Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC 45L3j7TMvrhzc6QqXNpgHVb S0066-782X2018001300039 S0066-782X2018005008103 10.5935/abc.20180109 Original Article Adropin and Irisin in Patients with Cardiac Cachexia Kalkan Ali Kemal 1 Cakmak Huseyin Altug 2 Erturk Mehmet 1 Kalkan Kübra Erol 3 Uzun Fatih 1 Tasbulak Omer 1 Diker Vesile Ornek 4 Aydin Suleyman 5 Celik Ahmet 6 Mehmet Akif Ersoy Thoracic and Cardiovascular Disease Education and Training Hospital Department of Cardiology Istanbul Turkey Mehmet Akif Ersoy Thoracic and Cardiovascular Disease Education and Training Hospital, Department of Cardiology, Istanbul, Turkey Mustafakemalpasa State Hospital Department of Cardiology Bursa Turkey Mustafakemalpasa State Hospital, Department of Cardiology, Bursa, Turkey Şişli Hamidiye Etfal Education And Research Hospital Department of Internal Medicine Istanbul Turkey Şişli Hamidiye Etfal Education And Research Hospital, Department of Internal Medicine, Istanbul, Turkey Mehmet Akif Ersoy Thoracic and Cardiovascular Disease Education and Training Hospital Department of Biochemistry Istanbul Turkey Mehmet Akif Ersoy Thoracic and Cardiovascular Disease Education and Training Hospital, Department of Biochemistry, Istanbul, Turkey Firat University School of Medicine Department of Clinical Biochemistry Elazig Turkey Firat University, School of Medicine, Department of Clinical Biochemistry, Elazig, Turkey. Mersin University School of Medicine Department of Cardiology Mersin Turkey Mersin University, School of Medicine, Department of Cardiology, Mersin, Turkey Mailing Address: Mehmet Erturk, Yesil Vadi Cad, Metrokent Sitesi C6 D69 Basak Mah. Postal Code 34000, Basaksehir - Istanbul. E-mail: drerturk@gmail.com

Author contributions

Conception and design of the research: Kalkan AK, Cakmak HA, Aydin S, Celik A; Acquisition of data: Kalkan AK, Uzun F, Tasbulak O, Diker VO; Analysis and interpretation of the data: Kalkan AK, Cakmak HA, Erturk M, Tasbulak O, Diker VO; Statistical analysis: Kalkan AK, Erturk M, Uzun F, Celik A; Obtaining financing: Kalkan AK, Aydin S, Celik A; Writing of the manuscript: Kalkan AK, Erturk M, Kalkan KE, Aydin S, Celik A; Critical revision of the manuscript for intellectual content: Kalkan AK, Kalkan KE.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 02 07 2018 07 2018 111 1 39 47 09 07 2017 14 12 2017 24 01 2018 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited Abstract Background:

Cardiac cachexia is an important predictive factor of the reduction in survival of patients with heart failure with reduced ejection fraction.

 Objectives:

The aims of the present study were to evaluate adropin and irisin levels in cachectic and non-cachectic subjects and the relationships between the levels of these proteins and clinical and laboratory parameters in patients with HFrEF.

 Methods:

The clinical records of patients who were admitted to the cardiology outpatient clinic for heart failure with reduced ejection fraction were screened. Cachectic patients were identified and assigned to the study group (n = 44, mean age, 65.4 ± 11.2 y; 61.4% men). Heart failure with reduced ejection fraction patients without weight loss were enrolled as the control group (n = 42, mean age, 61.0 ± 16.5 y; 64.3% men). The serum adropin and irisin levels of all patients were measured. A p-value < 0.05 was considered significant.

 Results:

Serum adropin and irisin levels were significantly higher in the cachexia group than in the controls (Adropin (ng/L); 286.1 (231.3-404.0) vs 213.7 (203.1-251.3); p < 0.001, Irisin (µg/mL); 2.6 (2.2-4.4) vs 2.1 (1.8-2.4); p = 0.001). Serum adropin and irisin levels were positively correlated with brain natriuretic peptide (BNP) levels and New York Heart Association (NYHA) class and negatively correlated with body mass index (BMI) and serum albumin levels (all p values: < 0.001). In a multivariate analysis, adropin was the only independent predictor of cachexia in the heart failure with reduced ejection fraction patients (OR: 1.021; 95% CI: 1.004−1.038; p = 0.017).

 Conclusions:

The results suggest that adropin and irisin may be novel markers of cardiac cachexia in heart failure with reduced ejection fraction patients. Adropin and irisin are related with the severity of heart failure.

 Keywords: Cachexia / complications Heart Failure / physiopathology, Hypertrophy, Left Ventricular Ventricular Function, Left Adropin Peptides Hormones Introduction

Heart failure with reduced ejection fraction, which is a multifactorial and common disease, is considered a major public health problem worldwide.1 Cardiac cachexia, which is characterized by loss of muscle, with or without loss of fat mass, is a serious and life-threatening complication of heart failure with reduced ejection fraction. Moreover, studies have demonstrated that it was an important independent prognostic factor for cardiovascular mortality after adjustment for age, left ventricular ejection fraction and functional capacity to perform physical activities.2-4

Adropin is a novel membrane-bound protein, which contains 76 amino acids and is encoded by the energy homeostasis-associated gene.5 It is expressed predominantly in the liver, brain, coronary arteries, vascular endothelium and heart (all layers).6 A recent study reported that elevated plasma levels of adropin in heart failure with reduced ejection fraction patients were positively correlated with disease severity, as classified by the New York Heart Association (NYHA).7 Irisin is a thermogenic protein, which is expressed in adipose tissue, cardiac muscle, heart and other peripheral tissues. The main functions of irisin are energy expenditure by converting white adipose tissue to brown adipose tissue and regulation of carbohydrate metabolism, resulting in improved glucose homeostasis and insulin sensitivity and weight loss.6-11

Cardiac cachexia in heart failure with reduced ejection fraction is associated with impaired energy homeostasis due to anabolic and catabolic imbalance, and serum adropin and irisin levels play important roles in energy balance and metabolism. Based on the aforementioned, we hypothesized that both serum adropin and irisin levels would differ in cachectic heart failure with reduced ejection fraction patients and non-cachectic individuals.

The aims of the present study were: 1) to investigate serum adropin and irisin levels in cardiac cachectic and non-cachectic patients with heart failure with reduced ejection fraction, and 2) to investigate the relationship between adropin and irisin levels and clinical and laboratory parameters in patients with heart failure with reduced ejection fraction.

 Methods Patient selection and study protocol

To identify cachectic patients, the clinical records of patients admitted to the cardiology outpatient clinic of a training and research hospital either for the diagnosis or treatment of heart failure with reduced ejection fraction were screened. Subsequently, the patients were contacted by phone and asked to attend the clinic. Heart failure with reduced ejection fraction patients without weight loss were enrolled as a control group.

The inclusion criteria were a diagnosis of heart failure with reduced ejection fraction according to the ‘2012 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure’ and treatment for heart failure with reduced ejection fraction for at least 6 months before enrolment in the study.12 The following were exclusion criteria: acute decompensated heart failure, heart failure with preserved ejection fraction, hospitalization for acute coronary syndromes, primary valvular heart disease, chronic obstructive pulmonary disease, peripheral vascular disease, musculoskeletal disease, acute/chronic inflammatory or infectious diseases, connective tissue diseases, neoplastic diseases, congenital heart diseases, hepatic failure, acute or chronic end-stage kidney failure, recent trauma or major surgery and pregnancy.

Demographic, clinical and laboratory data and the medical therapies administered to each patient during their index hospitalization were recorded by a systematic review of the patient files. To determine left ventricle ejection fraction values, all individuals underwent a transthoracic echocardiographic examination (Vivid S5; General Electric, Wisconsin, USA), which was performed by an experienced operator. The left ventricle ejection fraction was determined using Simpson’s method of discs and two-dimensional echocardiography.

All patients were older than 18 years and able to provide written informed consent, which was a prerequisite for enrolment. The study complied with the Declaration of Helsinki, and the trial protocol was approved by the Local Ethical Committee.

 Laboratory measurements

Blood samples were drawn by venipuncture into tubes containing anticoagulant ethylenediaminetetraacetic acid (EDTA). The samples were collected after a 12-hour overnight fast from the antecubital vein, with the patient in a sitting position. The serum was obtained by centrifugation at 4000 rpm at 4°C for 20 min. The obtained sera were stored at -80°C until used in the analysis. All routine biochemical and hematological parameters were measured on the same day as the blood sampling. Biochemical parameters, including fasting blood glucose, creatinine, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides (TG), were measured using an Abbott Diagnostics C8000i (Abbott, Germany) auto-analyzer with commercial kits. The LDL cholesterol was assayed by applying Friedewald’s formula to samples with TG ≤ 400 mg/dL. Hematological parameters were obtained using a Coulter LH 780 Hematology Analyzer (Beckman Coulter Ireland, Inc., Mervue, Galway, Ireland). Serum brain-natriuretic peptide (BNP) levels (pg/ml) were measured using commercially available kits (Phoenix Pharmaceuticals, Inc., Burlingame, CA, USA).

