Arq Bras CardiolabcArquivos Brasileiros de CardiologiaArq. Bras. Cardiol.0066-782X1678-4170Sociedade Brasileira de Cardiologia - SBCk3KfbLYW6PMBrFJfKHDxBbnS0066-782X2016004300348S0066-782X201600502410310.5935/abc.20160134Original ArticlesObesity, Serum Resistin and Leptin Levels Linked to Coronary Artery DiseaseMontazerifarFarzaneh1*BolouriAhmad2PaghaleaRaheleh Sharifian3MahaniMahbubeh Khodadadpour3KarajibaniMansour4*Zahedan University of Medical SciencesSchool of MedicineDepartament of NutritionZahedanIranPregnancy Health Research Center - Departament of Nutrition - School of Medicine - Zahedan University of Medical Sciences; Zahedan, IrãZahedan University of Medical SciencesZahedan University of Medical SciencesSchool of MedicineIranDepartament of Cardiology School of Medicine - Zahedan University of Medical Sciences; Zahedan, IrãZahedan University of Medical SciencesZahedan University of Medical SciencesSchool of MedicineZahedanIranSchool of Medicine - Zahedan University of Medical Sciences; Zahedan, IrãZahedan University of Medical SciencesZahedan University of Medical SciencesSchool of MedicineDepartament of NutritionZahedanIranHealth Promotion Research Center - Departament of Nutrition - School of Medicine - Zahedan University of Medical Sciences, Zahedan, Irã Zahedan University of Medical SciencesMailing Address: Farzaneh Montazerifar and Mansour Karajibani, Department of Nutrition - School of Medicine - Zahedan University of Medical Sciences, Zahedan - Iran. E-mail: fmontazerifar@gmail.com
Both authors contributed equally to this work.
Author contributions
Conception and design of the research: Montazerifar F, Karajibani M; Acquisition of data: Montazerifar F, Paghalea RS, Mahani MK; Analysis and interpretation of the data: Montazerifar F, Bolouri A, Karajibani M; Statistical analysis, Obtaining financing and Writing of the manuscript: Montazerifar F; Critical revision of the manuscript for intellectual content: Montazerifar F, Bolouri A, Karajibani M.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was reported.
120920161020161074348353210120161102201602062016This 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.AbstractBackground:
Clinical studies have demonstrated that adipocytokines play an important role in developing atherosclerotic cardiovascular diseases.
Objective:
The aim of study was to evaluate the relationship between serum resistin and leptin levels with obesity and coronary artery disease (CAD).
Methods:
In a cross-sectional study, we assessed the levels of serum resistin and leptin, C-reactive protein (CRP), lipid profile and cardiac enzyme tests (AST, CPK, LDH, CK-MB) in 40 CAD patients compared to 40 healthy controls. Anthropometric measurements including weight and height for calculating of body mass index (BMI), and waist circumference (WC) were performed for evaluation of obesity.
Results:
CAD patients had increased levels of leptin and CRP, (p < 0.001), cholesterol (p < 0.05), triglyceride (p < 0.01), and WC (p < 0.05) compared to healthy controls. There was no statistical difference between CAD and control subjects for resistin (p = 0.058). In a multiple regression analysis, only an association between serum leptin with BMI (β = 0.480, p < 0.05) and WC (β = 1.386, p < 0.05) was found.
Conclusions:
The findings suggest that leptin is a better marker of fat mass value than resistin and may be considered an independent risk factor for cardiac disorders that is largely dependent on obesity. However, further prospective studies are needed to confirm these results.
