
==== Front
J Res Med Sci
J Res Med Sci
JRMS
J Res Med Sci
Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences
1735-1995
1735-7136
Wolters Kluwer - Medknow India

JRMS-29-26
10.4103/jrms.jrms_478_22
Original Article
Negative association of apelin plasma levels with epicardial fat thickness in patients with stable angina and acute myocardial infarction: A case–control study
Babapour Behzad 1
Doustkami Hossein 1
Avesta Leli 1
Kiamehr Peyman 1
Aslani Mohammad Reza 23
1 Department of Cardiology, Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
2 Lung Diseases Research Center, Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
3 Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
Address for correspondence: Dr. Mohammad Reza Aslani, Lung Diseases Research Center, Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran. E-mail: mraslani105@yahoo.com, mr.aslani@arums.ac.ir
2024
11 7 2024
29 2606 7 2022
11 12 2023
23 12 2023
Copyright: © 2024 Journal of Research in Medical Sciences
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
Background:

Apelin is one of the endogenous peptides that play a key role in the homeostasis of cardiovascular diseases. The purpose of the current study was to evaluate the correlation between apelin levels and epicardial fat thickness (EFT) in patients with stable angina and acute myocardial infarction (AMI).

Materials and Methods:

In a case–control study, 90 patients nominated for angiography were enrolled in the study and divided into three groups: healthy subjects without angiographic findings (Con), stable angina pectoris group (SAP), and acute AMI group. Data collected from all subjects included biochemical, echocardiographic, and angiographical parameters. The Gensini score analyzed the severity of coronary artery disease (CAD).

Results:

A decrease in adjusted apelin levels was evident in the AMI and SAP groups compared with healthy individuals (for both P < 0.001), especially in the AMI group. In addition, a detectable negative association was identified between apelin and Gensini score (r = −0.288, P = 0.006), Ck-MB (r = −0.300, P = 0.004), EFT (r = −0.300, P = 0.004), and troponin-T (r = −0.288, P = 0.006).

Conclusion:

Myocardial injury in patients with CAD appears to play a significant role in apelin concentration independent of the role of adipose tissue, which requires further studies.

Acute myocardial infarction
angiography
apelin
epicardial fat thickness
==== Body
pmcINTRODUCTION

Recent data show the role of adipokines secreted from adipose tissue in the pathophysiology of various diseases, particularly chronic inflammatory diseases.[12] Apelin is an endogenous peptide highly expressed in various body tissues such as the adipose tissue, kidneys, vascular endothelium, lungs, cerebellum, cardiomyocytes, and pancreas.[3] Apelin has been suggested as a potent vasodilator and inotropic and has been shown in various studies as a key regulator of cardiovascular homeostasis.[4] Apelin is also a mitogen and angiogenic factor for endothelial and vascular smooth muscle cells.[5] The role of apelin in cardiovascular diseases (CVDs) in animal and human studies has been reported with contradictory findings. High apelin levels were reported in the early stages of heart failure, while values decreased in chronic heart failure (CHF).[5] Animal studies have shown that apelin in the ischemic/reperfusion model has protective effects against ischemia and, when administered, has inotropic effects on heart failure.[6] Decreased expression of the apelin receptor in the heart tissue of ischemic heart disease probably suggests its role in the pathogenesis of the disease.[5] In mice, it has been shown that apelin inhibits the formation of aortic aneurysms, possibly by activating chemokines and inhibiting inflammatory cytokines.[7] New evidence suggests that apelin is a beneficial adipokine in various diseases such as kidney disease, cardiopulmonary disease, dyslipidemia, and type 2 diabetes.[89]

Under pathological conditions, epicardial fat thickness (EFT) has played a key role in various CVDs by releasing proinflammatory and proatherogenic factors through paracrine or vasocrine pathways.[10] Elevated levels of apelin are associated with metabolic syndrome and the severity of CVD.[11] Accordingly, the current research aimed to assess apelin levels in acute myocardial infarction (AMI) patients compared with noncoronary artery disease (non-CAD) and stable angina. The association between apelin levels and some echocardiographic parameters, such as EFT, has also been investigated.

