European Heart Journal Advance Access originally published online on January 12, 2007
European Heart Journal 2007 28(3):274-275; doi:10.1093/eurheartj/ehl454
Adiponectin and risk of acute coronary syndromes: defining the obesity phenotype
1 Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany
2 Department of Nutrition, Harvard School of Public Health, Boston, MA, USA
3 Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
4 Channing Laboratory, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
* Corresponding author. Tel: +49 33200 88 710; fax: +49 33200 88 721. E-mail address: pischon{at}dife.de
This editorial refers to ‘Association between plasma adiponectin levels and unstable coronary syndromes’
by R. Wolk et al., on page 292
Obesity is a major risk factor for coronary heart disease (CHD), the leading cause of death worldwide.1 Acute coronary syndromes (ACS), including unstable angina pectoris and myocardial infarction, usually result from acute coronary thrombosis as a product of atherosclerotic CHD. There is no straightforward relationship between plaque size and likelihood of plaque rupture, and angiographic studies have shown that lesions preceding non-fatal acute events are usually not haemodynamically significant.2 Further, the majority of ruptured plaques heals without clinical consequence. Understanding the pathophysiology that leads to CHD in general and to ACS specifically and identifying the risk factors are crucial steps for efforts to prevent these diseases. Obese individuals have an ~1.5–2.0-fold increased risk for CHD, and between 15 and 20% of all cases of CHD can be attributed to overweight and obesity.1 In a general population level, a reduction in the prevalence of obesity will likely lead to a decrease in the incidence of CHD and, consequently, in the incidence of ACS. We have, however, only very limited data on whether the incidence of ACS would also be reduced in individuals with established CHD.3 The recommendation to maintain a healthy body weight (or even to lose weight in obese individuals), as stated in European and US guidelines for secondary prevention of CHD4,5 is presumably largely based on the assumption that the associated more favorable metabolic profile (e.g. reductions in blood pressure levels associated with weight loss) would improve the risk of recurrent events. Results from a recent meta-analysis cast doubt on this assumption.6 Among individuals with CHD, the authors reported lower total and cardiovascular mortality rates in overweight or mildly obese patients when compared with normal weight individuals.6 They also found no significant association between BMI and risk of re-infarction or revascularization. Meta-analyses, especially those on obesity, can be problematic because of the many methodological problems and differences that arise across studies and also because most studies rely on BMI as a marker of risk. Visceral adipose tissue is metabolically more active and secretes more cytokines and hormones compared with subcutaneous adipose tissue, yet BMI may only be a crude measure of visceral fat mass.7 Recent large studies have indicated that waist circumference or waist–hip ratio, which shows much closer correlations with the amount of visceral fat, may be better disease risk predictors.8 Even these anthropometric markers may be crude and include substantial measurement error. Thus, identification of biomarkers which quantitate metabolically active adipose may be the best way to define an ‘obesity phenotype’ that is relevant for cardiovascular disease (CVD).
Adiponectin may be such an obesity biomarker, especially for CVD risk. Contrary to other adipose-derived hormones, adiponectin circulates at relatively high concentrations in the blood stream, accounting for 0.05% of total serum proteins, but is inversely associated with obesity, insulin resistance, type 2 diabetes, and CVD.9–11 Data from animal studies suggest that administration of adiponectin improves insulin sensitivity and may have anti-atherogenic and anti-inflammatory properties.10 Adiponectin increases fatty acid oxidation and glucose uptake, reduces fatty acid synthesis, and decreases expression of molecules involved in gluconeogenesis in animal models.9 In vitro, adiponectin inhibits endothelial nuclear transcription factor NF-
B signaling, which mediates the effects of TNF-
and other pro-inflammatory cytokines.10 Adiponectin was also shown to stimulate the production of nitric oxide in vascular endothelial cells and to inhibit the expression of adhesion molecules of class A scavenger receptor expression in macrophages and of proliferation and migration of human aortic smooth muscle cells.9,10 These animal and in vitro studies suggest that adiponectin may affect glucose and lipid metabolism, inflammation, endothelial function, and thrombogenesis. It thus appears that adiponectin may be crucial in several steps in the pathogenetic pathway from obesity to CVD, including early biological functional changes, structural abnormalities, pre-clinical impairments, manifest disease, and, ultimately, fatal or non-fatal complications. However, although animal and in vitro studies may provide proof of principle, they do not tell us whether these findings are relevant in humans.
