Elsevier

Human Pathology

Volume 43, Issue 12, December 2012, Pages 2213-2222
Human Pathology

Original contribution
Histologic identification of brown adipose and peripheral nerve involvement in human atherosclerotic vessels

https://doi.org/10.1016/j.humpath.2012.03.013Get rights and content

Summary

The disease mechanisms and histology of plaque development associated with atherosclerosis remain incredibly complex and not entirely understood. Recent investigations have emphasized the importance of inflammation in atherosclerosis. Several studies have also indicated heterotopic or extraskeletal bone formation in atherosclerotic vessels. The mechanisms behind heterotopic ossification appear to have similarities to those underlying atherosclerosis, with inflammation being a key inductive component to heterotopic ossification. Therefore, in the present study, we evaluated the histology associated with pathologies of atherosclerosis and heterotopic ossification in 271 coronary vessel tissue samples. We examined the prevalence and features of the inflammatory response as well as new vessel and bone formation. Inflammation and neovascularization were observed both in the adventitia and within the atherosclerotic lesions of the vessels themselves. Intriguingly, neural changes, including collections of inflammatory cells and expression of neuroinflammatory factors, were detected in the adventitial nerves of the vessels. Mature lamellar bone was found in 18 coronary vessels (7%), often with hematopoietic elements and active bone remodeling. Brown adipocytes, which pattern heterotopic bone formation, were present within the atherosclerotic lesions (28%, or 75/271). As expected, there was a strong correlation between the presence of cholesterol and plaque formation (P < .0001), but there also seemed to be a trend toward a connection between the presence of brown adipocytes and plaque. From this histologic evaluation, along with cholesterol and dystrophic calcification, we noted a novel appearance of brown adipocytes as well as neural changes, which may provide new insights to further our understanding of atherosclerosis.

Introduction

Atherosclerosis, which is the common cause of heart disease and stroke, 2 major morbidities worldwide, involves the formation of plaques within the arterial blood vessel [1], [2], [3]. These plaques or lesions are typified by continuous lipid accumulation and inflammatory infiltration within the arterial wall. Inflammatory mechanisms have emerged as a central player in atherosclerotic plaque development [2], [4], [5]. However, drug therapies targeting the inflammatory response have had mixed results, not always showing a measurable effect on clinical outcome [5], [6], [7]. This phenomenon most likely results from the complex biology governing plaque formation and highlights the necessity of a fresh assessment of the histology of this process.

Adding to this complexity are reports of de novo or heterotopic bone formation within a subset of these plaques [8], [9], [10]. Recently, we [11] and others [12] have shown that inflammation in sensory neurons is a key regulator of heterotopic ossification (HO) in skeletal muscle. This neuroinflammation is associated with nerve remodeling or degradation of the epineurial-endoneurial matrix and the release of cells for the rapid production of brown adipose within the tissues [11], [13], [14]. One of the primary osteoinductive factors that appears to evoke neuroinflammation is bone morphogenetic protein 2 (BMP2) [11], [12]. Increased BMP2 signaling has recently been observed during atherosclerotic plaque formation and been shown to induce expression of proteins, such as CD68 and E-selectin, which are involved in the infiltration of inflammatory cells, such as monocytes [15]. Interestingly, cells expressing these same markers appear to infiltrate the site of de novo bone formation in response to neuroinflammation [12], [16], [17].

Sensory nerves innervate the arterial wall and are predominantly found in the adventitial layer [18]. These nerves have been shown to be associated with unique microvasculature, termed the vasa vasorum, in the adventitia (see review by Baikoussis et al [19]). This microvasculature has been implicated in plaque formation and associated with 2 neuroinflammatory factors, substance P (SP) and calcitonin gene-related peptide [19], [20], [21].

Therefore, in the present retrospective study, we evaluated histologic features of postmortem vessel tissue, with an emphasis on examining specific pathologies related to HO, including neuroinflammation, adipose, and bone. We investigated the incidence of each of these features in the human plaques and show the presence of altered peripheral nerves, consistent with the sensory nerve remodeling observed in HO, as well as the presence of brown adipose in these tissues. We used this histologic examination to view atherogenesis from a different perspective and to potentially identify new features within atherosclerotic plaques.

Section snippets

Histologic examination of vessels

Histologic slides from autopsy cases diagnosed with atherosclerosis plaque formation were retrieved from the files of the Michael E. DeBakey VA Medical Center in Houston following approved institutional review board protocols. Section retrieval was limited to the years of 1998 to 2004. Vessels identified with atherosclerotic plaques were identified by one of the authors (F. H. G.). This vascular subset of patient slides were then examined by 2 of the authors (F. H. G. and E. S.) for the

Histologic characterization of the adventitia

A total of 271 coronary vessels, from autopsy material, were examined for specific histologic features (Table). Atherosclerotic plaques were identified in 267 (99%) of the coronary vessels and further analyzed for the histologic variables outlined below. We also distinguished the presence of these variables within the specific layers (adventitial, medial, or intimal) of the vessel wall (Fig. 1).

Neovascularization was observed in the adventitial layer, surrounding the atherosclerotic vessel wall

Discussion

Atherosclerosis is a slowly progressing disease of the arterial walls, commonly leading to coronary artery disease, peripheral artery disease, and stroke [23]. The classic histologic features of atherosclerotic plaques have been previously described [24], [25] and refined [26] and are the basis for the current histologic grading system for atherosclerotic lesions established by the American Heart Association [26], [27]. These plaques continue to evolve throughout one's life, exhibiting complex

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  • Cited by (0)

    Grant support: American Heart Association (AHA 10815339F), Kirschstein-NRSA (T32 HL092332-08).

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