IN
Is it Over?
The Journal Club Conference
Shadwan Alsafwah, MD
Cardiology Fellow
The University of Tennessee at Memphis
Introduction
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In the Western world, calcific aortic stenosis is the most
common form of valvular heart disease, and its incidence
increases with age such that 3% of adults over 75 years of age
have aortic stenosis
It is a progressive disease that leads to a need for aortic-valve
replacement when stenosis becomes severe and symptoms
develop
Calcific aortic stenosis is now the leading indication for valve
replacement in North America and Europe
The growing number of aortic valve-replacement procedures
(currently 50,000 cases annually in the US) is a burden on the
health care systems
However, there are currently no effective disease-modifying
treatments, and the possibility of halting the disease process
would represent a therapeutic advance
Pathogenesis of Calcific AS
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“Degenerative” calcific aortic valve disease was thought
for many years to be a passive accumulation of calcium
binding to the aortic surface of the valve leaflet
Now, convincing data indicate aortic stenosis is an
active disease process with active inflammatory
component
At the tissue level, the valve leaflets show the following
features:
-Accumulation of LDL and Lp(a) with evidence of
oxidative modification
- An inflammatory cell infiltrate with activated T-lymphocytes and
macrophages
Activated macrophages and fibroblasts produce Osteopontin (a
noncollagenous, glycosylated phosphoprotein that is a prominent matrix
component of mineralized bone)
Osteopontin has several structural characteristics that lend support to the
potential roles it may play including:
1. Cellular adhesion via an Arg-Gly-Asp (RGD) motif
2. Hydroxyapatite binding via a sequence of nine consecutive aspartic acids
3. Calcium binding site
4. Also, osteopontin has been identified as a substrate for transglutaminase
and factor XIII, which may serve to covalently anchor the protein to
other extracellular matrix components.
- The noncollagenous matrix proteins such as osteopontin, as well as various
enzymes and growth factors, control the calcific process
Photomicrographs showing the association of osteopontin and macrophages in a
calcified aortic valve. A, Calcium staining with alizarin red S. B, Osteopontin identified
with anti-osteopontin peptide antibody. C, CD68-positive macrophages (brown) with
hematoxylin and eosin counterstaining. Macrophages were associated with osteopontin
and calcific deposits.
Mohler, III E, et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:547-552
-Production and activity of angiotensin converting enzyme and
AT1 and AT2 receptors
-Other inflammatory mediators such as interleukin-1-beta and
transforming growth factor beta-1
-Upregulation of adhesion molecules and alterations in matrix
metalloproteinase activity
- Hormones also influence the calcific process, as seen with states
of altered calcium metabolism, such as hyperparathyroidism,
Padget's disease, and renal failure, in which ectopic
calcification is not uncommon
Rajamannan NM, Otto CM. Circulation. 2004;110:1180-82
AS and CAD
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The active inflammatory component of calcific aortic-valve
disease has been recognized, and similarities with atherosclerotic
disease have been identified
Both calcific aortic-valve disease and atherosclerosis are
characterized by lipid infiltration, inflammation, neoangiogenesis,
and calcification, and the two diseases often coexist
Patients with any degree of aortic-valve disease (e.g., aortic
sclerosis, mild-to-moderate stenosis, or severe stenosis) have
increased cardiovascular morbidity and mortality
Also, endothelial dysfunction is present in patients with aortic
stenosis
AS and Statins
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From these observations, the hypothesis has emerged
that statins, which reduce the progression of
atherosclerotic disease and significantly improve the
clinical outcome among patients with coronary artery
disease, might also be beneficial in patients with aortic
stenosis
Since aortic stenosis, like atherosclerosis, is an active
disease process, it seems plausible that statins might
slow its hemodynamic progression
AS and Statins in Animal Models
Light microscopy of rabbit aortic valves from a
rabbit fed a conventional diet (left column), one
fed a high-cholesterol diet (middle column), and
one fed a high-cholesterol diet and treated with
atorvastatin (right column).
A1-A3, Hematoxylin and eosin stain.
B1-B3, Masson trichrome stain for collagen (blue
stain).
C1-C3, Macrophage RAM-11 stain for macrophages
and foam cells.
D1-D3, Stain for proliferating cell nuclear antigen.
