Relation between Serum Apelin Level and CAE

Relation between Serum Apelin Level and CAE Decreased Apelin Levels in Isolated Coronary Artery Ectasia M.Zihni Bilik, M.Ata Akal, Halit Acet, Abdulkadir Yaldaz, Murat Yà ¼ksel, Nihat Polat, Mesut Aydan, Mustafa Oylumlu, Sait Alan ,Faruk Ertaâ„ ¢Ã‚ ¹  ¹Department of Cardiology, Medicine Faculty, Dicle University, Diyarbakr, Turkey  Ã‚   Abstract Introduction: Etiopathogenesis of coronary artery ectasia (CAE) is completely unknown. Most of CAE develop with atherosclerosis. Association of atherosclerotic coronary artery disease and apelin has been examined in previous studies. In isolated coronary artery ectasia the role of plasma apelin has not been studied yet. Aim: In this study, we investigated the relation between plasma apelin levels and coronary artery ectasia. Material and methods: Study population included totally 54 patients. 26 patients with isolated CAE (53.6 ±8.1 years ); 28 patients as control group with normal coronary arteries (51.6 ± 8.8 years) and with similar risk factors and demographic properties . Apelin levels were measured using an enzyme immunoassay (ELISA) . Results: Apelin levels in CAE group were significantly lower [apelin= 0.116ng/ml (0.086-0.319) ] than those in control group [0.689ng/ml (0.077-1.067) ] (P =0.033).Glucose, creatinine,total cholesterol, triglyceride, LDL-C, HDL-C levels were not significantly different between groups (P >0.05). Conclusions: In this study we showed that patients with isolated CAE have decreased plasma apelin levels. Therefore there may be an association between decreased plasma apelin level and isolated CAE. Key words: apelin, coronary artery ectasia, atherosclerosis Introduction: Apelin is an adipocytokine and endogenous ligand for the angiotensin-like 1 receptor (APJ). The function of apelin is not clear in the cardiovascular system. Apelin may play an opposite role to the renin-angiotensin-aldosterone system as a compensatory mechanism. It is reduced in patients with heart failure.[1] Increased apelin expression has been found in coronary vessels, cardiomyocytes, large conduit vessels [2] vascular smooth muscle cells, and endothelial cells.[3] Some functions of apelin have been described, such as positive inotropism [4] ,endothelium-dependent vasodilation [5],cardiac contractility,[6] and the reduction of vascular wall inflammation. CAE has been defined as abnormal dilatation of a segment of coronary artery that 1.5 times larger than the diameter of adjacent normal segments of artery.[7] The incidence of CAE has been reported to account for 0.3% to 4.9% in patients underwent coronary angiography. [8] Although the exact mechanisms leading to CAE are not clear up to now, atherothrombosis, endothelial dysfunction and vasculit have been suggested as possible responsible factors. CAE has also been reported in association with various conditions such as congenital coronary anomalies, connective tissue diseases, and vasculitis and failed smooth muscle cells. [9,10] Apelin has a role in endothelium-dependent vasodilation. CAE may dependent to endothelium-dependent vasodilation mechanism. [5] So there may be relation between apelin and CAE. In our knowledge there is not any study in the literature about apelin and CAE. Aim: In this study we aimed to examine the relation between serum apelin level and CAE. Material and methods: Study population included totally 54 patients that were admitted to Cardiology Department of Dicle University. Twenty six patients with isolated CAE ( 53.6 ±8.1 years ) as CAE group and 28 patients as control group with normal coronary arteries that proven angiographically (51.6 ± 8.8 years) with similar risk factors and demographic properties to CAE group were included . Cases who had malignancy, heart failure ,acute coronary syndrome, renal disease, collagen tissue diseases, vasculitis,coronary artery disease were excluded from the study. The study was approved by the Local Ethics Committee and informed consent was obtained from each patient. Study design: All patients underwent detailed physical examination. Body mass index (BMI) was calculated as weight divided by square of height. Clinical laboratory analyses were performed in Dicle University Biochemistry Laboratories (Diyarbakar, Turkey). Biochemical tests were performed by Abbott C16000 (USA) biochemical autoanalyzer with original kits and hematological counts were measured by an automated hematology analyzer (Abbott Cell-Dyn 3700; Abboott Laboratory, Abbott Park, IL) in peripheral venous blood samples . Standart methods were used to measure total and high density lipoprotein cholesterol (HDL),triglycerides and fasting glucose. Serum obtained by centrifuge was stored at −80 °C until analysis for apelin measurement. These were studied at the Biochemistry Laboratory of Dicle University .Apelin levels were measured using an enzyme immunoassay (ELISA) (Phoenix Pharmaceuticals, Inc., California,USA) according to the manufacturer’s instructions, and expressed as ng/ml. Evaluation of coronary artery ectasia by coronary angiography Coronary angiography was routinely performed using the Allura Xper FD10 (Philips, Amsterdam, The Netherlands) through femoral artery by Judkins technique without use of nitroglycerine. The contrast agent was Iopamiro 370 (Bracco, Milan, Italy) that used in all patients. Each angiogram was evaluated concurrently by two interventional cardiologists who were blinded to the study and to each other. Angiographically CAE was accepted when diameter of dilated segment of coronary artery was 1.5 times larger than adjacent normal segments. Statistical analysis Data were analyzed with SPSS software version 18.0 for Windows (SPSS Inc, Chicago, Illinois). The Kolmogorov-Smirnov test was used to verify that continuous variables were normally distributed. Continuous variables are listed as mean  ± standard deviation, categorical variables are listed as percentages. The independent sample t-test or Mann-Whitney U test was used for continuous variables and the chi-square test for categorical variables. Statistical significance was defined as p Results: The study was included a total of 54 patients. CAE group included 26 patients with coronary ectasia (mean age 53.6 ±8.1 years) and %73.1 (n=19) of patients were male. Control group included 28 control patients with normal coronary arteries (mean age 51.6 ± 8.8 years) and 64.3% (n =18) of patients were male. There was no difference between two groups regarding basal demographical data (P>0.05). Demographic characteristics of the groups are presented in Table 1. We found apelin levels in CAE group significantly lower [apelin= 0.116ng/ml (0.086-0.319) ] than those in control group [0.689ng/ml (0.077-1.067) ] (P =0.033). Glucose, creatinine,total cholesterol, triglyceride, LDL-C, HDL-C levels were not significantly different between groups (P >0.05). Table 1: Baseline characteristics of the study population Ectasia Grup (n=26) Control Grup (n=28) P value Age (years) 53.6 ±8.1 51.6 ± 8.8 0.38 Male n(% ) 19 (%73.1) 18(%64.3) 0.49 Hypertension n(%) 15 (%58) 12(%43) 0.18 Diabetes Mellitus n(%) 4 (%15) 6 (%21) 0.57 BMI (kg/m ²) 28.1 ± 4 26.7  ±4.2 0.24 Smoking n(%) 13 (%50) 12 (%46) 0.79 Glucose mg/dl 106 ±20 124 ±53 0.1 Creatinine mg/dl 0.86 ±0.2 0.82 ±0.1 0.38 Total cholesterol mg/dl 196 ±47 195 ±37 0.98 LDL mg/dl 128 ±42 113 ±33 0.14 HDL mg/dl 41 ±10 40 ±10 0.92 Triglyseride mg/dl 145 ±77 184 ±115 0.15 Apelin ng/ml 0.116 (0.086-0.319)* 0.689 (0.077-1.067)* 0.033 *Median and interquartile range used. BMI:Body mass index ; LDL: Low-density lipoprotein cholesterol; HDL: High density lipoprotein cholesterol Figure-1: Comparison of the plasma apelin level between CAE and control group. P=0.033 Discussion : CAE has been defined as abnormal dilatation of a segment of coronary artery that 1.5 times larger than the diameter of adjacent normal segments of artery. [7] The etiology of CAE is not fully understood. Various mechanisms are thought to be the reason of CAE. Approximately a half of CAE is due to atherosclerosis of coronary artery. Atheromatous ulcerations in coronary artery or significant stenosis has been described in patients with ectasia.[11,12] Cardiovascular system is the main target of apelin and its receptor APJ . In regulation of cardiovascular homeostasis, apelin may have an important role.[13] Positive inotropism, vasodilation, decreased blood pressure and diuresis are some effects of apelin on cardiovascular system . Therefore apelin may have an antagonistic effect to the renin-angiotensin-aldosteron system .It is reduced in patients with heart failure.