Introduction
Aortic valve (AV) sclerosis (AVS) is a form of AV disease affecting an estimated 1
in 4 people above the age of 65 in the United States.
1
An aging population and more widespread use of noninvasive imaging are increasing
the incidence of AVS. AVS is typically defined as calcification of the aortic leaflets
without impairment in leaflet excursion or a significant transvalvular pressure gradient.
2
It is characterized by a gradual progression beginning with calcium deposition that
may ultimately transform to aortic stenosis (AS) with obstruction of outflow from
the left ventricle. Severe AS eventually leads to ventricular remodeling and hemodynamic
compromise with a high morbidity and mortality if not treated. Long considered an
incidental age‐related degenerative process as a result of progressive wear and tear,
there is substantial emerging evidence related to AVS that challenges this assumption.
Recent observations have shown that the development of AVS and AS may involve chronic
inflammatory infiltrates, deposition of atherosclerotic lipoproteins, and calcification,
akin to coronary artery disease (CAD). However, AVS has unique features, including
a calcium predominance on histology, gradual progression, and location at a site of
high pressure that serves as a gateway from the heart to the systemic circulation.
Some investigators have reported the frequent coexistence of either AVS or AS in patients
with underlying CAD.
3
Several studies have demonstrated that independent risk factors in the progression
of CAD, such as dyslipidemia, hypertension, and male sex, may also affect development
of AVS and its progression to AS.
4–6
These observations not only highlight the many shared characteristics of CAD and AVS
but have also prompted investigators to test the efficacy of medical interventions
that may have salutary effects on both conditions.
Heart disease is the leading cause of death in the United States. The majority of
these deaths are attributed to CAD.
7
Improvements in treatment for CAD, such as statins, angiotensin inhibitors (ACEI),
and revascularization, have resulted in a larger proportion of the population living
with CAD.
8
Realizing the potential similarities between the underlying pathophysiology for AVS
and CAD, many clinically relevant questions remain unanswered.
9–10
For instance, does the presence of AVS suggest existence or progression of underlying
CAD? Should AVS be considered a novel risk factor for the development of CAD? Does
the finding of AVS warrant the initiation and careful titration of medications with
lifestyle changes analogous to current strategies used in treating patients with diabetes
mellitus? In this review, we discuss the shared pathophysiological aspects of AVS
and CAD, summarize the present literature on mechanisms that lead to disease progression,
and provide insights for future research to identify novel therapeutic targets.
Pathophysiology of CAD and AVS
Mechanical Forces
The AV is equipped with the capacity for dynamic movement in a high‐pressure setting.
Endothelial injury from this stressful environment is thought to be the inciting factor
for AVS. Lesions frequently occur on the aortic side of the leaflets, an area of high
turbulent flow and tensile stress with low shear stress.
11
The center of the valve cusp has the greatest mechanical stress and is more frequently
involved than the commissures. Furthermore, there is a predilection for involvement
of the noncoronary cusp, likely secondary to the lower shear stress given the lack
of diastolic flow over this cusp.
2
In contrast, the coronary arteries passively fill during diastole in a lower pressure
environment. However, like AVS, coronary atherosclerotic lesions more commonly occur
at sites with the highest oscillatory shear stress, such as coronary branch vessel
bifurcations.
10
Bicuspid AV is the most common congenital heart condition due to failure of leaflets
to fuse during development, occurring in about 1% of the population.
12
The AV is derived from mesenchymal cells from the neural crest as well as the endocardium.
13
Genetic and molecular factors are thought to cause 2 of the leaflets to fuse, leaving
a remnant ridge called a raphe. The genetics of bicuspid AV pathology have not been
well defined but, at least in some cases, appear to be inherited in an autosomal dominant
fashion with incomplete penetrance. First‐degree relatives of those with a bicuspid
AV had a 9.1% chance of having a bicuspid AV in 1 investigation.
14
The bicuspid AV is subjected to altered mechanical forces that incite AVS and progression
to AS earlier than normal trileaflet AVs. In 1 study of patients undergoing AV replacement,
those with bicuspid AVs were on average 7 years younger than their trileaflet AV counterparts.
15
Using simulations of postmortem AVs, a study showed that bicuspid AVs typically have
restricted motion that does not allow them to fully open to the size of the aorta.
16
Furthermore, there is folding and redundancy of the valves with each cardiac cycle,
thereby subjecting them to increased stress and asymmetrical turbulence, which likely
explains their earlier compromise.
Early Lesions
The initial lesions in both AVS and CAD involve lipid deposition and focal sclerosis
(Figure 1).