Rajamannan NM, et al. Circulation 105:2660, 2002
AS and Statins in Humans
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Until recently, the effects of statin therapy on the
progression of aortic stenosis have been assessed only
in retrospective studies. Four such studies used
echocardiography to evaluate hemodynamic
progression and found a significantly lower rate of
progression of aortic stenosis among patients treated
with statins
Furthermore, an additional retrospective study that
used electron-beam computed tomography to
determine the degree of valvular calcification identified
a lesser degree of aortic-valve calcium accumulation
among patients receiving statins
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Each of these studies included between 65 and 211
patients, with a mean follow-up time between 21 and 44
months.
Although these studies consistently described a lower rate
of progression of aortic stenosis with statin therapy, they
were all limited by their nonrandomized, retrospective
nature
The slower rate of disease progression was related to
lowering of cholesterol levels in some of these studies but
not others, suggesting that pleiotropic effects of statins may
play a role
These observations provided the rationale for the first
prospective randomized (SALTIRE) trial
Scottish Aortic Stenosis and Lipid Lowering Trial,
Impact on Regression (SALTIRE)
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The aim of the Scottish Aortic Stenosis and
Lipid Lowering Trial, Impact on Regression
(SALTIRE) was to establish whether intensive
lipid-lowering therapy with 80 mg of
atorvastatin daily would halt the progression or
induce regression of the aortic-jet velocity on
Doppler echocardiography, and of the aorticvalve calcium score on computed tomography
(CT), in patients with calcific aortic stenosis
Cowell, SJ, Newby DE, Prescott RJ et al. N Engl J Med 2005; 352:2389
Methods
The Patients
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Patients older than 18 years of age with calcific aortic stenosis, an aorticjet velocity of at least 2.5 m per second, and aortic-valve calcification on
echocardiography were eligible for inclusion
Exclusion criteria were:
-Child-bearing potential without contraception
-Active or chronic liver disease
-History of alcohol or drug abuse
-Severe mitral-valve stenosis (mitral-valve area, <1 cm2), severe mitral or
aortic regurgitation, left ventricular dysfunction (ejection fraction <35
percent), a planned aortic-valve replacement
-Intolerance of statins, statin therapy or a potential benefit from statin
therapy (according to the treating physician), a baseline serum total
cholesterol concentration of less than 150 mg per deciliter
-Presence of a permanent pacemaker or defibrillator
Cowell, SJ, Newby DE, Prescott RJ et al. N Engl J Med 2005; 352:2389
Methods
Study Protocol
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Between March 2001 and April 2002, the blinded study
coordinator randomly assigned eligible patients by the
minimization technique with the use of a dedicated,
locked computer program incorporating the following
eight variables: age, sex, smoking habit, hypertension,
diabetes mellitus, serum cholesterol concentration,
aortic-jet velocity, and aortic-valve calcium score.
Patients were assigned to either 80 mg of atorvastatin
or matched placebo as a single daily dose
Methods
Study Protocol
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Patients were assessed at baseline, two months, and six
months and every six months thereafter for a minimum of
two years
Clinical evaluation included assessment of functional status
and adverse events, and the biochemical analysis of blood
Echocardiography and CT were performed at baseline, at
each annual visit, and before withdrawal from the study
Patients who underwent randomization and who were
subsequently started on open-label statin therapy by their
attending physician were immediately withdrawn from the
study
Methods
End Points
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The two primary end points were:
1. Progression of stenosis, determined according to
changes in aortic-jet velocity on Doppler echo
2. Progression of valvular calcification, as measured
by CT
Secondary end points were:
-A composite of clinical end points (death from cardiovascular causes,
aortic-valve replacement, or hospitalization attributable to severe aortic
stenosis)
-Aortic-valve replacement
-Death from any cause
-Death from cardiovascular causes
-Hospitalization for any cause
-Hospitalization for severe aortic stenosis
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The study was powered to detect a difference in the
primary end points of 0.15 m per second per year in
aortic-jet velocity and 500 agatston units (AU) per year
in aortic-valve calcium score. These differences are
equivalent to a reduction of more than 30 percent in
the rate of progression of aortic stenosis. This would
exclude a clinically significant effect in the majority of
older patients with established disease, although a
smaller effect may be clinically relevant in younger
patients with mild aortic stenosis
77 patients were assigned to atorvastatin, and
78 to placebo
 Median follow-up of 25 months (range: 7 to 36
months)
 Baseline characteristics were well matched:
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Mean aortic-jet velocity was 3.43±0.64 m/s
(range, 2.5 to 5.0)
Median aortic-valve calcium score was 5920 AU
(range, 2485 to 14,231)
Of the 155 patients, 119 had mild-to-moderate
aortic stenosis (aortic-jet velocity, 2.5 to 3.9
m/s), and 36 had severe stenosis (aortic-jet
velocity, 4.0 m/s)
Results:
Serum Cholesterol Concentrations
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The mean serum low-density lipoprotein (LDL)
cholesterol concentration remained at 130±30 mg per
deciliter in the placebo group and decreased by 53
percent to 63±23 mg per deciliter in the atorvastatin
group (P<0.001)
Serum total cholesterol was 209±35 mg per deciliter
and 132±27 mg per deciliter in the placebo and
atorvastatin groups, respectively (P<0.001), and is in
keeping with 97% adherence to the study treatment in
both groups, which was confirmed by a pill count
Effect of Atorvastatin on Disease Progression
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Intensive lipid-lowering therapy with 80 mg of atorvastatin daily had no effect on the
rate of change in aortic-jet velocity or valvular calcification.