Serum adropin levels were measured with a commercially available kit using an enzyme-linked immunosorbent assay (ELISA) method (Human adropin ELISA kit, catalogue n°. ck-e90267, Hangzhou Eastbiopharm Co., Blue Ocean International Times Mansion, China), with a low sensitivity limit of 2.49 ng/L. All samples were measured in duplicate in a single experiment. The intra- and inter-assay coefficients of variance of this kit were < 10% and < 12%, respectively. The detection range of adropin was 5-1000 ng/L. Serum irisin levels were detected with a commercially available kit, using the ELISA method (Human irisin ELISA kit, catalogue n°. CK-E90905, Hangzhou Eastbiopharm Co., Blue Ocean International Times Mansion, China). The sensitivity limit was 0.023 µg/mL, and the intra- and inter-assay coefficients of variance were < 10% and < 12%, respectively. The detection range of irisin was 0.05-15 µg/mL.

 Definitions

Cardiac cachexia can be defined as underlying disease and involuntary non-edematous weight loss ≥ 6% within the previous 6-12 month.12,13

Hypertension was diagnosed if systolic arterial pressure exceeded 140 mm Hg, diastolic arterial pressure exceeded 90 mmHg, or the patient was taking antihypertensive drugs. Hyperlipidemia was defined as fasting total serum cholesterol > 200 mg/dL, LDL cholesterol > 130 mg/dL, serum TG > 180 mg/dL or the use of lipid-lowering drugs. Diabetes mellitus was defined as a previous history of the disease, the use of insulin or oral antidiabetic drugs, or a fasting venous blood glucose level ≥ 126 mg/dL on two occasions in previously untreated patients.14 Anthropometric measurements were used to determine body mass index (BMI), triceps skinfold thickness (TST) and arm circumference (AC). The TST was measured using a Holtain skinfold caliper. The arm muscle area (AMA) was calculated by the formula (AC-TST × π) 2/4 × π and considered an indicator of body muscle mass.15 The heights and weights of the study participants were measured, and the BMI was calculated as body weight in kilograms divided by the square of the height in meters (kg/m2).

 Statistical Analysis

Descriptive analyses are presented using means and standard deviations or the median and the interquartile range (IQR, range from the 25th to 75th percentile). The standard effect size of the current trial was determined 0.62 with power of 80% and error of 5% according to the equation reported by Pardo et al.16 The sample size was established at a minimum of 41 volunteers per group to detect differences in irisin between cachectic and control patients.

The categorical variables are expressed as numbers and percentages. Visual (histograms and probability plots) and analytical methods (Kolmogorov-Smirnov) were used to determine whether the variables were normally distributed. The independent samples T-Test was used for the comparison of normally distributed continuous numerical variables, the Mann-Whitney U-test was used for non-normally distributed numerical variables, and the χ2-test was used for comparing categorical variables between the two groups. Receiver operating characteristic curves were plotted for BNP, adropin and irisin. When a significant cut-off value was observed, the sensitivity, specificity, positive and negative predictive values were recorded. Spearman’s correlation analysis was performed to determine the association of adropin and irisin levels with the examined variables. Multiple logistic regression analyses were performed to identify the independent risk factors associated with cachexia. Variables found to be statistically significant in the univariate analyses were entered into a multivariate logistic regression analysis. An overall 5% type-I error level was used to infer statistical significance, and a p-value less than 0.05 was considered significant. Statistical analyses were performed using the Statistical Package for Social Sciences (IBM SPSS 17 Statistics for Windows, Version 20.0. Armonk, NY, USA).

 Results

The present study included 86 heart failure with reduced ejection fraction patients: 44 with cardiac cachexia (mean age, 65.4 ± 11.2 y; 61.4% men) and 42 with a normal body weight (mean age, 61 ± 16.5 y; 64.3% men). The weight difference between two groups is shown in Figure 1. The baseline demographic and clinical characteristics of the study groups are summarized in Table 1. As expected, BMI, TST and AMA were significantly lower in the cardiac cachexia group than the non-cachectic group. The NYHA class of the two groups was also significantly different, with more patients in the cardiac cachexia group classified as NYHA class III and IV, and more in the non-cachectic group classified as NYHA class I and II.

Body weight difference between cachectic and non-cachectic groups.

Baseline demographic, clinical and laboratory characteristics of the study groups
CHF without cachexia (n = 42) CHF with cachexia (n = 44) p value
Age, (years), mean (SD) 61.0 (16.47) 65.4 (11.18) 0.179
Male Gender, n (%) 27 (64.3) 27 (61.4) 0.779
NYHA, class I-II, n (%) 30 (60) 20 (40) 0.015
class III-IV, n (%) 12 (33.3) 24 (66.7)
Ischemic Etiology, n (%) 28 (66.7) 26 (59.1) 0.468
LVEF, n (%)
Anthropometric parameters 31.7 (7.89) 31.4 (6.71) 0.882
BMI (kg/m2), mean (SD) 29.2 (4.25) 19.9 (1.12) < 0.001
TST (mm), mean (SD) 17.9 (3) 13.4 (2.45) < 0.001
AMA (cm2), mean (SD) 35.9 (8.7) 24.4 (4.03) < 0001
Comorbidities
Hypertension, n (%) 27 (64.3) 26 (59) 0.620
Diabetes mellitus, n (%) 18 (42.9) 26 (59.1) 0.290
Chronic renal failure, n (%) 14 (33.3) 15 (34.1) 0.941
Chronic obstructive lung disease, n (%) 8 (19) 8 (18.2) 0.918
Laboratory parameters
Glucose (mg/dL), mean (SD) 155.3 (78.5) 150.3 (48.3) 0.685
Creatinine (mg/dL), mean (SD) 1.15 (0.63) 1.19 (0.8) 0.997
Hemoglobine (%), mean (SD) 11.9 (1.38) 11.3 (1.34) 0.049
WBC (mg/L), mean (SD) 8.35 (4.2) 8.45 (3.98) 0.742
Adropin (ng/L) median (IQR) 213.7 (203.1-251.3) 286.1 (231.3-404.0) < 0.001*
Irisin ( µg/mL), median (IQR) 2.1 (1.8-2.4) 2.6 (2.2-4.4) 0.001*
BNP (pg/mL), median (IQR) 698.0 (340.0-1517.0) 1408.5 (725.0-4041.0) 0.001*
Albumin (mg/dL), mean (SD) 3.3 (0.46) 3.12 (0.36) 0.041
Sodium (mEq/L), mean (SD) 138.7 (10.1) 135.7 (9.7) 0.136
Total cholesterol (mg/dL), mean (SD) 164.5 (44.1) 153.2 (44.4) 0.240
LDL-cholesterol (mg/dL), mean (SD) 108.4 (40.5) 101.1 (32.7) 0.366
HDL-cholesterol (mg/dL), mean (SD) 36.2 (10.4) 31 (9.1) 0.015
Triglyceride (mg/dL), mean (SD)
Drug therapy 134.2 (50) 122.3 (56) 0.302
Furosemide, n (%) 35 (83.3) 40 (90.9) 0.293
ACE-i/ARB, n (%) 20 (47.6) / 11 (26.2) 28 (63.6) / 11 (25.2) 0.136
Spironolactone, n (%) 26 (61.9) 30 (68.2) 0.542
Statin, n (%) 16 (38.1) 18 (40.9) 0.790
Beta-blocker, n (%) 33 (78.6) 39 (88.6) 0.206
Ivabradine, n (%) 15 (25) 11 (25) 0.289
CRT, n (%) 9 (21.4) 6 (13.6) 0.341

n: number; SD: standard deviation; IQR: interquartile range; NYHA: New York Heart Association; LVEF: left ventricular ejection fraction; BMI: body mass index; TST; triceps skinfold thickness; AMA: arm muscle area; WBC: white blood cell; BNP: brain natriuretic peptide; LDL: low-density lipoprotein; HDL: high-density lipoprotein; ACE-i: angiotensin-converting-enzyme inhibitor; ARB: angiotensin receptor blocker; CRT: cardiac resynchronization therapy.

mann-whitney u-test.

The baseline laboratory characteristics of the two groups are presented in Table 1. Hemoglobin, albumin and HDL cholesterol levels were significantly higher in the non-cachectic individuals compared to the cachectic patients. Furthermore, the serum BNP, adropin and irisin levels were significantly higher in the cachectic group than in the non-cachectic group [adropin (ng/L): 286.1 (231.3-404.0) vs 213.7 (203.1-251.3), p < 0.001; irisin (µg/mL): 2.6 (2.2-4.4) vs 2.1 (1.8-2.4), p = 0.001; BNP (pg/mL): 698.0 (340.0-1517.0) vs 1408.5 (725.0-4041.0), p = 0.001]. Analysis of the association between adropin and irisin levels and the clinical and laboratory parameters of the patients (Table 2) revealed that NYHA class and BNP levels were significantly positively correlated with both adropin and irisin levels. However, BMI, AMA, TST and serum albumin, which were significant indirect clinical and laboratory indicators of cardiac cachexia, were significantly inversely correlated with adropin and irisin levels. In addition, there was a direct correlation between adropin and irisin levels and heart failure with reduced ejection fraction. Creatinine levels were also positively correlated with irisin levels.