9,17–20
The AV leaflets are composed of 3 layers—the ventricularis (on ventricular aspect
of the leaflet containing elastin), spongiosa (consisting of loose connective tissue
in the basal third of the valve), and fibrosa (composed of collagen core).
21
The deposition of lipids typically occurs on the aortic side of the leaflets, given
the aforementioned mechanical forces. Akin to arteries, endothelial cells line the
surface of valve leaflets, maintaining homeostasis via the trafficking of mechanical
and biochemical signals. In contrast to vascular endothelial cells, which assemble
parallel to the direction of flow, valvular endothelium aligns perpendicular to flow.
22
The difference in arrangement is accompanied by reorganization of focal adhesion complexes
at the ends of long axis of cells, which likely contributes to focal thickening of
leaflets at the sites with the highest turbulent flow. The endothelium in these high‐impact
areas responds by increasing adhesion molecules and inducing inflammatory genes. Inflammatory
cells then infiltrate and promote lipid deposition with disruption of the basement
membrane. In both disease states, macrophages, T lymphocytes, and intracellular and
extracellular lipids are present.
11,23–25
Figure 1.
Pathophysiology of aortic sclerosis, aortic stenosis, and coronary artery disease.
The evolution from normal vasculature to aortic stenosis and coronary artery disease
shares several important cellular mechanisms including lipid deposition, inflammatory
cell infiltration, cytokine release, and calcification. While a smooth muscle cap
overlying a lipid core develops in coronary artery disease, aortic stenosis is characterized
by thick calcifications. Pathology of human aortic valves and coronary arteries illustrates
this transition at the tissue level. ACE indicates angiotensin‐converting enzyme;
Ca, calcium; LDL, low‐density lipoprotein; M‐CSF, macrophage colony stimulating factor;
MMP, matrix metalloproteinase; NO, nitric oxide; PDGF, platelet‐derived growth factor;
TGF‐β, transforming growth factor β; TNF‐α, tumor necrosis factor α. Cynthia S. Gordon
© 2014 MedAnimations.com.
Progression of Lesions
Local endothelial damage occurs as a result of insults from mechanical, genetic, and
inflammatory cell–mediated factors in both CAD and AVS. Subsequent inflammation has
been proposed as the hallmark of CAD and AVS pathogenesis. Several mediators are released,
including tumor necrosis factor‐α, transforming growth factor‐β, and macrophage colony
stimulating factor.
9,17,26
Macrophage colony stimulating factor induces monocyte maturation into macrophages,
which then take up low‐density lipoproteins to form foam cells. Toll‐like receptors
are upregulated and serve to further activate macrophages, producing more cytokines
and free radicals.
27
While atherosclerosis is a known inflammatory disease, recent observations have suggested
that AVS progression also involves an inflammatory pathway in individuals with certain
common risk factors to initiate, propagate, and activate sclerotic lesions in the
AV. In fact, histology of human stenotic and sclerotic AVs and atheromas has demonstrated
active inflammatory cells.
17,23,28
Although AVS and CAD have similar histology at their onset, more mature lesions exhibit
structural differences. At the cellular level, an atheroma is characterized by a smooth
muscle cap, which is not present in AVS.
29
Instead, myofibroblasts encompass the predominant mesenchymal cell in AVS and release
cytokines as well as increase the expression of matrix metalloproteinases and bone
morphogenetic proteins, which promotes calcium deposition.
30
In vitro, matrix metalloproteinases appear to work at least partially via stimulation
of bone‐specific alkaline phosphatase.
31
Myofibroblasts are thought to be stimulated by low nitric oxide and growth factors
such as transforming growth factor‐β and platelet‐derived growth factor.
32
Angiotensin‐converting enzyme is present in both AVS and CAD lesions, leading to increased
angiotensin II.
33
Interestingly, this enzyme is often coupled with apolipoprotein B particles, thereby
implicating low‐density lipoprotein in the inflammatory process.
33
Heterotopic calcium deposition is common to both diseases, although it is much more
integral to the pathology of AVS. Examinations of valves with AS have demonstrated
increased expression of osteocalcin, bone‐specific alkaline phosphatase, CBFA‐1 (Core‐binding
factor α1), receptor activator of nuclear‐κB (RANK) ligand, osteopontin, and osteonectin,
all of which are implicated in the pathogenesis of calcification.
34
Notch1 is a transmembrane receptor that regulates bony differentiation in embryonic
development and is involved in AV calcification in animal models and in vitro studies.
