Cancer- and cardiac-induced cachexia: same fate through different inflammatory mediators?

BACKGROUND: Inflammation is widely recognized as the driving force of cachexia induced by chronic diseases; however, therapies targeting inflammation do not always reverse cachexia. Thus, whether inflammation per se plays an important role in the clinical course of cachectic patients is still a matter of debate. AIMS: To give new insights into cachexia's pathogenesis and diagnosis, we performed a comprehensive literature search on the contribution of inflammatory markers to this syndrome, focusing on the noncommunicable diseases cancer and cardiovascular diseases. METHODS: A systematic review was performed in PubMed using the keywords ("cancer" OR "cardiac" cachexia AND "human" OR "patient" AND "plasma" or "serum"). A total of 744 studies were retrieved and, from these, 206 were selected for full-text screening. In the end, 98 papers focusing on circulating biomarkers of cachexia were identified, which resulted in a list of 113 different mediators. RESULTS: Data collected from the literature highlight the contribution of interleukin-6 (IL-6) and C-reactive protein (CRP) to cachexia, independently of the underlying condition. Despite not being specific, once the diagnosis of cachexia is established, CRP might help to monitor the effectiveness of anti-cachexia therapies. In cardiac diseases, B-type natriuretic peptide (BNP), renin, and obestatin might be putative markers of body wasting, whereas in cancer, growth differentiation factor (GDF) 15, transforming growth factor (TGF)-ß1 and vascular endothelial growth factor (VEGF) C seem to be better markers of this syndrome. Independently of the circulating mediators, NF-κB and JAK/STAT signaling pathways play a key role in bridging inflammation with muscle wasting; however, therapies targeting these pathways were not proven effective for all cachectic patients. CONCLUSION: The critical and integrative analysis performed herein will certainly feed future research focused on the better comprehension of cachexia pathogenesis toward the improvement of its diagnosis and the development of personalized therapies targeting specific cachexia phenotypes.

The impact of chemotherapy on adipose tissue remodeling: The molecular players involved in this tissue wasting.

The depletion of visceral and subcutaneous adipose tissue (AT) during chemotherapy significantly correlates with diminished overall survival and progression-free survival. Despite its clinical significance, the intricate molecular mechanisms governing this AT loss and its chemotherapy-triggered initiation remain poorly understood. Notably, the evaluation of AT remodeling in most clinical trials has predominantly relied on computerized tomography scans or bioimpedance, with molecular studies often conducted using animal or in vitro models. To address this knowledge gap, a comprehensive narrative review was conducted. The findings underscore that chemotherapy serves as a key factor in inducing AT loss, exacerbating cachexia, a paraneoplastic syndrome that significantly compromises patient quality of life and survival. The mechanism driving AT loss appears intricately linked to alterations in AT metabolic remodeling, marked by heightened lipolysis and fatty acid oxidation, coupled with diminished lipogenesis. However, adipocyte stem cells' lost ability to divide due to chemotherapy also appears to be at the root of the loss of AT. Notably, chemotherapy seems to deactivate the mitochondrial antioxidant system by reducing key regulatory enzymes responsible for neutralizing reactive oxygen species (ROS), thereby impeding lipogenesis. Despite FDG-PET evidence of AT browning, no molecular evidence of thermogenesis was reported. Prospective investigations unraveling the molecular mechanisms modulated in AT by chemotherapy, along with therapeutic strategies aimed at preventing AT loss, promise to refine treatment paradigms and enhance patient outcomes.

The Association between Serum Levels of 25[OH]D, Body Weight Changes and Body Composition Indices in Patients with Heart Failure.

We try to determine the association between weight changes (WC), both loss or gain, body composition indices (BCI) and serum levels of 25[OH]D during heart failure (HF). WC was determined in 412 patients (14.3% female, aged: 53.6 ± 10.0 years, NYHA class: 2.5 ± 0.8). Body fat, fat percentage and fat-free mass determined by dual energy X-rays absorptiometry (DEXA) and serum levels of 25[OH]D were analyzed. Logistic regression was used to calculate odds ratios for 25[OH]D insufficiency (<30 ng/mL) or deficiency (<20 ng/mL) by quintiles of WC, in comparison to weight-stable subgroup. The serum 25[OH]D was lower in weight loosing than weight stable subgroup. In fully adjusted models the risk of either insufficient or deficient 25[OH]D levels was independent of BCI and HF severity markers. The risk was elevated in higher weight loss subgroups but also in weight gain subgroup. In full adjustment, the odds for 25[OH]D deficiency in the top weight loss and weight gain subgroups were 3.30; 95%CI: 1.37-7.93, p = 0.008 and 2.41; 95%CI: 0.91-6.38, p = 0.08, respectively. The risk of 25[OH]D deficiency/insufficiency was also independently associated with potential UVB exposure, but not with nutritional status and BCI. Metabolic instability in HF was reflected by edema-free WC, but not nutritional status. BCI is independently associated with deficiency/insufficiency of serum 25[OH]D.

Weight loss in heart failure is associated with increased mortality only in non-obese patients without diabetes.

