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Association of serum leptin with angiographically proven cardiovascular disease and with components of the metabolic syndrome: a cross-sectional study in East Azerbaijan

Khanbabaei, Nafiseha; Mozafar Saadati, Hosseinb; Valizadeh Shahbazloo, Shahnamc; Hoseinpoor, Reyhanehd; Naderi, Seyed Hosseina; Taghvamanesh, Royaa; Abolhasani, Sakhavata,,c

Author Information
Cardiovascular Endocrinology & Metabolism: March 2021 - Volume 10 - Issue 1 - p 45-50
doi: 10.1097/XCE.0000000000000227
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Abstract

Introduction

Metabolic syndrome (MetS) is a cluster of the interdependent physiological, biochemical, clinical, and metabolic risk factors, which is generally characterized by the high serum levels of triglycerides, Apo lipoprotein B (Apo B), glucose, high blood pressure, reduced high-density lipoprotein (HDL) along with the insulin resistance, and prothrombotic and proinflammatory events [1]. Diabetes and obesity are related with an increased risk of MetS [2]. Additionally, individuals with MetS are show an augmented risk of stroke, myocardial infarction (MI), and mortality [1]. Besides, MetS is the major risk factor underlying atherothrombotic complications, whereas its prevalence is likely to determine the long-term risk [3].

Owing to the fact that MetS correlates with the greater risk of CVD, therapeutic measures to prevent MetS are likely to decrease the incidence of CVD [4]. The risk factors such as diabetes, lipid profile, BMI, oxidative stress, heredity, smoking, blood pressure, and MetS are chiefly associated with CVD [5–7].

Leptin is an Adipokine with 167 amino acid residues, where its expression in adipocytes is regulated by ob gene; furthermore, leptin regulates body weight and energy homeostasis and is known to connect CVD with MetS [8]. Previous studies have reported that the BMI, age, gender, abdominal obesity, and waist circumference correlate with the levels of the serum leptin [9]. In addition, leptin regulates various processes, including vascular functions, inflammation, and immunity [10]. The relationship between leptin and blood pressure (BP) and insulin resistance are widely recognized [11]. Hyperleptinemia is a primary factor in the complex interaction of metabolic variations leading to Mets. A case-cohort study by Subirana et al. [5] reported a direct relationship between leptin levels and coronary artery disease events.

Recent findings have implicated the perivascular adipose tissue-derived leptin as a potential participant in coronary atherogenesis in MetS individuals [12]. To address this issue, the aim of this study was to assess relationship between the serum levels of leptin and angiographically proven cardiovascular disease and components of the metabolic syndrome. We also determined the prognostic value of the serum levels of leptin in diagnosis of CVD among the adult population of East Azerbaijan.

Method and material

The study was performed in the Department of Biochemistry of Shahid Beheshti University of Medical Sciences. In this cross-sectional study, the study groups comprised 60 healthy subjects without vascular obstruction (38 men and 22 women) as the control group and 120 patients (86 men and 34 women) with vascular obstruction diagnosed by angiography. The informed written consent was obtained from all subjects. The protocol of the study was approved by the ethical committee of the university (ethics approval number 91/2-3/5). The patients were excluded from the study if they had a history of any lung disease, liver dysfunction, renal disorder, autoimmune disease, infection, and cancer.

All blood samples were obtained from a peripheral vein following 12 h of overnight fasting, just before the angiography. Subsequent plasma and serum were separated within 30 min, and the samples were kept frozen at −70°C until the assays were carried out. BMI was calculated by weight/height. The LDL-cholesterol level was calculated by the Friedewald formula. ELISA was used to determine serum levels of leptin (Shanghai Korain Biotech Co., Ltd Cat. No: E1559Hu) and OX-LDL levels (Glory Science Co., Ltd Cat. No: 93614). The high-sensitivity turbidimetry method was used to determine the serum levels of hs-CRP using Biosystems kits (Barcelona Spain COD 31927). Lipid profile and other biochemical parameters were measured by enzymatic methods.

Statistical analyses

Quantitative variables were expressed as mean  ±  SD. By the quintiles of leptin levels, the serum levels of leptin were categorized into four quartiles (Q1, <3.5 ng/mL; Q2, 3.5 to <6.5 ng/mL; Q3, 6.5 to <9.1 ng/mL; and Q4 ≥ 9.1 ng/mL). Data were stored and all statistical analyses were performed using SPSS-22 software. Chi-square test, independent t-test, one-way ANOVA, and univariate linear regression were used as the univariate analysis. Co-linearity was examined using the standard criteria (Kolmogorov–Smirnov test and normal curve). Multivariate logistic regression was used to determine the relationship between the leptin levels and risk of developing MetS and cardiovascular disease (angiography positive). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from these models. The accuracy of the logistic regression model was evaluated with the receiver operating characteristic (ROC) curve, and the Hosmer–Lemeshow test was performed for goodness-of-fit. The P value <0.05 was considered to be statistically significant.

