Metabolic syndrome in coronary artery and occlusive vascular diseases: a systematic review

Abstract

Atualmente, a síndrome metabólica (SM) se mostra altamente prevalente, sendo associada a fatores de risco para doenças crônicas não transmissíveis, tais como diabetes mellitus tipo 2, doenças ateroscleróticas e coronarianas. O objetivo desta revisão sistemática foi descrever os resultados de estudos que investigaram a associação da SM com a doença arterial coronariana e doenças vasculares oclusivas. Foi realizada a revisão sistemática com dados de estudos originais publicados entre 1999 e 2008, escritos em inglês ou português, utilizando-se as bases de dados Medline, Pubmed, Highwire Press e Science Direct. Foram incluídos artigos que fizeram o diagnóstico da SM através do critério do National Cholesterol Education Program - Adult Treatment Panel III (NCEP ATP III, 2001). Foram excluídos estudos realizados com animais, de suplementação e que realizaram administração oral ou endovenosa de qualquer substância, assim como aqueles de baixa qualidade metodológica e com amostra inicialmente heterogênea. Apesar da heterogeneidade entre os estudos, observou-se que indivíduos com SM apresentam maior probabilidade (risco = 2,13) de desenvolverem as doenças vasculares oclusivas, doença coronariana, diabetes mellitus e acidente vascular encefálico. Mudanças no estilo de vida, como práticas alimentares saudáveis, atividade física regular e a cessação do tabagismo devem ser incentivadas pelos profissionais da saúde a fim de minimizar as complicações e a morbimortalidade associada à SM.

Síndrome metabólica; doença da artéria coronariana; doenças vasculares; metanálise

REVIEW ARTICLE

Instituto de Nutrição Josué de Castro - Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil

Mailing address

ABSTRACT

Nowadays, the metabolic syndrome (MS) is highly prevalent and is associated with risk factors for non-transmissible chronic diseases, such as type 2 diabetes mellitus, and coronary atherosclerotic disease. The objective of this systematic review is to describe the results of studies that investigated the association of MS with coronary artery disease and occlusive vascular diseases. We conducted a systematic review of data from original studies published between 1999 and 2008, written in English or Portuguese, using the databases Medline, Pubmed, Science Direct and HighWire Press. We included articles in which the diagnosis of MS was made by the criteria of the National Cholesterol Education Program - Adult Treatment Panel III (NCEP ATP III, 2001). We excluded studies with animals, supplementation studies, and those with oral or intravenous administration of any substance, as well as those of low methodological quality and those which had a heterogeneous initial sample. Despite the heterogeneity among studies, we observed that individuals with MS had a higher probability (risk = 2.13) of developing occlusive vascular diseases, coronary disease, diabetes and stroke. Lifestyle changes such as healthy eating habits, regular physical activity and cessation of smoking should be encouraged by health professionals to minimize the complications and morbidity associated with MS.

Key words: Metabolic syndrome; coronary artery disease; vascular diseases; meta-analysis.

Introduction

The metabolic syndrome (MS) is characterized by metabolic changes related to abdominal obesity and insulin resistance. According to the NCEP ATP III¹ the diagnosis is made when there is occurrence of three or more of the following conditions: abdominal obesity (waist circumference above 102 cm in men and 88 cm in women), hypertriglyceridemia (greater than or equal to 150mg/dl); low concentrations of HDL cholesterol (less than 40mg/dl in males and less than 50mg/dl in females); systolic blood pressure above or equal to 130 mmHg, and diastolic blood pressure above 85 mmHg; and fasting hyperglycemia (greater than or equal to 110mg/dl).

There are other proposed criteria for this diagnosis, such as: the World Health Organization² (WHO) criteria, which use microalbuminuria and insulin resistance values; the European Group for the Study of Insulin Resistance³ (EGIR) criteria, which consider insulin resistance as a mandatory risk factor associated with two or more risk factors; the American Heart Association/National Heart, Lung and Blood Institute⁴ (AHA/NHLBI) criteria, which require the presence of three or more risk factors associated with coronary artery disease (CAD); and the International Diabetes Federation⁵ (IDF) criteria, which use different values for waist circumference according to ethnicity. Despite the many similarities among the criteria, it is observed that the NCEP ATP III¹ criteria are the most used in the literature⁴.

