Serum Irisin Level Can Predict the Severity of Coronary Artery Disease in Patients with Stable Angina

Myokines are a type of cytokines that have autocrine, paracrine and endocrine effects, mostly secreted by skeletal muscle.1) Irisin is a recently reported novel myokine, which is generated by exercise and acts as an insulin-sensitizing hormone.2) Fibronectin type III domain containing protein 5 (FNDC5) is a plasma membrane protein that is proteolytically cleaved to Irisin. Irisin induces the browning of subcutaneous white adipocytes and stimulates thermogenic genes including uncoupling protein 1 (UCP1) both in stromal vascular fraction (SVF) cells and in mouse models.3) Mice injected with adenoviral vectors containing full-length FNDC5 showed a threefold-fourfold increase in plasma irisin levels, which provided to lower weight gain, improvement in glucose tolerance and insulin resistance.3) Human studies have shown that serum irisin levels are associated with other hormones, such as adipokines,4) myokines,5) obesity,6) insulin resistance7) and metabolic syndrome.8) However, the results of reported studies are conflicting. One study reported a positive relationship between body mass index and serum irisin levels, whereas, another study showed a negative relationship.6), 9), 10) Similar paradoxal association was found in patients with diabetes mellitus.10), 11) A cohort study conducted in nondiabetic patients showed that serum irisin levels were positively associated with body weight, body fat mass, fasting, two hours post-load insulin levels and carotid intima-media thickness; depite the negative correlation between serum irisin levels and insulin-stimulated glucose disposal.12) Furthermore, high irisin levels were related with major adverse cardiovascular events in the post-infarct period.

The synergy between percutaneous coronary intervention with taxus and cardiac surgery (SYNTAX) score is an angiographic score that defines the grade and complexity of coronary artery disease (CAD).13) Numerous studies confirmed that patients with a relatively high SYNTAX score have poor outcomes, and that the score is an independent predictor of major advanced cardiovascular outcomes (MACE) for percutaneous coronary intervention (PCI).14)

In this study, we aimed to investigate the relationship between irisin levels and the severity of coronary artery disease with the SYNTAX score in patients with stable coronary artery disease.

Clinical, demographic and laboratory variables of the groups were shown in Table 1. The patients in the higher SYNTAX group (score ≥23) was older than the lower SYNTAX group (score <23) and control group (62.40±8.05, 60.93±9.58 and 58.42±10.46, respectively; p=0.001). Body mass index, blood pressure (systolic and diastolic), smoking, fasting glucose, hemoglobin, TSH, serum creatinine and serum lipid levels were not statistically significant between groups. Compared with lower SYNTAX group (score <23) patients, higher SYNTAX group (score ≥23) patients had significantly higher serum hs-CRP levels (p<0.001), higher insulin resistance index (p=0.001) and lower left ventricular ejection fraction (p=0.002).

Table 1
Basic characteristics of the study participants

• Click for larger image
• Click for full table
• Download as Excel file

The patients with stable CAD with a higher SYNTAX score (score ≥23) had significantly lower serum irisin levels (127.91±55.38 ng/mL), as compared to patients with a low SYNTAX score (score <23) (224.69±92.99 ng/mL) and control group (299.54±123.20 ng/mL). Irisin levels showed significant differences between all groups (p<0.001). Irisin level showed a significant inverse correlation with SYNTAX score (p<0.001, r=-0.428) (Fig. 1).

Fig. 1
Correlation between Irisin level and SYNTAX score. SYNTAX: synergy between percutaneous coronary intervention with taxus and cardiac surgery.

• Click for larger image
• Download as PowerPoint slide

The results of the univariate and multivariate logistic regression analyses were listed in Table 2. In the multivariate regression analysis, hs-CRP (p=0.004, OR: 0.229, 95% CI: 0.265-1.348), and lower serum irisin levels (p<0.001, OR: -0.566, 95% CI: -0.072~-0.042) were independent predictors of SYNTAX score in the study subjects after adjusting other confounders.

Table 2
Multivariate linear regression analysis showing independent predictors of the SYNTAX score

• Click for larger image
• Click for full table
• Download as Excel file

In the present study, irisin levels were lower in the patients with higher SYNTAX score. Lower irisin levels are an independent predictor of coronary artery disease severity. Our findings highlight the role of irisin not only in metabolic disorders, but also in cardiovascular diseases.

