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 = À0.94; 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.

The role of metformin (MET) in the treatment of patients with advanced HFrEF and type 2 diabetes mellitus (DM) is not firmly established. We studied the impact of MET on metabolic profile, quality of life (QoL) and survival in these patients. A total of 847 stable patients with advanced HFrEF (57.4 ± 11.3 years, 67.7% NYHA III/IV, LVEF 23.6 ± 5.8%) underwent clinical and laboratory evaluation and were prospectively followed for a median of 1126 (IQRs 410; 1781) days for occurrence of death, urgent heart transplantation or mechanical circulatory support implantation. A subgroup of 380 patients (44.9%) had DM, 87 of DM patients (22.9%) were treated with MET. Despite worse insulin sensitivity and more severe DM (higher BMI, HbA1c, worse insulin resistance), MET-treated patients exhibited more stable HF marked by lower BNP level (400 vs. 642 ng/l), better LV and RV function, lower mitral and tricuspid regurgitation severity, were using smaller doses of diuretics (all p < 0.05). Further, they had higher eGFR (69.23 vs. 63.34 ml/min/1.73 m2) and better QoL (MLHFQ: 36 vs. 48 points, p = 0.002). Compared to diabetics treated with other glucose-lowering agents, MET-treated patients had better event-free survival even after adjustment for BNP, BMI and eGFR (p = 0.035). Propensity score-matched analysis with 17 covariates yielded 81 pairs of patients and showed a significantly better survival for MET-treated subgroup (p = 0.01). MET treatment in patients with advanced HFrEF and DM is associated with improved outcome by mechanisms beyond the improvement of blood glucose control.

Background Increased oxidative/dicarbonyl stress and chronic inflammation are considered key pathophysiological mediators in the progression of complications in obesity and type 2 diabetes (T2D). Lifestyle and diet composition have a major impact. In this study, we tested the effects of a vegan (V) and a conventional meat containg (M) meal, matched for energy and macronutrients, on postprandial oxidative and dicarbonyl stress, inflammatory markers and appetite hormones. Methods A randomised crossover design was used to evaluate T2D, obese with normal glucose tolerance and control participants (n = 20 in each group), with serum concentrations of analytes determined at 0, 120 and 180 min. Repeated-measures ANOVA was used for statistical analysis. Results In T2D subjects, we observed decreased postprandial concentrations of oxidised glutathione (p ˂ 0.001) and increased glutathione peroxidase activity (p = 0.045) after the V-meal consumption, compared with the M-meal. In obese participants, V-meal consumption increased postprandial concentrations of reduced glutathione (p = 0.041) and decreased methylglyoxal concentrations (p = 0.023). There were no differences in postprandial secretion of TNFα, MCP-1 or ghrelin in T2D or obese men, but we did observe higher postprandial secretion of leptin after the V-meal in T2D men (p = 0.002) compared with the M-meal. Conclusions The results show that a plant-based meal is efficient in ameliorating the postprandial oxidative and dicarbonyl stress compared to a conventional energy- and macronutrient-matched meal, indicating the therapeutic potential of plant-based nutrition in improving the progression of complications in T2D and obese patients. Registered under ClinicalTrials.gov Identifier No. NCT02474147.

Background: The role of metformin (MET) in the treatment of patients with advanced HFrEF and type 2 diabetes mellitus (DM) is not firmly established. We studied the impact of MET on metabolic profile, quality of life (QoL) and survival in these patients. Methods: A total of 847 stable patients with advanced HFrEF (57.4± 11.3 years, 67.7% NYHA III/IV, LVEF 23.6± 5.8%) underwent clinical and laboratory evaluation and were prospectively followed for a median of 1126 (IQRs 410; 1781) days for occurrence of death, urgent heart transplantation or mechanical circulatory support implantation. Results: A subgroup of 380 patients (44.9%) had DM, 87 of DM patients (22.9%) were treated with MET. Despite worse insulin sensitivity and more severe DM (higher BMI, HbA1c, worse insulin resistance), MET-treated patients exhibited lower BNP, higher eGFR, better LV and RV function, less mitral and tricuspid regurgitation, were using smaller doses of diuretics (all p< 0.05) and had better QoL (MLHFQ: 36 vs. 48 points, p= 0.002). Compared to diabetics treated with other glucose-lowering agents, MET-treated patients had better event-free survival even after adjustment for BNP, BMI and eGFR (p= 0.035). Propensity score-matched analysis with 17 covariates yielded 81 pairs of patients and showed a significantly better survival for MET-treated subgroup (p= 0.01).Conclusion: MET treatment in patients with advanced HFrEF and DM is associated with better quality of life and improved outcome, by mechanisms beyond the improvement of blood glucose control. MET should stay among frontline drugs for treatment of DM in patients with HFrEF.

Introduction: Patients with type 2 diabetes (DM) are known to have decreased metabolic flexibility when switching between carbohydrate and lipid oxidation. Our aim was to assess the energy substrates utilization in patients with isolated heart failure (HF) and HF with DM. Methods: A cross-sectional comparative trial with 77 subjects in 4 age matched groups. 21 healthy subjects (HF-DM-), 14 patients with HF alone (HF+DM-), 21 patients with diabetes alone (HF-DM+) and 21 patients with DM or prediabetes and heart failure (HF+DM+). The subjects underwent indirect calorimetry before and during hyperinsulinemic isoglycemic clamp. Results: Metabolic clearance of glucose (MCG) was significantly lower (p ˂ 0.05) in the groups of patients with DM+ (HF-DM-: 6.08 ± 2.03; HF+DM-: 5.86 ± 2.37; HF-DM+: 4.29 ± 2.2; HF+DM+: 3.9 ± 1.76 ml/kg.min). Compared to healthy subjects all the other groups had significantly smaller increase in respiratory quotient during clamp (p ˂ 0.01 for HF-DM- vs. HF+DM- and HF-DM- vs. HF-DM+; p ˂ 0.05 for HF-DM- vs. HF+DM+). Differences between groups with isolated HF and isolated DM were not significant, see Table. Conclusions: Our results on a unique group of patients show similarly deteriorated metabolic flexibility of carbohydrate versus lipid oxidation in patients with type 2 diabetes and heart failure supporting the comparable deleterious effect of both diseases on utilization of energy substrates. Disclosure E. Hošková: None. J. Kopecky: None. J. Veleba: None. K. Velebova: None. V. Melenovsky: None. T. Pelikanova: None. Funding Czech Health Research Council (AZV16-27496A)