35
When bound by ligand, its intracellular domain cleaves and translocates into the nucleus,
eventually inhibiting Runx2.
36–37
Inhibition of this transcriptional regulator of osteoblast fate leads to decreased
calcification. Therefore, mutations in the NOTCH1 gene may ultimately cause disinhibition
of calcium deposition, which can result in progressive AS. Moreover, NOTCH1 haploinsufficiency
has been well described in some families with bicuspid AVs.
13
Various growth and transcription factors such as transforming growth factor‐β, vascular
endothelial growth factor, ErbB, Wnt, and GATA families have also been implicated
in the pathogenesis of bicuspid AVs, although their roles are less defined.
13
These data highlight the importance of NOTCH1 in the normal development of the AV
and in its role in preventing AV calcification in adult‐onset disease.
As a result of the durable calcium cap, it takes many years to progress from AVS to
severe AS, which may manifest as angina, syncope, and heart failure. In contrast,
an atheroma is often more fragile and susceptible to rupture, causing a clot and acute
ischemia. Thus, CAD may be a gradual process accented by periods of rapid progression
to ischemia, heart failure, arrhythmias, and death.
Clinical Insights Into AVS and CAD
Clinical research has enhanced the understanding of the relationship between AVS and
CAD as well as specific patient populations that are affected by this association
(Tables 1 and 2).
4–6,4–44
Importantly, research to date has not been able to prove causality despite the frequent
coexistence of these entities. In one investigation, symptomatic patients with stable
angina (without prior cardiac history) who had AVS on a transthoracic echocardiogram
had a higher rate of significant CAD compared with those without AVS (75% versus 47%,
P<0.001).
44
After multivariate adjustment for traditional CAD risk factors, those with AVS had
an 8.6‐fold greater likelihood of having significant CAD, defined as >70% obstruction
of a major epicardial artery, as opposed to those without AVS (P<0.01). Similar results
have been reported in patients without known cardiac disease presenting to the hospital
with chest pain. AVS was found to be an independent predictor of obstructive CAD (odds
ratio [OR] 3.73, 95% CI 1.33 to 10.45).
40
However, when stratified by age, the association only remained statistically significant
for those <60 years old. In the younger group, 71% with AVS had significant CAD versus
24% without AVS (P=0.041). This suggests that the finding of AVS in a younger person
(<60 years) may be an early marker suggestive of a systemic atherosclerotic process,
as opposed to a degenerative condition. Renal failure is considered a risk factor
for CAD.
Studies have shown an increased prevalence of AVS and AS in patients on dialysis,
especially as the time on dialysis increases.
45–46
This may be secondary to concomitant cardiac risk factors and alterations in calcium
and phosphorus homeostasis. Furthermore, several investigations have found statistically
significant correlations between decreased glomerular filtration rate and the presence
of AVS, thereby suggesting that even mild renal insufficiency predisposes individuals
to the development of AVS.
5–6,47
However, whether renal insufficiency is an independent predictor for AVS remains an
area of uncertainty and subject to active research.
Table 1.
Retrospective Studies of AVS and CAD
Retrospective Study
Year
N
Patient Population
Risk of CAD (AVS vs Non‐AVS)
Soydinc et al
38
2006
160
Suspected CAD without significant valvular disease
1‐ and 2‐vessel CAD: nonsignificant3‐vessel CAD (40% vs 13.6%; P<0.001)Gensini score:
18±16.4 vs 40±38.05 (P<0.001)
Sui et al
39
2006
138
Known or suspected CAD
63.8% in AVS vs 28.8% in non‐AVS (P<0.05)
Conte et al
40
2007
93
Patients without known heart disease hospitalized for chest pain
OR 3.73 (95% CI 1.33 to 10.45)
Roy et al
41
2012
140
Known or suspected CAD
AVS was independent predictor of CAD (P=0.018)
AVS indicates aortic valve sclerosis; CAD, coronary artery disease; OR, odds ratio.
Table 2.