BACKGROUND: Weight loss (WL) is an independent predictor of mortality in patients with heart failure (HF). Moderate WL is recommended for overweight or obese patients with type 2 diabetes mellitus (DM). The aim of this study was to assess the prognostic impact of body weight reduction on survival in patients with both HF with reduced ejection fraction (HFrEF) and DM. METHODS: The study comprised patients with HFrEF at the outpatient clinic. WL was defined as a body weight reduction of at least 7.5% during at least 6 months. Clinical features and 1 year mortality were analysed in WL and DM groups. Multivariate regression model was chosen to assess the predictive role of WL in HF patients with and without DM. The analysis regarding obesity before HF was also performed. RESULTS: The study comprised 777 patients with HFrEF. Mean age was 53.2 ± 9.2, 12.0% were women, mean EF was 23.7 ± 6.0 %, and New York Heart Association III or IV class, DM, and WL were found in 60.5%, 33.3%, and 47.1% patients, respectively. WL was more prevalent in diabetic patients, comparing with those without DM (53.7% vs. 43.8%, respectively, 0.01), and was associated with higher 1 year mortality only in non-diabetic group (17.6% for WL vs. 8.2% for non-WL, log-rank 0.001). In the multivariate analysis, WL was associated with a higher risk of 1 year mortality in non-diabetic patients: HR 1.76 (1.05-2.95), 0.03 and only in the subgroup without obesity: HR 2.35 (1.28-4.32), 0.006. In non-diabetic patients with obesity and in diabetic patients regardless of weight status, WL was not associated with worse prognosis (thereof, WL was excluded from the multivariate models). CONCLUSIONS: Overall, WL in HFrEF has emerged as a predictor of unfavourable outcomes only in non-obese patients without DM. More importantly, this study has identified that the presence of DM (irrespective of weight status) or the presence of obesity in non-diabetic patients abolished the unfavourable impact of WL on long-term outcomes.

Body Weight Loss and Tissue Wasting in Late Middle-Aged Mice on Slightly Imbalanced Essential/Non-essential Amino Acids Diet.

Objective: Inadequate protein intake can impair protein balance thus leading to skeletal muscle atrophy, impaired body growth, and functional decline. Foods provide both non-essential (NEAAs) and essential amino acids (EAAs) that may convey different metabolic stimuli to specific organs and tissues. In this study, we sought to evaluate the impact of six diets, with various EAA/NEAA blends, on body composition and the risk of developing tissue wasting in late middle-aged male mice. Methods: Six groups of late middle-aged male mice were fed for 35 days with iso-nutrients, iso-caloric, and iso-nitrogenous special diets containing different EAA/NEAA ratios ranging from 100/0% to 0/100%. One group fed with standard laboratory rodent diet (StD) served as control. Preliminarily, we verified the palatability of the diets by recording the mice preference, and by making accessible all diets simultaneously, in comparison to StD. Body weight, food and water consumption were measured every 3 days. Blood and urine samples, as well as heart, kidneys, liver, spleen, triceps surae, retroperitoneal WAT, and BAT were harvested and weighed. Results: Mice consuming NEAA-based diets, although showing increased food and calorie intake, suffered the most severe weight loss. Interestingly, the diet containing a EAA/NEAA-imbalance, with moderate NEAAs prevalence, was able to induce catabolic stimuli, generalized body wasting, and systemic metabolic alterations comparable to those observed with diet containing NEAA alone. In addition, complete depletion of retroperitoneal white adipose tissue and a severe loss (>75%) of brown adipose tissue were observed together with muscle wasting. Conversely, EAA-containing diets induced significant decreases in body weight by reducing primarily fat reserves, but at the same time they improved the clinical parameters. On these basis we can deduce that tissue wasting was caused by altered AA quality, independent of reduced nitrogen or caloric intake. Conclusion: Our results indicate that diets containing an optimized balance of AA composition is necessary for preserving overall body energy status. These findings are particularly relevant in the context of aging and may be exploited for contrasting its negative correlates, including body wasting.

The impact of exercise training on adipose tissue remodelling in cancer cachexia.

Cachexia affects the majority of patients with advanced cancer and no effective treatment is currently available to address this paraneoplastic syndrome. It is characterized by a reduction in body weight due to the loss of white adipose tissue (WAT) and skeletal muscle. The loss of WAT seems to occur at an earlier time point than skeletal muscle proteolysis, with recent evidence suggesting that the browning of WAT may be a major contributor to this process. Several factors seem to modulate WAT browning including pro-inflammatory cytokines; however, the underlying molecular pathways are poorly characterized. Exercise training is currently recommended for the clinical management of low-grade inflammatory conditions as cancer cachexia. While it seems to counterbalance the impairment of skeletal muscle function and attenuate the loss of muscle mass, little is known regarding its effects in adipose tissue. The browning of WAT is one of the mechanisms through which exercise improves body composition in overweight/obese individuals. While this effect is obviously advantageous in this clinical setting, it remains to be clarified if exercise training could protect or exacerbate the cachexia-related catabolic phenotype occurring in adipose tissue of cancer patients. Herein, we overview the molecular players involved in adipose tissue remodelling in cancer cachexia and in exercise training and hypothesize on the mechanisms modulated by the synergetic effect of these conditions. A better understanding of how physical activity regulates body composition will certainly help in the development of successful multimodal therapeutic strategies for the clinical management of cancer cachexia.