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).

Receiver-operating characteristic curve for discriminative value of serum adropin, irisin and BNP levels in systolic heart failure with reduced ejection fraction patients with or without cachexia.

Receiver-operating characteristic curve analysis of adropin, irisin and brain natriuretic peptide (BNP) for predicting cachexia
Variable AUC SE CI (95%) P value Sensitivity Specificity PPV NPV
Adropin 0.770 0.052 0.668-0.872 0.0001 %77.3 %64.3 %69.4 %73.0
Irisin 0.705 0.056 0.596-0.815 0.001 75.0 %52.4 %62.3 %66.7
BNP 0.700 0.056 0.590-0.811 0.001 %72.7 %61.9 66.7 %68.4

AUC: area under the curve; SE: standard error; PPV: positive predictive value; NPV: negative predictive value.

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).

Logistic regression analyses to identify the independent risk factors associated with cardiac cachexia
Univariate Multivariate
p OR (95% CI) p OR (95% CI)
Albumin 0.044 0.331 0.113-0.972 0.387 0.571 0.161-2.029
BNP 0.013 1.000 1.000-1.001 0.770 1.000 1.000-1.000
Age 0.151 1.023 0.992-1.056
Gender 0.779 1.133 0.472-2.720
Irisin 0.025 1.865 1.081-3.218 0.776 0.880 0.378-2.047
Adropin 0.002 1.016 1.006-1.026 0.017 1.021 1.004-1.038
Creatinine 0.760 1.098 0.604-1.994
Glucose 0.720 0.999 0.992-1.005
LVEF 0.880 0.996 0.939-1.056
Total cholesterol 0.239 0.994 0.984-1.004
Triglyceride 0.302 0.996 0.987-1.004
LDL 0.363 0.995 0.983-1.006
HDL 0.022 0.941 0.893-0.991 0.102 0.950 0.893-1.010
NYHA III - IV 0.016 3.000 1.226-7.339 0.463 0.550 0.111-2.717

BNP: Brain Natriuretic Peptide; LVEF: Left Ventricular Ejection Fraction; LDL: Low-Density Lipoprotein; HDL: High-Density Lipoprotein; NYHA: New York Heart Association.

 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 levels and the severity of coronary artery atherosclerosis in diabetic patients. Zhang et al.25 have presented similar results for patients with stable coronary artery disease. In another study, they have reported an important association between decreased adropin levels, high SYNTHAX scores and the severity of stable coronary artery disease.26 Yu et al.27 have examined the role of adropin in acute myocardial infarction (MI) and have shown that serum adropin levels were reduced in cases of acute MI.

By elevating eNOS, adropin may have the potential to improve endothelial dysfunction, which has been widely reported in patients with heart failure with reduced ejection fraction, and decelerate left ventricular dysfunction in heart failure with reduced ejection fraction.28 Lian et al.7 have reported that an elevated level of adropin in heart failure with reduced ejection fraction was correlated with the severity of heart failure with reduced ejection fraction according to the NYHA class and BNP levels. The present study revealed similar findings and relations in cachectic patients with heart failure with reduced ejection fraction. Unlike the study by Lian et al., in which adropin levels and BMI were directly correlated with each other, there was an inverse relationship between adropin levels and BMI in cardiac cachexia in the present study, as expected.

Although irisin is predominantly expressed in muscle and is directly associated with muscle mass, it can be expressed in different tissues. Brown adipose tissue is known to dissipate energy in the form of heat via activation of uncoupling protein 1. This process increases energy expenditure, reduces body weight and improves metabolic parameters, such as insulin sensitivity. In white tissue, irisin stimulates BAT-like phenotype changes via a process known as browning. Based on the aforementioned properties, irisin has been proposed as a possible novel treatment for diabetes and obesity.29 Although some studies have reported positive correlations between irisin and BMI, others have reported contradictory results.6,29 The present study revealed an inverse correlation between irisin and BMI. In addition, AMA, TST and serum albumin levels were inversely related with irisin. In patients with heart failure with reduced ejection fraction, muscle, fat and bone loss were reported to be associated with worse outcomes.30 Moreover, a recent study reported a gradual decrease in irisin levels in patients with acute MI, suggesting that irisin may be a new diagnostic marker in this setting.31 In a recently published study, Shen et al.32 have reported that serum irisin level was significantly higher in deceased acute heart failure (AHF) patients compared to that in survived AHF and predicted 1-year all-cause mortality in AHF patients. In that study irisin and NT-pro-BNP were determined by ROC curve analysis. NT-pro-BNP (AUC: 0.670) had only moderate prognostic values for AHF mortality risk compared to serum irisin level (AUC: 0.753).32 The findings of that study are similar to ours. This increase may be the result of adipose tissue metabolism and insulin resistance. Studies are needed to determine whether irisin levels are the result of a reduced peripheral muscle mass in cachectic heart failure with reduced ejection fraction patients. In addition, in our study, adropin was found to be more predictive than irisin and BNP.

In our study, only adropin was found to be an independent predictor of cachexia in patients with heart failure. Although irisin predicted cardiac cachexia in univariate analysis, it did not predict in multivariate analysis. Irisin was found to be a predictive biomarker for 1-year all-cause mortality in the study by Shen et al.32 This difference may be due to the fact that the adropin molecule was not used in multivariate analysis at this work. Further studies are highly needed to examine this relationship.

Similar to adropin, irisin was significantly positively correlated with BNP levels and NYHA class. Natriuretic peptides, such as BNPs, in addition to diuretic peptides and vasodilators, trigger lipolysis in the human body and play a role in fat metabolism.7 Hence, we hypothesized that lipolysis by BNPs might be associated with adropin and irisin synthesis in cachectic heart failure with reduced ejection fraction patients. A further study will be necessary to elucidate the precise mechanism of adropin and irisin release in patients with cardiac cachexia.

Study Limitations

The present study had some limitations. Firstly, the study population was relatively small. However, the results pointed to an important relationship between adropin and irisin levels and cardiac cachexia in patients with heart failure with reduced ejection fraction. Secondly, a lack of follow-up data on future major adverse cardiovascular events, including mortality or hospitalization for heart failure with reduced ejection fraction, meant that the prognostic value of the levels of both proteins could not be evaluated.

 Conclusions

The present study showed that serum adropin and irisin levels were significantly increased in the cachectic heart failure with reduced ejection fraction group and that these were significantly associated with previously validated markers of heart failure with reduced ejection fraction severity, such as the BNP level and NYHA class. The results suggest that adropin and irisin may be novel markers of cardiac cachexia in heart failure with reduced ejection fraction patients. Adropin and irisin are related with the severity of heart failure.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any thesis or dissertation work.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Mehmet Akif Ersoy Thoracic and Cardiovascular Disease Education and Training Hospital under the protocol number 2015-23. All the procedures in this study were in accordance with the 1975 Helsinki Declaration, updated in 2013. Informed consent was obtained from all participants included in the study.