Obesity and coronary artery disease (CAD) are the most important health problems worldwide, especially in the adult Iranian population.1-3 CAD is one of the major atherosclerotic manifestations, and is associated with clinical demonstrations of acute coronary syndrome including angina and myocardial infarction.1 Obesity, the most important nutritional disorder in industrialized countries, is a prominent risk factor for CAD.4-6 Evidence shows that some forms of obesity, particularly elevated abdominal adiposity, might be responsible for metabolic disorders and vascular diseases.4,7,8 The distribution of regional fat, especially the amount of visceral fat around the heart, may affect coronary arteries and the myocardium,9 which may be considered a predictive factor for cardiovascular risk.10
Clinical studies have demonstrated that apart from classic risk factors such as hypertension, dyslipidaemia, and insulin resistance,11 adipocytokines also play an important role in developing atherosclerotic cardiovascular diseases.1,7,11 Adipose tissue, abundantly represented in obese rodents and humans, secretes some hormones, peptides, and other molecules that may potentially act as pro-atherogenic markers.4,8,9,12 Resistin and leptin, vasoactive substances produced by adipocytes, are potential mediators,7,12-14 which contribute to the inflammatory processes related to obesity in both vascular and non-vascular tissues,4,15,16 and activate endothelial cells.15,17,18 Because of these properties, resistin and leptin have been hypothesized to be a causal factor in the development of cardiovascular diseases, especially atherosclerotic coronary artery disease and congestive heart failure (CHD).14,16 Studies on adipokines and obesity have shown that elevated levels of resistin19,20 and leptin14,21-24 are linked to increased body mass index (BMI), and their receptors are increased in abdominal fat depots.4 Due to the high prevalence of CAD, the evaluation of serum levels of adipokines may be used as a prognostic marker in screening, diagnosing and predicting atherosclerosis. Thus, we designed this study to investigate the relationship between changes in resistin and leptin levels with obesity and CAD.
MethodsStudy patients
In a case-control study, forty patients aged 30-80 years old (mean age of 55.6 ±13.4 yr; BMI of 25 ± 4.8 kg/m2) admitted to the cardiology section of Emam Ali hospital of Zahedan , Iran, who had 50% or more coronary stenosis in at least one major coronary artery were enrolled in the CAD group. Exclusion criteria included medical history (e.g., diabetes mellitus, thyroid , liver or renal failure , cardiomyopathy, left ventricular systolic dysfunction or severe heart failure, acute or chronic inflammatory disorders, or the recent use of lipid-lowering drugs and corticosteroids or smoking). After matching for age and sex, 40 healthy volunteers aged 30-79 years old (mean age of 53 ±12 yr; BMI of 25.7± 4.9 kg/m2) without cardiovascular and any organ system disease and on no medications were selected as the control group. The study was performed between June and December of 2014.
Methodology
A demographic questionnaire, including age, sex, BMI, waist circumference (WC), medical history including smoking habit, presence of hypertension, hyperlipidemia and current medications was filled out by all subjects. Simple anthropometric measurements including weight and height to calculate BMI, and WC were performed for evaluation of obesity.25 The measurements of weight and height were performed with light clothing and without shoes, and approximated to the nearest 0.5 kg and 0.5 cm, respectively. The WC was measured with a non-stretchable standard tape, at the narrowest point between the costal margin and iliac crest. BMI ≥ 25 kg/m2 (general obesity), and WC > 102 cm in men and > 88 cm in women (abdominal obesity) were considered risk factors for cardiovascular disease.4,25
Blood samples were taken after a 12-hour overnight fast. Biochemical parameters including serum cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), creatine phosphokinas (CPK), lactate dehydrogenase (LDH), creatine kinase (CK-MB), and aspartate transaminase (AST) levels were measured by commercial kits (Pars azmun ,Tehran, Iran) using an auto-analyzer (Hitachi , Japan). Serum high-sensitivity C-reactive protein (hs-CRP) levels were assessed by latex- enhanced nephelometry (Behring BN II nephelometer, Germany).
Levels of serum resistin and leptin were measured by enzyme-linked immune-sorbent assay (ELISA) with commercial kits: [HUMAN resistin ELISA kit (Cat.No:EK0581; Boster biological technology; 40459 Encyclopedia Circle, Fermont, CA 94538, USA], and [HUMAN leptin ELISA kit (Cat. No: RD 191001100, USA).The serum samples were immediately frozen at -70ºC until analysis.
The study was approved by the ethics committee of (omitted to the review process) and informed consent was obtained from all subjects. (Approval date: 21 April 2014; Code No: 6696).
Statistical analysis
The analysis was performed by SPSS statistical software package program (version 18 for windows, Chicago, USA). Data were tested for normal distribution using the Kolmogorov- Smirnov test. Data were expressed as mean ± SD or mean ± SEM in accordance with their distribution. Variables with normal distribution were compared by unpaired Student's t-test and one-way ANOVA. Mann-Whitney U test was performed for non-normal distribution variables. Resistin and leptin values were compared using multivariable regression analysis, adjusted for age and sex. P value < 0.05 was considered significant.
Results
Demographic and chemical characteristics of subjects have been summarized in Table 1. Age, BMI, LDL and HDL levels were not significantly different between patients and controls. The mean WC (p < 0.05), serum cholesterol (p < 0.05), triglyceride (p < 0.01) and hs-CRP (p < 0.001) levels were markedly increased when compared to healthy controls.