The global prevalence of MS is high-between 20% and 25%-and varies according to the diagnostic criteria used^6-9. Regardless of the diagnostic criteria used, its prevalence is high in individuals with cardiovascular diseases (CVDs)¹⁰. There are no epidemiological studies to define its prevalence among Brazilians. However, in a regional study with 530 Japanese-Brazilians, a prevalence of 21%¹¹ was observed, and in a study conducted among the Spanish population of migrants and their descendants in Brazil, a prevalence of 35.6%¹² was observed.

MS is considered a risk factor as important as smoking habit for the development of occlusive vascular diseases and atherosclerotic diseases^1,9,13. Therefore, the diagnosis and treatment of MS are extremely important because its prevalence is increasing worldwide.

Objective

To describe the results of clinical studies that investigated the impact of MS, diagnosed by the NCEP ATP III criteria¹, on the occurrence of CAD and occlusive vascular disease in individuals aged over 18 years.

Methods

The bibliographic research was conducted in 2008, and the following electronic databases were reviewed: Medline, Scielo, Pubmed, Science Direct and HighWire Press. A retrospective search was limited to indexed original scientific articles, such as clinical, randomized and non-randomized, transversal, prospective, cohort and population-based studies, involving humans aged 18 years or over, published between 2004 and 2008, written in English or Portuguese, with a combination of the following keywords: metabolic syndrome and coronary artery disease, metabolic syndrome and vascular diseases. Another strategy we used was the manual selection of references in the articles found.

The articles, originally identified by three different researchers, were selected by the initial search strategy using the following eligibility criteria: (1) articles published in the last four years; (2) articles written in English or Portuguese; (3) Clinical observational studies; (4) randomized or non-randomized studies; (5) studies with adult or elderly human subjects with MS; (6) clinical diagnosis of coronary artery disease and/or occlusive vascular diseases; and (7) studies showing as the main outcome the association of metabolic syndrome abnormalities with these diseases. We included articles that used the NCEP ATP III¹ criteria for the diagnosis of MS and those which used the NCEP ATP III² with another criteria for the diagnosis of MS, such as the WHO², the EGIR³, the AHA/NHLBI⁴, the IDF⁵, or the American College of Endocrinology (ACE)¹⁴ criteria. According to a criterion defined before the search, we excluded studies with animals, supplementation studies, studies with oral or intravenous administration of any substance, studies of low methodological quality and with heterogeneous sample, as well as studies whose information was available in more recent articles.

The selected studies had as the primary outcome the association of metabolic abnormalities of individuals with MS in the presence of coronary artery disease and/or occlusive vascular diseases¹⁵. The methodological quality of the studies was evaluated considering several aspects: specification of the inclusion and exclusion criteria for the study; random allocation of participants in the study; similarities between the study groups and control groups in the initial phase of the study; and statistical analysis report. Finally, these articles were reviewed to avoid inclusion of duplicated data.

Data Analysis

We used the program RevMan version 5.0 (The Cochrane Collaboration, Copenhagen) to analyze the data¹⁶. To assess the heterogeneity among studies, we used the Chi² test, with n - 1 degrees of freedom, in which "n" is the number of studies. We calculated the significant heterogeneity using the fixed-effects model. The inconsistency (I²) was calculated so as to verify the differences between studies that included groups of subjects with and without MS who had CAD or occlusive vascular disease, and an inconsistency rate of 25% was considered low, 50% was considered moderate, and greater than 75% was considered high¹⁷.

Results

A total of 42 studies have been identified, of which 30 used the NCEP ATP III criterion (2001)¹ as the sole diagnostic criteron for MS, and 12 articles used other criteria for the diagnosis of MS besides the NCEP ATP III¹. A total of 42 articles have been selected, as follows: 14 cohort studies^13,15-27, 12 cross-sectional studies^10,30-40, 8 prospective cohort studies^41-48, 2 observational studies^49,50, 2 prospective studies^51,52, 1 prospective observational study⁵³, 1 cross-sectional and population cohort study⁵⁴, 1 case-control study⁵⁵, and 1 longitudinal community-based study⁵⁶.

The largest number of publications were from the United States (n = 17), of which only 12 articles used the NCEP ATP III criterion (2001), followed by Italy (n = 6) and Holland (n = 3). Two articles were selected from each of the following countries: England, Greece, France, Canada, Finland, Turkey. From Japan, Argentina, Norway and Austria, only 1 article was selected from each.