Result

Out of 120 CVD and 60 healthy controls participated in this study, there were 56 female and 124 male subjects.

Table 1 summarizes the descriptive statistics of demographic and biochemical characteristics of the study groups. Age and BMI were not significantly different between patients and controls. The mean serum levels of blood glucose, total cholesterol, leptin, triglyceride, LDL, OXLDL, and hs-CRP were significantly higher in subjects with cardiovascular disease compared to those in control group (P < 0.001 all of them), whereas HDL levels in CVD were lower than control subjects (P < 0.001).

Table 1 - Clinical characteristics of the participants according to cardiovascular disease situation
parameters CVD (angiography positive) Control P valuea
N = 120 (X + SD) N = 60 (X + SD) 0.15
Sex (male/female) 86/34 38/22 0.02
Age 60.15 ± 6.5 58.38 ± 1.8 0.2
FBS (mg/dL) 143.72 ± 10.3 102.00 ± 6.7 0.001
Total cholesterol (mg/dL) 190.37 + 12 157.80 0.001
leptin (ng/mL) 9.62 3.32 P = 0.001
Triglyceride (mg/dL) 189.02 ± 8.8 137.63 ± 6.7 0.001
LDL (mg/dL) 129.037 ± 7.5 105.90 ± 10.5 0.001
HDL (mg/dL) 33.78 ± 1.1 36.78 ± 0.8 0.001
BMI (kg/mL) 27.4 ± 0.8 28.3 ± 1 0.17
hs-CRP (mg/mL) 6.35 ± 0.4 1.71 ± 0.1 0.001
OXLDL (µg/mL) 2.84 ± 0.52 1.99 ± 0.30 0.001
Clinical characteristics were presented as mean for continuous variables and n for categorical variables.
CVD, cardiovascular disease; FBS, fasting blood glucose; LDL, low-density lipoprotein; HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; OXLDL, oxidized low-density lipoprotein.
aP values were derived through independent t-test for continuous variables and Chi-square test for categorical variables.

Table 2 shows the characteristics of the study groups by leptin quartiles. The serum levels of leptin were significantly higher in the CVD than in the healthy control group (9.62 versus 3.32 ng/mL, P = 0.001). There was a significant difference in BMI, LDL, HDL, fasting blood glucose, OXLDL, total cholesterol, and hs-CRP levels between the study groups. Furthermore, no significant difference was seen in blood pressure and age mean.

Table 2 - Descriptive characteristics of the participants according to leptin quartiles level (case = 120 and control = 60)
Characteristics Leptin quartiles level
Q1 Q2 Q3 Q4
Case, 0 (0%) Control, 17 (100%) Case, 9 (24.3%) Control, 28 (75.7%) Case. 30 (66.7%) Control, 15 (33.3%) Case, 81 (100%) Control, 0 (0%) P valuea
Age (X + SD) 59.4 ± 1.8 55.8 ± 1.1 58.6 ± 1.1 61.5 ± 1.7 56.7 ± 1.4 60.1 ± 1.1 0.6
BMI (kg/mL) (X + SD) 27.6 ± 1.0 26.8 ± 0.6 27.9 ± 0.8 28.7 ± 0.6 30.0 ± 2.1 26.9 ± 0.4 0.04
LDL (mg/dL) (X + SD) 102.8 ± 9.7 123.3 ± 6.5 104.1 ± 5.8 123.3 ± 3.1 112.6 ± 12.6 131.7 ± 4.8 0.003
HDL (mg/dL) (X + SD) 35.9 ± 1.0 35.0 ± 0.8 37.0 ± 0.7 34.1 ± 0.4 37.2 ± 1.6 33.5 ± 0.4 0.001
FBS (mg/dL) (X + SD) 93.0 ± 4.6 117.2 ± 11.4 104.0 ± 7.3 128.9 ± 11.7 108.4 ± 12.8 152.1 ± 11.3 0.003
Total cholesterol (mg/dL) (X + SD) 155.3 ± 6.4 193.6 ± 12.1 160.8 ± 4.1 178.6 ± 7.2 154.8 ± 8.1 191.0 ± 6.2 0.008
hs-CRP (mg/dL) (X + SD) 1.9 ± 0.1 4.8 ± 0.0 1.6 ± 0.1 6.1 ± 0.2 1.6 ± 0.1 6.6 ± 0.5 0.001
OXLDL (µg/mL) (X + SD) 1.98 ± 0.57 2.54 ± 0.24 1.96 ± 0.52 2.69 ± 0.45 2.08 ± 0.45 2.93 ± 0.40 0.001
Blood pressure 5 (29.4) 6 (66.7) 14 (50.0) 16 (53.3) 9 (60.0) 35 (43.2) 0.2
Tobacco use 1 (59) 6 (66.7) 10 (35.7) 11 (36.7) 2 (13.3) 42 (51.9) 0.001
FBS, fasting blood glucose; HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; OXLDL, oxidized low-density lipoprotein; Q1–Q4, leptin quartile levels: Q1, <3.5 ng/mL; Q2, 3.5 to <6.5 ng/mL; Q3, 6.5–<9.1 ng/mL; and Q4, ≥9.1 ng/mL.
Clinical characteristics were presented as mean ± standard error for continuous variables and n (%) for categorical variables.
aP values were derived through one-way ANOVA for continuous variables and Chi-square test for categorical variables.

