Obesity and coronary artery disease: role of vascular inflammation

Abstracts

A obesidade vem se tornando uma epidemia global. Cerca de 1,1 bilhões de adultos e 10% das crianças do mundo são atualmente considerados portadores de sobrepeso ou obesos. Classicamente associada a fatores de risco para doença cardiovascular, como diabete melito e hipertensão arterial sistêmica, a obesidade vem sendo cada vez mais encarada como fator de risco independente para doença arterial coronariana (DAC). A aterosclerose coronariana compreende uma série de respostas inflamatórias em nível celular e molecular, cujas reações se encontram mais exacerbadas em pacientes obesos. Antes considerado mero depósito de gordura, o tecido adiposo é visto hoje em dia como órgão endócrino e parácrino ativo, produtor de diversas citocinas inflamatórias, como as adipocinas. Este artigo visa alertar para o grave problema de saúde pública em que a obesidade se tornou nas últimas décadas e correlacionar o processo inflamatório exacerbado nos indivíduos obesos com a maior incidência de DAC nessa população.

Obesidade; doença da artéria coronariana; inflamação; proteína C

La obesidad se está tornando una epidemia global. Cerca de 1,1 billones de adultos y el 10% de los niños del mundo están considerados actualmente portadores de sobrepeso u obesos. Clásicamente asociada a factores de riesgo para enfermedad cardiovascular, como diabetes melitus e hipertensión arterial sistémica, la obesidad se está considerando cada vez más factor de riesgo independiente para enfermedad arterial coronaria (EAC). La aterosclerosis coronaria comprende una serie de respuestas inflamatorias a nivel celular y molecular, cuyas reacciones se encuentran más exacerbadas en pacientes obesos. Antes considerado mero depósito de grasa, el tejido adiposo está visto hoy en día como órgano endócrino y parácrino activo, productor de diversas citocinas inflamatorias, como las adipocinas. Este artículo apunta a alertar sobre el grave problema de salud pública en que se convirtió la obesidad en las últimas décadas y correlacionar el proceso inflamatorio exacerbado en los individuos obesos con la mayor incidencia de EAC en esta población.

Obesidad; enfermedad arterial coronaria; inflamación; proteína C

REVIEW ARTICLE

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - São Paulo, SP - Brasil

Mailing address

ABSTRACT

Obesity is becoming a global epidemic. Around 1.1 billion adults and 10% of the world's children are currently overweight or considered obese.

Generally associated with risk factors for cardiovascular disease, such as Diabetes Mellitus and systemic arterial high blood pressure, the obesity has been more and more seen as an independent risk factor for Coronary Artery Disease (CAD).

Coronary arteriosclerosis comprises a series of inflammatory responses at cellular and molecular level, whose reactions are stronger in obese patients.

In the past, the adipose tissue was regarded as a mere fat deposition. Now it is seen from a totally different standpoint, as an active endocrine and paracrine organ that produces several inflammatory cytokines, such as the adipokines.

This article aims to raise awareness about obesity as an increasingly significant public health issue over the past decades, as well as to relate the intense inflammatory process in obese individuals with an increased tendency for this group of individuals to develop CAD.

Key words: Obesity; coronary artery disease; inflammation; protein C.

Obesity as a health public issue

The obesity is currently considered as a global epidemic - an important health public issue, mainly to Western countries¹. According to data recently published in the United States, 67% of adult individuals are overweight, while 34% % present obesity, representing an increase of 75% versus 1991 (Figure 1)². For the first time in the History of mankind, the number of people who are overweight surpassed the people with malnutrition, amounting to more than one billion one hundred million people overweight people around the world.

Overweight is associated to an increasing morbidity and mortality. For instance, in the United States, for the first time since the Civil War, estimates are for a decrease in life expectancy arising out of diseases and disorders related to obesity - including high blood pressure, dyslipidemia, cardiovascular disease and some types of cancer³.

In Brazil, data from the 2003 Brazilian Household Budget Survey revealed that the overweight affects 41.1% of men and 40% of women. Out of this percent, 8.9% of adult men and 13.1% of adult women are considered obese⁴. Thus, we may consider obesity as the most common risk factor found in industrialized and developing countries (Figure 2).

