Ultrastructural Pathology of Atherosclerosis, Calcific Aortic Valve Disease, and Bioprosthetic Heart Valve Degeneration: Commonalities and Differences.

Alexander Kostyunin,Evgeniy Ovcharenko,Anton Kutikhin,Daria Shishkova,Leo Bogdanov,Nikolay Osyaev,Tatiana Glushkova,Rinat Mukhamadiyarov

doi:10.3390/ijms21207434

Alexander Kostyunin, Evgeniy Ovcharenko + Show 6 more

Open Access

https://doi.org/10.3390/ijms21207434

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Abstract

Atherosclerosis, calcific aortic valve disease (CAVD), and bioprosthetic heart valve degeneration (alternatively termed structural valve deterioration, SVD) represent three diseases affecting distinct components of the circulatory system and their substitutes, yet sharing multiple risk factors and commonly leading to the extraskeletal calcification. Whereas the histopathology of the mentioned disorders is well-described, their ultrastructural pathology is largely obscure due to the lack of appropriate investigation techniques. Employing an original method for sample preparation and the electron microscopy visualisation of calcified cardiovascular tissues, here we revisited the ultrastructural features of lipid retention, macrophage infiltration, intraplaque/intraleaflet haemorrhage, and calcification which are common or unique for the indicated types of cardiovascular disease. Atherosclerotic plaques were notable for the massive accumulation of lipids in the extracellular matrix (ECM), abundant macrophage content, and pronounced neovascularisation associated with blood leakage and calcium deposition. In contrast, CAVD and SVD generally did not require vasculo- or angiogenesis to occur, instead relying on fatigue-induced ECM degradation and the concurrent migration of immune cells. Unlike native tissues, bioprosthetic heart valves contained numerous specialised macrophages and were not capable of the regeneration that underscores ECM integrity as a pivotal factor for SVD prevention. While atherosclerosis, CAVD, and SVD show similar pathogenesis patterns, these disorders demonstrate considerable ultrastructural differences.

Highlights

Atherosclerosis and calcific aortic valve disease (CAVD) represent chronic inflammatory disorders which are characterised by endothelial dysfunction, lipid deposition, macrophage infiltration, and the maladaptive remodelling of the extracellular matrix (ECM) in the arterial wall and valve leaflets [1,2,3,4,5]
With the aim to solve this issue, we have previously developed an original protocol for the staining, embedding, and backscattered scanning electron microscopy visualisation of the mineralised cardiovascular specimens [17,18,19] which entirely retains the integrity of the calcified tissues and combines the advantages of light microscopy and transmission electron microscopy, providing high-resolution images and ultrastructural details of all the vascular and valvular tissue structures and cell types
CAVD, and SVD all involve macrophage infiltration and are largely driven by lipid accumulation, we primarily focused on the formation of foam cells

Summary

Introduction

Atherosclerosis and calcific aortic valve disease (CAVD) represent chronic inflammatory disorders which are characterised by endothelial dysfunction, lipid deposition, macrophage infiltration, and the maladaptive remodelling of the extracellular matrix (ECM) in the arterial wall and valve leaflets [1,2,3,4,5]. Bioprosthetic heart valves (BHVs) are fabricated from bovine/porcine pericardium or porcine heart valves and undergo structural deterioration (SVD) over time due to the lack of a regenerative capability upon chemical fixation [6,7,8]. In most of these cases, SVD is a consequence of ECM disintegration, fibrosis, and calcification, all provoked by haemodynamic stress and the infiltration of the immunogenic prosthetic tissue by the macrophages of the recipient. In spite of the current advances in the design and manufacturing of BHVs, SVD remains a common long-term complication [9,10,11] demanding a repeated valve replacement in half of the patients 15 years post-implantation [12]

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