 References 1 Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112(12):e154-235. Hunt SA Abraham WT Chin MH Feldman AM Francis GS Ganiats TG American College of Cardiology American Heart Association Task Force on Practice Guidelines American College of Chest Physicians International Society for Heart and Lung Transplantation Heart Rhythm Society ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society Circulation 2005 112 12 e154 e235 2 Pureza V, Florea VG. Mechanisms for cachexia in heart failure. Curr Heart Fail Rep. 2013;10(4):307-14. Pureza V Florea VG Mechanisms for cachexia in heart failure Curr Heart Fail Rep 2013 10 4 307 314 3 von Haehling S, Doehner W, Anker SD. Nutrition, metabolism, and the complex pathophysiology of cachexia in chronic heart failure. Cardiovasc Res. 2007;73(2):298-309. von Haehling S Doehner W Anker SD Nutrition, metabolism, and the complex pathophysiology of cachexia in chronic heart failure Cardiovasc Res 2007 73 2 298 309 4 Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox WJ, et al. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation. 1997;96(2):526-34. Anker SD Chua TP Ponikowski P Harrington D Swan JW Kox WJ Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia Circulation 1997 96 2 526 534 5 Kumar KG, Trevaskis JL, Lam DD, Sutton GM, Koza RA, Chouljenko VN, et al. Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metab. 2008;8(6):468-81. Kumar KG Trevaskis JL Lam DD Sutton GM Koza RA Chouljenko VN Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism Cell Metab 2008 8 6 468 481 6 Aydin S. Three new players in energy regulation: preptin, adropin and irisin. Peptides. 2014 Jun;56:94-110. Aydin S Three new players in energy regulation: preptin, adropin and irisin Peptides 2014 06 56 94 110 7 Lian W, Gu X, Qin Y, Zheng X. Elevated plasma levels of adropin in heart failure patients. Intern Med. 2011;50(15):1523-7. Lian W Gu X Qin Y Zheng X Elevated plasma levels of adropin in heart failure patients Intern Med 2011 50 15 1523 1527 8 Wu L, Fang J, Chen L, Zhao Z, Luo Y, Lin C, et al. Low serum adropin is associated with coronary atherosclerosis in type 2 diabetic and non-diabetic patients. Clin Chem Lab Med. 2014;52(5):751-8. Wu L Fang J Chen L Zhao Z Luo Y Lin C Low serum adropin is associated with coronary atherosclerosis in type 2 diabetic and non-diabetic patients Clin Chem Lab Med 2014 52 5 751 758 9 Topuz M, Celik A, Aslantas T, Demir AK, Aydin S, Aydin S. Plasma adropin levels predict endothelial dysfunction like flow-mediated dilatation in patients with type 2 diabetes mellitus. J Investig Med. 2013;61(8):1161-4. Topuz M Celik A Aslantas T Demir AK Aydin S Aydin S Plasma adropin levels predict endothelial dysfunction like flow-mediated dilatation in patients with type 2 diabetes mellitus J Investig Med 2013 61 8 1161 1164 10 Celik A, Balin M, Kobat MA, Erdem K, Baydas A, Bulut M, et al. Deficiency of a new protein associated with cardiac syndrome X; called adropin. Cardiovasc Ther. 2013;31(3):174-8. Celik A Balin M Kobat MA Erdem K Baydas A Bulut M Deficiency of a new protein associated with cardiac syndrome X; called adropin Cardiovasc Ther 2013 31 3 174 178 11 Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463-8. Boström P Wu J Jedrychowski MP Korde A Ye L Lo JC A PGC1-dependent myokine that drives brown-fat-like development of white fat and thermogenesis Nature 2012 481 7382 463 468 12 McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al. ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012;14(8):803-69. Erratum in: Eur J Heart Fail. 2013;15(3):361-2. McMurray JJ Adamopoulos S Anker SD Auricchio A Böhm M Dickstein K ESC Committee for Practice Guidelines ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC Eur J Heart Fail 2012 14 8 803 869 Erratum in: Eur J Heart Fail. 2013;15(3):361-2. 13 Okoshi MP, Romeiro FG, Paiva SA, Okoshi K. Heart failure-induced cachexia. Arq Bras Cardiol. 2013;100(5):476-82. Okoshi MP Romeiro FG Paiva SA Okoshi K Heart failure-induced cachexia Arq Bras Cardiol 2013 100 5 476 482 14 Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren WM, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): the Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur J Prev Cardiol. 2012;19(4):585-667. Perk J De Backer G Gohlke H Graham I Reiner Z Verschuren WM European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): the Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts) Eur J Prev Cardiol 2012 19 4 585 667 15 Kyle UG, Bosaeus I, De Lorenzo AD, Deurenberg P, Elia M, Manuel Gómez J, et al. Bioelectrical impedance analysis: utilization in clinical practice. Clin Nutr. 2004;23(6):1430-53. Kyle UG Bosaeus I De Lorenzo AD Deurenberg P Elia M Manuel Gómez J Bioelectrical impedance analysis: utilization in clinical practice Clin Nutr 2004 23 6 1430 1453 16 Pardo M, Crujeiras AB, Amil M, Aquera Z, Jimenez-Murcia S, Botella C, et al. Assocation of irisin with fat mass, resting energy expenditure, and daily activity in conditions of extreme body mass index. Int J Endocrinol. 2014;2014:857270. Doi 10.1155/2014/857270. Epub 2014 Apr 22. Pardo M Crujeiras AB Amil M Aquera Z Jimenez-Murcia S Botella C Assocation of irisin with fat mass, resting energy expenditure, and daily activity in conditions of extreme body mass index Int J Endocrinol 2014 2014 857270 857270 10.1155/2014/857270 Epub 2014 Apr 22 17 Invernizzi M, Carda S, Cisari C; Società Italiana per lo Studio della Sarcopenia e della Disabilità Muscolo-Scheletrica (SISDIM). Possible synergism of physical exercise and ghrelin-agonists in patients with cachexia associated with chronic heart failure. Aging Clin Exp Res. 2014;26(4):341-51. Invernizzi M Carda S Cisari C Società Italiana per lo Studio della Sarcopenia e della Disabilità Muscolo-Scheletrica Possible synergism of physical exercise and ghrelin-agonists in patients with cachexia associated with chronic heart failure Aging Clin Exp Res 2014 26 4 341 351 18 Doehner W, Frenneaux M, Anker SD. Metabolic impairment in heart failure: the myocardial and systemic perspective. J Am Coll Cardiol. 2014;64(13):1388-400. Doehner W Frenneaux M Anker SD Metabolic impairment in heart failure the myocardial and systemic perspective J Am Coll Cardiol 2014 64 13 1388 1400 19 Szabó T, Scherbakov N, Sandek A, Kung T, von Haehling S, Lainscak M, et al. Plasma adiponectin in heart failure with and without cachexia: catabolic signal linking catabolism, symptomatic status, and prognosis. Nutr Metab Cardiovasc Dis. 2014;24(1):50-6. Szabó T Scherbakov N Sandek A Kung T von Haehling S Lainscak M Plasma adiponectin in heart failure with and without cachexia: catabolic signal linking catabolism, symptomatic status, and prognosis Nutr Metab Cardiovasc Dis 2014 24 1 50 56 20 Von Haehling S, Lainscak M, Springer J, Anker SD. Cardiac cachexia: a systematic overview. Pharmacol Ther. 2009;121(3):227-52. Von Haehling S Lainscak M Springer J Anker SD Cardiac cachexia: a systematic overview Pharmacol Ther 2009 121 3 227 252 21 Sente T, Van Berendocks AM, Hoymans VY, Vrints CJ. Adiponectin resistance in skelatal muscle: pathophysiological implications in chronic heart failure. J Cachexia Sarcopenia Muscle. 2016;7(3):261-74. Sente T Van Berendocks AM Hoymans VY Vrints CJ Adiponectin resistance in skelatal muscle: pathophysiological implications in chronic heart failure J Cachexia Sarcopenia Muscle 2016 7 3 261 274 22 Ashrafian H, Frenneaux MP, Opie LH. Metabolic mechanisms in heart failure. Circulation. 2007;116(4):434-48. Ashrafian H Frenneaux MP Opie LH Metabolic mechanisms in heart failure Circulation 2007 116 4 434 448 23 Butler AA, Tam CS, Stanhope KL, Wolfe BM, Ali MR, O'Keeffe M, et al. Low circulating adropin concentrations with obesity and aging correlate with risk factors for metabolic diseaseand increase after gastric bypass surgery in humans. J Clin Endocrinol Metab 2012;97(10):3783-91. Butler AA Tam CS Stanhope KL Wolfe BM Ali MR O'Keeffe M Low circulating adropin concentrations with obesity and aging correlate with risk factors for metabolic diseaseand increase after gastric bypass surgery in humans J Clin Endocrinol Metab 2012 97 10 3783 3791 24 Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta M, et al. Adropin is a novel regulator of endothelial function. Circulation. 2010;122(11 Suppl):S185-92. Lovren F Pan Y Quan A Singh KK Shukla PC Gupta M Adropin is a novel regulator of endothelial function Circulation 2010 122 11 Suppl S185 S192 25 Zhang C, Zhao L, Xu W, Li J, Wang B, Gu X, et al. [Correlation of serum adropin level with coronary artery disease]. Zhonghua Yi Xue Za Zhi. 2014;94(16):1255-7. Zhang C Zhao L Xu W Li J Wang B Gu X Correlation of serum adropin level with coronary artery disease Zhonghua Yi Xue Za Zhi 2014 94 16 1255 1257 26 Zhao LP, Xu WT, Wang L, You T, Chan SP, Zhao X, et al. Serum adropin level in patients with stable coronary artery disease. Heart Lung Circ. 2015;24(10):975-9. Zhao LP Xu WT Wang L You T Chan SP Zhao X Serum adropin level in patients with stable coronary artery disease Heart Lung Circ 2015 24 10 975 979 27 Yu HY, Zhao P, Wu MC, Liu J, Yin W. Serum adropin levels are decreased in patients with acute myocardial infarction. Regul Pept. 2014;190-191:46-9. Yu HY Zhao P Wu MC Liu J Yin W Serum adropin levels are decreased in patients with acute myocardial infarction Regul Pept 2014 190-191 46 49 28 Kubo SH, Rector TS, Bank AJ, Williams RE, Heifetz SM. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation. 1991;84(4):1589-96. Kubo SH Rector TS Bank AJ Williams RE Heifetz SM Endothelium-dependent vasodilation is attenuated in patients with heart failure Circulation 1991 84 4 1589 1596 29 Novelle MG, Contreras C, Romero-Picó A, López M, Diéguez C. Irisin, two years later. Int J Endocrinol. 2013;2013:746281. Novelle MG Contreras C Romero-Picó A López M Diéguez C Irisin, two years later Int J Endocrinol 2013 2013 746281 746281 30 Anker SD, Sharma R. The syndrome of cardiac cachexia. Int J Cardiol. 2002;85(1):51-66. Anker SD Sharma R The syndrome of cardiac cachexia Int J Cardiol 2002 85 1 51 66 31 Aydin S, Aydin S, Kobat MA, Kalayci M, Eren MN, Yilmaz M, et al. Decreased saliva/serum irisin concentrations in the acute myocardial infarction promising for being a new candidate biomarker for diagnosis of this pathology. Peptides. 2014 Jun; 56:141-5. Aydin S Aydin S Kobat MA Kalayci M Eren MN Yilmaz M Decreased saliva/serum irisin concentrations in the acute myocardial infarction promising for being a new candidate biomarker for diagnosis of this pathology Peptides 2014 06 56 141 145 32 Shen S, Gao R, Bei Y, Li J, Zhang H, Zhou Y, et al. Serum Irisin Predicts Mortality Risk in Acute Heart Failure Patients. Cell Physiol Biochem. 2017;42(2):615-22. Shen S Gao R Bei Y Li J Zhang H Zhou Y Serum Irisin Predicts Mortality Risk in Acute Heart Failure Patients Cell Physiol Biochem 2017 42 2 615 622 Artigo Original Adropina e Irisina em Pacientes com Caquexia Cardíaca Kalkan Ali Kemal 1 Cakmak Huseyin Altug 2 Erturk Mehmet 1 Kalkan Kübra Erol 3 Uzun Fatih 1 Tasbulak Omer 1 Diker Vesile Ornek 4 Aydin Suleyman 5 Celik Ahmet 6 Mehmet Akif Ersoy Thoracic and Cardiovascular Disease Education and Training Hospital, Department of Cardiology, Istanbul, Turkey Mustafakemalpasa State Hospital, Department of Cardiology, Bursa, Turkey Şişli Hamidiye Etfal Education And Research Hospital, Department of Internal Medicine, Istanbul, Turkey Mehmet Akif Ersoy Thoracic and Cardiovascular Disease Education and Training Hospital, Department of Biochemistry, Istanbul, Turkey Firat University, School of Medicine, Department of Clinical Biochemistry, Elazig, Turkey. Mersin University, School of Medicine, Department of Cardiology, Mersin, Turkey Correspodência: Mehmet Erturk, Yesil Vadi Cad, Metrokent Sitesi C6 D69 Basak Mah. CEP 34000, Basaksehir - Istambul. E-mail: drerturk@gmail.com