Compared to the controls, serum levels of leptin were significantly higher in CAD patients (p < 0.001). Serum resistin levels differed between two groups, but this difference was not significant (p = 0.058).
Demographic and chemical characteristics of subjects
CAD Patients(n = 40)
Controls(n = 40)
p
Age (yr)
55.6 ± 13.4
53 ± 12
NS
Sex (M/F)
20/20
23/17
BMI (Kg/m2)
25 ± 4.8
25.7 ± 4.9
NS
WC(Cm)
Male
96.8 ± 13.5
86.1 ± 12.5
0.05
Female
91.7 ± 12.7
88.9 ±15.4
0.05
Cholesterol (mg/dL)
193.5 ± 49.6
169 ± 42.6
0.05
LDL-C (mg/dL)
89 ± 29.7
82.3 ± 23.7
NS
HDL-C (mg/dL)
42 ± 13.4
43.2 ± 12
NS
Triglyceride (mg/dL)
181 ± 94
119 ± 79.4
0.01
*AST (U/L)
97.6 ± 21.3
26 ± 7.4
0.001
*LDH (U/L)
711 ± 101.2
191 ± 40
0.0001
*CPK (U/L)
637.4 ± 195.6
97.2 ± 49
0.0001
*CK-MB (U/L)
81.5 ± 28
17 ± 4.1
0.001
*CRP (mg/L)
13.4 ± 3.5
1.3± 0.09
0.001
Resistin (ng/mL)
2.6 ± 1
2.1 ± 0.8
0.058
*Leptin (ng/mL)
41.7 ± 6.5
24.1 ± 2.9
0.001
(1.2 - 196)
(1.5 - 86)
Data are presented as mean ± SD.
Leptin, Cardiac enzyme tests (ALT, CPK, LDH, CK-MB) and CRP levels in patients are presented as mean ± SEM, because the data were not normally distributed. BMI: body mass index; WC: waist circumference; LDL: low density lipoprotein; HDL: high density lipoprotein; ALT: aspartate transaminase; CPK: creatine phosphokinas; LDH: lactate dehydrogenize; CK-MB: creatine kinase -MB; CRP: C-reactive protein; NS: not significant.
As shown in Figures1 and 2, a positive correlations between resistin and BMI (r = 0.56, p < 0.0001) and WC (r = 0.55, p < 0.0001), and between leptin with BMI (r = 0.57, p < 0.0001) and WC (r = 0.48, p < 0.001) were found.
Correlation between resistin with body mass index (BMI) (A) and waist circumference (WC) (B).
Correlation between leptin with body mass index (BMI) (A) and waist circumference (WC) (B)
In multiple regression analysis, leptin was associated with BMI ((β = 0.480, p < 0.05) and WC (β = 1.386, p < 0.05) in CAD patients, but this association was not significant for resistin.
Discussion
The present study evaluated the relationship between resistin and leptin levels with obesity and some risk factors of CAD. We demonstrated that the serum resistin concentration differed between CAD patients and the control group, but this difference was not significant, confirming results of previous studies.18,25 Several studies have reported serum resistin levels to be significantly elevated in CAD patients.4,19,26,27 In contrast, other studies16,28 found no such correlation. In clinical and experimental studies, resistin has been suggested to be an independent inflammatory marker in cardiovascular diseases, especially in CAD and heart failure.16,28-30
High serum leptin levels observed in patients with CAD in our study were consistent with earlier studies,22,31,32 suggesting the role of this hormone as a mediator in human atherosclerotic. By contrast, some data indicate that leptin may protect against atherosclerosis in specific animal models,33 and a study15 found no significant difference between CHD patients and controls.
Regarding BMI and WC findings, although BMI is recognized as a gold standard indicator for evaluation of obesity,4,34 it is not always a reliable measurement of body composition, because it cannot show the regional distribution of body fat. In fact, people with similar body mass indexes may have different amounts of fat in the bodies. Thus, WC was measured to determine visceral fat accumulation, and as an indicator of health risks associated with central obesity.4 Recent studies suggest that the central (abdominal, visceral) distribution of fat, particularly abdominal fat accumulation, which is a source of pro-inflammatory adipokines, has a more important role in the determination of risk.4,7,8 In the present study, after adjustment for sex, age, BMI and WC, obese patients with elevated BMI showed higher serum leptin levels compared to non-obese patients, but this difference was not significant when compared to the control group for resistin levels (data not shown). As well, resistin and leptin levels were significantly higher in abdominal obese patients than in patients without abdominal obesity or in the control group. Moreover, in multivariate regression analysis, we found an association between serum leptin with BMI and WC after adjusting of age and sex, but this association was not significant for resistin. Our findings were partly consistent with earlier reports,16,19,29 but not with some studies.21,26 It is worth noting that human resistin is more predominantly expressed in macrophages than adipocytes.12 Our findings suggest that leptin is a better marker of fat mass values.