Prospective Studies of AVS and CAD
Prospective Study
Year
N
Patient Population
Mean Follow‐up (y)
Main Outcome(s) (AVS vs Non‐AVS)
Aronow et al
42
1999
1980
Elderly without AS
3.8
MI or sudden cardiac death (RR 1.758, 95% CI 1.521 to 2.031)
Otto et al
6
1999
4073
No known CAD, population study
5
MI (RR 1.40, 95% CI 1.07 to 1.83)CHF (RR 1.28, 95% CI 1.01 to 1.63); cardiovascular
mortality (RR 1.52, 95% CI 1.12 to 2.05)All‐cause mortality (RR 1.35, 95% CI 1.12
to 1.61)
Chandra et al
4
2004
415
Patients in emergency department with chest pain
1
All‐cause mortality: 18.7% vs 2.4% (P<0.0001)Cardiovascular mortality: 14.7% vs 1.4%
(P<0.0001)No significant difference in cardiac death or MI after adjustment for risk
factors, CAD, and CRP
Shah et al
43
2007
814
Outpatients with known CAD without AS
4
MI (HR 1.8, 95% CI 1.1 to 3.1)Statin use attenuated this risk.
Kim et al
44
2009
165
Outpatients with angina and inconclusive treadmill stress test
0.9
No significant difference in cardiac eventsRisk of CAD (OR 8.58, 95% CI 3.74 to 19.67)
Owens et al
5
2012
6685
Population‐based without known heart disease
5.8
Major cardiovascular event (HR 1.50, 95% CI 1.10 to 2.03)Major coronary event (HR
1.72, 95% CI 1.19 to 2.49)
All studies underwent multivariate adjustment for cardiac risk factors. AVS indicates
aortic valve sclerosis; AS, aortic stenosis; CAD, coronary artery disease; ; MI, myocardial
infarction; RR, relative risk; CHF, congestive heart failure; CRP, C‐reactive protein;
HR, hazard ratio.
Importantly, when examining whether AVS is associated with adverse cardiovascular
events, a prospective study found a higher incidence of cardiovascular events (16.8%
versus 7.1%, P=0.002) and worse event‐free survival at 1 year between AVS and non‐AVS
groups.
4
However, after adjustment for confounders (such as baseline CAD and C‐reactive protein),
no statistically significant differences were found. Of note, the highest rate of
cardiac events was in patients with AVS and the highest quartile C‐reactive protein.
Taken together, these findings suggest that AVS is more likely to be a marker of CAD
or inflammation than a direct cause of mortality or cardiovascular events.
AV calcification has also been used to improve prognostication in patients with no
known cardiovascular disease for primary prevention. The Multi‐Ethnic Study of Atherosclerosis
(MESA) followed 6685 participants prospectively for the development of cardiovascular
events, including myocardial infarction, stroke, cardiac arrest, and cardiac death.
5
All subjects aged 45 to 84 received a computed tomography coronary calcium score,
which was used to assess the extent of coronary artery and AV calcification. Approximately
87% of those with AV calcium had coronary artery calcification as opposed to 45.1%
without calcified valves (P<0.0001). After adjustment for traditional risk factors,
the presence of AV calcification increased the chances of cardiovascular (hazard ratio
1.50, 95% CI 1.1 to 2.04) and coronary events (myocardial infarction 1.72, 95% CI
1.19 to 2.49) over a median follow‐up of 5.8 years. This is particularly interesting
because AVS normally does not cause sufficient hemodynamic compromise to impact cardiac
function. One limitation of this study is that the use of computed tomography calcium
score in this investigation may have included subjects with subclinical AS because
hemodynamics could not be assessed.
The large‐scale prospective Cardiovascular Health Study demonstrated similar findings.
After 5 years of follow‐up, subjects with AVS and no known CAD had a statistically
significantly higher risk of myocardial infarction (relative risk [RR] 1.4, 95% CI
1.07 to 1.83), cardiovascular mortality (RR 1.52, 95% CI 1.12 to 2.05), and all‐cause
mortality (RR 1.35, 95% CI 1.12 to 1.61) compared with those without AVS, even after
adjustment for traditional cardiac risk factors (but not CAD).
6
In those with known CAD at the beginning of the study, AVS did not significantly have
an impact on death. Hence, AVS may act as a marker of subclinical endothelial dysfunction
and inflammation that amplifies mortality rates via effects on coronary arteries.
Furthermore, in studies of elderly populations, AVS independently increased the risk
of a major coronary event by 1.8‐fold.
42,48
Retrospective studies of high‐risk patients also found AVS to be an independent predictor
of CAD (P<0.05).
39,41
The association of AVS with excess cardiovascular mortality warrants further research.
AVS has also demonstrated a correlation with the Gensini score, a qualitative and
quantitative angiographic measure of overall burden of coronary atherosclerosis.
38
In a high cardiovascular risk population with known or likely CAD, AVS was found to
be a risk factor for significant 3‐vessel CAD but not for 1‐ or 2‐vessel disease.
Other investigators have corroborated these findings, showing an association between
severity of CAD and AVS.