Progression in valvular calcification was 22.3±21.0 percent per year in the atorvastatin
group, and 21.7±19.8 percent per year in the placebo group (P=0.93; ratio of posttreatment aortic-valve calcium score, 0.998; 95 percent confidence interval, 0.947 to
1.050)
Secondary End Points
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The proportion of patients reaching secondary clinical
end points seemed to be less in the atorvastatin group,
but none of the comparisons achieved statistical
significance
Subgroup Analysis
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Subgroup analysis of the primary end-point data was conducted in patients with mild-to-moderate aortic
stenosis and severe aortic stenosis at baseline. As anticipated from earlier studies, patients with severe stenosis
at baseline progressed more rapidly (P=0.04), but the study findings were consistent regardless of the severity
of stenosis at baseline
Likewise, the length of follow-up did not influence outcome. In those followed for more than 24 months , the
increase in aortic-jet velocity was 0.21±0.20 m per second per year in the atorvastatin group and 0.17±0.14 m
per second per year in the placebo group. In those followed for 24 months or less, the increase in aortic-jet
velocity was 0.19±0.22 m per second per year in the atorvastatin group and 0.23±0.25 m per second per year in
the placebo group
Conclusion
“We conclude that intensive lipid-lowering therapy with 80 mg of
atorvastatin daily does not halt the progression of calcific aortic
stenosis or induce its regression. Nevertheless, this trial does not
rule out a small but potentially relevant reduction in the rate of
disease progression or a significant reduction in major clinical
end points. Our study reinforces the need for a long-term, largescale, randomized, controlled trial of intensive lipid-lowering
therapy in patients with calcific aortic stenosis, particularly in
those with early, mild disease. In the meantime, we do not
recommend statin therapy for patients with calcific aortic
stenosis in the absence of coexisting vascular disease”
Cowell, SJ, Newby DE, Prescott RJ et al. N Engl J Med 2005; 352:2389
Discussion:
Results
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In this randomized, double-blind, placebo-controlled, parallelgroup trial of lipid-lowering therapy in patients with calcific aortic
stenosis, a single coordinating center used a consistent and
reproducible approach to assess the severity of aortic stenosis
It has clearly shown that high-dose atorvastatin reduces serum LDL
cholesterol concentrations as anticipated, but it does not halt the
progression or induce regression of the valvular disease process.
This was shown with the use of two distinct measures of disease
severity — aortic-jet velocity assessed with Doppler
echocardiography and valvular calcification assessed with helical CT
Moreover, there was no relationship between serum LDL
cholesterol concentrations and the progression of aortic stenosis,
nor did high-dose atorvastatin have a demonstrable effect on
clinical end points
Strengths
1. The first prospective, randomized study assessing the effect of
statins in aortic stenosis
2. Although the characteristics of the patients in this study and in
the retrospective studies were similar, the present study differs
not only because of its prospective design but also because the
indications for therapy were different. In the retrospective
trials, statin therapy was indicated for the treatment of
hyperlipidemia, whereas in the prospective trial, patients in
whom statins were indicated for the treatment of
hyperlipidemia were excluded
3. In this study statins were prescribed at a high dose (80 mg of
atorvastatin per day). In the retrospective studies, the doses
were lower 10-20 mg per day of atorvastatin)
Weaknesses
1. The study excluded patients with an aortic-jet
velocity of less than 2.5 m per second,
although it acknowledged that intervening at
this earlier stage of the disease process may
have been more beneficial
2. The study was designed to detect a substantial
delay in disease progression and was not
powered to assess meaningful effects on
clinical end points, such as valve replacement
and cardiovascular death
Weaknesses
3. Although the study can exclude a treatment benefit of the
magnitude previously reported in retrospective observational
studies (a reduction in the aortic-jet velocity of 0.30 m per
second per year and valvular calcification of 30 percent per
year), the 95 percent confidence intervals indicate that the study
may have missed a modest treatment benefit (a delay in disease
progression of <0.07 m per second per year for aortic-jet
velocity and <5 percent per year for valvular calcification).
