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Segmental Heterogeneity of Vasa Vasorum Neovascularization in Human Coronary Atherosclerosis

Mario Gössl, MD^_*, Daniele Versari, MD^_*, Heike A. Hildebrandt^_*, Thomas Bajanowski, MD, Giuseppe Sangiorgi, MD^¶, Raimund Erbel, MD^||, Erik L. Ritman, MD, PhD, Lilach O. Lerman, MD, PhD, Amir Lerman, MD^_*,_*

^_* Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota
Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota
Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota
Institute of Forensic Medicine, West-German Heart-Center, University Duisburg-Essen, Essen, Germany
^|| Clinic of Cardiology, West-German Heart-Center, University Duisburg-Essen, Essen, Germany
^¶ Mediolanum Cardio Research, Milan, Italy

^_* Reprint requests and correspondence: Dr. Amir Lerman, Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First Street SW, Rochester, Minnesota 55905 (Email: lerman.amir{at}mayo.edu).

Objectives: Our aim was to investigate the role of coronary vasa vasorum (VV) neovascularization in the progression and complications of human coronary atherosclerotic plaques.

Background: Accumulating evidence supports an important role of VV neovascularization in atherogenesis and lesion location determination in coronary artery disease. VV neovascularization can lead to intraplaque hemorrhage, which has been identified as a promoter of plaque progression and complications like plaque rupture. We hypothesized that distinctive patterns of VV neovascularization and associated plaque complications can be found in different stages of human coronary atherosclerosis.

Methods: Hearts from 15 patients (age 52 ± 5 years, mean ± SEM) were obtained at autopsy, perfused with Microfil (Flow Tech, Inc., Carver, Massachusetts), and subsequently scanned with micro-computed tomography (CT). The 2-cm segments (n = 50) were histologically classified as either normal (n = 12), nonstenotic plaque (<50% stenosis, n = 18), calcified (n = 10) or noncalcified (n = 10) stenotic plaque. Micro-CT images were analyzed for VV density (number/mm²), VV vascular area fraction (mm²/mm²), and VV endothelial surface fraction (mm²/mm³). Histological sections were stained for Mallory's (iron), von Kossa (calcium), and glycophorin-A (erythrocyte fragments) as well as endothelial nitric oxide synthase, vascular endothelial growth factor, and tumor necrosis factor-alpha.

Results: VV density was higher in segments with nonstenotic and noncalcified stenotic plaques as compared with normal segments (3.36 ± 0.45, 3.72 ± 1.03 vs. 1.16 ± 0.21, p < 0.01). In calcified stenotic plaques, VV spatial density was lowest (0.95 ± 0.21, p < 0.05 vs. nonstenotic and noncalcified stenotic plaque). The amount of iron and glycophorin A was significantly higher in nonstenotic and stenotic plaques as compared with normal segments, and correlated with VV density (Kendall-Tau correlation coefficient 0.65 and 0.58, respectively, p < 0.01). Moreover, relatively high amounts of iron and glycophorin A were found in calcified plaques. Further immunohistochemical characterization of VV revealed positive staining for endothelial nitric oxide synthase and tumor necrosis factor-alpha but not vascular endothelial growth factor.

Conclusions: Our results support a possible role of VV neovascularization, VV rupture, and intraplaque hemorrhage in the progression and complications of human coronary atherosclerosis.

Key Words: vasa vasorum • human coronary atherosclerosis • micro-CT • calcification • intraplaque hemorrhage

Abbreviations and Acronyms   CT = computed tomography   eNOS = endothelial nitric oxide synthase   TNF = tumor necrosis factor   VEGF = vascular endothelial growth factor   VV = vasa vasorum

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