40
Flow‐mediated dilation is an ultrasound‐based measurement of endothelial function
whereby arterial diameter is measured before and after exposure to increased shear
stress.
49
Normal vasculature undergoing shear stress will release vasoactive mediators that
dilate the vessel; however, damaged endothelium will have an absent or a partial response.
This technique has been proposed as a noninvasive metric for CAD risk but may have
a relationship with AVS given similar pathophysiology. In a study of 102 hospitalized
patients, those with AVS had lower flow‐mediated dilation than did subjects with a
normal AV (2.2% versus 5.3%, P<0.01).
50
This finding is corroborated in a recent publication of 107 hypertensive patients
in whom flow‐mediated dilation was found to be an independent predictor of AVS after
multivariate adjustment (OR 0.691, P=0.001).
51
Furthermore, the presence of AVS had a 100% positive predictive value for endothelial
dysfunction. Interestingly, another investigation showed that peripheral flow‐mediated
dilation was impaired in those with bicuspid AVs compared with age‐matched controls,
which could be related to their altered hemodynamics and premature calcification.
52
Although research into this topic is sparse, these studies imply that systemic endothelial
dysfunction is enmeshed with the pathogenesis of AVS.
Imaging Characteristics
Aortic sclerosis is an echocardiographic diagnosis based on presence of AV calcification
without significant hemodynamic compromise—typically a peak velocity <2 m/s.
53
In contrast, AS has a peak velocity >2.5 m/s. The traditional classification of AVS
severity is based on the echocardiographer's assessment of the amount of calcification
on the AV and thus is a subjective measurement. Comparing early stages of AVS may
be difficult given that the rating is based on the reading cardiologist's discretion.
Along with severity, the type and location of AV calcification may also be important
for identifying the population with the greatest risk of CAD. Not all people with
AVS progress to AS, yet it has been difficult to predict which group is at greatest
risk for development of a hemodynamically significant stenosis. Prospective and retrospective
studies have produced varied results but range from 9% progression of AVS to AS in
5 years to 33% progression over 3.7 years.
54–55
Several studies have shown that more extensive calcifications in AVS, despite not
having a hemodynamic effect, amplify the likelihood of CAD and cardiovascular events.
5,40
Furthermore, in a study of 66 male veterans, diffuse and mixed patterns of AV calcification
on echocardiography had a much stronger association with CAD (OR 3.7, 95% CI 1.2 to
11.1) than localized nodular or nonnodular types.
56
This was replicated in another group of patients at high risk for CAD.
41
These findings suggest that specific patterns of AV leaflet calcification (Figure
2) could identify a subpopulation of patients that should be evaluated more thoroughly
for CAD.
Figure 2.
Patterns of aortic sclerosis seen on echocardiography. Diffuse (A) and mixed (B) types
are associated with higher rates of coronary artery disease than are localized nodular
(C) and localized nonnodular (D) forms. Arrows indicate areas of valvular sclerosis.
Potential Medical Therapies for AVS
Given the shared histological and clinical characteristics of AVS and CAD, many investigators
have tested medical interventions such as lipid‐lowering agents and proremodeling
agents (ie, ACEIs and angiotensin II receptor blockers [ARBs]) that may have salutary
effects on both conditions.
Statins
A large pool of data, based on basic and clinical research, support the concept that
dyslipidemia is often associated with AVS and AS.
4–6,41,49
In addition to lowering lipids, statins have anti‐inflammatory effects and have proved
to be beneficial in those with elevated C‐reactive protein but normal cholesterol.
57
Thus, theoretically, statins could prevent the lipid deposition and inflammation in
AVS. Whether there is causality for dyslipidemia and AVS remains undetermined.
Unfortunately, little research has been done on statin use in AVS, which may be a
more appropriate target given that these lesions are characterized more by inflammation
than their counterpart AS, which exhibits greater calcification and fibrosis. The
early stages of AVS, when valvular stiffening and obstruction to flow have not yet
developed, may provide a window of opportunity for statin treatment to potentially
slow progression to overt AS. A retrospective study of 1689 patients with AVS found
that statin use was associated with improved clinical outcomes, including decreased
cardiovascular mortality (OR 0.73, 95% CI 0.56 to 0.98) and diminished risk of progression
to AS (OR 0.64, 95% CI 0.42 to 0.97).
58
Another investigation found an increased rate of myocardial infarction in those with
AVS as opposed to normal valves, a difference that became insignificant after accounting
for statin use.