Contribuição dos autores

Concepção e desenho da pesquisa: Kalkan AK, Cakmak HA, Aydin S, Celik A; Obtenção de dados: Kalkan AK, Uzun F, Tasbulak O, Diker VO; Análise e interpretação dos dados: Kalkan AK, Cakmak HA, Erturk M, Tasbulak O, Diker VO; Análise estatística: Kalkan AK, Erturk M, Uzun F, Celik A; Obtenção de financiamento: Kalkan AK, Aydin S, Celik A; Redação do manuscrito: Kalkan AK, Erturk M, Kalkan KE, Aydin S, Celik A; Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Kalkan AK, Kalkan KE.

Potencial conflito de interesses

Declaro não haver conflito de interesses pertinentes.

 Resumo Fundamento:

A caquexia cardíaca é um importante preditor de redução de sobrevida em pacientes com insuficiência cardíaca com fração de ejeção reduzida (ICFER). O objetivo deste estudo foi avaliar os níveis de adropina e irisina em pacientes com ICFER caquéticos e não caquéticos, assim como a relação entre os níveis dessas proteínas e os parâmetros clínicos e laboratoriais nesses pacientes.

 Objetivos:

Os objetivos do presente estudo foram avaliar os níveis de adropina e irisina em indivíduos caquéticos e não caquéticos e as relações entre os níveis dessas proteínas e os parâmetros clínicos e laboratoriais em pacientes com ICFEN.

 Métodos:

Os prontuários de pacientes atendidos no ambulatório de cardiologia para ICFER foram triados. Aqueles com ICFER caquéticos foram identificados e constituíram o grupo de estudo (n = 44; idade média, 65,4 ± 11,2 anos; 61,4% de homens). Aqueles com ICFER e sem perda de peso foram arrolados como grupo controle (n = 42; idade média, 61,0 ± 16,5 anos; 64,3% de homens). Os níveis séricos de adropina e irisina de todos os pacientes foram medidos. Considerou-se significativo um p-valor < 0,05.

 Resultados:

Os níveis séricos de adropina e irisina foram significativamente mais altos nos pacientes caquéticos do que nos controles [adropina (ng/l): 286,1 (231,3-404,0) vs 213,7 (203,1-251,3); p < 0,001; irisina (µg/ml): 2,6 (2,2-4,4) vs 2,1 (1,8-2,4); p = 0,001]. Os níveis séricos de adropina e irisina correlacionaram-se positivamente com os níveis de peptídeo natriurético cerebral (BNP) e a classe funcional da New York Heart Association (NYHA), e negativamente com o índice de massa corporal (IMC) e os níveis séricos de albumina (todos os p-valores: < 0,001). Na análise multivariada, a adropina foi o único preditor independente de caquexia nos pacientes com ICFER (OR: 1,021; IC 95%: 1,004−1,038; p = 0,017).

 Conclusões:

Os resultados sugerem que a adropina e a irisina possam ser novos marcadores de caquexia cardíaca em pacientes com ICFER. Adropina e irisina estão relacionadas com a gravidade da insuficiência cardíaca.

 Palavras-chave: Caquexia / complicações Insuficiência Cardíaca / fisiopatologia Hipertrofia Ventricular Esquerda Função Ventricular Esquerda Adropina Peptídeos Hormônios Introdução

A insuficiência cardíaca com fração de ejeção reduzida (ICFER), uma doença multifatorial e comum, é considerada um importante problema de saúde pública no mundo todo.1 A caquexia cardíaca, caracterizada por perda muscular, com ou sem perda de massa gorda, é uma complicação grave da ICFER e representa risco de morte. Além disso, alguns estudos mostraram ser um importante e independente fator prognóstico de mortalidade cardiovascular após ajuste para idade, fração de ejeção ventricular esquerda e capacidade funcional para a prática de atividade física.2-4

A adropina é uma nova proteína ligada à membrana, que contém 76 aminoácidos, sendo codificada pelo gene envolvido na homeostase energética.5 É predominantemente expressa no fígado, cérebro, artérias coronárias, endotélio vascular e coração (todas as camadas).6 Um estudo recente relatou que níveis plasmáticos elevados de adropina em pacientes com ICFER foram positivamente correlacionados com a gravidade da doença, classificada segundo a New York Heart Association (NYHA).7 A irisina é uma proteína termogênica, expressa no tecido adiposo, músculo cardíaco, coração e outros tecidos periféricos. As principais funções da irisina são o consumo de energia ao converter tecido adiposo branco em tecido adiposo marrom e a regulação do metabolismo de carboidratos, resultando em melhor homeostase da glicose e sensibilidade à insulina, além de perda de peso.6-11

A caquexia cardíaca na ICFER associa-se com comprometimento da homeostase energética devido ao desequilíbrio anabólico e catabólico, e os níveis séricos de adropina e irisina desempenham importante papel no equilíbrio energético e metabolismo. Com base nisso, levantamos a hipótese de que os níveis séricos de adropina e irisina difeririam entre pacientes com ICFER caquéticos e não caquéticos.

Este estudo teve como objetivos: 1) investigar os níveis séricos de adropina e irisina em pacientes com ICFER caquéticos e não caquéticos, e 2) investigar a relação entre os níveis séricos de adropina e irisina e os parâmetros clínicos e laboratoriais em pacientes com ICFER.

 Métodos Seleção de pacientes e protocolo do estudo

Para identificar pacientes caquéticos, triamos os prontuários médicos de indivíduos atendidos no ambulatório de cardiologia de um hospital universitário para o diagnóstico ou tratamento de ICFER. Subsequentemente, os pacientes foram contatados por telefone e solicitados a comparecer ao ambulatório. Aqueles com ICFER sem perda de peso foram arrolados como grupo controle.

Os critérios de inclusão foram o diagnóstico de ICFER de acordo com a Diretriz para Diagnóstico e Tratamento de Insuficiência Cardíaca Aguda e Crônica da ESC de 2012 e tratamento para ICFER por pelo menos 6 meses antes do arrolamento no estudo.12 Os critérios de exclusão foram os seguintes: insuficiência cardíaca aguda descompensada, insuficiência cardíaca com fração de ejeção preservada, hospitalização por síndrome coronariana aguda, valvulopatia cardíaca primária, doença pulmonar obstrutiva crônica, doença vascular periférica, doença musculoesquelética, doença inflamatória ou infecciosa aguda/crônica, doenças do tecido conjuntivo, neoplasias, cardiopatia congênita, insuficiência hepática, insuficiência renal aguda ou crônica terminal, trauma ou grande cirurgia recente e gravidez.

