© 2001 American Heart Association, Inc.
Editorial |
Is Visceral Adiposity the "Enemy Within"?
From the University of Vermont College of Medicine, Colchester.
Correspondence to Dr Russell P. Tracy, University of Vermont, Departments of Pathology and Biochemistry, 55A South Park Dr, Colchester, VT 05446.
Key Words: obesity • inflammation • cardiovascular disease
Recently, data from diverse areas of investigation have come together to implicate chronic low-level inflammation as an important pathogenetic factor in atherosclerotic cardiovascular disease (CVD). As recently summarized by Ross,1 studies in cell biology, animal models, clinical research, and epidemiology have been remarkably consistent in validating the early work of Virchow2 and others, suggesting that atherosclerotic lesions are essentially an inflammatory response. In clinical research and epidemiology, 2 inflammation blood markers in particular, fibrinogen and C-reactive protein (CRP), have been used. Many studies have confirmed that these markers predict future cardiovascular events independently of more traditional cardiovascular risk factors, such as plasma lipid levels.3 4 5 Because of this, several investigators have suggested that CRP might prove useful in clinical practice,6 7 whereas others have favored fibrinogen.8 9 Although there are important details to work out before either of these markers enters the clinical domain, this interest provides a clear and compelling imperative for understanding how inflammation integrates into both normal physiology and atherothrombotic pathophysiology.
Focusing on CRP, population-based research efforts have revealed that in general, women have slightly higher values than men, blacks have higher values than whites, and those with clinical CVD have higher values than those without10 11 12 13 (M. Cushman, et al, manuscript in preparation). In those without clinical CVD, metabolic variables consistently correlated with CRP include body mass index (BMI), glucose tolerance status/diabetes status, and level of coagulation activation. In addition, depending on the population being studied, other correlates of CRP may include smoking status, plasma lipids (especially HDL cholesterol), hypertension, evidence of chronic infection, and measures of subclinical atherosclerotic disease, such as ankle-brachial blood pressure index (ABI).
Whether or not some variables have been identified as significant correlates appears to depend, at least in part, on the presence and/or extent of other variables in the analysis. For example, in the nonsmokers of the Cardiovascular Health Study, diabetes status was a strong correlate of CRP but ABI was not; in the smokers, in whom pack-years of smoking was strongly correlated with CRP, diabetes status was no longer significant but ABI was.11 In another example, all measures related to carbohydrate metabolism were correlated with CRP in the Insulin Resistance and Atherosclerosis Study (IRAS), which had participants within a broad range of insulin sensitivity and diabetes status.12 Neither smoking nor measures of subclinical atherosclerosis such as carotid artery wall thickness, however, were correlated with CRP in this group. This variability in correlation suggests that unless significant acute inflammation is present, ambient levels of CRP and underlying regulators such as interleukin-6 are tightly regulated and rarely exceed upper limits. This is logical, because the underlying inflammation system appears to be pervasive and connected to a wide variety of homeostatic and defensive processes.14
Despite this variability in the association of some variables with CRP, a measure of obesity (usually BMI) has been relatively strongly correlated with CRP in virtually all analyses done to date. Two articles in the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology address this now well-established association. Both articles extend our knowledge in this area and provide important new insights into the regulation of inflammation status. The report by Lemieux et al15 focuses on a detailed analysis of body composition in healthy middle-aged men with atherogenic dyslipidemia and a wide range of BMI (21 to 41 kg/m2). They used hydrostatic weighing and computed tomography to make state-of-the-art assessments of body fat, extending the work of Yudkin and others,10 11 13 finding strong positive correlations of CRP with body fat mass, waist girth, and visceral fat. Confirming the analysis done in IRAS,12 they also observed a strong relationship to insulin levels assessed over time during a 75-g oral glucose load. In this group of men, they failed to observe any significant association of CRP with plasma lipid levels, concluding that in men with atherogenic dyslipidemia associated with the metabolic syndrome, it is abdominal obesity that is the "critical correlate" of CRP.