43
It is possible that AVS and AS could be a disease continuum where medical therapy
may be more beneficial in the earlier stages.
Retrospective investigations into the impact of statin use on the progression of AS
have produced conflicting results (Table 3). Several studies ranging from 65 to 211
subjects showed a statistically significant trend toward slower evolution of AS with
administration of statins.
47,59–63
However, a larger‐scale study of 1257 patients found no significant statin effect.
64
In 1 analysis of people with existing AS, statins but not cholesterol levels affected
the progression of AS.
62
Thus, given the conflicting results and the inconsistencies in methodologies used
in these studies, it is difficult to draw conclusions regarding the anti‐inflammatory,
pleotrophic, or lipid‐lowering effects of statins on AS.
Table 3.
Retrospective Studies on the Impact of Statins on AVS and AS
Retrospective Study
Year
N
Patient Characteristics
Impact of Statin Use
Pohle et al
47
2001
104
Patients with coronary and AV calcification
Lower LDL associated with slower progression of AV calcification
Aronow et al
59
2001
180
Patients with mild AS and 2 echocardiograms >2 years apart
Slower progression of AS
Novaro et al
60
2001
174
Patients with mild‐to‐moderate AS and 2 echocardiograms >12 months apart
Slower progression of AS
Shavelle et al
61
2002
65
Patients with AV calcification and 2 electron beam tomography scans >6 months apart
Slower progression of AV calcification
Bellamy et al
62
2002
156
Patients with AS, mean transvalvular gradient 10 mm Hg and AVA 2.0 cm2
Slower progression of AS
Rosenhek et al
63
2004
211
Patients with aortic jet velocity >2.5 m/s and normal left ventricular ejection fraction
Slower AS progression, independent of LDL level
Antonini‐Canterin et al
64
2005
1257
Patients with AVS, mild or moderate AS
Overall, no significant difference in progression of AV pathology, but in subset with
AVS, the rate of change in velocity was lower.
Ardehali et al
58
2012
1689
Patients with AVS
Reduced cardiovascular mortality
AVS indicates aortic valve sclerosis; AS, aortic stenosis; AV, aortic valve; LDL,
low‐density lipoprotein; AVA, aortic valve area.
Although there are inconsistent retrospective reports on the use of statin therapy,
recent prospective studies have demonstrated failure to delay the progression of AS.
The largest randomized controlled trial to date (1873 participants with mild to moderate
AS) with the longest follow‐up (4.4 years) revealed that simvastatin in conjunction
with ezetimibe did not reduce a variety of major cardiovascular outcomes, including
those attributed to valvular dysfunction.
65
In fact, rates of AV replacement were the same (myocardial infarction 1.00, 95% CI
0.84 to 1.18). Similar results were observed in studies of rosuvastatin and atorvastatin
(Table 4).
66–69
Additionally, several meta‐analyses found no significant differences between subjects
treated with and without statins in terms of major echocardiographic findings (mean
AV pressure gradient and AV area) or overall clinical outcomes.
70–72
These collective findings suggest that (1) statins are unlikely to significantly affect
the course of AS, (2) AVS may be a more appropriate target for statins but further
research is needed given the scarcity of data, and (3) statins have multifactorial
effects that may not be fully characterized yet.
Table 4.
Prospective Studies on the Impact of Statins on AVS and AS
Prospective Study
Year
Study Design
N
Follow‐up (y)
Patient Characteristics
Impact of Statin Use
Cowell et al (SALTIRE)
66
2005
Double‐blind RCT
151
2.1
AS with aortic jet velocity >2.5 m/s with no statin indication
No difference in AS progression after treatment with atorvastatin
Moura et al (RAAVE)
67
2007
Open‐label, cohort
121
1.5
Moderate to severe AS with AVA 1.0 to 1.5 cm2, treated with statin only if indicated
by guidelines
Slower progression of AS and lower serum LDL with rosuvastastin
Rossebø et al (SEAS)
65
2008
Double‐blind RCT
1873
4.4
Mild‐to‐moderate asymptomatic AS with aortic jet velocity of 2.5 to 4.0 m/s
No difference in AS‐related cardiovascular outcomes with simvastatin and ezetimibe
treatment
Chan et al (ASTRONOMER)
68
2010
Double‐blind RCT
269
3.5
Mild‐to‐moderate AS with aortic jet velocity 2.5 to 4.0 m/s
No difference in AS progression after treatment with rosuvastatin
Panahi et al
69
2013
Double‐blind RCT
75
1
Mild‐to‐moderate AS
Lower mean and peak gradient in atorvastatin group but otherwise no difference in
AS progression
AVS indicates aortic valve sclerosis; AS, aortic stenosis; RCT, randomized controlled
trial; AVA, aortic valve area; LDL, low‐density lipoprotein.