The methodological characteristics, year of publication, country of origin, study population, study group, sample age range, criterion used for diagnosis of MS, type, duration and main results of these studies are presented in table 1.

Time duration of some studies was not mentioned. Among the studies in which these data were obtained we observed that no less than 6 months duration²⁸, was the largest follow-up time of 20 years⁵³.

The form of recruitment of participants was specified in all studies. The sample size ranged from 83 to 15,922 individuals; of the 42 studies selected, only 2 had lower total sample of 100 individuals; 83 and 87 individuals respectively^32,37.

Most studies included individuals of both genders (n = 36), with the exception of 5 studies that included only women^{28,34,37,48,50}, and 1 study that included only men in its sample⁴³. Of the studies selected, 50% did not mention the sample age range, but 31 (73.8%) selected articles mentioned the mean age and the standard deviation of the study groups. Of the articles which did not mention the standard deviation of the study groups' age, 3 reported only the mean age of the groups, 3 mentioned only the age range of the groups, and 5 mentioned the mean age and the age range of the groups.

Discussion

MS stands out due to its high prevalence and because it represents an important set of cardiovascular risk factors, often associated with central fat deposition and insulin resistance⁵⁷. From the epidemiological point of view, MS is responsible for an estimated increase in overall mortality by 1.5 times, and in mortality from CAD and occlusive vascular disease by 2.5 times⁵⁸. Despite its relevance, in Brazil there is still a lack of data on its characteristics and no epidemiological studies to assess its relationship with increased morbidity from occlusive vascular disease and CAD. The study of MS has also been hampered by the lack of consensus on the criterion for its diagnosis and the cut-off points for its risk factors, with important implications in clinical practice and public health measures. In this review, we selected articles that used the NCEP ATP III¹ criterion for the diagnosis of MS, not only because this is a criterion that has easy applicability in clinical practice, but it is also widely used in scientific publications.

Individually, the components of MS are independent risk factors for the development of atherosclerotic cardiovascular disease^{10,13,20,23,24,40,42}. The different criteria used for the diagnosis of MS are based on the principle that its risk factors may interact synergistically, or may increase the risk for CAD and atherosclerotic disease. Some studies have shown that the higher the number of components of MS in an individual, the greater the risk for or the severity of the MS-related disease^15,23,24,31.

The studies selected in this systematic review have shown an association of MS with the development of or mortality from CVD^{10,13,20,24,25,29,41,47,49,51}, CAD^{22,28,31,44,47,55}, diabetes mellitus 2 (DM 2)^20,26,56, and stroke (CVA)^29,43,45. Some studies also suggest that individuals with MS have higher mortality from CVDs^20,41 and higher prevalence of CVA⁴³, regardless of the presence of glucose intolerance or DM 2^20,41,45.

Among the selected articles, 4 assessed the mean carotid intima-media thickness^{23, 40,42,46}, showing an association of MS with the atherothrombotic process; increased blood pressure⁴², decreased concentration of HDL-C in men, and fasting hyperglycemia in women⁴⁶ were the most important components of MS in this association. It was reported that the higher the number of risk factors that characterize MS the greater the increase in the mean carotid intima-media thickness²³.

Some studies report the association of MS with higher body mass index (BMI)^28,30,56. It has been also highlighted that individuals with MS have higher BMI and higher risk of DM 2 and CVDs⁵⁶. Other studies showed the association of MS with increased cell adhesion molecular activity, hypoadiponectinemia³², and increased concentrations of oxidized LDL^34,53 and C-reactive protein^35,55. One study reports that there has been an increase of CVD mortality in patients with MS and increased concentration of C-reactive protein⁴⁴.

Studies that evaluated the concentration of circulating oxidized LDL showed that among the risk factors that characterize MS, those with a higher association with the oxidation of the lipoprotein are fasting hyperglycemia, hypertriglyceridemia, low concentration of HDL-C, and abdominal obesity^34,53. The adjusted odds ratio for the dichotomous effect of risk factors that characterize MS, versus the fifth quintile of oxidized LDL were 2.1 (95% CI, 1.2 to 3.6) for abdominal obesity; 2.4 (95% CI, 1.5 to 3.8) for fasting hyperglycemia; and 2.1 (95% CI, 1.1 to 4.0) for hypertriglyceridemia⁵³.

