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Background: Cachexia worsens long-term prognosis of patients with heart failure (HF). Effective treatment of cachexia is missing. We seek to characterize mechanisms of cachexia in adipose tissue, which could serve as novel targets for the treatment., Methods: The study was conducted in advanced HF patients (n = 52; 83% male patients) undergoing heart transplantation. Patients with ≥7.5% non-intentional body weight (BW) loss during the last 6 months were rated cachectic. Clinical characteristics and circulating markers were compared between cachectic (n = 17) and the remaining, BW-stable patients. In epicardial adipose tissue (EAT), expression of selected genes was evaluated, and a combined metabolomic/lipidomic analysis was performed to assess (i) the role of adipose tissue metabolism in the development of cachexia and (ii) potential impact of cachexia-associated changes on EAT-myocardium environment., Results: Cachectic vs. BW-stable patients had higher plasma levels of natriuretic peptide B (BNP; 2007 ± 1229 vs. 1411 ± 1272 pg/mL; P = 0.010) and lower EAT thickness (2.1 ± 0.8 vs. 2.9 ± 1.4 mm; P = 0.010), and they were treated with ~2.5-fold lower dose of both β-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACE/ARB-inhibitors). The overall pattern of EAT gene expression suggested simultaneous activation of lipolysis and lipogenesis in cachexia. Lower ratio between expression levels of natriuretic peptide receptors C and A was observed in cachectic vs. BW-stable patients (0.47 vs. 1.30), supporting activation of EAT lipolysis by natriuretic peptides. Fundamental differences in metabolome/lipidome between BW-stable and cachectic patients were found. Mitochondrial phospholipid cardiolipin (CL), specifically the least abundant CL 70:6 species (containing C16:1, C18:1, and C18:2 acyls), was the most discriminating analyte (partial least squares discriminant analysis; variable importance in projection score = 4). Its EAT levels were higher in cachectic as compared with BW-stable patients and correlated with the degree of BW loss during the last 6 months (r = -0.94; P = 0.036)., Conclusions: Our results suggest that (i) BNP signalling contributes to changes in EAT metabolism in cardiac cachexia and (ii) maintenance of stable BW and 'healthy' EAT-myocardium microenvironment depends on the ability to tolerate higher doses of both ACE/ARB inhibitors and β-adrenergic blockers. In line with preclinical studies, we show for the first time in humans the association of cachexia with increased adipose tissue levels of CL. Specifically, CL 70:6 could precipitate wasting of adipose tissue, and thus, it could represent a therapeutic target to ameliorate cachexia., (© 2020 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Introduction: Epicardial adipose tissue (EAT) may serve as a transducer of metabolic influences on the heart. The determinants of EAT gene expression in advanced heart failure (HF) are not known. Hypothesis: HF and associated clinical factors affect EAT gene expression profile. Methods: We examined EAT from 54 advanced HF patients undergoing heart transplantation (age: 49±7y, 83% males, 37% ischemic, LVEF: 20±5.9%, NYHA 3.3±0.5, BMI 25±4.0 kg.m-2) and 20 controls (HF-free organ donors, LVEF 57±8.9%) of similar BMI, age and gender. EAT from anterior interventricular area was harvested at TX. After RNA isolation (RNeasy Lipid Tissue MiniKit, Qiagen), gene expression analysis (qPCR) was performed (LightCycler, Roche Diagnostics) and normalized to the mean of GAPDH and EF-1A genes. Results: Compared to controls, EAT of HF patients displayed profound upregulation of metabolic transcription factors PGC1a and PPARa, upregulation of adipokines (leptin, adiponectin) and enhanced prolipolytic signalling (upregulated natriuretic peptide receptors A and C, hormone sensitive lipase, perilipin, ATGL) that correlated (p<0.05) with neurohumoral activation (log-BNP). PRDM16, marker of adipocyte browning, was not different between HF and controls. HF patients had higher expression of IL-6. Enhanced expression of lipolytic genes was coupled with enhanced lipogenesis (FAS, ACSL1) and triacyglycerol synthesis (DGAT1, 2). From studied clinical factors (DM, age, HF etiology, BMI) within HF group, EAT gene expression was most strongly influenced by cardiac cachexia (body weight-BW loss ≥5% in 6m, present in 46%). Cachectic HF patients markedly reduced expression of NP-C receptor (p<0.001). NPR-C expression in EAT of HF subjects correlated with BMI (r=0.43, p=0.001), log-BNP (r=-0.44, p=0.001). BW loss (%) correlated (p<0.05) with enhanced EAT expression of PGC-1a (r: -0.27), PPARa (r:-0.32) and reduced expression of NPR-C (r: 0.29) and leptin (r: 0.38). Conclusions: EAT in advanced HF is characterized by enhanced lipolysis and compensatory increase in lipogenesis. HF-related cachexia affects EAT transcription profile, is associated with loss of clearance receptor for natriuretic peptides (NPR-C) leading to more profound EAT metabolic activation. [ABSTRACT FROM AUTHOR]