New evidence on the potential role of the metabolic syndrome as a risk factor for venous thromboembolism
2009; Elsevier BV; Volume: 7; Issue: 5 Linguagem: Inglês
10.1111/j.1538-7836.2009.03327.x
ISSN1538-7933
AutoresWalter Ageno, Francesco Dentali, Anna Maria Grandi,
Tópico(s)Pharmacology and Obesity Treatment
ResumoThe metabolic syndrome is defined by a clustering of interrelated risk factors that identify individuals at increased risk for cardiovascular disease [1Grundy S.M. Cleeman J.I. Daniels S.R. Donato K.A. Eckel R.H. Franklin B.A. Gordon D.J. Krauss R.M. Savage P.J. Smith S.C. Spertus J.A. Costa F. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement.Circulation. 2005; 112: 2735-52Crossref PubMed Scopus (9383) Google Scholar]. Although a single underlying cause has never been proven, insulin resistance has been proposed from the beginning as the basis of most features of this syndrome. Insulin resistance is usually associated with obesity, and in particular with visceral or abdominal obesity. It has been hypothesized that obesity induces insulin resistance by means of increased visceral adiposity and a proinflammatory state, among other mechanisms [2Petersen K.F. Shulman G.I. Pathogenesis of skeletal muscle insulin resistance type 2 diabetes mellitus.Am J Cardiol. 2002; 90: 11G-18GAbstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar, 3Dandona P. Aljada A. Chaudhur A. Mohanty P. Garg R. Metabolic syndrome. A comprehensive perspective based on interactions between obesity, diabetes, and inflammation.Circulation. 2005; 111: 1448-54Crossref PubMed Scopus (1110) Google Scholar]. Because abdominal adipose tissue, which is best viewed as an endocrine organ [4Opie L.H. Metabolic syndrome.Circulation. 2007; 115: 32-5Crossref PubMed Scopus (68) Google Scholar], appears to play a central role in the etiology of the syndrome and thus in the clustering of its components, some experts have proposed the presence of abdominal obesity as a necessary condition for the diagnosis of the metabolic syndrome [5Alberti K.G. Zimmet P. Shaw J. IDF Epidemiology Task Force Consensus GroupThe metabolic syndrome – a new worldwide definition.Lancet. 2005; 366: 1059-62Abstract Full Text Full Text PDF PubMed Scopus (6101) Google Scholar]. Thus, according to the International Diabetes Federation, a person is defined as having the metabolic syndrome in the presence of abdominal obesity (defined by increased waist circumference) plus any two other features, which include raised triglyceride levels, reduced high-density lipoprotein cholesterol, raised blood pressure, and raised fasting plasma glucose [5Alberti K.G. Zimmet P. Shaw J. IDF Epidemiology Task Force Consensus GroupThe metabolic syndrome – a new worldwide definition.Lancet. 2005; 366: 1059-62Abstract Full Text Full Text PDF PubMed Scopus (6101) Google Scholar]. Conversely, according to the modified National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) definition, no specific single factor but the concomitant presence of three to five features of the metabolic syndrome is required for the diagnosis [1Grundy S.M. Cleeman J.I. Daniels S.R. Donato K.A. Eckel R.H. Franklin B.A. Gordon D.J. Krauss R.M. Savage P.J. Smith S.C. Spertus J.A. Costa F. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement.Circulation. 2005; 112: 2735-52Crossref PubMed Scopus (9383) Google Scholar]. This different diagnostic approach is justified by the observation that some patients can manifest features of insulin resistance and the metabolic syndrome even with only moderate increases in waist circumference [1Grundy S.M. Cleeman J.I. Daniels S.R. Donato K.A. Eckel R.H. Franklin B.A. Gordon D.J. Krauss R.M. Savage P.J. Smith S.C. Spertus J.A. Costa F. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement.Circulation. 2005; 112: 2735-52Crossref PubMed Scopus (9383) Google Scholar]. Furthermore, different definitions of the metabolic syndrome appear to make little difference to the prognostic implications [6Hanley A.J. Karter A.J. Williams K. Festa A. D’Agostino R.B. Wagenknecht L.E. Haffner S.M. Prediction of type 2 diabetes mellitus with alternative definitions of the metabolic syndrome: the Insulin Resistance Atherosclerosis Study.Circulation. 