ACEIs and ARBs
As previously illustrated, the angiotensin pathway has been implicated in the process
of AV calcification. Endothelial injury and lipid deposition during the early stages
of AVS stimulate local formation and action of angiotensin II, which enhances collagen
synthesis and attracts monocytes to accelerate disease progression.
73
Therefore, this pathway has been proposed as a target for prevention of AVS and AS.
In terms of patients with AVS, only 1 retrospective study has been performed, which
found no benefit to ACEIs or ARBs in preventing AVS progression or mortality.
58
ACEIs and ARBs have been retrospectively studied in AS with mixed results (Table 5).
58,63,74–77
They pose particular difficulty in their evaluation given their hemodynamic effects,
including afterload reduction (which may cause worsening symptoms of AS) and cardiac
remodeling (which can prolong life). Prospective trials are warranted to evaluate
whether ACEIs and ARBs are able to retard the progression of AVS and AS.
Table 5.
Effect of Angiotensin Pathway Inhibition on AVS and AS
Retrospective Study
Year
N
Patient Characteristics
Impact of ACEI/ARB
Rosenhek et al
63
2004
211
Patients with aortic jet velocity >2.5 m/s and normal left ventricular ejection fraction
No effect on progression of AS
Sverdlov et al
74
2004
212
Randomly selected patients, measured AV backscatter over 4 years
Slowed progression of AV backscatter, a marker of calcification/stenosis
O'Brien et al
75
2005
123
Patients with AV calcification and 2 electron beam tomography scans
Decreased AV calcification
Nadir et al
76
2011
2117
AS detected on echocardiography
Lower all‐cause mortality and cardiovascular events
Wakabayashi et al
77
2011
194
AS detected on echocardiography
Slower progression of AS according to peak velocity
Ardehali et al
58
2012
1689
Patients with AVS
Reduction in admissions for ischemic heart disease and CHF; no impact on mortality
or progression to AS
AS indicates aortic stenosis; ACEI, angiotensin‐converting enzyme inhibitor; ARB,
angiotensin II receptor blocker; AV, aortic valve; AVS, aortic valve sclerosis; CHF,
congestive heart failure.
Other Agents
Nonsteroidal anti‐inflammatory drugs (NSAIDs) have a complex relationship with cardiovascular
health, as is exemplified by the removal of many selective cyclooxygenase‐2 inhibitors
from the market after increased risks of heart attack and stroke were noted. The American
Heart Association recommends against nonaspirin NSAID use in patients with cardiovascular
disease based on clinical data confirming increased mortality and cardiac events.
78
However, given the inflammatory nature of AS and AVS, one may postulate that NSAIDs
could offer a potential benefit. A large‐scale study of 2 cohorts produced divergent
results, showing a slightly increased risk of worsening AV calcification in patients
using aspirin in the American cohort (RR 1.60, 95% CI 1.19 to 2.15), while the German
group experienced no difference (RR 1.06, 95% CI 0.87 to 1.28).
79
Nonaspirin NSAIDs had no significant effects on either population. These results should
be interpreted with caution given the lack of randomization, as well as other risk
factors not accounted for in the group taking aspirin. The cardioprotective antiplatelet
effect of aspirin likely outweighs any potential effect on AV calcification.
The osteogenic properties of AV lesions, which are also observed in atheromas, may
be another therapeutic target. In an investigation of 55 patients with AS, those undergoing
osteoporosis therapy (bisphosphonates, calcitonin, or estrogen receptor modulators)
had a slower rate of AS progression on echocardiography.
80
The mechanism of this intriguing result is not well delineated but may involve the
RANK pathway. The RANK receptor is present on precursor osteoclasts and binds RANK
ligand to promote maturation into active osteoclasts, which promote bone resorption
and remodeling. In 1 study, RANK ligand was present in higher levels in AS than in
controls.
81
Despite the theoretical advantages of bisphosphonates, a larger retrospective study
has not shown any benefit in slowing the progression of disease.
82
Denosumab, a monoclonal antibody used in osteoporosis, inhibits RANK ligand and thus
may be a potential therapeutic target for AVS. No research to date has been done on
AV disease, although animal and human studies into thoracic aorta calcification have
produced mixed results regarding the use of denosumab in preventing vascular calcification.
