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

BACKGROUND/OBJECTIVES: The aim of this post-hoc analysis was to evaluate if epicardial adipose tissue (EAT) quantity and quality, as evaluated by computed tomography (CT), have a different role in the risk of mortality and pulmonary embolism in critically ill COVID-19 patients admitted to an intensive care unit (ICU). SUBJECTS/METHODS: CT derived EAT volume and density, as well as anthropometric and blood biomarkers, were evaluated in a sample of 138 subjects, 109 men and 29 women, for whom CT images and information on pulmonary embolism were available from a total of 313 subjects who were consecutively admitted to the ICU for COVID-19 from the REINSURE-ARDS prospective registry. RESULTS: A total of 28 patients (20.3%) died during the first 28 days after ICU admission. 26 subjects out of 138 had pulmonary embolism (18.8%). Age, weight, BMI, IL-6 levels and pulmonary embolism prevalence were significantly higher across EAT volume tertiles. Subjects who died in the first 28 days from ICU admission were older, had higher EAT volume, D-dimer, LDH and IL-6 level. After adjustment for age and gender, participants in tertile 3 of EAT volume had lower survival at 28 days from ICU admission as compared to subjects in the tertile 1, HR 2.95 (95% C.I. 1.02-8.49), but after adjusting for potential confounders the relation was no longer significant. No relation between EAT density and mortality was observed. From a binary logistic regression, subjects in tertile 3 of EAT volume and in tertile 1 of EAT density showed a 4 times and 3.6 times increased risk of pulmonary embolism, respectively. CONCLUSIONS: ICU subjects affected by severe COVID-19 with higher EAT volume and low EAT density should be carefully monitored and managed with a prompt and aggressive approach, to prevent serious and life-threatening consequences and the increase of hospital treatment costs.

Worsening Disability and Hospitalization Risk in Sarcopenic Obese and Dynapenic Abdominal Obese: A 5.5 Years Follow-Up Study in Elderly Men and Women.

Background/Objectives: A general lack of studies comparing the effect of both dynapenic abdominal obesity and sarcopenic obesity on worsening disability and hospitalization risk should be recognized. The aim of the current study was to evaluate, with a 5.5-year follow-up, the prognostic value of sarcopenic obesity and dynapenic abdominal obesity definitions on worsening disability and hospitalization risk in a sample of older adults. Subjects/Methods: In 177 women and 97 men aged 68-78 years, the following outcomes were evaluated at baseline: appendicular skeletal muscle mass (ASMM), percent fat mass (FM%), leg isometric strength, body mass index (BMI), lipid profile, vitamin D3, albumin, fibrinogen, glycemia, physical activity level, income, smoking status, and comorbidities. The rate of reported disabilities and hospitalization were also assessed at baseline, 1, 2, 3, and 5.5-years follow-up. The study population was classified into: (i) non-sarcopenic/obese (NS/O), sarcopenic/non-obese (S/NO), sarcopenic/obese (S/O), non-sarcopenic/non-obese (NS/NO, reference category) according to relative ASMM/FM% tertiles; (ii) non-dynapenic/abdominal obese (ND/AO), dynapenic/non-abdominal obese (D/NAO), dynapenic/abdominal obese (D/AO), non-dynapenic/non-abdominal obese (ND/NAO, reference category) according to muscle strength/waist circumference tertiles. Results: The prevalence of D/AO and S/O was 12.0 and 8.0%, respectively. Only 2 subjects were both D/NAO and S/O (0.8%). D/NAO subjects showed a worsening disability risk of 1.69 times (95% CI: 1.11-2.57), ND/AO subjects showed a 2-fold increased risk (95% CI: 1.34-2.98), while being D/AO more than trebled the risk, even after adjustment for confounding factors (HR: 3.39, 95%; CI: 1.91-6.02). By dividing the study population according to the relative ASMM/FM% tertiles, no groups showed an increased risk of worsening disability. The hospitalization risk, even after adjustment for potential confounders, was 1.84 (95% CI: 1.06-3.19) for D/AO. Dividing the study population according to the relative ASMM/FM% tertiles, no groups showed increased risk of hospitalization. Conclusions: Our results showed that dynapenic abdominal obesity and sarcopenic obesity seem to indicate two distinct phenotypes associated with different health risk profiles. The distribution of participants in waist circumference and muscle strength tertiles allowed for a more accurate risk stratification for worsening disability and hospitalization.

Musculoskeletal adaptations to strength training in frail elderly: a matter of quantity or quality?