These findings have several important implications. First, the data fit well with a growing body of evidence implicating adipose tissue in general, and visceral adiposity in particular, as key regulators of inflammation, coagulation, and fibrinolysis.16 Adipose tissue secretes proinflammatory cytokines13 17 and fibrinolytic regulators such as plasminogen activator inhibitor-1.18 Along with many possible roles in atherogenesis and atherosclerotic progression, inflammatory mediators can activate coagulation by stimulating monocytes to express tissue factor19 (as can CRP itself20 ) and by causing disregulation in natural anticoagulation.21 They can affect fibrinolytic balance22 and have been implicated as a possible pathogenetic agent in the development of insulin resistance,23 the latter being consistent with the ability of inflammation markers to predict the future occurrence of diabetes.24 As a major source of proinflammatory cytokines, adipose tissue becomes linked at the molecular level to the disregulation of a variety of underlying systems, all of which are causally implicated in the development of atherosclerotic, thrombotic, and metabolic outcomes.
Second, although subcutaneous fat clearly plays an important role,17 the identification of visceral adiposity as a key correlate of CRP in these men is consistent not only with the emerging role of abdominal fat in the metabolic syndrome25 but also with the concept of "nonoverweight obesity" as proffered by Dvorak and colleagues.26 They suggested that the role of visceral fat may be more complex than suspected, because even people who are not obviously overweight may still have disproportionately too much visceral fat, with the result of a predisposition toward insulin resistance and atherosclerotic disease, possibly through inappropriate cytokine secretion. If true, this concept begs the question of whether the key variable might not be disproportionate visceral adiposity rather than what has traditionally been considered obesity as characterized by weight, waist girth, or BMI.
Finally, adiposity may offer a target for modification of inflammation status. The evidence that inflammation is a pathogenetic factor in atherosclerosis is strong, and Lemieux et al conclude their article by suggesting that inflammation may be a modifiable risk factor, citing recent clinical trial data involving aspirin, statins, and fibrates.27 28 29 30 They also suggest that because of the powerful association with obesity, weight loss may be another method for downregulating an individual’s inflammatory status. This point is directly addressed by the second article, the report by Heilbronn et al.31 They studied a group of healthy obese women, characterized by an average BMI of 34 kg/m2, with a range of 28 to 44 kg/m2. These subjects were placed on a very-low-fat diet for 12 weeks and achieved an average weight loss of 8 kg. CRP decreased by 26%, and the authors observed a strong correlation between weight loss and change in CRP (r=0.3, P=0.005).
This observation has important health implications. Although
there are no direct data involving CRP or the proinflammatory
cytokines it reflects in human atherosclerotic disease,
research using the murine model of atherosclerosis has
shown such results,32 and
the indirect data in humans are consistent and becoming
compelling. From a mechanistic standpoint, several possible pathways
for interleukin-6, tumor necrosis factor-
, and CRP have been
identified, eg, the activation of monocytes and
endothelial
cells.20 33
Clinically, in the Physicians Health Study, the ability of aspirin to
protect against a first CVD event was strongly linked to higher CRP
levels,29 and statins appear
to work most effectively in people with higher CRP
values.27 28
Although the ability of aspirin to lower CRP is uncertain, statins
clearly do
so.34 35
Therefore, it is reasonable to hypothesize that other methods that have
a CRP-lowering effect, such as weight loss, may prove more effective in
those with higher CRP values (ie, higher ambient inflammatory status).
Because CRP levels are also associated cross-sectionally with activity
status,36 this finding
suggests a similar hypothesis related to exercise.
We and others have recently observed that unlike statins, hormone replacement therapy in the form of estrogen, but not estrogen-like synthetic drugs, raises CRP levels dramatically.37 38 39 40 On the basis of observational studies, estrogen has traditionally been considered an influence for the better with regard to CVD risk. The recent results from the HERS trial, identifying a significant CVD risk for some women in the first year or so after the start of estrogen therapy,41 however, raise the question of whether drugs that raise CRP may carry an unwanted risk based on their effects on inflammation. In addition, one might ask whether those with greater visceral fat deposits might be at even greater risk because of a possibly increased potential for proinflammatory response. These hypotheses will be tested directly in several ongoing hormone replacement clinical trials.
In summary, an emerging body of evidence suggests that abdominal fat is a key regulatory site for the general processes of inflammation, coagulation, and fibrinolysis. These processes may be altered by behaviors, such as diet and exercise, that affect fat deposits, as well as by medications, in both positive and negative ways. These effects have long-term implications for chronic outcomes such as CVD and type 2 diabetes, which we are only beginning to understand.
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