Wolk et al.12 report on the relationship between plasma adiponectin levels and the likelihood of an ACS in a group of 499 individuals who were undergoing coronary angiography for clinical indications. They found that patients with ACS had significantly lower adiponectin levels than those without ACS, independent of a variety of cardiovascular risk factors. Most notably, the association was independent of whether or not the patients had underlying CHD. In exploratory subgroup analyses, the authors also found that these associations were stronger for men, for subjects with more severe forms of CHD, and for individuals with high CRP levels (
3 mg/L). These data suggest that adiponectin may be more relevant in more severe forms of CHD and in later stages of disease progression.
The study by Wolk et al.12 extends our knowledge about the role of adiponectin in CVD. Several limitations must be taken into account when interpreting the findings, however. First, the study used a cross-sectional design (measuring biomarkers in patients undergoing angiography), which limits interpretability about temporal relationships. It is unclear whether low adiponectin levels reflect abnormalities that triggered ACS or whether they are a consequence of ACS. Prospective studies are needed to determine whether adiponectin predicts ACS in individuals with CHD. Secondly, the authors decided to exclude subjects with strong risk factors for CHD risk, arguing that the inclusion could have ‘obscure(d) the association of other risk factors with atherosclerosis’. These exclusions limit the generalizibility of the results to patients with CHD in general, of which a majority usually has diabetes. Furthermore, subjects with strong risk factors for CHD are also likely to have more severe forms of CHD. As in most cross-sectional or traditional case–control studies, the study also did not include subjects with fatal coronary events. Exclusion of subjects with severe forms of CHD again limits the generalizability of results. As such, the range of absolute adiponectin levels provided in the results likely does not represent the true range expected in CHD patients. Also, the odds ratios presented may under- or overestimate the true strength in the association between adiponectin levels and ACS in individuals with established CHD. Thirdly, the study tried to disentangle the burden of atherosclerosis from plaque rupture; however, plaque ruptures resulting in instable angina or myocardial infarction reflect acute events that can be defined and assessed clinically with much more precision than the burden of atherosclerosis. This is even reflected by the authors' efforts to define and assess CHD on angiography (definitions based on the degree of stenosis vary among 10, 50, and 70%). Therefore, and as noted by the authors, the study does not rule out a role for adiponectin in the development of atherosclerosis. Fourth, the effects of adiponectin may depend on its quaternary structure in plasma, with high molecular weight adiponectin being more closely related to insulin sensitivity than other forms or the total amount of adiponectin.10 Finally, the metabolic effects of adiponectin may not only depend on its plasma concentration but also on the extent and the pattern of the expression of its receptors.10 Despite these apparent limitations, the authors12 found associations for adiponectin similar to what was previously reported for primary prediction of CHD in men.11 From a clinical point of view, the results are an important contribution to the literature because little is known about the association between adiponectin and risk of ACS in individuals with CHD. It is unlikely that adiponectin predicts ACS equally in all subgroups of the population. The study by Wolk et al.,12 therefore, aids to our understanding about the usefulness of adiponectin to identify subjects at risk for ACS.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehl361 
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[Abstract/Free Full Text] - Wolk R, Berger P, Lennon RJ, Brilakis ES, Davison DE, Somers VK. (2007) Association between plasma adiponectin levels and unstable coronary syndromes. Eur Heart J 28:292–298 First published on November 7, 2006, doi:10.1093/eurheartj/ehl361.
[Abstract/Free Full Text]
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Related articles in EHJ:
- Association between plasma adiponectin levels and unstable coronary syndromes
- Robert Wolk, Peter Berger, Ryan J. Lennon, Emmanouil S. Brilakis, Diane E. Davison, and Virend K. Somers
EHJ 2007 28: 292-298.[Abstract] [FREE Full Text]
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