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Degenerative Aortic Valve Disease
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phenotype to bone-forming cells. This process starts with secretion of Wnt3a by valvular
endothelial cell s into the sub-endothelial region in response to oxidative stress, inflammation
and high cholesterol levels. Wnt3a binds LDL receptor-related proteins 5 (LRP-5) and the
Frizzled receptor on the surface of the interstitial cells, forming a trimer. This elicits a
transduction cascade including glycogen synthase kinase (GSK) 3β, and ultimately regulating
the expression of transcription factors related to osteogenic bone formation (Cbfa1, Msx2 and
Sox9) (Figure). This prompts the expression of osteopontin, osteonectin, osteocalcin, the
receptor activator of nuclear factor kappa B (RANK) ligand, osteoprotegerin, bone alkaline
phosphatase and BMP2. BMP2 is considered a major driver of valve calcification. These
osteoblast-like cells proliferate and produce extracellular matrix resulting in ectopic
osteogenesis [14].
Non-osteogenic calcification is less well known, but it could be as important as
osteogenic calcification [15]. It was suspected thanks to the observation that some amorphous
calcium deposits from calcified valves do not contain live cells. The proposed mechanisms
are abnormal ions clearance and cell death secondary to local inflammation. Inflammation
induces macrophages and valvular interstitial cells to release extracellular vesicles, which
concentrate ions. On their membranes, annexin facilitates Ca2+ entrance in the lumen, while
tissue non-specific alkaline phosphatase (TNAP) converts pyrophosphate (PPi) to phosphate
(Pi) ions which goes into the lumen thanks to Na/Pi transporters (PiT-1). On the inner side of
the membrane, complexes of annexin and phosphatidylserine bind Ca2+ and Pi, which can
interact forming hydroxyapatite that accumulates and cause extracellular vesicles’ rupture. On
the extracellular space, amorphous hydroxyapatite forms structured crystals, because it
accumulates in the extra-cellular matrix where there are charged fragments of collagen and
proteoglycans, obtained after degradation by MMPs on the extracellular vesicles’ surface
(Figure 1). When systemic concentrations of Ca2+ and Pi are high as in chronic kidney
disease this mechanism is promoted, because cells produce high density ions extracellular
vesicles [15-16].
Apoptosis has a well-defined role in non-osteogenic calcification, while necrosis
importance has not been clarified yet, but for sure it can promote inflammation [17].
Apoptotic bodies can concentrate ions as extracellular vesicles previously described, but some
of them have phosphatidylserine also on the outer side of the membrane, so that they can
form calcifications directly on the extracellular space [18] (Figure 1).
Osteogenic and non-osteogenic mechanisms of calcification are linked and promote each
other. For example, extracellular vesicles contain dysfunctional miRNA as RUNX2 which
can induce osteogenic switch of valvular interstitial cells [16]. It is possible that osteogenic
calcification is prevalent in the early phases of degenerative aortic valve disease, while nonosteogenic mechanisms become more important in more advanced stages. However, it is
important to remember that mechanisms for the prevention of local calcifications exist, but in
the pathology they are no more sufficient. Among them, fetuin-A and matrix Gla protein have
a major role. Fetuin-A is a circulating glycoprotein constitutively secreted by the liver. It
binds small calcium-phosphate particles and promotes their phagocytosis and removal.
However, in aortic lesions of degenerative aortic valve disease it is mostly degraded by
MMPs overexpressed secondary to inflammation [19]. Matrix Gla protein (MGP) is a vitamin
K-dependent protein, it prevents calcification by inhibiting BMP signaling and it is expressed
by chondrocytes, vascular smooth muscle cells and by osteoblast-like myofibroblasts, as a
negative control of the calcification process [20].
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Genetic Factors
Many genetic factors are involved in degenerative aortic valve disease. Single-center
studies have identified a role of several polymorphisms. Most notably, polymorphisms
causing an overexpression of the LDL receptor and lipoprotein A display a strong association
with calcification of arteries and valves [21].
In two families, loss-of-function mutations in the NOTCH1 gene have been linked both
to a bicuspid anatomy and to the differentiation of mesenchymal cells toward an osteoblastlike phenotype [8-9]. In addition to influencing the development of degenerative aortic valve
disease, genetic factors might also affect the response to therapies, but this point has not been
investigated so far.
ROLE OF IMAGING
The natural history of degenerative aortic valve disease starts with microscopic calcific
phenomena and culminates in severe valve stenosis. Conventional non-invasive imaging
techniques have an average resolution of 1 mm, and detection of the earliest steps of valve
degeneration requires novel, more sophisticated techniques.
Transthoracic echocardiography is an essential examination to assess valve structure and
function, and valve characterization can be implemented by a transesophageal exam. Cardiac
computed tomography (CT) allows to assess the anatomy of the aortic valve and the aortic
root and the extent of calcification, and is essential to plan a percutaneous intervention.