Obesity as a risk factor for coronary artery disease

The association with classic risk factors for cardiovascular disease, such as arterial high blood pressure, Diabetes Mellitus, dyslipidemias and metabolic syndrome, is known for very long time now. However, more recent findings reveal that, even after the control of these associated diseases, the risk of cardiovascular events remains high, which makes obesity to be considered an independent cardiovascular risk factor⁵.

The association of obesity with clinically significant coronary artery disease is blatant in two classical prospective studies highly consulted: the Framingham Heart Study⁶ and the Nurses Health Study⁷.

The relative risk for Coronary Artery Disease (CAD) for adults with body mass index (BMI) of 21 kg/m² increased from 1.19 for patients with BMI from 21 to 22.9 kg/m², and to 3.56 in patients with BMI higher than 29 kg/m² (Table 1).

The Asia Pacific Cohort Collaboration Study⁸, with segment higher than 7 years and involving 430,000 adults, found an increase of 9% in ischemic cardiac events for each unit of change in BMI.

Relationship between obesity and death due to cardiovascular disease is even more conspicuous when concerning patients with abdominal obesity. In the Tandolapril Cardiac Evaluation (TRACE) study, a database analysis showed an increase in mortality around 23% compared to patients without abdominal obesity. This study disregarded Diabetes and arterial high blood pressure influences⁹.

When patients with diagnosed cardiovascular disease or after acute myocardial infarction are analyzed, the increase in BMI is inversely correlated to the increase of mortality¹⁰.

The overweight associated to fat accumulation in mesenteric region refers to a central, visceral or androgenic obesity¹¹. The so-called visceral obesity is well-known as associated to a higher mortality than the peripheral obesity. The cause of this difference lies in the fact that the visceral adipose tissue visceral is more metabolically active than the subcutaneous adipose tissue, causing, for instance, a higher glucose production and, consequently, type 2 Diabetes Mellitus and hyperinsulinism. This higher insulin secretion causes sodium retention, resulting in systemic arterial high blood pressure¹². These conditions characterize metabolic syndrome, considering currently a challenge for public health, once it represents a substantial increase in the risk of Diabetes Mellitus (twice), as well as of cardiovascular disease (twice to thrice)¹³.

Obesity, coronary artery disease, and vascular inflammation

For many years, the physiopathology of arteriosclerosis was considered merely as an accumulation of lipids on the arterial wall. However, over the two past decades, the growing development in the field of vascular biology has been elucidating the nature of atherosclerotic lesions: in fact, they correspond to a series of cellular and molecular responses highly specific and dynamic, with an inflammatory character^14,15.

In vulnerable patients, arteriosclerosis develops through the influence of stress conditions to the endothelium, such as aging, systemic arterial high blood pressure, hypercholesterolemia, Diabetes, tobacco addiction and obesity itself. These factors damage the endothelium and spur on an inflammatory/proliferative reaction on the vascular wall. Such reaction increases the secretion of primary proinflammatory cytokines, such as interleukin (IL)-1 and the tumoral necrosis factor-alpha (TNF-A). They are responsible for the expression of leukocyte adhesion molecules, by the intercellular adhesion molecule (ICAM)-1 and P-, E-, and L-selectins, and by the increase of chemotactic substances (monocyte chemotactic protein-1 [MCP-1] and the macrophage colony-stimulating factor [M-CSF], both amplifiers of the inflammatory cascade)^16,17 (Table 2).

Obesity is characterized as an excess of adipose tissue, with consequent weight gain, and associated with several comorbidities¹⁸. Regarded as a mere deposition of triacylglycerol and free fatty acids in the past, now the adipose tissue is seen as an important endocrine and paracrine organ, which produces several proinflammatory substances¹⁹.

In the process of differentiation of preadipocytes into mature adipocytes, the latter began capable of producing a number of proteins: enzyme, cytokines, growth factors and hormones involved in several metabolic events²⁰.

Components of adipogenesis include the lipoprotein lipase, angiotensinogen, adipsin, adiponectin, IL-6, prostaglandin, TNF-A and nitric oxide. These molecules have modulating action of lipid depositions and body fat distribution²¹.