Obesity is also linked to with several established risk factors of cardiovascular disease.7,8 Dyslipidemia is one of the most prevalent of CVD risk factors in obesity, especially in abdominal obesity.35 Several investigations have reported that dyslipidemia is one of the strongest factors independently associated with CAD in the Iranian population.1-3,36 When lipids accumulate within the cells of the arterial wall, it leads to systemic inflammation and atherosclerosis.4,37 In this study, we found no significant correlation between resistin and leptin with lipid profile, supporting results of other studies.15,17 In some studies, a significant positive association between serum resistin16,38 and leptin15 with triglyceride and cholesterol levels has been revealed. The reasons for inconsistencies between our findings and other studies may be explained by the study design and sample size.
It has been recently suggested that obesity is related to subclinical inflammation, as reflected by increased CRP levels.26,39,40 Evidence shows that resistin and leptin levels with inflammatory activity might play an important role in the development of inflammatory mechanisms and promote the progression of atherosclerotic disease.7,14,16,20,39 CRP is one of the best standardized markers for prediction of systemic inflammation degree.16,40 Resistin16,20,26 and leptin15,39 stimulate the production of CRP in coronary endothelial cells, and CRP induces vascular thrombosis that might be involved in the pathophysiology of acute coronary syndromes. In our study, no correlation of CRP was present in CAD patients with resistin and leptin, BMI and WC, suggesting that leptin and resistin are linked to CAD risk regardless of CRP.
Our study had several limitations, including a relatively small sample size. Because of the high cost of resisitin and leptin kits, only 80 subjects (patients and healthy volunteers) were enrolled in our study. Moreover, it was a cross-sectional design and did not prove causation. Therefore, the generalizability of our findings across social and ethnic groups is unknown.
Conclusion
The study indicated that circulating leptin levels, but not resistin levels, were higher in CAD patients in comparison to controls. As well, in the multivariate regression analysis, after adjusting of age and sex, only an association between serum leptin with BMI and WC was found. It suggests that leptin is a better marker of fat mass value than resistin and may be considered an independent risk factor for cardiac disorders that is largely dependent on obesity. However, further prospective studies are needed to confirm these results.
Sources of Funding
This study was funded by Zahedan University of Medical Sciences.
Study Association
This article is part of the thesis of Doctoral submitted by Farzaneh Montazerifar, from Zahedan University of Medical Sciences.
Acknowledgment
The authors gratefully acknowledge Dr. Ali-Reza Dashipour for his assistance in statistical analyses. We also thank the nurses of the CCU section in Zahedan Emam Ali Hospital for their kind cooperation.
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Obesity. 2012;20(4):856-61.MartinSSQasimANRaderDJReillyMPC-reactive protein modifies the association of plasma leptin with coronary calcium in asymptomatic overweight individualsObesity2012204856861Artigos OriginaisObesidade, Soro Resistina e Níveis de Leptina Ligados à Doença Arterial CoronarianaMontazerifarFarzaneh1*BolouriAhmad2PaghaleaRaheleh Sharifian3MahaniMahbubeh Khodadadpour3KarajibaniMansour4*Pregnancy Health Research Center - Departament of Nutrition - School of Medicine - Zahedan University of Medical Sciences; Zahedan, IrãDepartament of Cardiology School of Medicine - Zahedan University of Medical Sciences; Zahedan, IrãSchool of Medicine - Zahedan University of Medical Sciences; Zahedan, IrãHealth Promotion Research Center - Departament of Nutrition - School of Medicine - Zahedan University of Medical Sciences, Zahedan, IrãCorrespondência: Farzaneh Montazerifar and Mansour Karajibani, Department of Nutrition - School of Medicine - Zahedan University of Medical Sciences, Zahedan - Irã. E-mail: fmontazerifar@gmail.com
Os dois autores contribuíram igualmente para este artigo
Contribuição dos autores
Concepção e desenho da pesquisa: Montazerifar F, Karajibani M; Obtenção de dados: Montazerifar F, Paghalea RS, Mahani MK; Análise e interpretação dos dados: Montazerifar F, Bolouri A, Karajibani M; Análise estatística, Obtenção de financiamento e Redação do manuscrito: Montazerifar F; Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Montazerifar F, Bolouri A, Karajibani M.