2005; 112: 3713-21Crossref PubMed Scopus (224) Google Scholar]. A number of longitudinal studies have confirmed that individuals with the metabolic syndrome are at increased risk of cardiovascular events and death [7Gami A.S. Witt B.J. Howard D.E. Erwin P.J. Gami L.A. Somers V.K. Montori V.M. Metabolic syndrome and risk of incident cardiovascular events and death. A systematic review and meta-analysis of longitudinal studies.JACC. 2007; 49: 403-14Crossref Scopus (1494) Google Scholar], and that this risk increases linearly with the number of features of the syndrome [8Schillaci G. Pirro M. Vaudo G. Gemelli F. Marchesi S. Porcellati C. Mannarino E. Prognostic value of the metabolic syndrome in essential hypertension.J Am Coll Cardiol. 2004; 43: 1817-22Crossref PubMed Scopus (290) Google Scholar]. Because the metabolic syndrome is characterized by an inflammatory and a hypercoagulable state, we recently explored the hypothesis that this syndrome may also increase the risk of venous thromboembolism (VTE). In a case–control study, we compared the incidence of the metabolic syndrome in a group of 93 patients with a first episode of unprovoked deep vein thrombosis (DVT) and in 107 controls [9Ageno W. Prandoni P. Romualdi E. Ghirarduzzi A. Dentali F. Pesavento R. Crowther M.A. Venco A. The metabolic syndrome and the risk of venous thrombosis. A case control study.J Thromb Haemost. 2006; 4: 1914-18Crossref PubMed Scopus (144) Google Scholar]. In this study, the metabolic syndrome was significantly more prevalent in patients with unprovoked DVT than in controls, with an adjusted odds ratio of 2.16 [95% confidence interval (CI) 1.19–3.90]. This observation has been confirmed subsequently by the results of three other case–control studies [10Ambrosetti M. Ageno W. Salerno M. Pedretti R.F. Salerno-Uriarte J.A. Metabolic syndrome as a risk factor for deep vein thrombosis after acute cardiac conditions.Thromb Res. 2007; 120: 815-18Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 11Ay C. Tengler T. Vormittag R. Simanek R. Dorda W. Vukovich T. Pabinger I. Venous thromboembolism – a manifestation of the metabolic syndrome.Haematologica. 2007; 92: 373-9Crossref Scopus (140) Google Scholar, 12Jang M.J. Choi W. Bang S.M. Lee T. Kim Y.K. Ageno W. Oh D. Metabolic syndrome is associated with venous thromboembolism in the Korean population.Arterioscler Thromb Vasc Biol. 2009; 29: 311-5Crossref PubMed Scopus (54) Google Scholar]. The first was performed in 181 patients admitted to a rehabilitation center after an episode of acute coronary syndrome or congestive heart failure [10Ambrosetti M. Ageno W. Salerno M. Pedretti R.F. Salerno-Uriarte J.A. Metabolic syndrome as a risk factor for deep vein thrombosis after acute cardiac conditions.Thromb Res. 2007; 120: 815-18Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. In this patient population, the risk of subsequent development of DVT was significantly associated with the presence of the metabolic syndrome, with a non-adjusted odds ratio of 2.38 (95% CI 1.64–3.12). In the second study, the incidence of the metabolic syndrome was compared in 116 patients with objectively confirmed recurrent DVT and pulmonary embolism (PE), who had had at least one unprovoked event, and 129 healthy controls matched for age and sex [11Ay C. Tengler T. Vormittag R. Simanek R. Dorda W. Vukovich T. Pabinger I. Venous thromboembolism – a manifestation of the metabolic syndrome.Haematologica. 2007; 92: 373-9Crossref Scopus (140) Google Scholar]. The association was again confirmed, with an adjusted odds ratio of 2.2 (95% CI 1.1–4.2). Finally, a significant association between the metabolic syndrome and VTE, in particular unprovoked VTE, was recently documented in Korean patients (adjusted odds ratio 1.71, 95% CI 1.04–2.81) [12Jang M.J. Choi W. Bang S.M. Lee T. Kim Y.K. Ageno W. Oh D. Metabolic syndrome is associated with venous thromboembolism in the Korean population.Arterioscler Thromb Vasc Biol. 2009; 29: 311-5Crossref PubMed Scopus (54) Google Scholar]. Following the consistent results of the four case–control studies, this potential association between the metabolic syndrome and VTE required confirmation by longitudinal studies. To our knowledge, the first longitudinal study to be published was a post hoc analysis of the HOPE study, a trial carried out in patients with cardiovascular disease or diabetes mellitus [13Ray J.G. Lonn E. Yi Q. Rathe A. Sheridan P. Kearon C. Yusuf S. Arnold M.J. McQueen M.J. Pogue J. Probstfield J. Fodor G. Held C. Micks M. Genest Jr, J. HOPE-2 investigatorsVenous thromboembolism in association with features of the metabolic syndrome.Q J Med. 2007; 100: 679-84Crossref Scopus (34) Google Scholar]. In this study, the presence of the metabolic syndrome was not associated with an increased risk of either DVT