More recently, the adipose tissue is being regarded as a source of proinflammatory mediators which contribute to vascular injury, insulin resistance and atherogenesis. The adipokines, as known nowadays, include: TNF-A, IL-6, leptin, plasminogen activator inhibitor 1 (PAI)-1, angiotensinogen, resistin and C-reactive Protein (CRA). Some of them have a protective role against vascular inflammation and insulin resistance, namely: the adiponectin and the nitric oxide, among others¹⁸.

The adipokines are found high in obese patients and in patients with insulin resistance, and are more produced by the abdominal adipose tissue than in other places. The weight loss is associated with the decrease of these substances²².

Main inflammatory markers in obesity

C-reactive protein

The CRA is an acute phase protein (APP) synthesized in the liver and regulated by the circulating levels of IL-6. In their turn, IL-1 and TNF-A may induce expression of messenger RNA for production of CRA. Recently, high levels of CRA in plasma were considered as independent predictors of Coronary Artery Disease²³. Circulating plasma levels of CRA are high in obese and are directly related to the amount of body fat, estimated by means of body mass index, visceral obesity, abdominal circumference, insulin resistance, metabolic syndrome and Diabetes Mellitus²⁴.

The CRA is not a mere marker of inflammatory activity: it participates directly in the process of atherogenesis and modulates the endothelial function. It also induces the expression of several molecules (ICAM-1, VCAM-1, MCP-1 and selectins). It acts as regulator of the production of nitric oxide in the endothelium and coordinates the production and secretion of several cytokines, increasing the proinflammatory activity of several adipokines²⁵.

Leptin

The leptin is a specific adipocyte hormone, which functions as a signaling molecule in the brain, which makes it complete the negative feedback of the lipostatic theory of weight control²⁶. The knowledge that obese individuals are not mostly leptin-deficient, rather, to the contrary, they have high serum concentrations of these substances, set the stage for the leptin resistance theory².

In this vein, resistance to leptin may be explained by a low sensibility to the action of the hormone or by the high leptin serum levels that could lead to an improper response (relative leptin deficiency).

The leptin resistance theory became noticeable after a dose scaling study of recombining leptin, randomized and placebo-controlled, obtained disappointing results while trying to evaluate the weight loss after injecting recombining leptin. Serum concentration twenty to thirty times higher were necessary for the weight loss²⁷. It is not clear why high serum concentrations of endogenous leptin are found in obese individuals and in individuals resistant to leptin. One knows, however, that these high levels and exogenous supplements of leptin are not sufficient to keep a healthy weight.

There are several theories that explain this mechanism, but none was scientifically proved: genetic mutation, self-regulation, tissue access limited by the blood-brain barrier and the action of molecules in cellular and circulatory levels.

There are many therapeutic implications of fighting resistance to leptin, insomuch this condition seems to be associated to various risk factors for CVD and other pathological conditions, such as obesity, metabolic syndrome, resistance to insulin, type 2 Diabetes Mellitus, systemic arterial high blood pressure, atherothrombosis and myocardial disease.

TNF-A

High amounts of secretion of inflammatory cytokine produced by obese individuals and by insulin-resistant patients not only give rise, but spread the formation of atherosclerotic lesion. The TNF-A participates in the acceleration of atherogenesis by inducing the expression of VCAM-1, ICAM-1, MCP-1 and E-selectin. It also reduces the bioavailability of nitric oxide in endothelial cells and impairs endothelium-dependant vasodilation, promoting the endothelial dysfunction. Besides this, is causes apoptosis in endothelial cells, contributing for endothelial injury²⁸.

Resistin

It is a hormone specific of the adipose tissue recently discovered, which directly induces the insulin resistance in muscles and liver. The resistin induces the expression of messenger RNA producer of endothelin-1 in endothelial cells, thus contributing to endothelial dysfunction. It also significantly increases the expression of the cellular adhesion molecule VCAM-1 and the MCP-1, hey factors in formation of early atherosclerotic lesion²⁹.