Myokines are novel biomarkers identified in patients with cardiovascular diseases, which are proposed to modulate energy metabolism. Among myokines, myostatin, irisin, leukemia inhibitory factor (LIF) are most well-known. FNDC5 is enzymatically cleaved and secreted as the hormone peptide irisin, as first reported by Bostrom et al.3) As demonsrated in Fig. 2, it enhances metabolic uncoupling and hence caloric expenditure in the situation of exercise or temperature by converting the WAT to brown to brown adipose tissue (BAT).3), 16) Heart and skeletal muscle, adipose tissue, liver, kidneys, peripheral nerve sheath, dermis and hypodermis of the skin secrete irisin.17) Reduction in energy level cause decrease the irisin concentration in circulation, and further ischemia in the cardiac tissues.16)

Fig. 2
Irisin synthesis and the principle biochemical effects of irisin. FNDC5: fibronectin type III domain-containing protein 5, UCP-1: uncoupling protein 1.

• Click for larger image
• Download as PowerPoint slide

Our study demonstrated that the patient with lower irisin levels had higher insulin resistance index. Irisin is considered a cellular ‘energy sensor’ blocking white adipose tissue to brown adipose tissue, resulting in decreased metabolic thermogenesis. The first studies showed that irisin was associated with increased risk of the metabolic syndrome, cardiometabolic variables, and cardiovascular disease in subjects with a history of myocardial infarction or stroke.8) Positive association was reported between irisin levels and adverse metabolic phenotypes, such as obesity and the metabolic syndrome (MS).9), 18) On the other hand, few studies demonstrated an inverse association between circulating irisin levels and obesity or diabetes.18), 19), 20)

The role of irisin in human physiology remains largely unknown despite recently published studies. High irisin concentration causes a loss of ATP because of its uncoupling properties and decreased irisin level protects energy loss of myocardial cells.3) Cardiac muscle cells produce more irisin than skeletal muscle.3), 21) Recently, a link between myocardial infarction and circulated irisin concentration was suggested.16) Aronis et al.22) demonstrated that circulating irisin levels do not predict the development of ACS in healthy individuals, however increased irisin levels prospectively predict the development of MACE in patients with established CAD after PCI. Theirs was the first study to evaluate the relationship between circulating irisin levels and ACS in human subjects, as well as clinical outcomes in patients with established CAD.22) In a study with animal models, Kuloglu et al.16) showed that serum irisin level was gradually decreased in the isoproterenol-induced myocardial infarction.

Parallel to the our study, Park et al.21) showed that irisin is independently associated with the general Framingham risk score profile, demonstrating that patients with lower circulating irisin levels have an increased event-free survival rate 12 months after PCI.8) Emanuele et al.23) demonstrated that healthy centenarians are characterized by increased serum irisin levels, whereas levels of this molecule were significantly lower in young patients with myocardial infarction. On the other hand, their data indicated that circulating irisin levels may be significantly associated with successful aging and could also serve as a potential vascular risk marker.23) As noted above, irisin level was associated with coronary disease severity but the exact mechanism between irisin and coronary artery disease or atherosclerosis is unknown. Although increased irisin level may be the cause or consequence of coronary artery disease, a mouse study by Lu et al.24) showed that irisin might have a preventive role in atherosclerosis; they reported systemic administration of irisin protected against endothelial injury and ameliorated atherosclerosis by inhibition of oxidative stress.24) In the same study, they reported that irisin decreased the plaque area and the infiltrating macrophages and T lymphocytes in the plaques, and down-regulated the mRNA expression of inflammatory cytokines in the aortas.24) According to our results, the mean age was lower in control group. Löffler et al.25) also showed a negative association between age and serum irisin levels. Our results indicated that age was associated with high SYNTAX score in the study group. However, in the regression analyses, only hs-CRP and irisin levels were independent predictors of high SYNTAX score.

Our study had some limitations. First, our study has relatively small sample size of selected patients. Secondly, it is a cross-sectional study. Irisin concentration was only measured at admission and without correction for potential variability in levels. Further large, multicenter follow up studies are needed to confirm this relation.

In conclusion, this is the first study to show that decreased irisin levels predict the severity of stable coronary artery disease and higher SYNTAX score. Future studies are needed to assess whether irisin is associated with cardiometabolic disease, reactively expressed as a protective mechanism, or uninvolved in the pathophysiology of patients with coronary artery disease. Elucidating the correct mechanism would lead to a better understanding of the clinical role of irisin.