MATERIALS AND METHODS

In a case–control study, 90 male patients nominated for angiography were included at Imam Khomeini Hospital in Ardabil, Iran. Based on angiographic results, patients were divided into three groups, including the AMI group, n = 30, stable angina pectoris group (SAP group, n = 30), and patients clinically with chest pain but no angiographic findings (Con group, n = 30).

Previously, the inclusion and exclusion criteria were fully addressed.[1] The exclusion criteria were individuals with a history of myocarditis, AMI, pericardial effusion, heart failure, valvular heart diseases, respiratory diseases, steroid therapy, infectious diseases, poor echocardiographic imaging, autoimmune diseases, and chronic renal failure. Diagnostic criteria in the AMI group were based on laboratory analyses (elevated troponin T and creatine kinase-MB [CK-MB] levels) or changes in electrocardiogram (ECG) (elevated ST segment). Patients with stable angina were also included in the study based on ECG findings during exercise testing.

Data collected in the current study included demographics (age, weight, and height), waist-to-hip ratio (WHR), body mass index (BMI), and laboratory parameters (hemoglobin [Hb], blood urea nitrogen [BUN], white blood cell [WBC], creatinine [Cr], low-density lipoprotein [LDL], high-sensitivity troponin T, total cholesterol [TC], fasting blood glucose (FBG), high-density lipoprotein [HDL], CK-MB, and triglyceride). Before angiography, three cc blood samples were taken from all patients. Stored plasma samples (at −70°C) were used to determine apelin plasma levels using commercial ELISA kits and standard methods.

Parameters measured for echocardiography in the current study included EFT, mitral valve septal annular systolic velocity (e’ Septal), tricuspid lateral annular systolic velocity (TV TDI), annular plane systolic excursion (TAPSE), left ventricular ejection fraction (LVEF), and mitral valve lateral annular systolic velocity (e’ Lateral). Echocardiography was performed by an echocardiologist and examined blindly by two cardiologists. The angiographic procedure was performed by standard Judkins technique as well as 5 or 6 Fr catheters by interventional cardiologists through radial or femoral arteries. Gensini score was used to evaluation of the disease severity.[12] Briefly, the Gensini score was calculated as follows: a severity score for each coronary stenosis was assigned depending on the degree of luminal narrowing and the location of the stenosis. Luminal stenosis of 25%, 50%, 75%, 90%, 99%, and complete occlusion were scored as 1, 2, 4, 8, 16, and 32, respectively. These scores were then multiplied by a factor according to the location: 5 for the left main coronary artery; 2.5 for the proximal segment of the left anterior descending coronary artery and proximal segment of the circumflex artery; 1.5 for mid-segment of the left anterior descending coronary artery; 1.0 for right coronary artery, the distal segment of the left anterior descending coronary artery, posterior descending artery, and obtuse marginal artery; and 0.5 for other segments.

Statistical analysis

The data are presented as mean ± standard deviation. Normal distribution was performed using Shapiro and Kolmogorov test. ANOVA test (with Tukey’s post hoc test) was used for data analysis. Pearson’s test was used to determine the correlation coefficient. Analysis of ANOVA was used to adjust the results for WHR, BMI, and age. The P < 0.05 in terms of the significance of the results. SPSS (version 21; IBM Corp.; USA) and GraphPad Prism 7.0 (GraphPad Software, LLC; USA) were used to analyze the results and draw graphs.

RESULTS

Clinical and demographic characteristics are summarized in Table 1. The significant parameters in the comparison between the groups were mean age (P < 0.01), CK-MB (P < 0.001), WHR (P < 0.05), troponin T (P < 0.001), TC (P < 0.05), HDL-C (P < 0.01), LDL-C (P < 0.001), Gensini score (P < 0.001), and WBC (P < 0.001).