It was recently demonstrated the proinflammatory action of resistin in smooth muscle cells: it induces the proliferation of such cells, suggesting the action of these hormones is restenosis of coronary lesions in patients with Diabetes³⁰.

Angiotensinogen

It is a precursor of angiotensin II, expressed and produced in adipocytes. The angiotensin II directly stimulates the expression of ICAM-1, VCAM-1, MCP-1 and M-CSF in vascular cells. The increased production of angiotensinogen by the adipose tissue is associated with high blood pressure and angiogenesis, both related to endothelial dysfunction. Similarly, the angiotensin II acts in the formation of oxygen-derived free radicals, decreasing the availability of nitric oxide and causing damages to the vascular tissue³¹.

Adiponectin

Opposed to what happens to other adipokines already referred to, the levels of adiponectin are lower in obese patients, functioning and an inhibitor agent of the inflammatory process³². Clinical and experimental studies suggest that low levels of adiponectin contribute for the development of diseases related to obesity, including cardiovascular diseases³³.

Levels of adiponectin in plasma generally range from 3 to 30 μg/ml in healthy individuals. In obese individuals, these levels are significantly reduced, with negative correlation between BMI and adiponectin levels in plasma³⁴. The reason for the reduction of the levels of adiponectin in obese individuals seem to be related with proinflammatory cytokines, such as the IL-6, which, due to the fact they increase in obese individuals, may cause a reduction in the expression of the messenger RNA producer of adiponectin and its release by adipocytes³⁵.

In vascular levels, actions of the adiponectin comprise reduction in expression of ICAM-1, VCAM-1 and E-selectin. They also inhibit the transformation of macrophages in foam cells and the proliferation and migration of smooth muscle cells³⁶.

Qasim et al., in a sub-analysis of the database of SIRCA (Study of Inherited Risk of Coronary Atherosclerosis), examined the association between leptin and adiponectin and the risk factor for CVD and coronary arterial calcification (CAC). The plasma leptin associated positively with the CAC after adjustment for age, gender, traditional risk factor and Framingham risk score (Tobit regression relationship of 2.42 [IC 95%: 1.48 - 3.95; p=0. 002]). In their turn, the levels of plasma adiponectin did not associate to the CAC³⁷ (Figure 3).

Endothelial dysfunction present in obesity: cardiovascular worsening factor

The coronary endothelial dysfunction is considered an early stage of the coronary arteriosclerosis and may occur in epicardic vessels, resistance vessels or both³⁸. Suwaidi et al³⁹ assessed the impact of obesity in coronary endothelial function in patients with normal coronary or slightly sick coronary when examined with angiography. A total of 397 consecutive patients with such characteristics were subject to coronary vascular reactivity using intracoronary adenosine, acetylcholine and nitroglycerin. The patients were divided into three groups, based on the Body Mass Index (BMI), since the one considered normal (BMI < 25 kg/m²), until the overweight group (BMI from 25 to 30 kg/m²) and the obese patients (BMI > 30 kg/m²). The increase in coronary flow as a response to acetylcholine was significantly lower than in the group of obese patients than in the of patients with normal BMI (see Figure 4). By means of multivariate analysis, the group of overweight and obese patients was independently associated to coronary endothelial dysfunction. The study demonstrated that the obesity is independently associated to coronary endothelial dysfunction in patients with normal coronaries under angiography exam or else with mild coronary artery disease.

Therapeutic implications

The overweight leads not only to changes in the development of insulin resistance, but also influences the process of endothelial dysfunction by means of proinflammatory and prothrombotic effects of adipokines. The treatment which aims at reducing the percent of body fat, as well as the visceral fat, tends to reduce such effects⁴⁰.

The magnitude of the protective effect seems to be related with the reduction of the body mass index. In overweight women who experience slight weight loss (>10%), a reduction of up to 20% % in premature mortality was found, also associated to the control of risk factors, such as Diabetes Mellitus, dyslipidemia and systemic arterial high blood pressure⁴¹.

The current knowledge that the production of adipokines is increased in obesity and insulin resistance conditions leads to a new field of research aiming at developing treatments that interfere in this situation.