or PE, and the risk of VTE did not increase in proportion to the number of features of the metabolic syndrome. However, these results should be interpreted with extreme caution, as the authors measured only four of the five features of the metabolic syndrome, and the cut-offs used for defining hypertension, dyslipidemia and insulin resistance were different from those that are commonly proposed for diagnosis of the metabolic syndrome. In this issue of the Journal of Thrombosis and Haemostasis, the results of two new longitudinal studies evaluating the association between the metabolic syndrome and VTE are reported [14Borch K.H. Braekken S.K. Mathiesen E.B. Njolstad I. Wilsgaard T. Stormer J. Hansen J.B. Abdominal obesity is essential for the risk of venous thromboembolism in the metabolic syndrome – The Tromso Study.J Thromb Haemost. 2009; 7: 739-45Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 15Steffen L.M. Cushman M. Peacock J.M. Heckbert S.R. Jacobs D.R. Rosamond W.D. Folsom A.R. Metabolic syndrome and risk of venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE).J Thromb Haemost. 2009; 7: 746-51Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar]. In the first study, 6170 individuals enrolled in the Tromso Study were assessed for the presence of the metabolic syndrome and were followed up for a median of 12.3 years [14Borch K.H. Braekken S.K. Mathiesen E.B. Njolstad I. Wilsgaard T. Stormer J. Hansen J.B. Abdominal obesity is essential for the risk of venous thromboembolism in the metabolic syndrome – The Tromso Study.J Thromb Haemost. 2009; 7: 739-45Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar]. The metabolic syndrome was defined according to the modified NCEP ATP III criteria [1Grundy S.M. Cleeman J.I. Daniels S.R. Donato K.A. Eckel R.H. Franklin B.A. Gordon D.J. Krauss R.M. Savage P.J. Smith S.C. Spertus J.A. Costa F. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement.Circulation. 2005; 112: 2735-52Crossref PubMed Scopus (9383) Google Scholar], although hemoglobin A1c was used as a marker for impaired glucose metabolism instead of fasting blood glucose. In these Caucasian patients, the prevalence of the metabolic syndrome at baseline was 21.9%. During follow-up, the overall incidence of VTE was 2.92 per 1000 person-years (194 validated events), and the metabolic syndrome was independently associated with an increased risk of VTE, with an adjusted hazard ratio of 1.65 (95% CI 1.22–2.23). The risk of VTE increased linearly with an increasing number of the features of the metabolic syndrome, but this association remained significant only if abdominal obesity was included. Abdominal obesity was also the only component of the metabolic syndrome to be independently associated with VTE. In the second study, which was carried out in the population of the Longitudinal Investigation of Thromboembolism Etiology (LITE) study, the number of evaluated individuals was 20 374 and the mean follow-up was 12.5 years [15Steffen L.M. Cushman M. Peacock J.M. Heckbert S.R. Jacobs D.R. Rosamond W.D. Folsom A.R. Metabolic syndrome and risk of venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE).J Thromb Haemost. 2009; 7: 746-51Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar]. Mean age and gender were substantially similar between the two studies, whereas in the LITE study 23% of the enrolled subjects were African Americans. The incidence of the metabolic syndrome in the LITE study was 34% in women and 30% in men, and the number of adjudicated VTE events was 358. In this study, a significant association between the metabolic syndrome and VTE was found only in men, with a hazard ratio of 1.84 (95% CI 1.30–2.59). Abdominal obesity was again independently associated with an increased risk of VTE, in both men and women, whereas the clustering of at least three other features of the metabolic syndrome in the absence of abdominal obesity was not. The results of these longitudinal studies provide additional evidence on the role of the metabolic syndrome as a risk factor for VTE, substantially corroborating previous observations from case–control studies, and offer important insights into the mechanisms underlying such an association. In both studies, the clustering of metabolic risk factors was an independent predictor of VTE. This was consistent between genders in the Tromso study [14Borch K.H. Braekken S.K. Mathiesen E.B. Njolstad I. Wilsgaard T. Stormer J. Hansen J.B. Abdominal obesity is essential for the risk of venous thromboembolism in the metabolic syndrome – The Tromso Study.J Thromb Haemost. 