Abdominal Obesity and CVD

• Metabolic studies have shown that in both men and women the amount of visceral adipose tissue is strongly linked to metabolic abnormalities that increase the risk of type 2 diabetes and CVD.
• Overall obesity increases CVD risk. A wealth of data also indicates that obese individuals with high levels of abdominal fat—visceral fat in particular—form an obese subgroup with the worst metabolic profile.
• Because not every obese patient is at increased risk of CVD, the challenge for clinicians is to identify the subgroup of patients at highest risk of CVD. This requires clinicians to do more than measure body weight and calculate BMI.
• In order to properly evaluate CVD risk among overweight/obese patients, emphasis should be placed on estimating visceral adipose tissue using simple tools such as waist circumference.

Most clinicians agree that obesity is a health hazard because of its ties to a host of metabolic complications such as dyslipidemia, type 2 diabetes, and cardiovascular disease (CVD) [1]. In today’s society, obesity is the driving force behind the rise in CVD [2]. The American Heart Association has singled out obesity as a major modifiable risk factor for heart disease [3,4]. Moreover, the Framingham Heart Study—a 26-year follow-up analysis conducted in men and women—revealed that body weight was independently related to development of CVD [5]. Additional studies have provided further evidence for a univariate relationship between obesity and CVD [6-10]. Although many epidemiological studies have linked body weight and coronary artery disease (CAD) [11-13], other studies using multivariate analysis have failed to identify obesity as an independent CVD risk factor [14,15]. In some cases, obesity’s contribution to CAD was no longer found to be significant after controlling for traditional CAD risk factors [6]. The exact relationship of CVD to body weight remains controversial and is still debated within the scientific community.

The equivocal data on obesity and mortality may be explained by the fact that most epidemiological studies have used anthropometric correlates of total body fat (the most commonly used being body mass index—BMI—expressed in kg/m²) instead of taking into account the location of excess body fat, which seems to play a greater role in obesity-related health hazards. However, indices of overall obesity do not take into account the remarkable heterogeneity among overweight/obese patients [16]. In this regard, physicians are constantly challenged by the absence of metabolic complications in some very obese patients with a relatively “normal” metabolic profile despite their obvious excess body fat. Conversely, slightly overweight patients can display a cluster of atherogenic metabolic abnormalities that increase their risk of CVD. This variation in body fat distribution among obese patients was first noted by French physician Jean Vague in the mid-forties [17]. He reported that the complications generally found in obese patients depended more on the location of the excess fat rather than on obesity per se [17]. Vague used the term “android obesity” to describe the high-risk form of obesity, which is characterized by an accumulation of adipose tissue in the trunk and is commonly found in men. He described the accumulation of body fat in the gluteo-femoral region—the common fat pattern of premenopausal women—as “gynoid obesity.” This type of obesity is rarely associated with the common complications of excess adiposity [18,19]. However, it took the medical community some time to realize the significance of Vague’s clinical observations about sex differences in body fat distribution. The concept of regional adipose tissue distribution only received serious consideration in the 1980s, when prospective studies also showed that abdominal fat was associated with mortality, independent of total adiposity as estimated by BMI [20-22]. These studies provided sound evidence that regional fat distribution—as evaluated by anthropometric indices such as waist circumference and trunk skinfolds—was tied to increased CVD risk [20,21,23].

According to international guidelines, obesity is defined as a BMI of 30 kg/m² or more [24]. BMI is commonly used as a valuable index of relative body weight and a crude estimate of total adiposity [25]. Although of great use in estimating overall obesity, this clinical tool has serious limitations. First, the index assumes that weight is distributed evenly over the body [1] and does not take into account the heterogeneity of obesity [16]. For example, individuals with large muscle mass but without excess body fat (e.g., American football and ice hockey or rugby players) could be misclassified as having a high-risk body weight. In addition, BMI does not provide information on body fat location, which has been shown to be a critical correlate of metabolic disturbances leading to CVD [26]. In this regard, several studies relating BMI to CVD outcomes in healthy individuals have reported inconsistent results. Some studies have found a linear relationship between BMI and cardiovascular risk, whereas others have failed to find an association [20,21,27-29]. However, most studies on the issue have not measured abdominal adiposity. In the Heart Outcomes Prevention Evaluation (HOPE) prospective study conducted in men and women with stable CVD, Dagenais et al. [30] found that BMI was no longer an independent predictor of myocardial infarction after adjusting for abdominal obesity indices such as waist-to-hip ratio (WHR) and waist circumference. Moreover, after adjusting for traditional risk factors such as BMI, waist circumference and WHR were independent predictors of CVD death, myocardial infarction, and total mortality [30]. Other studies carried out in subjects without known CVD have also reported that WHR and waist circumference were better predictors of coronary heart disease than BMI [20,31]. For example, a 13-year follow-up study of 792 men reported that a high WHR increased ischemic heart disease risk while indices of total obesity had no predictive value [21]. The authors concluded that although the association between WHR and CVD risk was not significant in multivariate analyses when cholesterol levels and blood pressure were taken into account, WHR was more closely related to CVD risk than other indices of obesity such as skinfold thickness or BMI [21]. An additional prospective study conducted in women also reported similar findings [20].