Although such modest reductions are unlikely to be meaningful
in the majority of older patients, a small decrease in disease
progression may be clinically important in younger patients with
mild disease that may progress over many years
Weaknesses
4. Although the observation periods in this study in
comparison to the prior retrospective studies were
similar. However, in the retrospective studies, the
patients were already receiving therapy at the time of
inclusion in the study and many of them were started
therapy long before the study. Thus, one cannot rule
out the need for longer overall treatment periods to
observe an effect of statin therapy
5. Although all the studies were similar in size, they were
all relatively small, and it is too early to draw
conclusions on the value of statin therapy in aortic
stenosis
Given the strength of the data linking aortic
stenosis with atherosclerosis and
hypercholesterolemia, this study failed to
halt the progression of calcific aortic
stenosis?
One potential explanation is that, although these
features may drive the initiation of aortic stenosis, the
disease progression may depend on other factors
AS vs CAD
At the tissue and cellular level:
 in contrast to atherosclerosis, aortic stenosis is
associated with a significantly less degree of smoothmuscle-cell proliferation and lipid-laden macrophages.
On the other hand, it is dominated by earlier and more
extensive mineralization
 Hence, decreasing the lipid pool and strengthening the
fibrous cap may be less relevant to the progression of
aortic stenosis than they are for the reduction in
atherosclerotic-plaque rupture with statin therapy in
patients with coronary heart disease
AS vs CAD
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However, perhaps the most important difference is the
mechanism of clinical events:
In atherosclerosis, plaque instability is key; in aortic
stenosis, the shear bulk of the lesion is the problem.
Early in the disease process, small areas of
inflammation and lipid infiltration are interspersed with
areas of normal leaflet so that the valve leaflets remain
flexible and open normally in systole. Late in the
disease process, the abnormal areas become confluent
with prominent calcification and increased fibrosis,
resulting in increased leaflet stiffness and obstruction to
left ventricular outflow
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Inhibition of lipid accumulation in the valve tissue is the
first pathway to be studied; however, other more specific
therapies targeting endothelial disruption, inflammation,
or tissue calcification may be more effective
Hence, therapy may need to be tailored to the stage of
the disease process; some may prevent initiation of
disease process, whereas others may be more effective in
slowing calcium accumulation in end-stage disease
Rajamannan NM, Otto CM. Circulation. 2004;110:1180-82
So What is the Rest of the
Story?
Other Proposed Mechanisms for the
Development of AS
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Abnormalities in Calcium Metabolism:
- Hyperparathyroidism
Primary
Secondary
- Certain Vitamin D receptor genotype (allele B)
ACE activity
AS and Hyperparathyroidism
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Multiorgan soft tissue calcification commonly occurs in patients
with chronic renal failure; secondary hyperparathyroidism is
thought to be the major causative factor
-Asymptomatic calcification of heart valves has been reported in
up to a third of such patients
-Hemodynamically significant AS is found in 3% in those
patients
In a postmortem study, parathyroid hyperplasia was found in all
six patients with chronic renal failure, who were shown to have
extensive cardiac calcification. (Terman D, et al. Cardiac calcification in uremia.