Potencial conflito de interesse
Declaro não haver conflito de interesses pertinentes.
ResumoFundamento:
Estudos clínicos demonstraram que adipocitocinas têm papel importante no desenvolvimento de doenças cardiovasculares ateroscleróticas.
Objetivo:
Avaliar a relação entre níveis de leptina e resistina em soro com obesidade e doença arterial coronariana (DAC).
Métodos:
Em estudo transversal, avaliamos os níveis de resistina e leptina em soro, proteína C-reativa (CPR), perfil lipídico e testes de enzimas cardíacas (AST, CPK, LDH, CK-MB) em quarenta pacientes com DAC comparados a 40 controles saudáveis. Para avaliação de obesidade, foram feitas as medições antropométricas, incluindo peso e altura para o cálculo do índice de massa corporal (IMC) e circunferência da cintura (CC).
Resultados:
Pacientes com DAC apresentaram aumento nos níveis de leptina e CPR, (p < 0,001), colesterol (p < 0,05), triglicérides (p < 0,01) e CC (p < 0,05) em comparação aos controles. Não houve diferença significativa entre DAC e controles com relação à resistina (p = 0,058). Na análise de regressão múltipla, foi encontrada apenas uma associação entre leptina em soro ao IMC (β = 0,480, p < 0,05) e CC (β = 1,386, p < 0,05).
Conclusões:
Os achados sugerem que a leptina é melhor marcadora de valor de massa gorda do que a resistina, e pode ser considerada um fator de risco, dependente da obesidade, independente para distúrbios cardíacos. Contudo, outros estudos prospectivos serão necessários para a confirmação desses resultados.
Obesidade e doença arterial coronariana (DAC) são os principais problemas de saúde no mundo, especialmente na população iraniana adulta.1-3 A DAC é uma das principais manifestações ateroscleróticas, associada a demonstrações clínicas de síndrome coronariana aguda, incluindo angina e infarto do miocárdio.1 A obesidade, distúrbio nutricional mais importante em países industrializados, é um fator de risco proeminente para a DAC.4-6 Evidências mostram que algumas formas de obesidade, especialmente adiposidade abdominal elevada, podem ser responsáveis por distúrbios metabólicos e doenças vasculares.4,7,8 A distribuição de gordura regional, principalmente a quantidade de gordura visceral ao redor do coração, podem afetar artérias coronárias e o miocárdio,9 o que é considerado um fator preditivo para o risco cardiovascular.10
Estudos clínicos demonstraram que além de fatores de risco tradicionais, como hipertensão, dislipidemia e resistência à insulina,11 adipocitocinas também têm papel importante no desenvolvimento de doenças cardiovasculares ateroscleróticas.1,7,11 O tecido adiposo, amplamente presente em humanos e ratos obesos, secreta hormônios, peptídeos e outras moléculas que podem potencialmente agir como marcadores pró-aterogênicos.4,8,9,12 A resistina e a leptina, substâncias vasoativas produzidas por adipócitos, são potenciais mediadoras,7,12-14 que contribuem para o processo inflamatório relacionado à obesidade em tecidos vasculares e não-vasculares,4,15,16 e ativam células endoteliais.15,17,18 Devido a essas propriedades, já sugeriu-se que a resistina e a leptina podem ser fatores causais no desenvolvimento de doenças cardiovasculares, especialmente a doença aterosclerótica coronariana e insuficiência cardíaca congestiva (ICC).14,16 Estudos sobre adipocinas e obesidade mostram que níveis elevados de resistina19,20 e leptina14,21-24 estão ligados ao aumento do índice de massa corporal (IMC), e há aumento de seus receptores em depósitos de gordura abdominal.4 Devido à alta prevalência de DAC, a avaliação de níveis séricos de adipocinas pode ser usada como marcadora prognóstica na avaliação, diagnóstico e predição de aterosclerose. Portanto, elaboramos este estudo para investigar a relação entre mudanças nos níveis de resistina e leptina e obesidade e DAC.