[1] Relation between apelin and coronary artery disease especially atherosclerosis is known. Kadoglou et al. showed that apelin concentrations are lower in CAD patients and it is negatively correlated with severity of CAD. [14]. Additionally, decreased apelin levels are observed in subjects with stable angina. Plasma apelin may have a role in the progression and destabilization of atherosclerotic plaques.[15]. Attenuation of the vessel wall has been shown by Rath et al. in nonatherosclerotic forms of CAE .In their study vessel media degeneration and smooth muscle cell replacement by hyalinized collagen with intact vessel intima has been demonstrated.[16] In the pathogenesis of CAE, loss of the musculoelastic components of the vessel media have an important effect. [12,17] Several factors other than atherosclerosis have a role in development of CAE such as endothelial dysfunction, vasculitis, congenital coronary anomalies, connective tissue diseases [9,10], oxidative stres, vascular smooth muscle proliferation, abnormal collagen synthesis and increased inflammatory response. [18] Li L. et al. showed that apelin have a regulatory effect on proliferation of vascular smooth muscle cell and nitric oxide production.[19] Nitric oxide is a potent vasodilator and plays important roles in protecting the cardiac vascular system against myocardial damage. It inhibits leukocyte adhesion ,platelet aggregation and vascular smooth muscle cell proliferation. [18] In some studies there was a relation between apelin and nitric oxide. It is demonstrated that in the rat model, myocardial damage significantly reduces by oxidative injury reduction and enhancement of nitric oxide production when rats treated with apelin in postinfarct period.[20] Tatemoto K., et al. reported that apelin may be present in the endothelium and reduce blood pressure via nitric oxide dependent mechanism.[21] Additionally polymorphism in the endothelial nitric oxide synthase gene has been explored in several studies in patients with CAE. [22] According to this ,impaired nitric oxide dependent vasodilation mechanism may consist to be the reason of ectasia. Malyszko et al. reported that in patients with transplanted kidneys apelin level is correlated with intracellular adhesion molecule, adiponectin and the presence of coronary arery disease in patients with transplanted kidneys. [23] Apelin is a member of adipocytokin like adiponectin. Dagli N. et al. examined a negative correlation between coronary artery ectasia diameter and plasma adiponectin level .[24] Also in our study we obtained similar results that plasma apelin level in isolated CAE patients is significantly lower than in controls. According to recent data adiponectin and apelin have cardioprotective effects . Despite exact mechanism is not clear it seems that, both of them protect vessel from atherosclerosis and ectasia. However, further studies are required to show the role of apelin in development of CAE. Conclusion : In this study we showed that patients with isolated coronary artery ectasia have decreased plasma apelin level compared with normal coronary arteries. According to these data we suggest that apelin may have a role in developing CAE. Limitations of the study Because isolated CAE is rare entity ,the number of cases were limited. our study have a small population. Additionally, it is an important limitation on the part of the study that intravascular ultrasound (IVUS) was not conducted in the diagnosis of patients, as IVUS and autopsy can demonstrate atherosclerotic plaques in a wide area of the vessel lumen in patients whose coro-nary angiography is normal Conflict of Interest The authors declare no conflict of interest. References 1.Chandrasekaran B, Dar O, McDonagh T. The role of apelin in cardiovascular function and heart failure. European journal of heart failure 2008;10:725-732 2.Kleinz MJ, Davenport AP. Emerging roles of apelin in biology and medicine. Pharmacology therapeutics 2005;107:198-211 3.Ronkainen VP, Ronkainen JJ, Hanninen SL, et al. Hypoxia inducible factor regulates the cardiac expression and secretion of apelin. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2007;21:1821-1830 4.Hashimoto T, Kihara M, Ishida J, et al. Apelin stimulates myosin light chain phosphorylation in vascular smooth muscle cells. Arteriosclerosis, thrombosis, and vascular biology 2006;26:1267-1272 5.Malyszko J, Malyszko JS, Pawlak K, Mysliwiec M. Visfatin and apelin, new adipocytokines, and their relation to endothelial function in patients with chronic renal failure. Advances in medical sciences 2008;53:32-36 6.Farkasfalvi K, Stagg MA, Coppen SR, et al. Direct effects of apelin on cardiomyocyte contractility and electrophysiology. Biochemical and biophysical research communications 2007;357:889-895 7.Hartnell GG, Parnell BM, Pridie RB. Coronary artery ectasia. Its prevalence and clinical significance in 4993 patients. British heart journal 1985;54:392-395 8.Yamanaka O, Hobbs RE. Coronary artery anomalies in 126,595 patients undergoing coronary arteriography. Catheterization and cardiovascular diagnosis 1990;21:28-40 9.Seabra-Gomes R, Somerville J, Ross DN, et al. Congenital coronary artery aneurysms. British heart journal 1974;36:329-335 10.Di Mario C, Zanchetta M, Maiolino P. Coronary aneurysms in a case of Ehlers-Danlos syndrome. Japanese heart journal 1988;29:491-496 11.Cross SJ, Lee HS, Kenmure AC, Jennings KP. Coronary artery ectasia: is it associated with myocardial ischaemia and infarction? Scottish medical journal 1993;38:28-29 12.Befeler B, Aranda MJ, Embi A, et al. Coronary artery aneurysms: study of the etiology, clinical course and effect on left ventricular function and prognosis. The American journal of medicine 1977;62:597-607 13.Lee DK, Cheng R, Nguyen T, et al. Characterization of apelin, the ligand for the APJ receptor. Journal of neurochemistry 2000;74:34-41 14.Kadoglou NP, Lampropoulos S, Kapelouzou A, et al. Serum levels of apelin and ghrelin in patients with acute coronary syndromes and established coronary artery diseaseKOZANI STUDY. Translational research : the journal of laboratory and clinical medicine 2010;155:238-246 15.Li Z, Bai Y, Hu J. Reduced apelin levels in stable angina. Internal medicine 2008;47:1951-1955 16.Rath S, Har-Zahav Y, Battler A, et al. Fate of nonobstructive aneurysmatic coronary artery disease: angiographic and clinical follow-up report. American heart journal 1985;109:785-791 17.Markis JE, Joffe CD, Cohn PF, et al. Clinical significance of coronary arterial ectasia. The American journal of cardiology 1976;37:217-222 18.Calvert JW. Cardioprotective effects of nitrite during exercise. Cardiovascular research 2011;89:499-506 19.Li L, Li L, Xie F, et al. Jagged-1/Notch3 signaling transduction pathway is involved in apelin-13-induced vascular smooth muscle cells proliferation. Acta biochimica et biophysica Sinica 2013;45:875-881 20.Azizi Y, Faghihi M, Imani A, Roghani M, Nazari A. Post-infarct treatment with [Pyr1]-apelin-13 reduces myocardial damage through reduction of oxidative injury and nitric oxide enhancement in the rat model of myocardial infarction. Peptides 2013;46:76-82 21.Tatemoto K, Takayama K, Zou MX, et al. The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regulatory peptides 2001;99:87-92 22.Arif Yalcin A, Faruk Akturk I, Celik O, et al. Coronary Artery Ectasia Is Associated with the c.894G>T (Glu298Asp) Polymorphism of the Endothelial Nitric Oxide Synthase Gene. The Tohoku journal of experimental medicine 2014;232:137-144 23.Malyszko J, Malyszko JS, Pawlak K, Wolczynski S, Mysliwiec M. Apelin, a novel adipocytokine, in relation to endothelial function and inflammation in kidney allograft recipients. Transplantation proceedings 2008;40:3466-3469 24.Dagli N, Ozturk U, Karaca I, et al. Adiponectin levels in coronary artery ectasia. Heart and vessels 2009;24:84-89 Table 1: Baseline characteristics of the study population Grup 1 (n=26) Grup 2 (n=28) P value Age (years) 53.6 ±8.1 51.6 ± 8.8 P>0,05 0,38 Male % 19 (%73,1) 18(%64,3) P>0,05 Hypertension % 15 (%58) 12(%43) P>0,05 Diabetes Mellitus % 4 (%15) 6 (%21) p>0,05 BMI (kg/m ²) 28.1 ± 4 26.7  ±4.2 P>0,05 Smoking % 13 (%50) 12 (%46) P> 0,05 Glucose mg/dl 106 ±20 124 ±53 0.1 Creatinine mg/dl 0,86 ±0,2 0,82 ±0,1 0.38 Total cholesterol mg/dl 196 ±47 195 ±37 0.98 LDL mg/dl 128 ±42 113 ±33 0.14 HDL mg/dl 41 ±10 40 ±10 0.92 Triglyseride mg/dl 145 ±77 184 ±115 0.15