We have read the interesting report of Grau et al.1 on reference values for carotid intima-media thickness in the Spanish population and their association with cardiovascular risk factors. In their study, involving 3161 patients of both sexes, the authors found that the major predictors of carotid intima-media thickness were age and pulse pressure, as well as smoking in men and high-density lipoprotein cholesterol in women.
Aging is accompanied by atherosclerosis, which explains why age is predictive of the carotid intima-media thickness; as the authors point out,1 the association of smoking in men is explained by the higher prevalence of this habit in male patients (24.2%).
The predictive nature of high-density lipoprotein cholesterol exclusively in women can be explained by the effect of 2 confounding variables that are not considered in the study: abdominal obesity and menopausal status. In men, fat is most commonly deposited in the abdominal region, a phenomenon referred to as android obesity, which is associated with increased insulin resistance.
In insulin resistance, the flow of fatty acids from the visceral fat to the liver is enhanced, resulting in triglyceride accumulation (hepatic steatosis) and an increase in very low-density lipoprotein synthesis. The increase in plasma lipoproteins due to their enhanced formation in the liver raises serum triglyceride levels, a process favored by the reduced activity of lipoprotein lipase, an insulin-dependent endothelial enzyme.2
Hypertriglyceridemia affects the pattern of other lipoproteins by increasing the activity of cholesteryl ester transfer protein, which augments the triglyceride content of high-density lipoproteins particles and the cholesterol ester concentration in very low-density lipoprotein particles.3 Ultimately, low-density lipoproteins become small and dense, allowing them to pass through the vascular endothelium and form atheromatous plaques; in addition, these lipoproteins are taken up preferentially by macrophage scavenger receptors, enabling them to evade the normal mechanisms for their elimination by means of low-density lipoproteins receptors. Triglyceride-rich high-density lipoproteins particles are more easily eliminated by hepatic lipase, which reduces serum high-density lipoprotein cholesterol concentrations.
Another factor that could influence the negative association between high-density lipoprotein cholesterol and carotid intima-media thickness in women is menopausal status.4 During menopause, there are profound metabolic and hormonal changes due to a loss of ovarian function and a reduction in circulating estrogen levels. These changes contribute, among other effects, to fat distribution in the abdominal region, increased insulin resistance, and the resulting dyslipidemia. If the prevalence of menopause in the sample analyzed had not been high,1 the presence of these disorders would have been less marked, which partially explains the higher high-density lipoprotein cholesterol concentrations in women and the negative association with the carotid intima-media thickness observed in this group.
Another factor that could contribute to dyslipidemia and favor atherosclerosis is the chronic low-grade inflammation that accompanies abdominal obesity. Visceral adipose tissue is an important source of proinflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha, and high blood concentrations of these proteins favor the inflammatory process and promote insulin resistance.5
We suggest that Grau et al.1 include measurement of abdominal circumference as an indicator of abdominal obesity, take into account menopausal status in women, and determine low-density lipoprotein cholesterol and triglyceride levels. As demonstrated in a number of studies,6 these variables are easy to determine noninvasively and are useful. Despite the questions raised in the present article, we consider the work carried out by these authors to be excellent.
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