MétodosPacientes do estudo
Em estudo caso-controle, 40 pacientes entre 30 e 80 anos de idade (idade média de 55,6 ±13,4 anos, IMC de 25 ± 4,8 kg/m²), internados na área de cardiologia do hospital Emam Ali em Zahedan, Irã, com 50% ou mais de estenose coronária em pelo menos uma das principais artérias coronárias, foram inscritos no grupo da DAC. Critérios de exclusão foram histórico médico (ex., diabetes mellitus, tireoide, insuficiência hepática ou renal, cardiomiopatia, disfunção sistólica ventricular esquerda ou insuficiência cardíaca grave, distúrbios inflamatórios agudos ou crônicos ou uso recente de hipolipemiantes e corticoides ou tabagismo). Após combinação por idade e gênero, 40 voluntários saudáveis entre 30 e 79 anos de idade (idade média de 53 ±12 anos; IMC de 25.7± 4,9 kg/m²), sem doenças cardiovasculares ou doenças dos sistemas de órgãos e sem uso de medicamentos, foram selecionados para o grupo controle. O estudo foi feito entre junho e dezembro de 2014.
Metodologia
Todos os participantes preencheram um questionário demográfico sobre idade, gênero, IMC, circunferência da cintura (CC), histórico médico, incluindo tabagismo, presença de hipertensão, hiperlipidemia e uso atual de medicamentos. As medições antropométricas simples, incluindo peso e altura para o cálculo do IMC e CC, foram feitas para avaliação de obesidade.25 As medições de peso e altura foram feitas com roupas leves e sem calçados, e arredondados para o 0,5 kg e 0,5 cm mais aproximados. A CC foi medida com fita-métrica padrão não-elástica, no ponto mais estreito entre a margem costal e a crista ilíaca. IMC ≥ 25 kg/m2 (obesidade geral) e CC > 102 cm em homens e > 88 cm em mulheres (obesidade abdominal) foram consideradas fatores de risco para doença cardiovascular.4,25
Amostras sanguíneas foram extraídas após um período de 12 horas de jejum durante a noite. Parâmetros bioquímicos, incluindo níveis de colesterol sérico, triglicérides, colesterol de lipoproteína de alta densidade (HDL), colesterol de lipoproteína de baixa densidade (LDL), creatinofosfoquinase (CPK), lactato desidrogenase (LDH), creatina quinase (CK-MB), aspartato transaminase (AST) foram medidos por kits comercias (Pars azmun, Teerã, Irã) com auto-analisador (Hitachi, Japão). Níveis de proteína C-reativa ultra sensível em soro foram avaliados por nefelometria reforçada com látex (Behring BN II nefelômetro, Germany).
Níveis de resistina e leptina em soro foram medidos por ensaio imunossorvente ligado a enzima (ELISA) com kits comerciais: [HUMAN resistin ELISA kit (Cat.No:EK0581; Boster biological technology; 40459 Encyclopedia Circle, Fermont, CA 94538, EUA], e [HUMAN leptin ELISA kit (Cat. No: RD 191001100, EUA). As amostras de soro foram imediatamente congeladas a -70°C até a análise.
O estudo foi aprovado pelo Comitê de Ética (omitido no processo de revisão) e formulário de consentimento informado foi obtido de todos os participantes (Data de aprovação: 21 de abril de 2014; Código N° 6696).
Análise estatística
A análise foi feita pelo programa de software estatístico SPSS (versão 18 para Windows, Chicago, EUA). Os dados foram testados para distribuição normal com o teste Kolmogorov- Smirnov. Os dados foram expressos como média ± DP ou media ± EPM, de acordo com sua distribuição. Variáveis com distribuição normal foram comparadas pelo teste t de Student não pareado e ANOVA unilateral. O teste Mann-Whitney U foi feito para variáveis de distribuição não-normal. Valores de resistina e leptina foram comparados por meio de análise de regressão multivariada, ajustados para idade e gênero. Valores de p < 0,05 foram considerados significativos.
Resultados
Características químicas e demográficas dos indivíduos estão resumidas na Tabela 1. Idade e níveis de IMC, LDL e HDL não apresentaram diferença significativa entre pacientes e controles. A CC média (p < 0,05) e níveis de colesterol sérico (p < 0,05), triglicérides (p < 0,01) e hs-CRP (p < 0,001) mostraram-se significativamente elevados em comparação aos controles. Níveis séricos de leptina mostraram-se significativamente mais altos em pacientes com DAC, quando comparados aos controles (p < 0,001). Níveis de resistina em soro mostraram-se diferentes entre os dois grupos, porém a diferença não foi significativa (p = 0,058).