Measures not related to use of drugs, such as change of life style, are still the crux of the treatment. Drugs such as glitazons, estatins, acetylsalicylic acid, angiotensin converter enzyme inhibitors and angiotensin receptor blockers are being tested and seem to be active in the decrease of anti-inflammatory adipokines² (Table 3).

Conclusions

The obesity is a chronic metabolic disorder associated to the CAD, with increase indexes of morbidity and mortality. The inflammatory process causes not only endothelial dysfunction, but also triggers cellular proliferation and migration, oxidative stress, apoptosis, thrombus and cellular necrosis. The adipokines have an important role in this process, mainly in endothelial dysfunction. The weight loss, although not scientifically proven to decrease mortality, seems to reduce risk for CAD and Diabetes Mellitus, mainly in obese individuals.

Potential Conflict of Interest

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

Sources of Funding

There were no external funding sources for this study.

Study Association

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

References

• 1. Poirier P, Thomas D, Bray G, Hong Y, Stern J, Pi-Sunyer X, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity and Metabolism. Circulation. 2006; 113: 898-918.
• ²
  National Center for Health Statistics. Health, United States, 2007 with chartbook on trends in the health of Americans. Hyattsville, MD; 2007. p. 567.
• 3. Olshansky SJ, Passaro DJ, Hershow RC. A potential decline in life expectancy in the United States in the 21st century. N Engl J Med. 2005; 52: 1138-45.
• ⁴
  IBGE - Instituto Brasileiro de Geografia e Estatística. Pesquisa de orçamento familiar (POF) 2002/2003. [Acesso em 2008 set. 20]. Disponível em http://www.ibge.gov.br
• 5. Haslam DW, James WP. Obesity. Lancet. 2005; 366: 1197-209.
• 6. Manson JE, Colditz GA. A prospective study of obesity and risk of coronary heart disease in women. N Engl J Med. 1990; 322: 882-9.
• 7. Manson JE, Willet WC, Stampfer MJ, Colditz GA, Hunter DJ. Body weight and mortality among women. N Engl J Med. 1995; 333: 677-85.
• 8. Ni Mhurchu C, Rodgers A. Body mass index and cardiovascular disease in the Asia-Pacific Region: an overview of 33 cohorts involving 310,000 participants. Int J Epidemiol. 2004; 33: 751-8.
• 9. Kragelund C, Hassager C. TRACE study group. Impact of obesity on long-term prognosis following acute myocardial infarction. Int J Cardiol. 2005; 98: 123-31.
• 10. Dagenais GR, Yi Q. Prognostic impact of body weight and abdominal obesity in women and men with cardiovascular disease. Am Heart J. 2005; 149: 54-60.
• 11. Sociedade Brasileira de Cardiologia. IV Diretriz brasileira sobre dislipidemias e prevenção da aterosclerose. Arq Bras Cardiol. 2007; 88 (supl 1): 1-18.
• 12. Sugerman H. The pathophysiology of severe obesity and the effects of surgically induced weight loss. Surg Obes Relat Dis. 2005; 1: 109-19.
• 13. Zimmet P, Alberti G. The metabolic syndrome: progress towards one definition for an epidemic of our time. Nature. 2008; 4 (5): 239.
• 14. Rocha VZ, Libby P. Obesity, inflammation, and atherosclerosis. Nat Rev Cardiol. 2009; 6 (6): 399-409.
• 15. Serrano CV Jr, Souza JA, Paiva MSMO. Fatores desencadeantes da instabilização da placa aterosclerótica. Rev Soc Cardiol Estado de São Paulo. 2001; 4: 724-32.
• 16. Fernandes JL, Soeiro A, Ferreira CB, Serrano CV Jr. Síndromes coronárias agudas e inflamação. Rev Soc Cardiol Estado de São Paulo. 2006; 3: 178-87.
• 17. Serrano CV Jr, Souza JA, Heinisch RH. A agressão vascular no desencadeamento das síndromes isquêmicas miocárdicas instáveis. In: Nicolau JC, Marin JA. (eds.). Síndromes isquêmicas miocárdicas instáveis. São Paulo: Atheneu; 2001. p. 25-36.
• 18. Bergman R, Mittelman S. Central role of the adipocyte in insulin resistence. J Basic Clin Physiol Pharmacol. 1998; 9: 205-21.