Table 1 Demographic and laboratory findings in study groups

Variable	Control (n=30)	SAP (n=30)	AMI (n=30)	P	
Age (year)	61.96±13.08	62.73±8.50	54.43±10.63*,+	0.007	
Weight (kg)	74.50±12.85	77.90±13.90	81.16±11.04	0.131	
Height (m)	1.68±0.07	1.70±0.05	1.71±0.06	0.180	
BMI (kg/m2)	26.00±3.03	26.74±4.10	27.46±3.31	0.278	
Waist circumference (cm)	94.20±5.69	95.76±8.24	97.73±6.22	0.138	
Hip circumference (cm)	100.76±4.89	99.56±8.00	102.03±8.38	0.425	
WHR	0.93±0.04	0.96±0.02*	0.96±0.05*	0.027	
TC (mg/dL)	154.30±20.58	168.46±31.35	172.50±27.12*	0.025	
TG (mg/dL)	113.16±44.94	128.56±54.71	126.23±40.96	0.400	
HDL-C (mg/dL)	44.76±7.90	40.16±5.50*	40.40±4.88*	0.007	
LDL-C (mg/dL)	81.16±18.44	99.13±18.67**	106.46±19.26***	0.000	
FBG (mg/dL)	98.36±9.49	102.43±9.44	100.43±8.45	0.233	
BUN (mg/dL)	36.76±9.26	38.00±11.21	43.80±29.59	0.316	
Creatinine (mg/dL)	1.21±0.21	1.24±0.29	1.27±0.40	0.808	
Uric acid (mg/dL)	5.45±1.37	5.79±1.83	6.01±1.80	0.432	
Hemoglobin (g/dL)	14.37±1.79	14.13±1.22	14.58±2.25	0.633	
WBC (103/mm3)	7.32±1.73	8.70±1.19**	9.28±1.77***	0.000	
CK-MB (ng/mL)	2.62±0.79	3.67±1.57***	33.38±11.50***,+++	0.000	
HsTnT (ng/L)	2.83±2.10	10.66±5.19***	34.58±11.38***,+++	0.000	
Gensini score	Not done	31.46±14.63	45.70±17.38+++	0.000	
Apelin (pg/mL)	380.82±100.84	363.80±93.32	302.80±48.52	0.001	
Apelin (adjusted), (pg/mL)a	389.03±9.91	347.85±4.67	311.44±9.35	0.000	
For statistical differences between the control group and other groups: *P<0.05, **P<0.01, ***P<0.001. For statistical differences between SAP with AMI: +P<0.05, +++P<0.001. Comparison between groups was done using ANOVA test. Data are expressed as mean±SD. SAP=Stable angina pectoris; AMI=Acute myocardial infarction; BMI=Body mass index; TC=Total cholesterol; TG=Triglyceride; LDL-C=Low-density lipoprotein cholesterol; HDL-C=High-density lipoprotein cholesterol; FBG=Fasting blood glucose; BUN=Blood urea nitrogen; WBC=White blood cell; CK-MB=Creatine kinase-MB; HsTnT=High-sensitivity troponin T; SD=Standard deviation; WHR=Waist–hip ratio

AMI group had a significantly lower mean age compared to SAP and Con groups. W.H.R., WBC, LDL-C, and T.C. were significantly lower in the Con group compared to the AMI and SAP groups, while HDL-C was significantly higher. In addition, troponin T and CK-MB plasma levels were higher in the AMI group than SAP and Con groups (P < 0.001 for both). Concerning the Gensini score, there was a significant difference between the AMI group and the SAP and Con groups (P < 0.001 for both). No significant differences were observed about other parameters such as FBG, triglycerides, BMI, uric acid, BUN, platelets, Cr, and Hb between groups [Table 1].

Decreased levels of apelin were observed in the AMI group (302.80 ± 48.52) compared with SAP (363.80 ± 93.32, P < 0.05) and Con groups (380.82 ± 100.84, P < 0.01), but no significant difference was identified between SAP and Con groups [Figure 1a]. Interestingly, after adjusting the plasma level of apelin with age, WHR, and BMI, plasma levels of apelin were significantly lower in AMI patients compared to SAP and Con groups (P < 0.001 for both) as well as SAP group compared to Con group (P < 0.001) [Figure 1b].