Cardiac magnetic resonance is not the optimal tool to assess calcified structures, and has a
limited role in this setting. The use of gadolinium-containing immunomicelles targeting the
macrophage scavenger receptor has been proposed to visualize the early stages of
degenerative aortic valve disease [8].
The use of two positron emission tomography (PET) tracers has been proposed. 18F-
fluorodeoxyglucose (18F-FDG) is typically trapped in inflammatory macrophages, whereas
18F-sodium fluoride (18F-NaF) is incorporated in hydroxyapatite during tissue calcification.
18F-NaF can detect early calcification (microcalcification) as an increased 18F-NaF activity
was observed in 45% of patients with aortic sclerosis, 91% of those with mild or moderate
AS, and 100% of those with severe AS [22]. In the same study, increased 18F-FDG activity
was observed in 20% of patients with aortic sclerosis, 35% of those with mild or moderate
AS, and 52% of those with severe AS. Interestingly, inflammation should be reduced in
advanced degenerative aortic valve disease, but an increase in 18F-FDG is still detected. This
could be explained by considering that, under hypoxic conditions, macrophages increase the
uptake of glucose while reducing the release of inflammatory cytokines. On the other hand,
18F-FDG uptake by surrounding cardiomyocytes may interfere with signal detection;
therefore, while 18F-NaF is a reliable marker of early calcification, the results of 18F-FDG
imaging should be interpreted with more caution [23].
Optical molecular imaging employs near-infrared fluorescence imaging agents to assess
the process of osteogenesis. Molecular imaging allows to clearly identify three stages of
degenerative aortic valve disease, which are defined as initiation phase, propagation phase
and late stage [8]. The late stage is characterized by irreversible changes in valve structure,
Degenerative Aortic Valve Disease
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which are easily detectable by conventional imaging techniques. Micro-optical coherence
tomography (mOCT) has a spatial resolution of 1 μm. Molecular features, such as
macrophages and calcium crystals, can be visualized with near-histological detail. Contrary to
near-infrared molecular imaging, mOCT does not require the use of contrast agents. Both
techniques are characterized by limited tissue penetration [24].
PHARMACOLOGICAL STRATEGIES
The medical management of AS is discussed in Chapter 12. Herein, we will present the
possible approaches to modify the natural history of this condition, highlighting some
experimental and clinical findings specifically related to degenerative aortic valve
Lipid-Lowering Drugs
Studies in mice and rabbits showed that statins effectively slow down the degeneration of
aortic valves, and results from some retrospective studies were in agreement with this
conclusion. Among four clinical trials (SALTIRE [Scottish Aortic Stenosis and Lipid
Lowering Trial], [25]; RAAVE [Rosuvastatin Affecting Aortic Valve Endothelium to Slow
the Progression of Aortic Stenosis], [26]; SEAS [Simvastatin and ezetimibe in aortic
stenosis], [27]; ASTRONOMER [Aortic Stenosis Progression Observation: Measuring the
Effects of Rosuvastatin], [28]), only the RAAVE trial demonstrated an efficacy of statins on
disease progression [8]. The relatively small size of these trials, the limited follow-up period,
and the enrolment of patients with rather advanced degenerative aortic valve disease may
contribute to these neutral results. Additionally, patients from retrospective cohorts were
often on statins for hypercholesterolemia since many years. Therefore, statins could be
effective in preventing disease progression only when started early [29], and a beneficial
effect of statins could become appreciable only after many years of treatment. Research on
statins and other lipid-lowering drugs, such as niacin, ISIS-APO(a)Rx, recombinant
apolipoprotein A-1 Milano or Proprotein Convertase Subtilisin/Kexin-type 9 (PCSK9)
inhibitors, is ongoing (30). To date, statin treatment is not recommended by European Society
of Cardiology [31] and American College of Cardiology/American Heart Association
guidelines [32] for the sole purpose of preventing disease progression.
Drugs Acting on the Renin-Angiotensin-Aldosterone System
ACEi and ARBs may exert beneficial effects on degenerative aortic valve disease
progression by improving hemodynamics and then shear stress, and also by blunting the
detrimental effects of angiotensin II and aldosterone on the valve tissue. On the other hand,
this hypothesis has not been adequately explored in preclinical studies, and evidence from
clinical trials that ACEi/ARBs can have a favorable impact on disease progression is limited
(as discussed in Chapter 12).
disease.
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Modulators of Valve Calcification
Some drugs modulating the calcification process have been evaluated. Denosumab is a
promising inhibitor of RANK ligand (RANKL), which decreases calcium deposition up to
50% in in murine models [33]. Bisphosphonates have raised some expectations, also given
their anti-inflammatory and lipid-lowering effects, but a retrospective analysis of 801 women
with mild to moderate degenerative aortic valve disease did not show any positive effects.