Am J Med. 1971;50:744-55)
AS and Hyperparathyroidism
Although up till recently enhanced progression
of valve stenosis in the presence of secondary
hyperparathyroidism has not been studied
systematically, but there are many case reports in
the literature to support that:
-Depace NL, et al. Arch Intern Med
1981;141:1663-5
-McFalls EO, et al. Am Heart J 1990;120:206-8
-Fujise K, et al. Br Heart J 1993;70:282-4
The vitamin D receptor genotype predisposes to the
development of calcific aortic valve stenosis
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The distribution of one polymorphism of the vitamin D
receptor (BsmI B/b) was examined in 100 consecutive
patients with calcific valvar aortic stenosis and compared
with a control group of 100 patients (paired match for
age, sex, and the presence of coronary artery disease
from a total of 630 patients without calcified aortic
valves)
RESULTS: There was a significant difference in vitamin
D receptor allele and genotype frequencies between the
two groups. The allele B had a higher prevalence in
patients with calcific aortic stenosis (B = 0.56, b = 0.44)
than in the control cohort (B = 0.40, b = 0.60)
(p = 0.001)
Ortlepp, Jr, et al. Heart 2001;85:635-638
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This study found an association between the B allele which
seems to predispose gene carriers to blunted calcium absorption,
more rapid bone loss, reduced bone mineral density, and raised
parathormone secretion and the prevalence of calcific aortic
valve stenosis
There might be several hypotheses to explain the relation
between genotype and the development of aortic stenosis.
Individuals with a slightly unfavorable bone mineral density
might develop mechanisms to overcome this alteration of
calcium homeostasis. Like parathormone, other hormones,
proteins, or second messengers might trigger calcification of
extraosseous structures like the aortic valve. The aortic valve is
likely to be one of the first extraosseous structures involved
because of the high level of mechanical stress to which it is
subjected
Ortlepp, Jr, et al . Heart 2001;85:635-638
Rajamannan NM, Otto CM. Circulation. 2004;110:1180-82
Angiotensin-Converting Enzyme Inhibitors
and Change in Aortic Valve Calcium
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Background: Because lipoproteins, angiotensin-converting
enzyme, and angiotensin II colocalize with calcium in aortic
valve lesions, the study hypothesized an association between
ACEI use and lowered aortic valve calcium (AVC) accumulation,
as measured by electron beam computed tomography
Rates of change in volumetric AVC scores were determined
retrospectively for 123 patients who had undergone 2 serial
electron beam computed tomographic scans. The mean (±SD)
interscan interval was 2.5 (±1.7) years; 80 patients did not receive
ACEIs and 43 received ACEIs. The relationship of ACEI use to
median rates of AVC score change (both unadjusted and
adjusted for baseline AVC scores and coronary heart disease risk
factors) was determined
Obrien, KD, et al. Arch Intern Med. 2005;165:858-862.
Association of angiotensin-converting enzyme inhibitor (ACEI) use with lower rate
of change in aortic valve calcium (AVC) scores. Box plots display the median and
25th and 75th percentiles, and bars show the 10th and 90th percentiles. Median
values are shown to the right of each box. Median rate of change was significantly
lower for the ACEI group (Mann-Whitney test).
Obrien, KD, et al. Arch Intern Med. 2005;165:858-862.
Association of angiotensin-converting enzyme inhibitor (ACEI) use with
lower likelihood of definite progression in AVC scores (Fisher exact
test).
Obrien, KD, et al. Arch Intern Med. 2005;165:858-862.
Obrien, KD, et al. Arch Intern Med. 2005;165:858-862.
So, is this is the End of the Story
for Statins and AS?
In The Horizon
At least 2 prospective, randomized, placebo-controlled
multicenter studies of lipid-lowering therapy to prevent disease
progression in aortic stenosis are in progress:
-The Aortic Stenosis Progression Observation
Measuring Effect of Rosuvastatin (ASTRONOMER)
study in Canada
-Simvastatin and Ezetimide in Aortic Stenosis (SEAS)
study in Europe
 We should await the results of these trials to determine whether
it will become appropriate to prescribe statin therapy routinely in
patients with calcific valve disease.
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Summary
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Calcific aortic stenosis is an active disease process with active
inflammatory component
There is evidence in the literature (animal models and retrospective
studies) that statins may be beneficial in slowing down the progression
of AS
SALTIRE trial, the first randomized prospective trial, failed to show a
beneficial effect of atorvastatin on AS progression.
However, SALTIRE trial had many limitations and final conclusions
about the benefits of statins on the progression of AS should wait
further studies
Interfering with lipid metabolism in the valve tissue was the first
pathway to be studied prospectively; however, further studies are
needed to address the other pathways involved in the pathogenesis of
AS including endothelial disruption, inflammation, tissue ACE system,
and tissue calcification
Thank You