Although hyperhomocysteinemia (Hhcy) is a known marker of occlusive vascular diseases, there are still few studies that assess its association with MS. Among the studies selected in this systematic review, only two assessed the association of Hhcy with MS and its risk factors^19,49. A recent study showed that plasma homocysteine (Hcy) was higher in subjects with MS when compared to those without MS. Its concentration also increased according to the number of risk factors that characterize MS. When individuals without MS were compared with those who had all five risk factors for MS, the plasma concentration of Hcy increased significantly (from 12.7 mmol/L to 15.9 mmol/L)¹⁹. These findings suggest that MS and Hhcy have synergistic effect in increasing the risk for occlusive vascular diseases.

Of the studies selected in this review, one showed no association of MS with CAD⁵⁴, and another showed no association of MS with atheromatous plaque formation¹⁸. However, most studies showed the association of MS and some of its components with higher risk of general morbidity and mortality and of CVD. Therefore, we must highlight the importance of taking measures for the prevention and control of MS and its associated risk factors, in order to reduce CVDs, the main cause of mortality worldwide.

The heterogeneity among the selected studies is shown in Figure 1, and probably is a result of the different markers used for the diagnosis of vascular disease or coronary occlusion. An increased probability (risk = 2.13) of individuals with MS to develop vascular or coronary disease has also been demonstrated. But the results remain contradictory and require further research to obtain more consistent results.

The adoption, preferably from childhood and by the entire population, of healthy lifestyles, such as a balanced diet and the regular practice of physical activity is a basic component of MS prevention. The benefits of the regular practice of physical exercise on the reduction of CVD morbidity have been shown in scientific literature as part of a lifestyle change (LC), along with a reduction in body fat deposition, especially in the abdominal region, which represents an important risk factor for the diagnosis of MS. The success of the intervention in the control and treatment of MS is closely related to the LC, and non-drug therapy is the treatment of choice, with a food plan for reducing body weight associated with physical activity⁵⁷, besides cessation of smoking and excessive alcohol consumption and reduction of stress. These behavioral changes may improve the quality of life and life expectancy of individuals with MS¹¹.

Although LC is essential for the prevention and treatment of MS, only one study revealed in its conclusion the importance of LC for the reduction of CVD and occlusive vascular disease morbidity and mortality in patients with MS¹⁰. Another study showed only the importance of the prevention of MS and its risk factors for the reduction in the incidence of stroke²⁹.

Therefore, in order to achieve the remission of MS and reduce the prevalence of CAD and occlusive vascular diseases, health professionals should encourage healthy eating habits, such as reducing the consumption of saturated and hydrogenated fats, increasing the consumption of fruits, vegetables, fiber, and whole grains, and lifestyle changes such as cessation of smoking, which is fundamental and a priority measure in preventing the individual components of MS. Moreover, the practice of aerobic physical exercise promotes a reduction in plasma triglycerides and an increase in HDL-c concentration⁵⁸, which are important risk factors that characterize MS.

A balanced diet combined with a regular practice of physical activity can promote body weight reduction and improve the clinical condition of patients with MS, with a reduction in the risks and the morbidity and mortality from CVD and vascular occlusive disease.

Conclusion

The aggregation of MS components and the pathophysiological mechanisms that trigger it are not yet fully understood. But despite controversial literature reports and heterogeneity among studies, the impact of MS on the occurrence of CAD and occlusive vascular diseases has been observed in this review.

Therefore, it is critical that randomized studies be conducted, using more reliable markers for the diagnosis of CAD and occlusive vascular diseases, and thus generating more consistent results.

Acknowledgments

We would like to thank the support of the National Council for Scientific and Technological Development (CNPq) and the Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro (FAPERJ).

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

This study was funded by CNPq and FAPERJ.

Study Association

This study is not associated with any post-graduation program.

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Metabolic syndrome in coronary artery and occlusive vascular diseases: a systematic review

Daniela Reis Elbert Farias; Avany Fernandes Pereira; Glorimar Rosa

Publication Dates

• Publication in this collection
  12 July 2010
• Date of issue
  June 2010

History

• Accepted
  30 Apr 2009
• Reviewed
  18 Feb 2009
• Received
  09 Oct 2008