BACKGROUND: The improvement in muscle strength generally exceeds the increase in muscle size following strength training in frail elderly, highlighting the complex aetiology of strength deficit in aging. The aim of this study was to investigate the effect of heavy-load strength training on a broad number of factors related to specific strength in frail elderly. METHODS: Thirty-four frail elderly men (n = 18) and women (n = 16) aged 67 to 98 (86 ± 7 years) were randomized to either a group performing strength training twice a week for 10 weeks (ST) or a non-exercising control group (CON). Knee extensor muscle strength was tested as one-repetition maximum (1RM) and isometric maximal voluntary contraction (MVC) torque. Muscle activation was assessed by the interpolated twitch technique, and muscle density [mean Hounsfield units (HU)] and intermuscular adipose tissue (IMAT) by computed tomography scans of the quadriceps femoris. Muscle biopsies from the vastus lateralis were obtained to investigate changes in intramyocellular lipids and single-fibre specific tension. RESULTS: In ST, knee extension 1RM and MVC improved by 17 and 7%, respectively. Muscle cross-sectional area of the quadriceps femoris increased by 7%, accompanied by a 4% increase of muscle density. No changes in IMAT, voluntary activation level, single-fibre specific tension, or lipid content were observed. CONCLUSIONS: In contrast to several previous reports, the improvements in isometric muscle strength and muscle area were in good agreement in the present study. The training-induced increase in muscle density was not due to changes in skeletal muscle lipid content. Instead, the increase in muscle density may reflect increased packing of contractile material or simply an increased ratio of muscle tissue relative to IMAT.

Weight Loss and Hypertension in Obese Subjects.

Arterial hypertension is strongly related to overweight and obesity. In obese subjects, several mechanisms may lead to hypertension such as insulin and leptin resistance, perivascular adipose tissue dysfunction, renal impairment, renin-angiotensin-aldosterone-system activation and sympathetic nervous system activity. Weight loss (WL) seems to have positive effects on blood pressure (BP). The aim of this review was to explain the mechanisms linking obesity and hypertension and to evaluate the main studies assessing the effect of WL on BP. We analysed studies published in the last 10 years (13 studies either interventional or observational) showing the effect of WL on BP. Different WL strategies were taken into account-diet and lifestyle modification, pharmacological intervention and bariatric surgery. Although a positive effect of WL could be identified in each study, the main difference seems to be the magnitude and the durability of BP reduction over time. Nevertheless, further follow-up data are needed: there is still a lack of evidence about long term effects of WL on hypertension. Hence, given the significant results obtained in several recent studies, weight management should always be pursued in obese patients with hypertension.

Predictors of self-reported adherence to direct oral anticoagulation in a population of elderly men and women with non-valvular atrial fibrillation.

There is a general lack of studies evaluating medication adherence with self-report scales for elderly patients in treatment with direct oral anticoagulants (DOACs). The aim of the study was to assess the degree of adherence to DOAC therapy in a population of elderly outpatients aged 65 years or older affected by non-valvular atrial fibrillation (NVAF), using the 4-item Morisky Medication Adherence Scale, and to identify potential factors, including the geriatric multidimensional evaluation, which can affect adherence in the study population. A total of 103 subjects, anticoagulated with DOACs for NVAF in primary or secondary prevention, were eligible; 76 showed adequate adhesion to anticoagulant therapy, while 27 showed inadequate adherence. Participants underwent biochemical assessment and Morisky Scale, Instrumental Activities of Daily Living, CHA2DS2-VASc, HAS-BLED, mental status and nutritional evaluations were performed. 2% of subjects assumed Dabigatran at low dose, while 7.8% at standard dose, 9.7% assumed low-dose of Rivaroxaban and 30.1% at standard dose, 6.8% assumed Apixaban at low dose and 39.7% at standard dose, and finally 1% assumed Edoxaban at low dose and 2.9% at standard dose. Most subjects took the DOACs without help (80.6%), while 16 subjects were helped by a family member (15.5%) and 4 were assisted by a caregiver (3.9%). Binary logistic regression considered inappropriate adherence as a dependent variable, while age, male sex, polypharmacotherapy, cognitive decay, caregiver help for therapy assumption, duration of DOAC therapy and double daily administration were considered as independent variables. The double daily administration was an independent factor, determining inappropriate adherence with an OR of 2.88 (p = 0.048, CI 1.003-8.286).

Dynapenic Abdominal Obesity as a Predictor of Worsening Disability, Hospitalization, and Mortality in Older Adults: Results From the InCHIANTI Study.