Dados demográficos, clínicos e laboratoriais e os tratamentos médicos administrados a cada paciente durante sua hospitalização-índice foram registrados em uma revisão sistemática dos prontuários médicos. Para determinar os valores da fração de ejeção ventricular esquerda, todos os indivíduos foram submetidos a ecocardiografia transtorácica (Vivid S5; General Electric, Wisconsin, EUA) por um profissional experiente. Determinou-se a fração de ejeção ventricular esquerda com o método de discos de Simpson e a ecocardiografia bidimensional.

Todos os pacientes tinham mais de 18 anos e assinaram o termo de consentimento livre e informado, que foi um pré-requisito para o arrolamento. O estudo estava de acordo com a Declaração de Helsinque, e o protocolo do ensaio foi aprovado pelo Comitê de Ética local.

 Medidas laboratoriais

As amostras de sangue foram obtidas por punção venosa em tubos contendo o anticoagulante ácido etilenodiamino tetra-acético (EDTA). As amostras foram colhidas da veia antecubital, com o paciente sentado, após jejum noturno de 12 horas. O soro foi obtido por centrifugação a 4000 rpm a 4°C por 20 minutos, sendo então armazenado a -80°C até a análise. Todos os parâmetros bioquímicos e hematológicos de rotina foram medidos no mesmo dia da coleta. Os parâmetros bioquímicos, incluindo glicemia de jejum, creatinina, colesterol total, colesterol da lipoproteína de alta densidade (HDL), colesterol da lipoproteína de baixa densidade (LDL) e triglicerídeos (TG), foram medidos usando um auto-analisador com kits comerciais Abbott Diagnostics C8000i (Abbott, Alemanha). O colesterol-LDL foi estimado aplicando-se a fórmula de Friedewald para amostras com TG ≤ 400 mg/dl. Os parâmetros hematológicos foram obtidos usando-se o analisador hematológico Coulter LH 780 (Beckman Coulter Ireland, Inc., Mervue, Galway, Irlanda). Os níveis séricos do peptídeo natriurético cerebral (BNP) (pg/ml) foram medidos com os kits comerciais (Phoenix Pharmaceuticals, Inc., Burlingame, CA, EUA).

Os níveis séricos de adropina foram medidos com kits comerciais usando o método enzyme-linked immunosorbent assay (ELISA) (Human adropin ELISA kit, catálogo no. ck-e90267, Hangzhou Eastbiopharm Co., Blue Ocean International Times Mansion, China), com um baixo limite de sensibilidade de 2,49 ng/l. Todas as amostras foram medidas em duplicata em um único experimento. Os coeficientes de variação intra- e inter-ensaio desse kit foram < 10% e < 12%, respectivamente. O intervalo de detecção da adropina foi 5-1000 ng/l. Os níveis séricos de irisina foram detectados com um kit comercial, usando o método ELISA (Human irisin ELISA kit, catálogo no. CK-E90905, Hangzhou Eastbiopharm Co., Blue Ocean International Times Mansion, China). O limite de sensibilidade foi 0,023 µg/ml, e os coeficientes de variação intra-e inter-ensaio desse kit foram < 10% e < 12%, respectivamente. O intervalo de detecção da irisina foi 0,05-15 µg/ml.

 Definições

A caquexia cardíaca pode ser definida como doença subjacente e perda de peso involuntária não edematosa ≥ 6% nos 6-12 meses anteriores.12,13

Diagnosticou-se hipertensão se a pressão arterial sistólica fosse superior a 140 mmHg, a pressão arterial diastólica fosse superior a 90 mmHg, ou o paciente estivesse usando anti-hipertensivos. Definiu-se hiperlipidemia como níveis séricos de jejum de colesterol total > 200 mg/dl, LDL colesterol > 130 mg/dl, TG > 180 mg/dl ou uso de hipolipemiantes. Definiu-se diabetes mellitus como história prévia da doença, uso de insulina ou hipoglicemiantes orais, ou glicemia de jejum ≥ 126 mg/dL em duas ocasiões em pacientes não tratados previamente.14 Usaram-se medidas antropométricas para determinar índice de massa corporal (IMC), espessura da prega cutânea tricipital (PCT) e circunferência do braço (CB). Mediu-se a espessura da PCT com um plicômetro do tipo Holtain. A área muscular do braço (AMB) foi calculada pela fórmula (CB-PCT × π) 2/4 × π, sendo considerada um indicador de massa muscular corporal.15 As alturas e os pesos dos participantes do estudo foram medidos, sendo o IMC calculado pela divisão do peso corporal em quilograma pelo quadrado da altura em metro (kg/m2).

 Análise estatística

As análises descritivas foram apresentadas como médias e desvios-padrão ou mediana e intervalo interquartil (IIQ, variando do percentil 25 ao 75). O tamanho do efeito padrão deste estudo foi determinado em 0,62 com poder de 80% e erro de 5% de acordo com a equação relatada por Pardo et al.16 O tamanho da amostra foi estabelecido em um mínimo de 41 voluntários por grupo para detectar as diferenças nos níveis de irisina entre pacientes caquéticos e controle.

As variáveis categóricas foram expressas como números e porcentagens. Os métodos visual (histogramas e gráficos de probabilidade) e analítico (Kolmogorov-Smirnov) foram usados para determinar se as variáveis tinham distribuição normal. O teste T de amostras independentes foi usado para comparar as variáveis numéricas contínuas de distribuição normal, o teste U de Mann-Whitney foi usado para comparar as variáveis numéricas de distribuição não normal, e o teste do qui-quadrado foi usado para comparar as variáveis categóricas entre os dois grupos. Curvas ‘receiver operating characteristic’ foram construídas para BNP, adropina e irisina. Ao se observar um ponto de corte significativo, registraram-se a sensibilidade, a especificidade e os valores preditivos positivo e negativo. Realizou-se análise de correlação de Spearman para determinar a associação dos níveis de adropina e irisina com as variáveis examinadas. Análises de regressão logística múltipla foram realizadas para identificar os fatores de risco independentes associados com caquexia. As variáveis que se mostraram estatisticamente significativas nas análises univariadas foram introduzidas na análise de regressão logística múltipla. Um nível geral de erro tipo I de 5% foi usado para inferir significância estatística, sendo um valor de p < 0,05 considerado significativo. As análises estatísticas foram realizadas usando-se a versão 20.0 do programa Statistical Package for Social Sciences (IBM SPSS 17 Statistics for Windows, Armonk, NY, EUA).

 Resultados

O presente estudo incluiu 86 pacientes com ICFER: 44 com caquexia cardíaca (idade média, 65,4 ± 11,2 anos; 61,4% de homens) e 42 com peso corporal normal (idade média, 61 ± 16,5 anos; 64,3% de homens). A Figura 1 mostra a diferença de peso entre os dois grupos. A Tabela 1 apresenta as características basais demográficas e clínicas dos grupos do estudo. Como esperado, IMC, PCT e AMB foram significativamente menores no grupo de caquexia cardíaca do que no não caquético. Além disso, a classe funcional segundo a NYHA dos grupos diferiu significativamente, com mais pacientes do grupo de caquexia cardíaca classificados como classe funcional III e IV da NYHA, e mais pacientes do grupo não caquético classificados como classe funcional I e II da NYHA.

Diferença de peso corporal entre os grupos caquético e não caquético.