• 19. Mazurek T, Zhang L, Zalewski A. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation. 2003; 108; 2460-6.
• 20. Lau D, Dhillon B, Yan H, Szmitko P, Verma S. Adipokines: molecular links between obesity and atherosclerosis. Am J Heart Circ Physiol. 2005; 288: 2031-41.
• 21. Reilly MP, Rohatgi A, McMahon K, Wolfe ML, Pinto SC, Rhodes T, et al. Plasma cytokines, metabolic syndrome, and atherosclerosis in humans. J Invest Med. 2007; 55: 26-35.
• 22. Lau D, Yan H, Abdel-Hafez M, Kermouni A. Adipokines and the paracrine control of their production in obesity and diabetes. Int J Obes Relat Metab Disord. 2002; 26: S111.
• 23. Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation. 2003; 107: 363-9.
• 24. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000; 102: 2165-8.
• 25. Lemieux I, Pascot A, Prud'home D, Alméras N, Bogaty P, Nadeau A, et al. Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity. Arterioscler Thromb Vasc Biol. 2001; 21: 961-7.
• 26. Martin S, Qasim A, Reilly M. Leptin resistance. J Am Coll Cardiol. 2008; 52: 1201-10.
• 27. Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA. 1999; 282: 1568-75.
• 28. Hotamisligil G, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistence. J Clin Invest. 1995; 95: 2409-15.
• 29. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al. The hormone resistin links obesity to diabetes. Nature. 2001; 409: 307-12.
• 30. Calabro P, Samudio I, Willerson JT, Yeh ET. Resistin promotes smooth muscle cell proliferation through activation of extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3-kinase pathways. Circulation. 2004; 10: 3335-40.
• 31. Tham DM, Martin-McNulty B, Wang YX, Wilson DW, Vergona R, Sullivan ME, et al. Angiotensin II is associated with activation of NF-_B-associated genes and downregulation of PPARs. Physiol Genomics. 2002; 11: 21-30.
• 32. Hopkins T, Ouchi N, Shibata R, Walsh K. Adiponectin actions in the cardiovascular system. Cardiovasc Res. 2007; 74: 11-8.
• 33. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, et al. Paradoxical decrease of an adipose-especific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999; 270: 79-83.
• 34. Ouchi N, Kihara S, Funahashi T. Obesity, adiponectin and vascular inflammatory disease. Curr Opin Lipidol. 2003; 14: 561-6.
• 35. Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, et al. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NFkappaB signaling through a cAMP-dependent pathway. Circulation. 2000; 102: 1296-301.
• 36. Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y, et al. Adipocyte-derived plasma protein, adiponectin suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation. 2001; 103: 1057-63.
• 37. Qasim A, Mehta NN, Mahet G. Adipokines, insulin resistence, and coronary artery calcification. J Am Coll Cardiol. 2008; 52: 231-6.
• 38. Egashira K, Inou T, Yamada A, Hirooka Y, Yamada A, Maruoka Y, et al. Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. J Clin Invest. 1993; 91: 91-7.
• 39. Suwaidi JA, Higano ST, Holmes Jr DR, Lennon R, Lerman A. Obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries. J Am Coll Cardiol. 2001; 37: 1523-8.
• 40. Goldstein D. Beneficial health effects of modest weight loss. Int J Obes. 1991; 16: 397-415.
• 41. Ziccardi P, Nappo F, Giugliano G, Esposito K, Marfella R, Cioffi M, et al. Reduction of inflammatory cytokine concentrations and improvement after weight loss over one year. Circulation. 2002; 105: 804-9.

Obesity and coronary artery disease: role of vascular inflammation

Fernando Gomes; Daniela F. Telo; Heraldo P. Souza; José Carlos Nicolau; Alfredo Halpern; Carlos V. Serrano Jr.

Publication Dates

• Publication in this collection
  05 May 2010
• Date of issue
  Feb 2010

History

• Accepted
  08 June 2009
• Reviewed
  18 May 2009
• Received
  09 Jan 2009