Although obesity has been established as an independent risk factor for the development of atheros-
Table 25.1 Ventricular dysfunction reported in severely obese patients
1. Impaired ventricular function
2. Abnormal response to exercise
3. Depressed contractility related to ventricular mass
4. Reduced atrial dimension
5. Reduced ventricular wall and septal size
Adapted from Benotti et al. (8)
clerotic cardiovascular disease (ACVD), obese people often present well-recognized coronary risk factors such as hypertension, lipid abnormalities, and type 2 diabetes (Table 25.2). There is now evidence that fat distribution rather than excess fatness is more commonly associated with these risk factors for ACVD. Abdominal fat deposition, which is principally observed in males and in postmenopausal females, is not only independently associated with ischaemic heart disease, but is a clinical condition in which the traditional risk factors for atherosclerosis are determined by the presence of insulin resistance which has likewise been associated with increased cardiovascular risk (11). The clinical aggregation of all these risk factors is also called the '(pluri)meta-bolic syndrome or syndrome X'. Regardless of these linguistic bagatelles, these patients will be exposed throughout their life to an excess risk for ACVD.
Obese people not only have an excess of traditional risk factors, they also have an excess presence of emerging risk factors such as a altered en-dothelial function and inappropriate production of cytokines, which are believed to play an important role in the development and progression of ACVD.
Lipid and lipoprotein abnormalities are commonly present in obese patients. Population studies have shown a linear relationship between body weight and lipoprotein levels in blood plasma (12). In patients of both sexes between the ages of 20 and 50 years there is a linear relationship between body weight, triglyceride and cholesterol concentrations. In people older than 50 years this relationship is no longer observed (13). Moreover, there is an inverse correlation between body weight and high density lipoprotein (HDL) cholesterol; this reciprocity is observed at all ages and in both sexes. Reduction in
Table 25.2 Atherogenic risk factors in obesity
Lipid and lipoprotein abnormalities
Impaired glucose tolerance/type 2 diabetes Abnormalities of coagulation and fibrinolysis
Endothelial dysfunction f Triglycerides f Cholesterol f Small dense LDL I HDL cholesterol IHDL2/HDL3 cholesterol f Postprandial free fatty acids f von Willebrand f Fibrinogen f PAI-1 antigen/activity I tPA
f Factor VII f C-reactive protein f TNFa f Interleukin-6
I Endothelium-dependent vasodilation
I Effect of insulin to augment endothelium-dependent vasodilation
LDL, low density lipoprotein; HDL, high density lipoprotein; PAI-1, plasminogen activator inhibitor 1; tPA, tissue plasminogen activator; TNFa, tumour necrosis factor a.
Although the relationship between body weight and lipid abnormalities is weak and appreciable only in long-term prospective studies, the effects of obesity on lipoprotein metabolism are more profound than those predicted by the determination of their plasma levels. This concept is supported by kinetic studies which demonstrate that in obese people there is an increase of both production and clearance of very low density lipoprotein (VLDL) without significant alterations in their prevailing plasma concentrations (15).
In obese patients there is an increased hepatic synthesis of VLDL. However, a substantial fraction of these lipoproteins are removed from the circulation without being converted to LDL which are themselves removed faster than in non-obese subjects (16). The reduction of HDL-cholesterol in obese subjects is partly determined by the increased mass of triglyceride-rich lipoproteins (17).
More recently it has been shown that lipoprotein abnormalities are more profound in visceral than in subcutaneous adiposity (18). While excess fat does not appear to be significantly associated with lipid abnormalities, abdominal obesity is a better indicator of the lipoprotein abnormalities commonly used to quantify the risk for ACVD, particularly the
In the general population, waist-to-hip ratio (WHR), an index of abdominal fat accumulation, correlates with VLDL triglyceride concentration and with HDL cholesterol. Furthermore, WHR has been reported to be negatively correlated with HDL2 cholesterol, and positively with both the 'small dense' LDL and with the 'intermediate density lipoprotein' (20). In the light of these findings fat localization rather than total fat mass plays a major role in determining an atherogenic lipid profile. There exists much evidence suggesting a major role for the oxidized low density lipoprotein (LDL) and VLDL particles in the pathogenesis of atherosclerosis (21). In obese subjects there are not only quantitative but also qualitative alterations in circulating lipoproteins. Van Gaal et al. measured the oxidizability in vitro of lipoproteins in 21 obese premeno-pausal women and compared them to 18 age-matched non-obese controls (22). They found that TBARS, an index of lipid oxidation, measured every 30 minutes, increased in non-obese controls up to a maximum of 59.6 at 180 minutes in contrast to a maximum of 77.1 at 180 minutes (P < 0.001) in obese, but healthy, normocholesterolaemic subjects. At each measurement the TBARS were significantly higher (P < 0.01-0.001) in obese subjects. Also the lag-time (period from zero to the start of the particle oxidation process) was significantly lower in obese subjects, when compared to lean controls. BMI correlates significantly with TBARS formation. Thus in vitro oxidizability of non-HDL lipoproteins is significantly increased in obese, non-diabetic subjects and related to increased body weight (23). Thus patients present five main lipid abnormalities: (1) high triglycerides; (2) low HDL cholesterol; (3) reduced HDL2 cholesterol; (4) increased proportion of small dense LDL; (5) increased susceptibility to oxidation of non-HDL lipoproteins.
Obesity and particularly abdominal obesity is associated with lipid and lipoprotein abnormalities not only in the fasting but also in postprandial state. In patients with visceral obesity there is an exaggerated postprandial free fatty acid (FFA) response which suggests that abdominal distribution of fat may contribute to both fasting and postprandial hypertrygliceridaemia by altering FFA metabolism in the postprandial state (16).
The negative effect of obesity on FFA metabolism appears to be determined by different components. First, insulin appears to have a blunted anti-lipolytic effect and this favours the delivery of FFA to the liver. Second, in viscerally obese women reduced post-heparin lipoprotein lipase activity has been observed. In viscerally obese patients, increased activity in another lipase, the hepatic lipase which operates on small triglyceride-rich lipop-roteins, has also been observed (Figure 25.2) (24). This leads to an enrichment of LDL and HDL with triglycerides while VLDL become filled up with cholesterol esters. This process is the result of the action of plasma lipid transfer proteins which leads to increased levels of small dense LDL, a reduced HDL cholesterol (25,26).
Fasting hypertriglyceridaemia is a common feature of visceral obesity (27,28). This metabolic alteration is the result of an increased inflow of FFA to the liver. Several studies have shown that in obese subjects the lipolytic action of catecholamines in subcutaneous fat is reduced. This defect is caused by decreased expression and function of ^-adrenoceptors, increased antilipolytic action of ^-adrenoceptors and impaired ability of cyclic AMP to activate lipolysis (29). In contrast, visceral adipocytes show an enhanced lipolytic response to catecholamines due to an increased lipolytic activity of the 02-adrenoceptors and to decreased antilipolytic activity of the ^-adrenoceptors. Moreover, visceral adipocytes show an inappropriately elevated lipolytic activity which is poorly inhibited by insulin. This
High triglycerides i i
Î Small dense HDL-cholesterol cholesterol-depleted ▼
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