Pro-inflammatory lipid profile in isolated adipocyte cultures from patients with congestive heart failure: a possible role in the development of cardiac cachexia

Background Cardiac cachexia, which affects 5 to 15% of patients with congestive heart failure (CHF), is an extremely poor prognosis condition with a significant clinical and social impact. The activation of the beta-adrenergic, renin-angiotensin-aldosterone and natriuretic peptide systems is recognised as the main pathophysiological driver of both lipolysis and sarcopenia. However, recent evidence suggests that adipose tissue may also play a role in cachexia development. by releasing several adipocytokines and free fatty acids (FFA). Purpose To characterise lipid metabolism and the profile of free fatty acids (FFA) in adipocytes isolated from subcutaneous adipose tissue of subjects with CHF complicated or not by cardiac cachexia (CXC). Methods A total of 16 patients with CHF, including 6 with CXC, were analysed and compared with 5 healthy age-matched subjects (CTRL). Cachexia was defined as a non-oedematous body weight loss ≥7.5% in six months. The release of FFA from primary cultures of mature adipocytes was assessed under basal conditions and following stimulation with isoproterenol, BNP and ANP by gas-liquid chromatography. Secondly, adipocytes (n=14) were tested with norepinephrine in association with combinations of zinc-alpha-2-glycoprotein (ZAG), arachidonic acid (AA), and anti-ZAG antibodies. Glycerol release was assessed as an indicator of the lipolytic response. Results As expected, CXC patients had significantly higher plasma levels of FFA, BNP and norepinephrine, as well as increased HSL activity in subcutaneous adipose tissue and reduced adipocyte volume, compared to CHF subjects and CTRL. FFA release in adipocyte cultures from cachectic patients was significantly increased under basal conditions and following stimulation with isoproterenol BNP and ANP. Specifically, the FFA profile from CXC adipocytes showed a significant increase in oleic, stearic and, in particular, AA levels, along with a decrease in linolenic and linoleic acids. No difference in Stearoyl-CoA desaturase activity was observed when assessed by palmitoleic/palmitic acid and oleic/stearic acid ratios. Furthermore, adipocyte treatment with AA, in addition to enhancing ZAG lipolytic activity, induced a significant lipolytic effect when added to norepinephrine alone. Conclusion(s) Our findings strengthen the hypothesis that CXC is not merely a consequence of energy catabolism, but rather an active process involving complex interactions among accelerated lipolysis, altered FFA release profile, and activated inflammatory pathways. The association between increased HSL activity, reduced adipocyte volume, and selective release of proinflammatory FFA suggests a role for these mechanisms in CXC pathogenesis. Further prospective studies on larger cohorts and in clinical settings are essential to confirm these observations, expand on them, and identify potential therapeutic avenues for managing cardiac cachexia through targeted metabolic interventions.