Características demográficas e clínicas dos indivíduos
Pacientes com DAC(n = 40)
Controles(n = 40)
p
Idade (anos)
55,6 ± 13,4
53 ± 12
NS
Sexo (M/F)
20/20
23/17
IMC (Kg/m2)
25 ± 4,8
25,7 ± 4,9
NS
CC (Cm)
Homens
96,8 ± 13,5
86,1 ± 12,5
0,05
Mulheres
91,7 ± 12,7
88,9 ± 15,4
0,05
Colesterol (mg/dL)
193,5 ± 49,6
169 ± 42,6
0,05
LDL-C (mg/dL)
89 ± 29,7
82,3 ± 23,7
NS
HDL-C (mg/dL)
42 ± 13,4
43,2 ± 12
NS
Triglicérides (mg/dL)
181 ± 94
119 ± 79,4
0,01
*AST (U/L)
97,6 ± 21,3
26 ± 7,4
0,001
*LDH (U/L)
711 ± 101,2
191 ± 40
0,0001
*CPK (U/L)
637,4 ± 195,6
97,2 ± 49
0,0001
*CK-MB (U/L)
81,5 ± 28
17 ± 4,1
0,001
*CRP (mg/L)
13,4 ± 3,5
1,3 ± 0,09
0,001
Resistina (ng/mL)
2,6 ± 1
2,1 ± 0,8
0,058
*Leptina (ng/mL)
41,7 ± 6,5
24,1 ± 2,9
0,001
(1,2 - 196)
(1,5- 86)
Dados apresentados como média ± DP.
Leptina, Testes de enzimas cardíacas (ALT, CPK, LDH,CK-MB) e níveis de CRP em pacientes estão apresentados como média ± EPM, pois os dados não foram normalmente distribuídos. IMC: índice de massa corporal; CC: circunferência da cintura; LDL: lipoproteina de baixa densidade; HDL lipoproteina de alta densidade; AST: aspartato transaminase; CPK: creatinafosfoquinase; LDH: lactato desidrogenase; CK-MB: creatina quinase –MB; CRP: proteína C-reativa; NS : Não significativa.
Conforme demonstrado nas Figuras 1 e 2, foi encontrada correlação positiva entre a resistina e o IMC (r = 0,56, p < 0,0001) e CC (r = 0,55, p < 0,0001), e também entre leptina e IMC BMI (r = 0,57, p < 0,0001) e CC (r = 0,48, p < 0,001).
Correlação entre a resistina e índice de massa corporal (IMC) (A) e circunferência da cintura (CC) (B).
Correlação entre a leptina e índice de massa corporal (IMC) (A) e circunferência da cintura (CC) (B).
Na análise de regressão múltipla, a leptina mostrou-se associada ao IMC (β = 0,480, p < 0,05) e à CC (β = 1,386, p < 0,05) em pacientes com DAC, mas essa associação não foi significativa para a resistina.
Discussão
O presente estudo avaliou a relação entre os níveis de resistina e leptina e obesidade e fatores de risco para DAC. Demonstramos que houve diferença na concentração de resistina em soro entre pacientes com DAC e indivíduos no grupo controle; porém, essa diferença não foi significativa, confirmando resultados de estudos prévios.18,25 Diversos estudos relatam que níveis de resistina em soro são significativamente elevados em pacientes com DAC.4,19,26,27 Por outro lado, outros estudos não encontraram tal correlação. Em estudos experimentais e clínicos, foi sugerido que a resistina é marcadora inflamatória independente em doenças cardiovasculares, especialmente em DAC e insuficiência cardíaca.16,28-30
Altos níveis de leptina em soro observados, em nosso estudo, em pacientes com DAC foram consistentes com estudos prévios,22,31,32 sugerindo o papel desse hormônio como mediador na aterosclerose. Ao contrário, alguns dados indicam que a leptina pode proteger contra aterosclerose em modelos animais específicos,33 e outro estudo15 não encontrou diferença significativa entre pacientes com ICC e controles.