Table 3 presents the relationship of the leptin levels with cardiometabolic risk factors in the CVD and control groups. The leptin levels were significantly positively related to OXLDL (P = 0.001), LDL cholesterol (P = 0.001), and total cholesterol (P = 0.02) in CVD patients. After adjusting for age, BMI, and gender, similar results were obtained.

Table 3 - Univariate analysis of leptin levels with cardiometabolic risk factors (case = 120 and control = 60)
Cardiometabolic risk factors Model 1a Model 2b
Unadjusted Adjusted
Case Control Case Control
B (SE) P valuec B (SE) P valuec B (SE) P valuec B (SE) P valuec
BMI (kg/mL) 0.008 (0.12) 0.9
LDL (mg/dL) 0.04 (0.01) 0.001 0.005 (0.005) 0.3 0.05 (0.01) 0.001 0.005 (0.004) 0.2
HDL (mg/dL) −0.11 (0.13) 0.4 0.01 (0.03) 0.6 −0.1 (0.1) 0.4 0.01 (0.03) 0.6
FBS (mg/dL) 0.009 (0.005) 0.08 0.004 (0.005) 0.3 0.009 (0.006) 0.1 0.004 (0.005) 0.3
OXLDL (µg/mL) 5.7 (0.9) 0.001 0.34 (0.3) 0.3 5.9 (0.9) 0.001 0.1 (0.3) 0.7
Total cholesterol (mg/dL) 0.02 (0.009) 0.02 0.004 (0.007) 0.5 0.02 (0.009) 0.02 0.003 (0.007) 0.6
hs-CRP (mg/dL) 0.13 (0.1) 0.2 −0.4 (0.2) 0.1 0.14 (0.11) 0.2 −0.1 (0.2) 0.7
Triglyceride (mg/dL) 0.01 (0.008) 0.08 0.004 (0.005) 0.3 0.01 (0.009) 0.07 0.001 (0.004) 0.8
blood pressure −0.21 (0.9) 0.8 0.55 (0.3) 0.1 −0.18 (0.9) 0.8 0.28 (0.3) 0.4
Tobacco usage 0.89 (0.9) 0.3 0.001 (0.4) 0.9 0.94 (0.9) 0.3 −0.24 (0.4) 0.5
LDL, low-density lipoprotein; HDL, high-density lipoprotein; FBS, fasting blood glucose; hs-CRP, high-sensitivity C-reactive protein; OXLDL, oxidized low-density lipoprotein.
aUnadjusted.
bAdjusted for age, gender, and BMI.
cP values were derived through univariate and multivariate linear regression.

The association between MetS and serum leptin quartiles was calculated using two models; without (model 1) and with (model 2) adjusted for age, BMI, and gender (Table 4). A significantly increased OR was seen in both models. In model 1, compared to the reference Quartile, the OR and 95% CIs for MetS were 2 (0.75–5.3) in Q2, 3. 2 (1.1–8.8) in Q3, and 4.9 (1.9–12.9) in Q4. After adjusting for age, gender and BMI decreased the OR and CIs of MetS; 1.5 (0.54–4.5) in Q2, 2.5 (1.1–7.2) in Q3, and 4.3 (1.6–11.7) in Q4.