BACKGROUND: There are relatively few prospective studies evaluating the combined effect of abdominal obesity and low muscle strength on mortality, hospitalization, and incident disability. The aim of this study was to prospectively evaluate the prognostic value of dynapenic abdominal obesity on incident disability, hospitalization, and mortality in the population of the InCHIANTI study. METHODS: In 370 men and 476 women aged between 65 and 95 years, handgrip strength, waist circumference (WC), body mass index, interleukin-6, C-reactive protein, education, medications, smoking status, and comorbidities were evaluated at the baseline. Difficulties in performing basic activities of daily living were assessed at baseline and at 3-, 6-, and 9-year follow-ups, using a standardized questionnaire. Hospitalization and mortality rates were evaluated during an 11-year follow-up. The study population was categorized as nondynapenic nonabdominal obese (ND/NAO, reference group), dynapenic nonabdominal obese (D/NAO), nondynapenic abdominal obese (ND/AO), and dynapenic abdominal obese (D/AO), according to handgrip strength/WC tertiles. RESULTS: D/AO participants presented more than a twofold increase in risk of worsening disability (odds ratio = 2.10; 95% confidence interval [CI]: 1.14-3.88) and significantly higher risk of hospitalization (1.36; 95% CI: 1.04-1.78) compared with ND/NAO participants. After adjustment for potential confounders, the relative risk of death was 1.47 (95% CI: 1.09-1.97) for D/NAO compared with the ND/NAO group. CONCLUSIONS: Dynapenic abdominal obese participants are at higher risk of worsening disability and hospitalization than ND/NAO participants. Mortality risk was higher in participants with dynapenia without central fat distribution compared with the reference group.

Adipocytes WNT5a mediated dedifferentiation: a possible target in pancreatic cancer microenvironment.

A significant epidemiological association between obesity and pancreatic ductal adenocarcinoma (PDAC) has previously been described, as well as a correlation between the degree of pancreatic steatosis, PDAC risk and prognosis. The underlying mechanisms are still not completely known.After co-culture of 3T3-L1 adipocytes and MiaPaCa2 with an in vitro transwell system we observed the appearance of fibroblast-like cells, along with a decrease in number and size of remaining adipocytes. RT-PCR analyses of 3T3-L1 adipocytes in co-culture showed a decrease in gene expression of typical markers of mature adipocytes, in parallel with an increased expression of fibroblast-specific and reprogramming genes. We found an increased WNT5a gene and protein expression early in MiaPaCa2 cells in co-culture. Additionally, EMSA of c-Jun and AP1 in 3T3-L1 demonstrated an increased activation in adipocytes after co-culture. Treatment with WNT5a neutralizing antibody completely reverted the activation of c-Jun and AP1 observed in co-cultured adipocytes.Increasing doses of recombinant SFRP-5, a competitive inhibitor for WNT5a receptor, added to the co-culture medium, were able to block the dedifferentiation of adipocytes in co-culture.These data support a WNT5a-mediated dedifferentiation process with adipocytes reprogramming toward fibroblast-like cells that might profoundly influence cancer microenvironment.

Dynapenic abdominal obesity as predictor of mortality and disability worsening in older adults: A 10-year prospective study.

UNLABELLED: There are relatively few prospective studies evaluating the combined effect of abdominal obesity and low muscle strength on worsening disability and on mortality. The study aimed at evaluating prospectively the prognostic value of dynapenic abdominal obesity definition on disability worsening in a 5.5-year follow-up and mortality in a 10-year follow-up. METHODS: In 93 men and 169 women aged between 66 and 78 years, leg isometric strength, waist circumference (WC), BMI, glycemia, HOMA, lipid profile, vitamin D3, albumin, fibrinogen, physical activity level, income, smoking status and comorbidities were evaluated at the baseline. Reported disabilities were measured at baseline, 1-y, 2-y, 3-y and 5.5-y follow-up and mortality rate was evaluated during a 10-y follow-up. The study population was categorized in dynapenic abdominal obese (D/AO), nondynapenic abdominal obese (ND/AO), dynapenic nonabdominal obese (D/NAO), nondynapenic nonabdominal obese (ND/NAO) according to muscle strength/WC tertiles. RESULTS: D/NAO subjects presented a disability worsening risk of 1.69 times (95%CI:1.11-2.57), ND/AO subjects showed a 2-fold increase in risk (95%CI:1.34-2.98), while being D/AO more than trebled the risk, even after considering confounding variables (HR:3.39,95%CI:1.91-6.02). Mortality risk after adjustment for other confounding variables was 1.57 (95%CI:1.16-2.13) for ND/AO and 2.46 (95%CI:1.34-4.52) for D/AO. CONCLUSIONS: Dynapenic abdominal obese subjects are at higher risk of worsening disability and mortality than subjects with dynapenia or central fat distribution only.

Iron primes 3T3-L1 adipocytes to a TLR4-mediated inflammatory response.

