandemic despite high population density. We provide a biochemical hypothesis for the connection between low COVID-19 incidence, mortality rates, and high visceral adiposity in Southeast Asian populations. The SARS-CoV-2 virus uses angiotensin-converting enzyme 2 (ACE2) as a gateway into the human body. Although the highest expression levels of ACE2 are found in people's visceral adipose tissue in Southeast Asia, this does not necessarily make them vulnerable to COVID-19. Hypothetically, high levels of visceral adiposity cause systemic inflammation, thus decreasing the ACE2 amount on the surface of both visceral adipocytes and alveolar epithelial type 2 cells in the lungs. Extra weight gained during the pandemic is expected to increase visceral adipose tissue in Southeast Asians, further decreasing the ACE2 pool. In contrast, weight gain can increase local inflammation in fat depots in Western people, leading to worse COVID-related outcomes. Because of the biological mechanisms associated with fat accumulation, inflammation, and their differential expression in Southeast Asian and Western populations, the second wave of the pandemic may be more severe in Western countries, while Southeast Asians may benefit from their higher visceral fat depots.

The role of visceral adiposity in the severity of COVID-19: Highlights from a unicenter cross-sectional pilot study in Germany.

BACKGROUND AND AIMS: Overall obesity has recently been established as an independent risk factor for critical illness in patients with coronavirus disease 2019 (COVID-19). The role of fat distribution and especially that of visceral fat, which is often associated with metabolic syndrome, remains unclear. Therefore, this study aims at investigating the association between fat distribution and COVID-19 severity. METHODS: Thirty patients with COVID-19 and a mean age of 65.6 ±â€¯13.1 years from a level-one medical center in Berlin, Germany, were included in the present cross-sectional analysis. COVID-19 was confirmed by polymerase chain reaction (PCR) from nasal and throat swabs. A severe clinical course of COVID-19 was defined by hospitalization in the intensive care unit (ICU) and/or invasive mechanical ventilation. Fat was measured at the level of the first lumbar vertebra on routinely acquired low-dose chest computed tomography (CT). RESULTS: An increase in visceral fat area (VFA) by ten square centimeters was associated with a 1.37-fold higher likelihood of ICU treatment and a 1.32-fold higher likelihood of mechanical ventilation (adjusted for age and sex). For upper abdominal circumference, each additional centimeter of circumference was associated with a 1.13-fold higher likelihood of ICU treatment and a 1.25-fold higher likelihood of mechanical ventilation. CONCLUSIONS: Our proof-of-concept study suggests that visceral adipose tissue and upper abdominal circumference specifically increase the likelihood of COVID-19 severity. CT-based quantification of visceral adipose tissue and upper abdominal circumference in routine chest CTs may therefore be a simple tool for risk assessment in COVID-19 patients.

Obesity in patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: Obesity is common in patients with coronavirus disease 2019 (COVID-19). The effects of obesity on clinical outcomes of COVID-19 warrant systematical investigation. OBJECTIVE: This study explores the effects of obesity with the risk of severe disease among patients with COVID-19. METHODS: Body mass index (BMI) and degree of visceral adipose tissue (VAT) accumulation were used as indicators for obesity status. Publication databases including preprints were searched up to August 10, 2020. Clinical outcomes of severe COVID-19 included hospitalization, a requirement for treatment in an intensive care unit (ICU), invasive mechanical ventilation (IMV), and mortality. Risks for severe COVID-19 outcomes are presented as odds ratios (OR) and 95% confidence interval (95%CI) for cohort studies with BMI-defined obesity, and standardized mean difference (SMD) and 95%CI for controlled studies with VAT-defined excessive adiposity. RESULTS: A total of 45, 650 participants from 30 studies with BMI-defined obesity and 3 controlled studies with VAT-defined adiposity were included for assessing the risk of severe COVID-19. Univariate analyses showed significantly higher ORs of severe COVID-19 with higher BMI: 1.76 (95%: 1.21, 2.56, P = 0.003) for hospitalization, 1.67 (95%CI: 1.26, 2.21, P<0.001) for ICU admission, 2.19 (95%CI: 1.56, 3.07, P<0.001) for IMV requirement, and 1.37 (95%CI: 1.06, 1.75, P = 0.014) for death, giving an overall OR for severe COVID-19 of 1.67 (95%CI: 1.43, 1.96; P<0.001). Multivariate analyses revealed increased ORs of severe COVID-19 associated with higher BMI: 2.36 (95%CI: 1.37, 4.07, P = 0.002) for hospitalization, 2.32 (95%CI: 1.38, 3.90, P = 0.001) for requiring ICU admission, 2.63 (95%CI: 1.32, 5.25, P = 0.006) for IMV support, and 1.49 (95%CI: 1.20, 1.85, P<0.001) for mortality, giving an overall OR for severe COVID-19 of 2.09 (95%CI: 1.67, 2.62; P<0.001). Compared to non-severe COVID-19 patients, severe COVID-19 cases showed significantly higher VAT accumulation with a SMD of 0.49 for hospitalization (95% CI: 0.11, 0.87; P = 0.011), 0.57 (95% CI: 0.33, 0.81; P<0.001) for requiring ICU admission and 0.37 (95% CI: 0.03, 0.71; P = 0.035) for IMV support. The overall SMD for severe COVID-19 was 0.50 (95% CI: 0.33, 0.68; P<0.001). CONCLUSIONS: Obesity increases risk for hospitalization, ICU admission, IMV requirement and death among patients with COVID-19. Further, excessive visceral adiposity appears to be associated with severe COVID-19 outcomes. These findings emphasize the need for effective actions by individuals, the public and governments to increase awareness of the risks resulting from obesity and how these are heightened in the current global pandemic.

Visceral adipose tissue in patients with COVID-19: risk stratification for severity.

PURPOSE: To assess visceral (VAT), subcutaneous (SAT), and total adipose tissue (TAT) estimates at abdominopelvic CT in COVID-19 patients with different severity, and analyze Body Mass Index (BMI) and CT estimates of fat content in patients requiring hospitalization. METHODS: In this retrospective IRB approved HIPPA compliant study, 51 patients with SARS-CoV-2 infection with abdominopelvic CT were included. Patients were stratified based on disease severity as outpatient (no hospital admission) and patients who were hospitalized. Subset of hospitalized patient required mechanical ventilation (MV). A radiologist blinded to the clinical outcome evaluated single axial slice on CT at L3 vertebral body for VATL3, SATL3, TATL3, and VAT/TATL3. These measures along with age, gender, and BMI were compared. A clinical model that included age, sex, and BMI was compared to clinical + CT model that also included VATL3 to discriminate hospitalized patients from outpatients. RESULTS: There were ten outpatients and 41 hospitalized patients. 11 hospitalized patients required MV. There were no significant differences in age and BMI between the hospitalized and outpatients (all p > 0.05). There was significantly higher VATL3 and VAT/TATL3 in hospitalized patients compared to the outpatients (all p < 0.05). Area under the curve (AUC) of the clinical + CT model was higher compared to the clinical model (AUC 0.847 versus 0.750) for identifying patients requiring hospitalization. CONCLUSION: Higher VATL3 was observed in COVID-19 patients that required hospitalization compared to the outpatients, and addition of VATL3 to the clinical model improved AUC in discriminating hospitalized from outpatients in this preliminary study.