Periadventitial Fat: Regional Source of Inflammation in Atherosclerosis

Archives of Pathology & Laboratory Medicine, Mar 2007 by Tellides, George

Atherosclerosis is considered an inflammatory disease.1 There is convincing mechanistic experimental evidence as well as descriptive clinical studies that convey that the interactions of leukocytes and vascular cells are related to the initiation, progression, and complications of atherosclerotic arterial disease. The site of inflammation may be local within the artery wall, or distant and exert effects on atherosclerotic plaques through circulating inflammatory factors. It is likely that both local and distant inflammation contribute to the pathogenesis of atherosclerosis and systemic inflammatory markers.2 In this month's issue of Archives of Pathology & Laboratory Medicine, Vela et al3 provide new data and review the evidence for a role of periadventitial fat as a regional source of inflammation in vascular injury and remodeling.

The extravascular compartment is often overlooked as a modifier of vascular disease, and Vela et al3 provide a timely and thoughtful examination of the subject. The most striking example of the influence of extravascular tissue on atherosclerosis is the relative absence of disease in epicardial artery segments that are buried within the myocardium. 4 The most common explanations for this phenomenon are putative hemodynamic factors. Vela et al postulate that the absence of atherosclerosis in intramyocardial vessels is instead the result of the lack of periadventitial fat in these vessel segments. This is an interesting and plausible explanation that emphasizes the proatherosclerotic properties of periadventitial fat; however, the authors did not address whether the adventitia and vasa vasorum, 2 other anatomic factors that play a role in atherosclerosis, are altered in intramyocardial arteries. More commonly, the proximal coronary arteries are heavily invested in epicardial fat and are significantly more susceptible to atherosclerotic plaques than the distal vessels. These clinical observations support a negative and positive correlation between the absence or presence of periadventitial fat and coronary artery atherosclerosis, respectively.

What data do the authors provide to support their contention for a proinflammatory state of the periadventitial fat? First, they demonstrate that intravenous injection of iron particles into atherosclerosis-prone mice accumulate within phagocytes, expressing macrophage markers in the neointima and more prominently in the periadventitial fat. Second, they document greater numbers of periadventitial infiltrating macrophages in clinical specimens of coronary atherosclerosis with large lipid cores than in fibrocalcific or nonatherosclerotic vessels. Finally, they review the literature and provide an extensive list of studies that have implicated periadventitial fat as a site into which vascular inflammation extends or as a site in which inflammation may originate. The next step, to prove a causative role of periadventitial fat in atherosclerosis, is more challenging. Biologic agents and genetic manipulations are not selective for adipose tissue around vessels. Injection or transfection of proinflammatory agents into perivascular fat may test whether contiguous inflammation elicits arterial remodeling, akin to studies performed in the adventitia.5 Transplantation of artery segments with the surrounding fat from donor mice that have a targeted deficiency of inflammatory factors in adipocytes to atherosclerosis-prone recipient mice may be informative, similar to grafting studies performed in apolipoprotein E-deficient animals.6

Is the periadventitial fat an extravascular compartment? The artery wall is generally considered to consist of 3 layers: the tunicae intima, media, and adventitia. Vela et al3 noted that murine arteries lacked a well-defined adventitia and that the lack of a clear boundary between the adventitia and the surrounding fat of human coronary arteries suggested that the 2 structures functioned as a single unit. Similar observations have been made after balloon angioplasty of porcine coronary arteries.7 The blurring of the boundary between the adventitia and fat is likely secondary to inflammation. Dissection of normal human coronary arteries is relatively straightforward along natural planes inside the periadventitial fat, whereas this boundary fuses in the presence of advanced atherosclerosis. The fat pad of the heart is variable in patients, and the extent does not always correlate with obesity. Epicardial fat consistently obscures the proximal coronary arteries and is often absent from the superficial aspect of distal coronary arteries. Unlike the sudden transition of rabbit coronary arteries from being surrounded by epicardial fat to penetration of the myocardium as illustrated by Vela et al, human secondary epicardial coronary arteries are visible on the surface of the heart and are directly amenable to revascularization procedures by cardiac surgeons. These bare areas of coronary arteries often have visible focal lesions, demonstrating that periadventitial fat is not always necessary for plaque formation.