ABC | Volume 111, Nº1, July 2018

Original Article Kalkan et al Adropin and Irisin Arq Bras Cardiol. 2018; 111(1):39-47 Table 2 – The correlations of adropin and irisin with clinical and laboratory parameters of patients Age BMI AMA TST Albumin BNP NHYA Irisin LVEF Creatinine Adropin r 0.077 -0.463 -0.386 -0.415 -0.250 0.676 0.762 0.669 -0.042 0.177 p 0.480 < 0.001 < 0.001 < 0.001 0.02 < 0.001 < 0.001 < 0.001 0.704 0.104 Irisin r 0.044 -0.384 -0.279 -0.374 -0.323 0.403 0.523 0.123 0.232 p 0.687 < 0.001 < 0.001 < 0.001 0.002 < 0.001 < 0.001 0.259 0.031 BMI: body mass index; AMA: arm muscle area; TST: triceps skinfold thickness; BNP: brain natriuretic peptide; NYHA: New York Heart Association; LVEF: left ventricular ejection fraction. To investigate the discriminative value of serum BNP, adropin and irisin in cachectic and non-cachectic heart failure with reduced ejection fraction patients, a receiver operator characteristic curve was generated for sensitivity and specificity, using the respective areas under the curve (AUC) (Figure 2 and Table 3). The results indicated that adropin levels greater than 229.4 pg/mL had sensitivity of 77.3% and specificity of 64.3% for cardiac cachexia in heart failure with reduced ejection fraction patients [AUC: 0.770; 95% confidence interval (CI): 0.668-0.872; p < 0.001]. Moreover, the sensitivity of irisin levels of more than 2.2 pg/mL was 75.0%, whereas the specificity was 52.4% for cachexia (AUC: 0.705; 95% CI: 0.596-0.815; p < 0.001). Variables found to be statistically significant in the univariate analyses were entered into a multivariate logistic regression analysis. In the multivariate analysis, adropin [odds ratio (OR) 1.021, 95% CI: 1.004-1.038; p = 0.017] was the only independent predictor of the presence of cachexia in patients with heart failure with reduced ejection fraction (Table 4). Discussion The main findings of the study were as follows: 1) serum adropin and irisin levels were significantly higher in the cachexia group than in the non-cachectic subjects; 2) NYHA class and BNP levels, which are validated indicators of heart failure with reduced ejection fraction severity, were significantly positively associated with both adropin and irisin levels; 3) there was a direct relation between adropin and irisin levels; 4) sensitivity of adropin and irisin were higher than their specificity for predicting cardiac cachexia. Both adropin and irisin sensitivity higher than BNPs sensitivity; and 5) adropin was the only independent predictor of the presence of cachexia in patients with heart failure with reduced ejection fraction. The annual incidence of cardiac cachexia in patients with NYHA class III-IV was reported to be 10%, and the prevalence was reported to be 12-15% among those with NYHA class II-IV. 13 Several factors, including impaired food intake and absorption, immunological and neurohormonal activation, endothelial dysfunction, increased insulin resistance, triggered pro-inflammatory cytokine production and anabolic and catabolic imbalance, play a pivotal role in the complex process of cardiac cachexia. 13,17 This complex is associated with poor short- and long-term prognoses, unfavorable response to drug treatment and poor quality of life. 18 Previous studies reported elevated levels of some hormones and peptides, such as adiponectin, ghrelin, leptin and melanocortin, in cachectic heart failure with reduced ejection fraction patients. 17,19-20 However, there are no studies on the levels of adropin and irisin in this patient population in the literature. In the present study, the levels were significantly elevated in the cardiac cachexia group with heart failure with reduced ejection fraction compared to the non-cachectic group. Sente et al. 21 have reported that cardiac and skeletal muscle energy deficiency played a major role in the pathophysiology of heart failure, which results in a hyperadrenergic state. Plasma free fatty acids increase under a hyperadrenergic state and inhibit glycolysis and glucose uptake by heart and skeletal muscle, with subsequent increases in plasma glucose. Multifactorial pancreatic damage, together with hyperglycemia, causes both systemic and myocardial insulin resistance. 22 The concept of metabolic failure in heart failure with reduced ejection fraction includes both catabolic over‑reactivity (lipolysis) and anabolic deficiency, with catabolic over-reactivity activating glycolytic and lipolytic pathways and anabolic deficiency inducing loss of skeletal muscle mass and function. 18 Adropin is a recently identified protein, which has been implicated in the maintenance of energy homeostasis. 5 A study of adropin-deficient mice suggested that this peptide hormone was required for maintaining insulin sensitivity and protecting against impaired glucose tolerance. 23 Thus, we hypothesized that adropin might increase as a consequence of insulin resistance in heart failure with reduced ejection fraction patients. Kumar et al. 5 have reported that overexpression or systemic administration of adropin in diet-induced obese mice resulted in a marked improvement in insulin sensitivity and weight loss. Thus, weight loss in cachectic heart failure with reduced ejection fraction patients could contribute to the elevation of plasma adropin levels. The findings of the present study pointed to a metabolic association of increased serum adropin with muscle wasting and lipolysis in cachectic heart failure with reduced ejection fraction patients. In addition to important metabolic effects of adropin, Lovren et al. have reported a potential endothelial protective role for this protein that was likely mediated by upregulation of endothelial nitric oxide synthase (eNOS) expression. They suggested that adropin might help protect against vascular diseases by markedly elevating eNOS expression of coronary artery endothelial cells. 24 Topuz et al. 9 have reported reduced adropin levels in type 2 diabetic patients with endothelial dysfunction. Wu et al. 8 have demonstrated an inverse and independent association between adropin 43