Figure 1 The mean ± standard deviation of plasma levels of (a) apelin, and (b) Adjusted apelin for the age, body mass index, waist–hip ratio, and group. Con = Control group, SAP = Stable angina pectoris group, AMI = Acute myocardial infarction. For statistical differences between the control (con) group and other groups: **: P <0.01, ***; P < 0.001. For statistical differences between SAP with AMI: +: P <0.05, +++; P < 0.001. Comparison between groups was done using ANOVA test

On the other hand, the EFT was significantly higher in the AMI (7.75 ± 1.19, P < 0.001) group compared to SAP (6.02 ± 0.96) and Con groups (4.28 ± 1.05, P < 0.001). EFT was also significantly higher in the SAP patients than in the Con subjects [P < 0.001, Figure 2a]. Furthermore, adjusting EFT results demonstrated that there was still a significant difference [Figure 2b]. LVEF (%) in the AMI group (36.56 ± 9.92) was less than SAP (43.50 ± 7.44, P < 0.001) and Con groups (53.33 ± 7.58, P < 0.001). LVEF (%) in SAP patients was significantly also lower than in Con individuals (P < 0.001). There was no significant difference concerning other echocardiographic parameters (e’ Septal, e’ Lateral, TAPSE, and TV TDI) [Table 2].

Figure 2 The mean ± standard deviation of the epicardial fat thickness of (a) baseline, and (b) adjusted for the age, body mass index, waist–hip ratio, and group. Con = Control group, SAP = Stable angina pectoris group, AMI = Acute myocardial infarction. For statistical differences between the control group and other groups: ***; P < 0.001. For statistical differences between SAP with AMI: +++; P < 0.001. Comparison between groups was done using ANOVA test

Table 2 Echocardiographic finding

Variable	Control	SAP	AMI	P	
LVEF (%)	53.33±7.58	43.50±7.44	36.56±9.92	0.000	
e’ septal (cm/s)	6.80±1.35	6.24±1.69	6.79±1.97	0.354	
e’ lateral (cm/s)	9.66±2.24	9.59±2.41	9.27±2.51	0.803	
TAPSE (mm)	19.41±3.43	17.69±3.08	17.68±3.08	0.059	
TV TDI (cm/s)	11.63±1.61	12.27±1.89	11.29±2.08	0.131	
EFT (mm)	4.28±1.05	6.02±0.96	7.75±1.19	0.000	
EFT (adjusted) (mm)a	4.27±0.17	6.04±0.09	7.76±0.23	0.000	
aMean±SD by general linear model with adjustment for age, BMI, WHR, and group. Data are expressed as mean±SD. Comparison between groups was done using ANOVA test. SAP: Stable angina pectoris group, AMI=Acute myocardial infarction; SD=Standard deviation; LVEF=Left ventricular ejection fraction; TAPSE=Tricuspid annular plane systolic excursion; TV TDI=Tissue velocity tissue Doppler imaging; WHR=Waist–hip ratio; BMI=Body mass index; EFT=Epicardial fat thickness

A significant negative correlation was evident between apelin and EFT [r = −0.300, P = 0.004; Figure 3e], CK-MP [r = −0.300, P = 0.004; Figure 3a], Gencini score (r = −0.288, P = 0.006; Figure 3c], troponin-T [r = −0.288, P = 0.006; Figure 3b], and a positive association with LVEF [r = 0.237, P = 0.025; Figure 3d].

Figure 3 Pearson’s correlation analysis of (a) apelin and creatine kinase-MB, (b) apelin and troponin-T, (c) apelin and Gensini score, (d) apelin and left ventricular ejection fraction (%), and (e) apelin and epicardial fat thickness. EFT = Epicardial fat thickness, CK-MB = Creatine kinase-MB, LVEF = Left ventricular ejection fraction

DISCUSSION

The main findings of the current study were (1) decreased levels of apelin in patients with acute MI and stable angina and (2) negative association between apelin and EFT, CK-MB, Gensini score, and troponin-T.