The SALTIRE II is testing the efficacy of denosumab or alendronic acid in degenerative
aortic valve disease (Marquis-Gravel et al. 2016). Osteoprotegerin, a RANKL inhibitor used
to treat osteoporosis, slowed the degeneration of aortic valve in mice, but studies in humans
are lacking (Weiss et al. 2013). Vitamin D supplementation is another possible approach for
reducing calcemia and is especially studied in patients with hyperparathyroidism or renal
dysfunction [30]. Finally, vitamin K antagonists have emerged as risk factors for tissue
calcification, possibly because of MGP inhibition. It has been proposed that they should be
preferentially replaced by non-vitamin K antagonists, although evidence is currently lacking
[20, 30].
Other Pharmacological Strategies
MMPs play an important role in valvular degeneration. Doxycycline at subantimicrobial
doses acts as nonselective MMPs’ inhibitor with a double action. It binds directly the MMPs’
zinc domain, which is crucial for the interaction with substrates, and downregulate the
transcription of MMPs mRNA [34]. However, when this drug was tested in apolipoprotein E−
/− mice it did not slow degenerative aortic valve disease progression neither clinically nor
histopatologically. Longer periods of treatment or the therapy with selective inhibitors have
been considered as perspectives for future studies [35].
Pioglitazone is a peroxisome proliferator-activator γ (PPARγ) agonist. PPARγ is involved
in cellular metabolism and its stimulation inhibits myofibroblasts switch to osteoblast-like
cells, while promoting their switch to adipocyte-like cells. Pioglitazone seems to attenuate
aortic valve degeneration in LDL receptor-/-/ApoB100/100 mice by decreasing lipid
deposition, cell death and calcification. This drug has not been tested in humans [36].
Ectonucleotidases are membrane enzymes that metabolize secreted nucleotides into
phosphate and pyrophosphate, which then accumulate in the extracellular spaces. They are
overexpressed by pathologic myofibroblasts promoting calcification. In animal models,
inhibitors of ectonucleotidases showed good results in slowing the aortic valve degeneration
[37].
INTERVENTIONAL THERAPIES
Tissue Engineering
Aortic valve replacement and transcatheter aortic valve implantation are established
therapeutic options for severe symptomatic AS, as extensively discussed in other chapters.
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Valves implanted through either a surgical or percutaneous approach are susceptible to
the same process of degeneration as native valves [8]. Tissue engineering of heart valves
(TEHV) has been proposed as a possible alternative strategy. The general idea is an
interaction between host cells and a template material to produce a native-like structures [5].
In vitro TEHV involves the culture and seeding of different types of autologous cells on a
scaffold. The prosthesis is tailored to the heart anatomy of the patient, and after implantation
behaves as a living tissue, responding to stressors and adapting to local environment. TEHV
can be successfully placed percutaneously into the aortic valve position, thereby fully
excluding the native leaflets while not compromising the coronary perfusion. Unfortunately,
this approach is extremely time-consuming and expensive, does not exclude an immunogenic
response, and carries a risk of neoplastic transformation [38]. In vivo TEHV is based on the
percutaneous positioning of an acellular biodegradable scaffold in the aortic valve position to
recruit endogenous cells. A transapical implantation technology is used by means of a
transcatheter delivery system. After implantation of an in situ TEHV, the scaffold material is
the main load-bearing structure. As the material is degraded and replaced by extra-cellular
matrix and cells, the mechanical properties of the valve change, but integrity has to be
maintained throughout the whole process. This process is more rapid, less invasive and less
susceptible to infections than in vitro TEHV. The drawbacks of this approach include the low
rate of recruitment of endogenous cells and possible toxic effects from scaffold degradation
[39].
TEHVs have obtained a remarkable success in animal models even though they have not
been yet tested in human patients. Dogs, primates, rodents, sheep and pigs have been all
valuable models for the study of scaffold remodeling and recellularization. Hence, a future
application in humans should be implemented [8].
CONCLUSION
Degenerative aortic valve disease is a major cause of mortality and morbidity that shares
some mechanisms with atherosclerosis. Imaging techniques, including PET and mOCT,
might allow to capture early disease manifestations, thus potentially allowing specific
treatments. Despite the similarities with atherosclerosis, the efficacy of statins in degenerative
aortic valve disease is controversial, while angiotensin converting enzyme inhibitors,
molecules targeting inflammation, tissue remodeling or calcification are still under
evaluation. Aortic valve replacement or transcatheter aortic valve implantation are the
treatments of choice for degenerative aortic valve disease, but prosthetic valves are still
susceptible to degeneration and thrombosis. TEHV 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.
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