83–84
Because calcium deposition is integral to the development of both CAD and AVS, some
have hypothesized that higher levels of calcium and vitamin D may promote calcification.
The relationship between CAD and vitamin D appears complex given that vitamin D increases
coronary calcification in animal models.
85
However, in humans, it appears to be protective against atherosclerosis.
86
One potential explanation is that vitamin D has a therapeutic window with both very
low and very high levels promoting calcium deposition. In terms of AV disease, information
comes solely from animal research. One study found that vitamin D supplementation
promoted AVS in rabbits when given alone and induced AS when given in conjunction
with a high‐cholesterol diet.
87
Yet, another study showed no difference in the development of AVS between rabbits
treated with cholesterol and vitamin D versus those without either of these supplements.
88
In contrast, a recent report demonstrated increased calcification in the aortic root
of vitamin D receptor knockout mice, suggesting vitamin D deficiency may stimulate
osteogenic factors involved in vascular calcification.
89
Given the evidence that has emerged regarding the complex relationship between calcium
and vitamin D supplementation and CAD, this topic should be investigated further with
respect to AV disease. Paucity of appropriate animal models for AVS is a major limitation
to pursue research in this area.
Antioxidants may also decrease inflammation and progression of AV disease. An in vitro
study comparing normal AV, AVS, and AS discovered that there were lower levels of
antioxidants in diseased valves.
90
After exposure to reactive oxygen species, Runx2 levels were tripled, DNA repair was
hindered, and calcification was increased in AS and AVS compared with controls. This
suggests that calcified valves are more susceptible to osteogenic factors when exposed
to reactive oxygen species. This effect was partially reversed when antioxidants were
administered. Although these are exciting initial findings, they need to be replicated
in human and animal models. Other targets may include matrix metalloproteinase inhibitors,
Notch pathway augmentation, and enhancement of the nitric oxide signaling pathway,
which require further research.
74
Clinical Applicability
Results of the clinical studies reviewed here suggest that AVS may have a role in
the evaluation of a patient with potential CAD. Combining echocardiography with an
exercise treadmill test may increase the sensitivity and specificity of diagnosing
CAD and avoid unnecessary coronary catheterizations.
45
The presence of AVS in younger people should be of particular concern because it more
likely represents an inflammatory as opposed to a degenerative process. However, because
younger patients with AVS are normally asymptomatic, it is difficult to screen these
individuals without an underlying clinical suspicion. Younger individuals with a family
history of early AS, CAD, bicuspid valves, traditional risk factors such as diabetes
mellitus, or chronic inflammatory diseases would be reasonable initial targets. For
instance, patients with systemic lupus erythematosus have a higher risk of CAD compared
with age‐matched controls according to a recent systematic review of 28 studies.
91
The development of AVS on screening echocardiography could signify underlying CAD
and prompt more aggressive management of risk factors.
The association of CAD with AVS presents an opportunity for screening. If early detection
of AVS accelerated the diagnosis and treatment of CAD, this could theoretically decrease
morbidity and mortality. However, currently there is no confirmatory evidence to support
routine AV evaluation to screen patients for CAD. Understanding the mechanisms underlying
the development of AVS and unraveling its association with CAD will undoubtedly generate
potential areas for therapeutic interventions. It is possible that after further rigorous
research, AVS could be used in concert with other factors such as family history,
comorbidities, and C‐reactive protein, to help risk‐stratify patients and delineate
how aggressive lifestyle and medical interventions should be pursued. This could be
especially useful in the case of borderline patients without known CAD.
Future Directions
For many years, AV disease has been considered a progressive obstructive lesion that
would ultimately require a mechanical approach to ameliorate symptoms and provide
survival benefit. Surgical and recently transcatheter AV replacements with concomitant
revascularization have been the standard management strategy for patients with severe
AS and CAD.
AVS begins and progresses in a setting of complex interactions between mechanical
forces and a dynamically changing tissue milieu that has both similarities and differences
with CAD. The rapidly expanding body of knowledge regarding regulation and disruption
of homeostasis in the AV and coronary vasculature will help with the discovery of
common molecular pathways and therapeutic targets for clinical application. However,
we should be cautious that treatment of surrogate risk factors, such as inflammation
and calcification, may not provide functional benefit but allow us to identify patients
at risk.
Finally, imaging methods, including molecular imaging that could identify sites of
inflammation and calcification, with subsequent targeted therapy will be valuable.
Future discovery of medical therapies to treat or slow progression of AVS will be
challenging but necessary given the imminent aging population and significant financial
costs.