OBJECTIVE: Iron participates in several mechanisms involving inflammation and innate immunity, yet the dysregulation of its homeostasis is a major cause of metabolic syndrome. Adipocytes should play a major role in iron metabolism, as an impairment in iron turnover is closely related to insulin resistance, obesity, and type 2 diabetes. The aim of this study was to investigate the role of iron in an in vitro-inflamed adipocyte model. METHODS: Gene expression of tumor necrosis factor-α, interleukin-6, inflammatory chemokines (CCL3, CCL4, and CXCL12), and molecules involved in iron metabolism were evaluated in an in vitro mouse 3T3-L1 cell model. Cells underwent treatment with FeSO4 heptahydrate and lipopolysaccharide (LPS) stimulation. Toll-like receptor 4 (TLR4) membrane expression, lipid droplet immunohystochemistry, and lipolysis were also evaluated. RESULTS: Iron sulphate heptahydrate elicited gene expression of hepcidin, hemojuvelin, and ferroportin at different time courses. Additionally, it activated lipolysis but did not trigger any adipokine gene expression. When cells treated with physiological doses of iron were also stimulated with LPS, an enhancement in the LPS-induced gene expression of cytokines and chemokines was observed. The enhancement occurred with different patterns depending on different time courses and investigated genes, showing its maximal effect for IL-6 gene expression. CONCLUSIONS: FeSO4 heptahydrate at a relatively physiological dose, induced gene expression of iron modulatory proteins and also enhanced RNA transcripts of several inflammatory cytokines and chemokines through a priming/synergistic mechanism involving membrane TLR4.

Adipose tissue, diet and aging.

Age related increase in body fat mass, visceral adipose tissue (AT), and ectopic fat deposition are strongly related to worse health conditions in the elderly. Moreover, with aging higher inflammation in adipose tissue may be observed and may contribute to inflammaging. Aging may significantly affect AT function by modifying the profile of adipokines produced by adipose cells, reducing preadipocytes number and their function and increasing AT macrophages infiltration. The initiating events of the inflammatory cascade promoting a greater AT inflammatory profile are not completely understood. Nutrients may determine changes in the amount of body fat, in its distribution as well as in AT function with some nutrients showing a pro-inflammatory effect on AT. Evidences are sparse and quite controversial with only a few studies performed in older subjects. Different dietary patterns are the result of the complex interaction of foods and nutrients, thus more studies are needed to evaluate the association between dietary patterns and changes in adipose tissue structure, distribution and function in the elderly.

Myosteatosis and myofibrosis: relationship with aging, inflammation and insulin resistance.

The mechanisms impairing muscle quality and leading to myofibrosis (MF) and myosteatosis (MS) are incompletely known. In biopsies of paraspinous muscle (PM) of 16 elderly men undergoing elective vertebral surgery, we histologically determined the area of MF and MS expressed as muscle quality index (MQI), in order to investigate the relation between them, as well as the main predictors of muscle quality. Total PM area and intermuscular adipose tissue (IMAT) were evaluated by MRI and body composition by DXA. Circulating fasting glucose, insulin, hs-CRP, leptin, adiponectin and IL-6 were measured and HOMA index calculated. Quantification of gene expression in PM and in subcutaneous adipose tissue (SAT) overlying the muscle was performed by rt-PCR. The degree of MS and MF was significantly and positively related to each other and positively associated with BMI, waist, FM and FM% as well as with IMAT. The area of PM was negatively related with MF even after adjustment for weight. Leptin was positively associated with MF and MS, whereas hs-CRP to MF. In backward regression analyses, larger waist and smaller PM area explained 90% of MF variance, whereas leptin about 80% of MS variance. IL-6 expression in SAT was significantly higher in participants with higher MQI values. In PM biopsies we found significantly higher expression of SOCS-3 and a trend toward higher expression of myostatin with greater degrees of MQI. MS and MF are related phenomena that concur to alter muscle quality and both should be considered in further studies on the evolution of sarcopenia.

Sarcopenia, cachexia and congestive heart failure in the elderly.

Skeletal muscle abnormalities and loss are frequently present in patients with mild or moderate cardiac heart failure (CHF) and may contribute to fatigue and dyspnea. These muscle abnormalities may be associated with age related body composition changes, such as sarcopenia. Muscle damage has also been observed in subjects with cardiac cahexia, a serious CHF complication, associated with poor prognosis independently of functional disease severity, age, and measures of exercise capacity and cardiac function. Loss of muscle mass is a feature of cachexia, whereas most sarcopenic subjects are not cachectic. Individuals with no weight loss, no anorexia, and no measurable systemic inflammatory response may be sarcopenic. Patients with severe CHF show multiple marked histological abnormalities of skeletal muscle, such as muscle fiber atrophy. These abnormalities are different in sarcopenia and cachexia. The majority of mechanisms involved in sarcopenia play a role even in the determination of cachexia and they are amplified in cachexia where they may induce both muscle damage as well as other abnormalities, such as fat and weight loss, through activation of lypolisis or anorexia. To distinguish cachexia and sarcopenia in CHF patients, even if not easy, should be clinically relevant, because no specific treatment is available for cachectic patients whereas treatment options are possible for sarcopenia.