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Advanced Imaging and Functional Tools for Aortic Valve Assessment
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In: Perspectives in Aortic Valve Disease ISBN: 978-1-53618-769-4
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Editor: Giovanni Concistrè © 2020 Nova Science Publishers, Inc.
Chapter 5
DEGENERATIVE AORTIC VALVE DISEASE
1,2,
Michele Emdin
Alberto Aimo1 and Claudio Passino
1
Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy
The spectrum of degenerative aortic valve disease ranges from aortic valve sclerosis
to severe calcification with aortic stenosis. degenerative aortic valve disease is a
progressive disease that affects about 30% of the population over 65 years in the United
States and is the most common aortic valve pathology. It shares some pathophysiological
mechanisms with atherosclerosis: most notably, mechanical stress triggers a local
inflammation with lipid infiltration and calcification, and genetics may influence patient
susceptibility, disease evolution and the response to treatment. Conversely, there are
substantial differences in the process of calcification, which in degenerative aortic valve
disease involves a switch of interstitial cells to an osteoblast-like phenotype together with
non-osteogenic mechanisms, such as the mineralization of dead cells. Imaging
techniques, including positron emission computed tomography and micro-optical
coherence tomography, might allow to capture early disease manifestations, thus
potentially allowing specific treatments. Despite the similarities with atherosclerotic
disease, the efficacy of statins is controversial, while angiotensin converting enzyme
inhibitors and molecules targeting inflammation, tissue remodeling or calcification are
still under investigation. Aortic valve replacement or transcatheter aortic valve
implantation are the treatments of choice for degenerative aortic valve disease, but
prosthetic valves are susceptible to degeneration and thrombosis. Tissue engineering
combines host cells and template materials to induce a natural regeneration of valve
structures, either in vivo or in vitro, and is another potential approach under evaluation.
This chapter will provide an overview of the pathophysiology of degenerative aortic
valve disease, the role of imaging techniques for its management and the perspectives for
treatment.
2
Fondazione G. Monasterio, Pisa, Italy
, Lucio Teresi1, Samuele Cannas1,
1,2
ABSTRACT
Corresponding Author’s Email: emdin@ftgm.it.
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Keywords: aortic valve degenerative disease, calcific aortic valve, aortic stenosis, molecular
imaging, tissue engineering
ABBREVIATIONS
ACE Angiotensin converting enzyme
ACE-I ACE inhibitors
ARBs Angiotensin receptor blockers
AS Aortic stenosis
BMP Bone morphogenic protein
FDG Fluorodeoxyglucose
LDL Low-density lipoprotein
MGP Matrix Gla protein
MMP Metalloproteinase
mOCT Micro-optical coherence tomography
NaF Sodium fluoride
PET Positron emission tomography
Pi Phosphate
PPARγ Peroxisome proliferator-activator γ
RAAVE Rosuvastatin affecting aortic valve endothelium
RANK Receptor activator of nuclear factor kappa B
RANKL Receptor activator of nuclear factor kappa B ligand
ROS Reactive oxygen species
TEHV Tissue engineering of heart valves.
INTRODUCTION
Aortic valve disease is a major cause of morbidity and mortality worldwide, and its
prevalence is increasing in parallel with population ageing [1]. The most common form is
degenerative aortic valve disease. In populations above 65 years of age, the prevalence of
aortic valve sclerosis, calcification, or thickening is reported to be 21–31% [2]. Moreover, in
the older population there is a high prevalence (2–9%) of end-stage degenerative aortic valve
disease with high-grade aortic stenosis (AS) often necessitating a therapeutic intervention [3].
The phenotypic spectrum of degenerative aortic valve disease ranges from a progressive
thickening of valve cups (aortic sclerosis) to reduced leaflet motion that may limit forward
blood flow (aortic stenosis) [4]. Far from being a simple deterioration of aortic valve cusps,
degenerative aortic valve disease is now interpreted as the result of an active process
including extracellular matrix remodeling and the activation of molecular pathways that
promote calcification and angiogenesis. Some of these mechanisms are common to
atherosclerosis, and many risk factors are shared between this process and coronary artery
disease (CAD), including elderly age, male gender, diabetes, hypercholesterolemia,
hypertension, and smoking. On the other hand, only 40-50% of patients with atherosclerosis
Degenerative Aortic Valve Disease
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develop degenerative aortic valve disease [5], suggesting an incomplete overlap between
these two conditions.