Características basais demográficas, clínicas e laboratoriais dos grupos do estudo
ICC sem caquexia (n = 42) ICC com caquexia (n = 44) p valor
Idade, (anos), média (DP) 61,0 (16,47) 65,4 (11,18) 0,179
Sexo masculino, n (%) 27 (64,3) 27 (61,4) 0,779
NYHA, classe I-II, n (%) 30 (60) 20 (40) 0,015
classe III-IV, n (%) 12 (33,3) 24 (66,7)
Etiologia isquêmica, n (%) 28 (66,7) 26 (59,1) 0,468
FEVE, n (%)
Parâmetros antropométricos 31,7 (7,89) 31,4 (6,71) 0,882
IMC (kg/m2), média (DP) 29,2 (4,25) 19,9 (1,12) < 0,001
PCT (mm), média (DP) 17,9 (3) 13,4 (2,45) < 0,001
AMB (cm2), média (DP) 35,9 (8,7) 24,4 (4,03) < 0001
Comorbidades
Hipertensão, n (%) 27 (64,3) 26 (59) 0,620
Diabetes mellitus, n (%) 18 (42,9) 26 (59,1) 0,290
Insuficiência renal crônica, n (%) 14 (33,3) 15 (34,1) 0,941
Doença pulmonar obstrutiva crônica, n (%) 8 (19) 8 (18,2) 0,918
Parâmetros laboratoriais
Glicemia (mg/dl), média (DP) 155,3 (78,5) 150,3 (48,3) 0,685
Creatinina (mg/dl), média (DP) 1,15 (0,63) 1,19 (0,8) 0,997
Hemoglobina (%), média (DP) 11,9 (1,38) 11,3 (1,34) 0,049
Leucócitos (mg/l), média (DP) 8,35 (4,2) 8,45 (3,98) 0,742
Adropina (ng/l) mediana (IIQ) 213,7 (203,1-251,3) 286,1 (231,3-404,0) < 0,001*
Irisina (µg/ml), mediana (IIQ) 2,1 (1,8-2,4) 2,6 (2,2-4,4) 0,001*
BNP (pg/ml), mediana (IIQ) 698,0 (340,0-1517,0) 1408,5 (725,0-4041,0) 0,001*
Albumina (mg/dl), média (DP) 3,3 (0,46) 3,12 (0,36) 0,041
Sódio (mEq/l), média (DP) 138,7 (10,1) 135,7 (9,7) 0,136
Colesterol total (mg/dl), média (DP) 164,5 (44,1) 153,2 (44,4) 0,240
LDL-colesterol (mg/dl), média (DP) 108,4 (40,5) 101,1 (32,7) 0,366
HDL-colesterol (mg/dl), média (DP) 36,2 (10,4) 31 (9,1) 0,015
Triglicerídeos (mg/dl), média (DP)
Terapia medicamentosa 134,2 (50) 122,3 (56) 0,302
Furosemida, n (%) 35 (83,3) 40 (90,9) 0,293
IECA/BRA, n (%) 20 (47,6) / 11 (26,2) 28 (63,6) / 11 (25,2) 0,136
Espironolactona, n (%) 26 (61,9) 30 (68,2) 0,542
Estatina, n (%) 16 (38,1) 18 (40,9) 0,790
Betabloqueador, n (%) 33 (78,6) 39 (88,6) 0,206
Ivabradina, n (%) 15 (25) 11 (25) 0,289
TRC, n (%) 9 (21,4) 6 (13,6) 0,341

n: número; DP: desvio-padrão; IIQ: intervalo interquartil; NYHA: New York Heart Association; FEVE: fração de ejeção ventricular esquerda; IMC: índice de massa corporal; PCT: prega cutânea tricipital; AMB: área muscular do braço; BNP: peptídeo natriurético cerebral; LDL: lipoproteína de baixa densidade; HDL: lipoproteína de alta densidade; IECA: inibidor da enzina de conversão da angiotensina; BRA: bloqueador do receptor de angiotensina; TRC: terapia de ressincronização cardíaca.

teste U de Mann-Whitney.

A Tabela 1 apresenta as características laboratoriais basais dos dois grupos. Os níveis de hemoglobina, albumina e HDL colesterol foram significativamente mais altos nos indivíduos não caquéticos do que nos caquéticos. Ademais, os níveis séricos de BNP, adropina e irisina foram significativamente maiores no grupo caquético do que no não caquético [adropina (ng/l): 286,1 (231,3-404,0) vs 213,7 (203,1-251,3), p < 0,001; irisina (µg/ml): 2,6 (2,2-4,4) vs 2,1 (1,8-2,4), p = 0,001; BNP (pg/ml): 698,0 (340,0-1517,0) vs 1408,5 (725,0-4041,0), p = 0,001]. A análise da associação entre os níveis de adropina e irisina e os parâmetros clínicos e laboratoriais dos pacientes (Tabela 2) revelou que a classe funcional da NYHA e os níveis de BNP correlacionaram-se de maneira significativa e positiva com os níveis de adropina e irisina. Entretanto, IMC, AMB, PCT e albumina sérica, que foram significativos indicadores clínicos e laboratoriais indiretos de caquexia cardíaca, correlacionaram-se de maneira significativa e inversa com os níveis de adropina e irisina. Além disso, os níveis de adropina e irisina correlacionaram-se diretamente com a ICFER, e os níveis de creatinina correlacionaram-se positivamente com os de irisina.

Correlações de adropina e irisina com os parâmetros clínicos e laboratoriais dos pacientes
Idade IMC AMB PCT Albumina BNP NHYA Irisina FEVE Creatinina
Adropina 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
Irisina 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

IMC: índice de massa corporal; AMB: área muscular do braço; PCT: prega cutânea tricipital; BNP: peptídeo natriurético cerebral; NYHA: New York Heart Association; FEVE: fração de ejeção ventricular esquerda.

Para investigar o valor discriminativo dos níveis séricos de BNP, adropina e irisina em pacientes com ICFER caquéticos e não caquéticos, construiu-se uma curva ‘receiver operating characteristic’ para sensibilidade e especificidade, usando-se as respectivas áreas sob a curva (AUC) (Figura 2 e Tabela 3). Os resultados indicaram que os níveis de adropina superiores a 229,4 pg/ml tinham sensibilidade de 77,3% e especificidade de 64,3% para caquexia cardíaca em pacientes com ICFER [AUC: 0,770; intervalo de confiança (IC) 95%: 0,668-0,872; p < 0,001]. Ademais, a sensibilidade dos níveis de irisina superiores a 2,2 pg/ml foi de 75.0%, enquanto a especificidade foi de 52,4% para caquexia (AUC: 0,705; IC 95%: 0,596-0,815; p < 0,001).

Curva receiver-operating characteristic para valor discriminativo dos níveis séricos de adropina, irisina e BNP em pacientes com ICFER sistólica com e sem caquexia.

Análise da curva receiver-operating characteristic de adropina, irisina e peptídeo natriurético cerebral (BNP) para predição de caquexia
Variável AUC EP IC 95% P valor Sensibilidade Especificidade VPP VPN
Adropina 0,770 0,052 0,668-0,872 0,0001 %77,3 %64,3 %69,4 %73,0
Irisina 0,705 0,056 0,596-0,815 0,001 75,0 %52,4 %62,3 %66,7
BNP 0,700 0,056 0,590-0,811 0,001 %72,7 %61,9 66,7 %68,4

AUC: área sob a curva (area under the curve); EP: erro-padrão; VPP: valor preditivo positivo; VPN: valor preditivo negativo.

As variáveis que se mostraram estatisticamente significativas nas análises univariadas foram introduzidas na análise de regressão logística multivariada, na qual a adropina [odds ratio (OR) 1,021; IC 95%: 1,004-1,038; p = 0,017] foi o único preditor independente da presença de caquexia nos pacientes com ICFER (Tabela 4).

Análises de regressão logística para identificar os fatores de risco independentes associados com caquexia cardíaca
Univariada Multivariada
p OR IC 95% p OR IC 95%
Albumina 0,044 0,331 0,113-0,972 0,387 0,571 0,161-2,029
BNP 0,013 1,000 1,000-1,001 0,770 1,000 1,000-1,000
Idade 0,151 1,023 0,992-1,056
Sexo 0,779 1,133 0,472-2,720
Irisina 0,025 1,865 1,081-3,218 0,776 0,880 0,378-2,047
Adropina 0,002 1,016 1,006-1,026 0,017 1,021 1,004-1,038
Creatinina 0,760 1,098 0,604-1,994
Glicose 0,720 0,999 0,992-1,005
FEVE 0,880 0,996 0,939-1,056
Colesterol total 0,239 0,994 0,984-1,004
Triglicerídeos 0,302 0,996 0,987-1,004
LDL 0,363 0,995 0,983-1,006
HDL 0,022 0,941 0,893-0,991 0,102 0,950 0,893-1,010
NYHA III - IV 0,016 3,000 1,226-7,339 0,463 0,550 0,111-2,717

BNP: peptídeo natriurético cerebral; FEVE: fração de ejeção ventricular esquerda; LDL: lipoproteína de baixa densidade; HDL: lipoproteína de alta densidade; NYHA: New York Heart Association.

 Discussão

Os principais achados deste estudo foram: 1) níveis séricos de adropina e irisina significativamente mais altos no grupo de caquexia do que no não caquético; 2) classe funcional da NYHA e níveis de BNP, que são indicadores validados da gravidade da ICFER, significativa e positivamente associados com os níveis de adropina e irisina; 3) relação direta entre os níveis de adropina e irisina; 4) sensibilidades de adropina e de irisina mais altas do que suas especificidades para predizer caquexia cardíaca, além de sensibilidades de adropina e de irisina mais altas do que a sensibilidade do BNP; e 5) a adropina foi o único preditor independente da presença de caquexia em pacientes com ICFER.