Com relação aos achados de IMC e CC, embora o IMC seja reconhecido como indicador padrão ouro para avaliação de obesidade,4,34 ele não é sempre uma medição confiável de composição corporal, pois não mostra a distribuição regional de gordura corporal. Na verdade, indivíduos com IMCs similares podem ter quantidades diferentes de gordura no corpo. Portanto, a CC foi medida para determinar a acumulação de gordura visceral, e como indicador de riscos de saúde associados à obesidade central.4 Estudos recentes sugerem que a distribuição central (abdominal, visceral) de gordura, especialmente o acúmulo de gordura abdominal, fonte de adipocinas pró-inflamatórias, tem maior importância na determinação de risco.4,7,8 No presente estudo, após ajuste para gênero, idade, IMC e CC, pacientes obesos com IMC elevado mostraram níveis mais elevados de leptina em soro em comparação a pacientes não obesos, mas a diferença nos níveis de resistina, entre pacientes DAC e controle, não foi significativa (dados não apresentados). Além disso, níveis de resistina e leptina estavam significativamente mais altos em pacientes com obesidade abdominal do que em pacientes sem obesidade abdominal e controles. Ademais, na análise de regressão multivariada, encontramos uma associação entre leptina em soro e IMC e CC após ajuste para idade e gênero, mas essa associação não foi significativa com relação à resistina. Nossos achados foram parcialmente consistentes com relatos anteriores,16,19,29 mas não foram consistentes com alguns estudos.21,26 De nota, a resistina humana é mais predominantemente expressa em macrófagos do que adipócitos.12 Nossos achados sugerem que a leptina é melhor marcadora de valores de massa de gordura.
A obesidade também está ligada a diversos fatores de risco de doenças cardiovasculares estabelecidos.7,8 A dislipidemia é um dos fatores de risco de DCV mais prevalentes na obesidade, especialmente obesidade abdominal.35 Diversas investigações relatam que a dislipidemia é um dos fatores, independentemente associados à DAC, mais proeminentes na população iraniana.1-3,36 A acumulação de lipídeos dentro das células da parede arterial leva à inflamação e aterosclerose.4,37 Nesse estudo, não encontramos correlação significativa entre a resistina e a leptina e o perfil lipídico, consistentemente com outros estudos.15,17 Já em alguns estudos, uma associação positiva significativa entre resistina em soro16,38 e leptina15 com níveis de triglicérides e colesterol foi encontrada. As razões da inconsistência demonstrada entre nossos achados e outros estudos podem estar relacionadas ao formato do estudo e tamanho da amostra.
Recentemente foi sugerido que a obesidade está relacionada à inflamação subclínica, refletida por níveis elevados de CRP.26,39,40 Evidências mostram que níveis de resistina e leptina com atividade inflamatória podem ter um papel importante no desenvolvimento de mecanismos inflamatórios e promover a progressão da doença aterosclerótica.7,14,16,20,39 CRP é dos marcadores mais bem padronizados na predição do nível de inflamação sistêmica.16,40 A resistina16,20,26 e a leptina15,39 estimulam a produção de CRP em células endoteliais coronárias, e a CRP induz trombose vascular que pode estar envolvida na fisiopatologia de síndromes coronárias agudas. Em nosso estudo, em pacientes com DAC, não houve correlação entre CRP e resistina e leptina, IMC e CC, sugerindo que a leptina e a resistina estão ligadas ao risco de DAC independentemente da CRP.
Nosso estudo teve diversas limitações, incluindo o tamanho da amostra que era relativamente pequena. Devido ao alto custo de kits de resistina e leptina, apenas 80 indivíduos (pacientes e voluntários saudáveis) foram inscritos no estudo. Além disso, optamos por um modelo transversal, e não houve causalidade comprovada. Portanto, a transferibilidade de nossos achados para outros grupos étnicos e sociais é desconhecida.
Conclusão
O estudo sugeriu que níveis circulantes de leptina, porém não de resistina, mostraram-se mais elevados em pacientes com DAC em comparação a controles. Além disso, em análise de regressão multivariada, após ajuste para idade e gênero, apenas uma associação entre leptina em soro e IMC e CC foi encontrada. Isso sugere que a leptina é melhor marcadora de valor de massa gorda do que a resistina e pode ser considerada um fator de risco independente para distúrbios cardíacos, significativamente dependente da obesidade. Contudo, estudos prospectivos futuros são necessários para confirmar esses resultados.
Fontes de financiamento
O presente estudo foi financiado por Zahedan University of Medical Sciences.
Vinculação acadêmica
Este artigo é parte de tese de Doutorado de Farzaneh Montazerifar pela Zahedan University of Medical Sciences.
Agradecimentos
Os autores agradecem ao Dr. Ali-Reza Dashipour pela assistência com análises estatísticas. Também gostaríamos de agradecer a equipe de enfermagem da unidade coronariana do Hospital Zahedan Emam Ali por sua colaboração.