Adipose tissue is a source of energy storage and an endocrine organ. Adipose tissue plays an endocrine role in releasing various adipokines such as visfatin, leptin, adiponectin, interleukin-6 (IL-6), fatty acid binding protein-4, tumor necrosis factor (TNF)-α, nesfatin, adipolin, and apelin.[13141516] Studies have shown that changes in adipokine secretory levels play a crucial role in the pathogenesis of diseases, especially chronic inflammatory diseases.[171819] As an adipokine, apelin expression has been reported in various tissues such as the kidneys, adipose tissue, brain, heart, liver, lungs, and cardiovascular system.[3] Interestingly, the level of apelin gene expression in the tissues of the heart and kidneys was significantly higher than in adipose tissues.[20] In addition, increased apelin expression in the atria in cardiac tissue compared with the ventricles has been reported, suggesting that heart tissue is the main source of circulating apelin.[20] A variety of physiological functions have been demonstrated for apelin, such as fluid balance regulation, cardiac contractile function, carbohydrate use, vascular tone, angiogenesis, neuroprotection, cellular proliferation, and immunologic functions.[21]

The current study demonstrated that plasma levels of apelin were lower in patients with AMI and stable angina. Moreover, the decrease in apelin was also more significant in AMI patients than in stable angina patients. Compared to healthy individuals, decreased serum/plasma apelin levels were reported in ST-elevation AMI,[22] unstable angina,[23] stable angina,[24] AMI,[24] and patients with acute or CHF.[25] Some studies also compared healthy subjects; increased apelin levels in patients with CVD or lack of differences have been reported, in contrast to us.[26] In addition, the present study showed a clear negative association between apelin plasma concentrations and some cardiac markers (troponin-T and CK-MB). Although this association’s exact mechanism is unclear, it may be linked to the depletion of myocardial cells or coronary endothelial lesions, which requires further study.[27] In AMI status, many myocardial cells develop infarction, leading to elevation in cardiac markers (CK-MB), and may be a factor in reducing the production of apelin.

In the present study, it was also shown for the first time that there was a significant association between some echocardiographic parameters and apelin, with a positive relationship with LVEF (%) and a negative relationship with EFT. Indeed, the results suggest that apelin plasma levels were independent of epicardial fat thickness (EFT). In previous studies, EFT was reported to be correlated with coronary severity in patients with AMI and stable angina based on the Gencini score.[115] Epicardial fat tissue affects coronary artery involvement in acute coronary syndrome patients by releasing paracrine/endocrine inflammatory mediators.[115] Based on the results of the present study, it was found that although apelin is mainly released from adipose tissue, myocardial cell damage in patients with AMI had a more significant effect on apelin levels than EFT.

Although the exact mechanism of apelin on its cardioprotective effects is unclear, several possible mechanisms can be considered for apelin. The anti-atherogenic effects of apelin have been observed by reducing macrophage foam cell formation and promoting intracellular cholesterol efflux.[28] Increased apelin and apelin receptor expression levels in the arteriosclerotic coronary artery may indicate an increase in the anti-inflammatory activity of macrophages in the coronary plaque and thus limit its instability.[5] Apelin has also been shown to reduce the progression of atherosclerosis by inhibiting the effects of angiotensin II.[28] One of the factors influencing the onset and development of atherosclerotic disease is the presence of inflammation. Atherosclerosis is associated with inflammatory markers such as IL-1β, TNF-α, and IL-6.[1] Interestingly, animal studies have demonstrated apelin injection to reduce the expression of monocyte chemoattractant protein-1, macrophage inflammatory protein-1, TNF-α, and IL-6 reflecting its anti-inflammatory effects.[29] Apelin cardioprotective effects have also been observed under ischemia–reperfusion (I/R) conditions. Apelin administration in I/R injury has been shown to have protective effects on the heart, including reducing the size of the infarct, reducing the number of damaged cardiomyocytes, regulating myocardial regeneration, and recovering cardiac function after AMI.[26]

The limitations seen in the current study were the moderate sample size, which requires a large sample size to more accurately investigate the association of apelin in patients with CAD. Since serial apelin measurement was not available in AMI patients, the effects of treatment on changes in apelin concentration were known. Another limitation of the study was the inclusion of only the male sex, which should be considered sex differences in future studies.