A incidência anual de caquexia cardíaca em pacientes com classe funcional III-IV da NYHA foi relatada em 10%, sendo a prevalência de 12-15% entre aqueles com classe funcional II-IV da NYHA.13 Vários fatores, incluindo comprometimento da ingestão e absorção de alimentos, ativação imunológica e neuro-hormonal, disfunção endotelial, aumento da resistência insulínica, desencadeamento da produção de citocinas pró-inflamatórias e desequilíbrio anabólico e catabólico, desempenham papel fundamental no complexo processo de caquexia cardíaca.13,17 Isso se associa com mau prognóstico de curto e longo prazo, resposta desfavorável ao tratamento medicamentoso e má qualidade de vida.18 Estudos prévios relataram elevação dos níveis de alguns hormônios e peptídeos, como adiponectina, grelina, leptina e melanocortina, em pacientes caquéticos com ICFER.17,19-20 Entretanto, não há estudos sobre os níveis de adropina e irisina nesses pacientes na literatura. No presente estudo, os níveis foram significativamente elevados nos pacientes com ICFER e caquexia cardíaca em comparação aos daqueles não caquéticos.

Sente et al.,21 relataram que a deficiência energética cardíaca e muscular esquelética tem importante papel na fisiopatologia da insuficiência cardíaca, resultando em um estado hiperadrenérgico. Os níveis séricos dos ácidos graxos livres aumentam com o estado hiperadrenérgico e inibem a glicólise e a captação de glicose no coração e no músculo esquelético, com subsequentes elevações da glicemia. Injúria pancreática multifatorial, associada a hiperglicemia, causa resistência insulínica sistêmica e miocárdica.22 O conceito de insuficiência metabólica na ICFER inclui excesso de reatividade catabólica (lipólise) e deficiência anabólica, com o excesso de reatividade catabólica ativando as vias glicolítica e lipolítica, enquanto a deficiência anabólica induz perda de massa e função do músculo esquelético.18

A adropina é uma proteína recentemente identificada, implicada na manutenção da homeostase energética.5 Um estudo de camundongos com deficiência de adropina sugeriu que esse hormônio peptídico seja necessário à manutenção da sensibilidade insulínica e proteção contra a intolerância à glicose.23 Portanto, levantamos a hipótese de que os níveis de adropina possam aumentar como consequência de resistência insulínica em pacientes com ICFER.

Kumar et al.,5 relataram que a superexpressão ou administração sistêmica de adropina em camundongos com obesidade induzida por dieta resultou em significativa melhora na sensibilidade insulínica e perda de peso. Logo, a perda de peso em pacientes caquéticos com ICFER poderia contribuir para a elevação dos níveis séricos de adropina. Os achados deste estudo apontam para a associação metabólica de aumento da adropina sérica com perda muscular e lipólise em pacientes caquéticos com ICFER.

Além dos importantes efeitos metabólicos da adropina, Lovren et al.,24 atribuíram um potencial papel endotelial protetor a essa proteína que é provavelmente mediada pela superexpressão da sintase de óxido nítrico endotelial (eNOS). Aqueles autores sugeriram que a adropina possa auxiliar na proteção contra doenças vasculares ao elevar de maneira significativa a expressão da eNOS das células endoteliais das artérias coronárias.24 Topuz et al.,9 relataram níveis reduzidos de adropina em pacientes com diabetes tipo 2 e disfunção endotelial. Wu et al.,8 mostraram uma associação inversa e independente entre os níveis de adropina e a gravidade da aterosclerose coronariana em pacientes diabéticos. Zhang et al.,25 apresentaram resultados similares para pacientes com doença arterial coronariana estável. Esses mesmos autores, em outro estudo, relataram uma importante associação entre os níveis reduzidos de adropina, a alta pontuação no escore SYNTHAX e a gravidade da doença arterial coronariana estável.26 Yu et al.,27 examinaram o papel da adropina no infarto agudo do miocárdio (IAM) e mostraram redução dos níveis séricos de adropina em casos de IAM.

Ao elevar a eNOS, a adropina pode melhorar a disfunção endotelial, o que foi amplamente relatado em pacientes com ICFER, assim como desacelerar a disfunção ventricular esquerda na ICFER.28 Lian et al.,7 correlacionaram os níveis elevados de adropina na ICFER com a gravidade da ICFER de acordo com a classe da NYHA e os níveis de BNP. O presente estudo revelou achados e relações similares em pacientes caquéticos com ICFER. Diferentemente do estudo de Lian et al.,7 no qual os níveis de adropina e o IMC correlacionaram-se diretamente entre si, houve uma relação inversa entre os níveis de adropina e o IMC na caquexia cardíaca no presente estudo, como esperado.

Embora a irisina seja predominantemente expressa no músculo e diretamente associada com a massa muscular, pode ser expressa em diferentes tecidos. Sabe-se que o tecido adiposo marrom dissipa energia na forma de calor através da ativação da proteína 1 desacopladora. Esse processo aumenta o gasto energético, reduz o peso corporal e melhora os parâmetros metabólicos, como a sensibilidade à insulina. No tecido adiposo branco, a irisina estimula as alterações fenotípicas BAT-like (tipo tecido adiposo marrom) através de um processo conhecido como ‘tornar amarronzado’. Com base nessas propriedades, propôs-se que a irisina fosse um possível novo tratamento para diabetes e obesidade.29 Embora alguns estudos tenham relatado correlações positivas entre irisina e IMC, outros obtiveram resultados contraditórios.6,29 O presente estudo revelou uma correlação inversa entre irisina e IMC. Além disso, AMB, PCT e níveis séricos de albumina foram inversamente relacionados com irisina. Em pacientes com ICFER, perdas muscular, adiposa e óssea foram associadas com piores desfechos.30 Ademais, um estudo recente demonstrou uma redução gradual nos níveis de irisina em pacientes com IAM, sugerindo que a irisina possa ser um novo marcador diagnóstico nesse contexto.31 Em um estudo recentemente publicado, Shen et al.,32 relataram níveis séricos de irisina significativamente mais altos em pacientes que morreram por insuficiência cardíaca aguda (ICA) em comparação aos daqueles que sobreviveram à ICA, sendo preditores de mortalidade por todas as causas em 1 ano em pacientes com ICA. Naquele estudo, determinaram-se a irisina e o NT-pró-BNP por análise da curva ROC. O NT-pró-BNP (AUC: 0,670) apresentou apenas valor prognóstico moderado para risco de mortalidade por ICA em comparação ao nível sérico de irisina (AUC: 0,753).32 Os achados daquele estudo são similares aos nossos. Isso pode ser consequência do metabolismo do tecido adiposo e da resistência insulínica. Estudos são necessários para determinar se os níveis de irisina resultam da reduzida massa muscular periférica em pacientes caquéticos com ICFER. Além disso, o nosso estudo mostrou que a adropina é melhor preditor do que a irisina e o BNP.

No nosso estudo, apenas a adropina mostrou ser preditor independente de caquexia em pacientes com insuficiência cardíaca. Ainda que a irisina tenha predito caquexia cardíaca na análise univariada, não o fez na análise multivariada. A irisina mostrou-se um biomarcador preditivo de mortalidade por todas as causas em 1 ano no estudo de Shen et al.32 Tal diferença pode dever-se ao fato de que a molécula de adropina não foi usada na análise multivariada desse estudo. Investigação adicional é necessária para examinar essa relação.

À semelhança da adropina, a irisina correlacionou-se de maneira significativa e positiva com os níveis de BNP e a classe funcional da NYHA. Os peptídeos natriuréticos, como BNP, além dos peptídeos diuréticos e vasodilatadores, desencadeiam lipólise em seres humanos e desempenham um papel no metabolismo da gordura.7 Logo, levantamos a hipótese de que a lipólise pelo BNP deve estar associada com a síntese de adropina e irisina em pacientes caquéticos com ICFER. Estudo adicional se faz necessário para elucidar o mecanismo preciso da liberação de adropina e irisina em pacientes com caquexia cardíaca.

Limitações do estudo

O presente estudo tem limitações. Em primeiro lugar, sua amostra foi relativamente pequena. Entretanto, os resultados apontam para uma importante relação entre os níveis de adropina e irisina e a caquexia cardíaca em pacientes com ICFER. Em segundo, a falta de dados de seguimento sobre futuros eventos cardiovasculares adversos maiores, incluindo mortalidade ou hospitalização por ICFER, indica que o valor prognóstico dos níveis das duas proteínas não pôde ser avaliado.

 Conclusões

O presente estudo mostrou níveis séricos de adropina e irisina significativamente elevados nos pacientes caquéticos com ICFER, e que tais níveis estavam significativamente associados com marcadores previamente validados de gravidade da ICFER, como nível de BNP e classe funcional da NYHA. Esses resultados sugerem que a adropina e a irisina possam ser novos marcadores de caquexia cardíaca em pacientes com ICFER. A adropina e a irisina estão relacionadas com a gravidade da insuficiência cardíaca.

Fontes de financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação.

Aprovação ética e consentimento informado

Este estudo foi aprovado pelo Comitê de Ética do Mehmet Akif Ersoy Thoracic and Cardiovascular Disease Education and Training Hospital sob o número de protocolo 2015-23. Todos os procedimentos envolvidos nesse estudo estão de acordo com a Declaração de Helsinki de 1975, atualizada em 2013. O consentimento informado foi obtido de todos os participantes incluídos no estudo.