Table 4 - Odds ratio of metabolic syndromes with leptin quartiles levels
Quartiles of leptin Model 1 Model 2
OR (CI) P value OR (CI) P value
Quartile 1 1 Reference 1 Reference
Quartile 2 2.0 (0.75–5.3) 0.1 1.5 (0.54–4.5) 0.3
Quartile 3 3.2 (1.1–8.8) 0.02 2.5 (1.1–7.2) 0.04
Quartile 4 4.9 (1.9–12.9) 0.001 4.3 (1.6–11.7) 0.003
P value for trend <0.01 <0.01
The results were presented as OR with a 95% CI. Model 1: unadjusted. Model 2: adjusted for age, gender and BMI.
CI, confidence interval; OR, odds ratio.

As provided in Table 5, the association between angiography positive case and the serum leptin quartiles was calculated without considering age, BMI, and gender criterion in two models. In model 1, compared to Quartile 1, the OR and 95% CIs for the angiography positive case were 1.7 (0.42–7.2) in Q2, 6.1 (1.5–25.2) in Q3, and 78.4 (14.1–433.9) in Q4. After adjusting for age, gender and BMI increased the odds ratio and CIs of MetS; 3.4 (0.76–15.5) in Q2, 12.2 (2.6–57.0) in Q3, and 141.7 (22.2–904.1) in Q4.

Table 5 - Odds ratio of angiography positive case with leptin quartiles levels
Quartiles of leptin Model 1 Model 2
OR (CI) P value OR (CI) P value
Quartile 1 1 Reference 1 Reference
Quartile 2 1.7 (0.42–7.2) 0.4 3.4 (0.76–15.5) 0.1
Quartile 3 6.1 (1.5–25.2) 0.01 12.2 (2.6–57.0) 0.001
Quartile 4 78.4 (14.1–433.9) 0.001 141.7 (22.2–904.1) 0.001
P value for trend <0.001 <0.001
The results were presented as OR with a 95% CI. Model 1: unadjusted. Model 2: adjusted for age, gender, and BMI.
CI, confidence interval; OR, odds ratio.

Using ROC analysis, the predictive value of leptin levels for MetS and CVD was determined (Fig. 1). Along with the elevation of the leptin levels, the risk of MetS and CVD significantly increased by 4.3 folds (1.6–11.7), 141.7 (22.2–904.1), respectively. Furthermore, the criteria of variable were specified with reference to appearance levels in both healthy subjects and CVD patients, cutoff for leptin 5.5. The sensitivity and specificity for CVD were 85 and 87.5%, and for MetS 75 and 60%, respectively. The prognostic value of leptin levels for MetS and CVD was further explored after adjusting for age, gender, and BMI. The area under the ROC curves were 0.676 (0.606–0.765) and 0.907 (0.850–0.967), respectively. In addition, the Hosmer–Lemeshow test (χ2 = 10.93 with P = 0.21 and χ2 = 1.06 with P = 0.99) performed for apprizing goodness of fitness of the model was also applicable for MetS and CVD models, respectively.

Fig. 1
Fig. 1:
ROC analysis of leptin, adjusted model-age for CVD. CVD, cardiovascular disease; ROC, receiver operating characteristic.

Discussion

The aim of this study was to assess relationship between the serum levels of leptin with the angiographically proven cardiovascular disease and with components of the metabolic syndrome. The result of the present study demonstrated that the increased serum levels of leptin were statistically significant in CVD patients compared with the control group. An underlying association between leptin and CVD is unclear, although high leptin levels have been shown to be associated with the elevated risk of atherosclerosis via various mechanisms, characterized by platelet aggregation, intimal monocyte recruitment, macrophage to foam cell transformation, and eventually increasing angiogenesis [13]. Additionally, leptin was reported to play an additional proatherogenic cytokine role that modulates inflammatory responses and induce proliferation and migration of vascular smooth muscle cells [14]. Furthermore, leptin, as a body weight and energy regulating hormone, inhibits intracellular lipid concentrations by reducing fatty acids and synthesis of triglyceride and increase lipid oxidation [14,15]. Overall, most obese individuals have increased circulating levels of leptin, and therefore, it is hypothesized that the increased leptin may stem from leptin resistance in obese individuals. Consequently, the increased leptin levels are likely to mark the incidence of CVD. In the present study, significant differences in CVD risk factors with increasing leptin levels were observed, and the similar findings were reported by other studies [16,17]. In a study, Li et al. [18] showed that leptin levels were correlated with CVD risk in men and women. Additionally, a clinical and experimental study revealed that leptin may be a novel and independent risk factor for coronary heart disease [19].