CONCLUSION

In summary, the results revealed that apelin levels decreased in AMI and stable angina patients and a detectable negative association with EFT. In addition, the results of the current study showed that changes in apelin levels were more independently associated with cardiac tissue damage. Despite the association between apelin and EFT levels, further studies are needed to understand its role in the pathophysiology of CADs.

Financial support and sponsorship

Ardabil University of Medical Sciences.

Conflicts of interest

There are no conflicts of interest.

Acknowledgments

This study was conducted after getting approval from the Ethics Committee of Ardabil University of Medical Sciences (IR.ARUMS.REC.1397.242).
==== Refs
REFERENCES

1. Babapour B Doustkami H Avesta L Moradi A Saadat S Piralaei K Correlation of serum adipolin with epicardial fat thickness and severity of coronary artery diseases in acute myocardial infarction and stable angina pectoris patients Med Princ Pract 2021 30 52 61 32438366
2. Aslani MR Ghazaei Z Ghobadi H Correlation of serum fatty acid binding protein-4 and interleukin-6 with airflow limitation and quality of life in stable and acute exacerbation of COPD Turk J Med Sci 2020 50 337 45 31905499
3. Li C Cheng H Adhikari BK Wang S Yang N Liu W The role of apelin-APJ system in diabetes and obesity Front Endocrinol (Lausanne) 2022 13 820002 35355561
4. Askin L Askin HS Tanrıverdi O Ozyildiz AG Duman H Serum apelin levels and cardiovascular diseases North Clin Istanb 2022 9 290 4 36199867
5. Pitkin SL Maguire JJ Kuc RE Davenport AP Modulation of the apelin/APJ system in heart failure and atherosclerosis in man Br J Pharmacol 2010 160 1785 95 20649580
6. Zeng XJ Zhang LK Wang HX Lu LQ Ma LQ Tang CS Apelin protects heart against ischemia/reperfusion injury in rat Peptides 2009 30 1144 52 19463748
7. Leeper NJ Tedesco MM Kojima Y Schultz GM Kundu RK Ashley EA Apelin prevents aortic aneurysm formation by inhibiting macrophage inflammation Am J Physiol Heart Circ Physiol 2009 296 H1329 35 19304942
8. Akbari H Hosseini-Bensenjan M Salahi S Moazzen F Aria H Manafi A Apelin and its ratio to lipid factors are associated with cardiovascular diseases: A systematic review and meta-analysis PLoS One 2022 17 e0271899 35913970
9. Podzolkov V Pokrovskaya A Bazhanova U Vargina T Knyazeva SA Vanina D The role of adipokines in cardiovascular pathology Open Access Maced J Med Sci 2021 9 794 800
10. Parisi V Conte M Petraglia L Grieco FV Bruzzese D Caruso A Echocardiographic epicardial adipose tissue thickness for risk stratification of patients with heart failure Front Physiol 2020 11 43 32116756
11. Chen YC Lee WH Lee MK Hsu PC Tsai WC Chu CY Epicardial adipose tissue thickness is not associated with adverse cardiovascular events in patients undergoing haemodialysis Sci Rep 2020 10 6281 32286459
12. Gong P Luo SH Li XL Guo YL Zhu CG Xu RX Relation of ABO blood groups to the severity of coronary atherosclerosis: An Gensini score assessment Atherosclerosis 2014 237 748 53 25463115
13. Nejati A Doustkami H Babapour B Ebrahimoghlou V Aslani MR Serum correlation of nesfatin-1 with angiographic, echocardiographic, and biochemical findings in patients with coronary artery disease Iran Red Crescent Med J 2021 23 1 7