This latter study examined whether an android phenotype—the high-risk form of abdominal obesity commonly found in men—also increased CVD risk in women. Over a 12-year follow-up, the authors found that WHR was a better predictor of myocardial infarction in women than other indices of total adiposity. Accordingly, the study concluded that women with a typically masculine distribution of adipose tissue could represent a subgroup at high risk of CVD.

In the Nurses’ Health Study [32]—a follow-up study conducted on a cohort of more than 44,000 women free of coronary heart disease (CHD) at baseline—Rexrode et al. examined the 8-year incidence of CHD among tertiles of baseline BMI and waist circumference values. They found that both elevated WHR and waist circumference were independently associated with a twofold increase in CHD risk, even after adjusting for hypertension, diabetes, and high cholesterol. They also reported that higher waist circumference values increased CHD risk, regardless of BMI tertile. In addition, they found that the CHD risk of overweight/obese women (BMI>25.2 kg/m²) who were not abdominally obese (waist circumference <73.7 cm) was similar to the CHD risk of non-obese women (BMI <22.2 kg/m²) with higher levels of abdominal fat (waist circumference >81.8 cm). These findings highlight the need to go beyond body weight and BMI and take into account adipose tissue distribution in evaluating CHD risk.

A large myocardial infarction cases/controls study—INTERHEART [33]—was conducted in a sample of 27,098 participants from 52 countries. The study showed that WHR and waist circumference were closely tied to risk of myocardial infarction even after adjusting for other risk factors. The risk of myocardial infarction not only rose progressively with increasing WHR values, it also increased in each BMI category, suggesting that WHR is a good predictor of myocardial infarction in lean (BMI<25 kg/m²), overweight (BMI>25 kg/m²), and obese individuals (BMI>30 kg/m²). The authors concluded that WHR was a stronger anthropometric correlate of myocardial infarction and could be significantly better than BMI in assessing the risk of myocardial infarction in the general population.

Moreover, a prospective case-control study by Kuk et al. [34] examined 192 men (97 decedents and 194 controls) to establish whether abdominal fat was independently linked to mortality. The study revealed that visceral adipose tissue was a strong independent predictor of all-cause mortality in men. These findings could suggest that visceral fat should become a target of strategies to reduce obesity-related mortality and morbidity. Measuring waist circumference—which is the best anthropometric parameter for evaluating the absolute amount of abdominal visceral fat—therefore facilitates the identification of patients with visceral obesity, insulin resistance, and metabolic complications increasing the risk of CVD [35]. Although common indices of overall adiposity have been shown to predict CVD in both men and women, visceral fat accumulation appears to be the crucial factor tying obesity to CVD.

In order to highlight the limitations of BMI, 40 years ago Ruderman et al. [36,37] introduced the concept of the metabolically obese, normal weight (MONW) subject. These MONW individuals, who have normal BMI values, nonetheless suffer from metabolic complications commonly found in obese people. MONW individuals display a constellation of risk factors such as insulin resistance, abdominal adiposity, low HDL cholesterol levels, elevated triglycerides, impaired fasting glucose, and hypertension. Together these risk factors are also known as the metabolic syndrome [38]. Conversely, metabolically healthy obese (MHO) individuals described by other research groups have a BMI above 30 kg/m² but are not characterized by features of insulin resistance [39,40]. Initially described by Jean Vague, these two phenotypes illustrate obesity’s remarkable heterogeneity when estimated using BMI as well as this index’s limitations in clinical practice. As demonstrated by Meigs et al. [41], subgroups of overweight or obese individuals have a heterogeneous metabolic risk profile. For instance, the authors observed that some normal weight men and women had features of the metabolic syndrome or insulin resistance, whereas some obese individuals had no metabolic abnormalities despite their significant obesity.

The notion of normal weight, metabolically obese subjects has also been documented by St-Onge et al. [42], who quantified the metabolic syndrome’s prevalence among normal weight and slightly overweight individuals. In this report, subjects in the upper (23.0-24.5 kg/m²) and just above normal BMI range (25.0-26.9 kg/m²)—also referred to as MONW individuals—were more likely to have the metabolic syndrome than individuals with a BMI below 20.9 kg/m². These results suggest that CVD risk may increase far below the normal BMI cutoff of 25 kg/m².

Given the crucial role played by visceral adiposity in the metabolic abnormalities of overweight and obesity, a key factor underpinning the difference in CVD risk between MONW and MHO individuals is likely the presence of excess visceral adipose tissue, which has been shown to increase CVD risk [43-45]. Most MONW individuals with relatively low BMI likely have a significant amount of visceral fat, and most MHO individuals with a high BMI likely have much less visceral adipose tissue [46]. Similarly, Matsuzawa et al. [47] have demonstrated that very obese individuals with a small amount of visceral adipose tissue—active sumo wrestlers, for example—are quite insulin sensitive, whereas retired sedentary sumo wrestlers with greater amounts of visceral adipose tissue tend to be insulin resistant and have a high prevalence of metabolic complications such as type 2 diabetes and CVD. These observations lend weight to the notion that visceral adipose tissue is the key factor behind the metabolic complications found in MONW individuals and strongly suggest that we need to look further than BMI, which is a weak correlate of the metabolic syndrome.