2009; 7: 739-45Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar], but not in the LITE study [15Steffen L.M. Cushman M. Peacock J.M. Heckbert S.R. Jacobs D.R. Rosamond W.D. Folsom A.R. Metabolic syndrome and risk of venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE).J Thromb Haemost. 2009; 7: 746-51Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar]. Some previous studies evaluating the association between the metabolic syndrome and cardiovascular disease have also found a significant association in men, but no association, or a much smaller one, in women [16Dekker J.M. Girman C. Rhodes T. Nijpels G. Stehouwer C.D.A. Bouter L.M. Heine R.J. Metabolic syndrome and 10-year cardiovascular disease in the Hoorn Study.Circulation. 2005; 112: 666-73Crossref PubMed Scopus (494) Google Scholar, 17Wilson P.W. D’Agostino R.B. Parise H. Sullivan L. Meigs J.B. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus.Circulation. 2005; 112: 3066-72Crossref PubMed Scopus (1501) Google Scholar]. The mechanisms underlying this potential sex-related difference have not been completely elucidated. Consistent with the results of many studies evaluating the metabolic syndrome as a risk factor for cardiovascular disease, the Tromso study has shown that the more features of the metabolic syndrome the patients had, the greater was the risk for VTE [14Borch K.H. Braekken S.K. Mathiesen E.B. Njolstad I. Wilsgaard T. Stormer J. Hansen J.B. Abdominal obesity is essential for the risk of venous thromboembolism in the metabolic syndrome – The Tromso Study.J Thromb Haemost. 2009; 7: 739-45Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar]. This analysis, which was not performed in the LITE study, supports the hypothesis that the metabolic syndrome is more than the sum of its parts. However, in both studies, the clustering of components of the metabolic syndrome was predictive of VTE only in the presence of abdominal obesity. Although the results of subgroup analyses must be treated cautiously, because of a high potential for low statistical power, this observation is of paramount importance. Abdominal obesity has been reported previously to be an independent predictor of VTE [18Hansson P.O. Eriksson H. Welin L. Svardsudd K. Wilhelmsen L. Smoking and abdominal obesity: risk factors for venous thromboembolism among middle-age men: the study of men born in 1913.Arch Intern Med. 1999; 159: 1886-90Crossref PubMed Scopus (294) Google Scholar]. If, on the one hand, abdominal obesity is an important, but not always necessary, feature of the metabolic syndrome for the prediction of atherothrombosis, on the other hand we can hypothesize that the proinflammatory and prothrombotic activity of abdominal fat is a necessary condition to provoke venous thrombi in these patients. The risk is then further increased with the addition of other features of the metabolic syndrome, which identify patients with a more severe condition. Thus, as the main purpose of defining the metabolic syndrome is to identify patients at increased long-term risk of vascular events, it may be reasonable to propose, for both future research projects and for clinical practice, a specific definition of the metabolic syndrome for predicting VTE, which makes the presence of abdominal obesity necessary for diagnosis. Finally, because regular physical activity [19Van Stralen K.J. Le Cessie S. Rosendaal F.R. Doggen C.J. Regular sports activities decrease the risk of venous thrombosis.J Thromb Haemost. 2007; 5: 2186-92Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar] and a diet reach in plant food and fish [20Steffen L.M. Folsom A.R. Cushman M. Jacobs D.R. Rosamond W.D. Greater fish, fruit, and vegetable intakes are related to lower incidence of venous thromboembolism: the longitudinal investigation of thromboembolism etiology.Circulation. 2007; 115: 188-95Crossref PubMed Scopus (128) Google Scholar] have been shown to reduce the incidence of VTE, and because these are key elements for the primary intervention in patients with the metabolic syndrome [5Alberti K.G. Zimmet P. Shaw J. IDF Epidemiology Task Force Consensus GroupThe metabolic syndrome – a new worldwide definition.Lancet. 2005; 366: 1059-62Abstract Full Text Full Text PDF PubMed Scopus (6101) Google Scholar], future studies specifically designed to address these strategies in this patient population are now needed. The authors state that they have no conflict of interest.
Referência(s)