In this chapter we will reappraise the pathophysiology of degenerative aortic valve
disease, highlighting the similarities and differences with atherosclerosis, and some
approaches proposed to prevent or relieve the degeneration of aortic cusps.
PATHOPHYSIOLOGY
Degenerative Aortic Valve Disease and Atherosclerosis
Degenerative aortic valve disease shares many characteristics with atherosclerotic
disease, including a crucial role played by endothelial dysfunction in both conditions.
The aortic valve is chronically exposed to complex shear forces. It has been shown that
directional shear stress is responsible for arterial endothelial alignment in vivo [6]. Cultured
aortic endothelial cells dispose perpendicularly to flow direction, in contrast to the typical
parallel alignment to flow seen in other endothelial culture studies [7]. Calcification occurs
primarily on the aortic side of aortic valve leaflets, where flow is most turbulent, suggesting
that shear stress and its interaction with valvular endothelium plays a role in calcification.
Following abnormal shear stress conditions, endothelial cells produce more reactive
oxygen species and less nitric oxide. Oxidative stress promotes the expression of adhesion
molecules such as vascular cell adhesion molecule 1 and intercellular adhesion molecule 1
(VCAM-1, ICAM-1) and chemokines such as monocyte chemoattractant protein-1 (MCP-1)
by endothelial cells. Monocytes are recruited and activated into macrophages, which further
amplify oxidative stress and inflammation [8]. Additionally, low density lipoproteins (LDLs)
begin to accumulate in valve tissues. Both macrophages and LDLs display angiotensinconverting enzyme (ACE) activity, which converts angiotensin I to angiotensin II; the same
activation may be catalyzed by chymase, which is released by mast cells. Angiotensin II type
1 receptor (AT1-R) is expressed constitutively by smooth muscle cells in vessels, and in
pathologic conditions it is also expressed by fibroblasts in the aortic valve. Angiotensin II
works as a chemotactic factor for monocytes, increases oxidative cellular stress, promotes
LDLs uptake in the valve and the conversion of macrophages into foam cells [9-10]
(Figure 1).
Early lesions in both atherosclerosis and degenerative aortic valve disease involves
disruption of the basement membrane, macrophage and T-lymphocyte migration, and
infiltration of lipoproteins. The inflammatory response drives activation of myofibroblasts,
release of cytokines such as tumor necrosis factor alpha and transforming growth factor beta,
and the expression of matrix metalloproteinases (MMPs).
However, specific cellular and genetic mechanisms of degeneration affect the aortic valve
substrate. Shear stress forces are different in the aortic valve and arteries, because of the much
more complex anatomy of the aortic valve. A bicuspid structure or the reduced elasticity and
compliance of degenerated cusps are usually the mechanical triggers of the pathology [11],
and calcification occurs primarily on the aortic side of the leaflets, where mechanical stress is
higher [8]. Valvular endothelial cells are phenotypically different from other endothelial cells
in the cardiovascular system as they tend to dispose perpendicularly to blood flow, instead of
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parallel. Therefore, also their response to pathological mechanical stimuli can be supposed to
be different [8, 12].
LRP5, LDL receptor-related protein 5; Pi phosphate; PIT-1, phosphate transporter-1; PPi,
pyrophosphate; PS, phosphatidylserine; TNAP, tissue non-specific alkaline phosphatase; VEC,
valvular endothelial cells; VIC, valvular interstitial cells.
Figure 1. Degenerative aortic valve disease pathophysiology.
Valves lack smooth muscle cells, which are an important feature of atherosclerotic
lesions in the vasculature. By contrast, valves contain myofibroblasts that proliferate in
response to decreased nitric oxide levels, angiotensin II; and local hormones, including tissue
growth factor and platelet-derived growth factor.
There are as many smooth muscle cells in aortic valve leaflets as in vessels, but in the
aortic valve there are also interstitial myofibroblasts that are activated and proliferate in
response to inflammatory stimuli. They release tumor necrosis factor (TNF) α and
transforming growth factor (TGF) β1, which promote calcification by up-regulating MMPs
and the bone morphogenic protein (BMP). The calcification process is more pronounced and
develops during an earlier disease stage than in atherosclerosis. Finally, neovascularization
induced by inflammation is much less significant in degenerative aortic valve disease than in
atherosclerosis [13].
Calcification
Calcification is a distinguishing feature of degenerative aortic valve disease. The
osteogenic mechanism of calcification has been well characterized and is traditionally
considered to be more relevant. It is driven by interstitial valve myofibroblasts switching their
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