Besides, Wallace et al. [20] reported that the increased plasma leptin levels are correlated with high BMI, and elevated levels of plasma triglycerides, CRP, and fasting blood glucose. Nonetheless, previous studies have reported leptin levels are merely associates with increased BMI [21]. According to the current findings, leptin levels were significantly and positively associated with LDL cholesterol and total cholesterol in cardiovascular disease with and without adjustment for age, BMI, and gender. In stark contrast, however, Wannamethee et al. [22] showed that there is no significant relationship between cholesterol and leptin in the age adjustment model. Consistent with our findings, Mohamed et al. [23] and Chu et al. [24] showed that leptin had a significant positive correlation with LDL cholesterol and total cholesterol in obese patients. Generally, leptin levels in most obese people have been shown to increase blood circulation, and the most plausible hypothesis is that high levels of leptin associate with leptin resistance in these individuals. Particularly, the elevated circulating levels of leptin in obese individuals have been shown to associate with undesirable outcomes such as hypertension, atherosclerosis, and stroke. Hence, the increased levels of leptin correlates with obesity and body fat percentage [25].

From our findings, a significant increase in leptin levels was associated with the significant increase in the incidence of MetS and angiography positive cases. To it, the risk associated with leptin quartiles levels remained significant after adjustment age, gender, and BMI. Consistent with our findings, data from several different studies have shown strong correlations between leptin and MetS risk factors [26,27]. MetS is a clustering of metabolic risk factors such as obesity, hypertension, atherogenic dyslipidemia, insulin resistance, and proinflammatory and prothrombotic states and is considered one of the most important risk factors for CVD [28,29]. Notably, leptin is an adipose tissue-derived hormone that regulates body weight by acting on the hypothalamus, stimulating energy consumption by decreasing neuropeptide Y (NPY) secretion which is involved in energy homeostasis; hence, leptin can be regarded as a marker of fat mass values [30,31]. Current studies have proposed that during the development of obesity and increasing BMI, leptin levels increase and lead to the accumulation of lipids in the liver and cardiac muscle, therefore leading to the MetS and cardiovascular events [32]. Hence, leptin levels may be considered as a diagnostic biomarker of MetS and CVD. Furthermore, we also reported that the significant higher serum leptin levels in patients with MetS and CVD compared with healthy individuals.

ROC curve analysis showed satisfactory diagnosis power of leptin in patients with CVD, where the diagnosis had the highest sensitivity (85%) and specificity (87.5%), and interestingly after adjustment, specificity improved (92%). Furthermore, ROC curve analysis displayed acceptable diagnosis power of leptin index, in subjects with MetS. Thus, application of the value of this biomarker as a prognosis and diagnosis biomarker in patients with CVD and MetS can be suggested.

Our study had some limitations, such as the study designed was cross-sectional, which restricts us to determine a temporal sequence and causality between leptin and the outcomes of interest. Furthermore, we cannot consider the variation of leptin during the time. Second, the findings of this study are limited to a small population in a concentrated area; therefore, our results cannot be applied to the large population with racial and ethnic heterogeneity. Finally, due to the increased incidence of cardiovascular diseases, a greater sample size is required to get more accurate results.

In conclusion, our study showed a high serum concentration of leptin (≥5.05 ng/mL) levels can diagnose the risk of CVD and also it associated with the components of the MetS in a sample from the population in East Azerbaijan. Moreover, leptin was found to be an independent significant biomarker of CVD. Besides, the adjustment of the serum leptin can increase the sensitivity and accuracy of the assessments, thereby can play a vital role in an early diagnosis of CVD. Therefore, the results suggested that considering the serum levels of leptin can be used for population screening and for monitoring patients with CVD. However, further studies are required to approve this hypothesis. Eventually, we propose the need to prevent and/or treat obesity – the greatest risk factor of MetS and CVD – as a reliable and applicable strategy.

Acknowledgements

The authors are thankful of all patients and the staff of Shahid Madani hospital in East Azerbaijan. Also, we appreciate our favorite Tractor club for its spiritual support during the study.

S.A. was involved in conception and design of the research and obtaining financing. S.A. and R.H. were involved in acquisition of data. S.A. and R.T. were involved in Analysis and interpretation of the data. H.M.S. was involved in statistical analysis. S.A. and N.K. were involved in writing of the manuscript. N.K. and S.N. were involved in critical revision of the manuscript for intellectual content. All authors participated in reading and revising the draft and preparing the final version of submit.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

cardiovascular disease; biomarker; leptin; metabolic syndrome; population in East Azerbaijan

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