Arterial stiffness is the most consistent manifestation of vascular aging, and occurs even in healthy individuals without any clinical CVD [1
]. However, some individuals exhibit unsuccessful vascular aging characterized by increased arterial stiffness beyond that which occurs due to normal aging. The presence of CVD risk factors, such as increased visceral fat, may accelerate vascular changes that result in arterial stiffening [1
]. Pfat is a visceral fat depot that potentially poses a significant risk for arterial stiffness due to its close proximity to the vasculature. Thus, in the present study we investigated the association between Pfat and carotid stiffness and found that 1) higher Pfat is associated with higher carotid stiffness in both men and women, and 2) the relationship between Pfat and carotid stiffness is independent of BMI and waist circumference.
There is strong evidence that Pfat affects cardiovascular structure and function. For example, Pfat has not only been associated with LV hypertrophy and impaired LV function, but is also a stronger predictor of LV mass than abdominal visceral fat, BMI, and waist circumference [4
]. Similarly, Pfat was found to be a stronger predictor of coronary artery [4
] disease in Japanese men than other measures of obesity [16
]. In the Framingham study investigators reported that Pfat is highly associated with CAC, independent of abdominal visceral fat [17
]. We and others have confirmed the association with CAC [9
]. While Pfat is highly correlated with a number of metabolic factors [5
], our data suggest that Pfat has independent effects on the vascular wall. In the present study we also observed strong associations between Pfat and CVD risk factors. Even after adjusting for these risk factors, Pfat was strongly associated with carotid stiffness. More importantly, Pfat was a stronger predictor of carotid stiffness than either BMI or waist circumference.
We also found that when stratifying by obesity, the association between Pfat and carotid stiffness was generally stronger in women, but not men, who were non-obese or had a normal waist circumference. Similar findings have been reported with other outcomes. Taguchi et al. found that the association between Pfat and coronary artery disease is stronger in lean vs. obese men [16
]. Gorter et al. found that Pfat is associated with coronary artery disease severity and CAC only in patients with a BMI<27 kg/m2
]. These findings suggest that having excess Pfat is more detrimental when the overall amount of body fat is low or normal. On the other hand, in obese persons the increased amount of fat mass throughout the body may have cumulative effects that outweigh the risk of having excess fat in a more localized area.
It has been hypothesized that increased Pfat may compress the adjacent blood vessel and mechanically impair vascular function [19
]. Another potential mechanism underlying the association between Pfat and arterial stiffness is altered adipokine-mediated signaling between adipose tissue and blood vessels, which may contribute to arterial stiffness and subsequent CVD through pathways involving oxidative stress, endothelial dysfunction, and inflammation. Pfat is highly lipolytic and has a high expression of chemokines and inflammatory cytokines [18
]. Fat around blood vessels has also been shown to promote vascular smooth muscle cell growth, vasoconstriction, and inflammatory cell recruitment [21
]. Thus, in the presence of excess Pfat, these pro-inflammatory activities are likely to be increased and thereby promote the development of vascular dysfunction. We were surprised to find that adjustment for CRP, CAC, and carotid IMT generally did not alter the relationship between Pfat and carotid stiffness. However, systemic levels of inflammatory markers do not correlate well with local inflammation at the tissue level. In addition, although arterial stiffness and atherogenesis share common pathological processes, their etiologies are very distinct.
There are a few limitations in this study. First, this study was cross-sectional and therefore we cannot determine whether an increase in Pfat causes carotid stiffness. Second, carotid stiffness indices were calculated using brachial BP rather than carotid BP. This approach is generally considered less accurate due to pulse pressure amplification between central and peripheral arteries, which can be altered with aging. However, we do not believe that this would differentially affect the observed associations with Pfat in this population of middle-aged and older men and women. Third, because we did not measure adipokines in this study, we cannot address whether they play a mediating role in the association between Pfat and carotid stiffness. Fourth, waist circumference was used as a measure of abdominal obesity, which provides no distinction between subcutaneous and visceral fat areas. Although waist circumference is highly correlated with abdominal visceral fat, we cannot determine whether the association between Pfat and carotid stiffness is independent of visceral fat. Similarly, we cannot rule out the possibility that fat adjacent to the carotid arteries is driving the association between Pfat and carotid stiffness, as these fat depots are likely to be highly correlated. Nevertheless, we are the first to describe the association between Pfat and arterial stiffness in a large, multi-ethnic population of men and women. We found that higher Pfat is associated with higher carotid stiffness, independent of traditional CVD risk factors and obesity. Although more studies are needed to address whether fat around the heart and blood vessels is a distinct risk factor or simply a marker of visceral fat, this fat depot may prove to be a therapeutic target in reducing CVD morbidity and mortality.