14. Keyhanmanesh R Alipour MR Ebrahimi H Aslani MR Effects of diet-induced obesity on tracheal responsiveness to methacholine, tracheal visfatin level, and lung histological changes in ovalbumin-sensitized female wistar rats Inflammation 2018 41 846 58 29380115
15. Ghobadi H Mokhtari S Aslani MR Serum levels of visfatin, sirtuin-1, and interleukin-6 in stable and acute exacerbation of chronic obstructive pulmonary disease J Res Med Sci 2021 26 17 34084196
16. Aslani MR Keyhanmanesh R Alipour MR Increased visfatin expression is associated with nuclear factor-κb in obese ovalbumin-sensitized male wistar rat tracheae Med Princ Pract 2017 26 351 8 28420006
17. Aslani MR Ghobadi H Panahpour H Ahmadi M Khaksar M Heidarzadeh M Modification of lung endoplasmic reticulum genes expression and NF-kB protein levels in obese ovalbumin-sensitized male and female rats Life Sci 2020 247 117446 32081662
18. Akhavanakbari G Babapour B Alipour MR Keyhanmanesh R Ahmadi M Aslani MR Effect of high fat diet on NF-кB microRNA146a negative feedback loop in ovalbumin-sensitized rats Biofactors 2019 45 75 84
19. Aslani MR Sharghi A Boskabady MH Ghobadi H Keyhanmanesh R Alipour MR Altered gene expression levels of IL-17/TRAF6/MAPK/USP25 axis and pro-inflammatory cytokine levels in lung tissue of obese ovalbumin-sensitized rats Life Sci 2022 296 120425 35202642
20. Yokoyama H Saito S Higuma T Hanada H Osanai T Daitoku K Plasma apelin level is decreased in patients with coronary artery disease Hirosaki Med J 2010 61 58 64
21. Wang XL Tao Y Lu Q Jiang YR Apelin supports primary rat retinal Müller cells under chemical hypoxia and glucose deprivation Peptides 2012 33 298 306 22240274
22. Kuklinska AM Sobkowicz B Sawicki R Musial WJ Waszkiewicz E Bolinska S Apelin: A novel marker for the patients with first ST-elevation myocardial infarction Heart Vessels 2010 25 363 7 20676956
23. Kadoglou NP Lampropoulos S Kapelouzou A Gkontopoulos A Theofilogiannakos EK Fotiadis G Serum levels of apelin and ghrelin in patients with acute coronary syndromes and established coronary artery disease – KOZANI STUDY Transl Res 2010 155 238 46 20403579
24. Guzelburc O Demirtunc R Altay S Kemaloglu Oz T Tayyareci G Plasma apelin level in acute myocardial infarction and its relation with prognosis: A prospective study JRSM Cardiovasc Dis 2021 10 1 7
25. Berezin AA Fushtey IM Berezin AE The effect of SGLT2 inhibitor dapagliflozin on serum levels of apelin in T2DM patients with heart failure Biomedicines 2022 10 1751 35885056
26. Abd-Elbaky AE Abo-ElMatty DM Mesbah NM Ibrahim SM Omentin and apelin concentrations in relation to obesity, diabetes mellitus type two, and cardiovascular diseases in Egyptian population Int J Diabetes Dev Ctries 2016 36 52 8
27. Cosansu K Cakmak HA Ikitimur B Yildirim E Can G Karadag B Apelin in ST segment elevation and non-ST segment elevation acute coronary syndromes: A novel finding Kardiol Pol 2014 72 239 45 24142748
28. Zhong JC Yu XY Huang Y Yung LM Lau CW Lin SG Apelin modulates aortic vascular tone via endothelial nitric oxide synthase phosphorylation pathway in diabetic mice Cardiovasc Res 2007 74 388 95 17359956
29. Li A Zhao Q Chen L Li Z Apelin/APJ system: An emerging therapeutic target for neurological diseases Mol Biol Rep 2024 50 1639 53
