The Journal Club Conference

1
IN
Is it Over?

• The Journal Club Conference
• Shadwan Alsafwah, MD
• Cardiology Fellow
• The University of Tennessee at Memphis

2
Introduction

• 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

3
Pathogenesis of Calcific AS

• 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

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• - 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

5
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. 199717547-552
6

• -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

7
Rajamannan NM, Otto CM. Circulation.
20041101180-82
8
AS and CAD

• 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

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AS and Statins

• 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

10
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 1052660, 2002
11
AS and Statins in Humans

• 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

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Scottish Aortic Stenosis and Lipid Lowering
Trial, Impact on Regression (SALTIRE)

• 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 aortic-valve 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 3522389
15
Methods The Patients

• Patients older than 18 years of age with calcific
  aortic stenosis, an aortic-jet 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, lt1 cm2), severe mitral or
• aortic regurgitation, left ventricular
  dysfunction (ejection fraction lt35
• 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 3522389
16
MethodsStudy Protocol

• 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

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MethodsStudy Protocol

• 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

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MethodsEnd Points

• 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

20

• 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 3.430.64 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)

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ResultsSerum Cholesterol Concentrations

• The mean serum low-density lipoprotein (LDL)
  cholesterol concentration remained at 13030 mg
  per deciliter in the placebo group and decreased
  by 53 percent to 6323 mg per deciliter in the
  atorvastatin group (Plt0.001)
• Serum total cholesterol was 20935 mg per
  deciliter and 13227 mg per deciliter in the
  placebo and atorvastatin groups, respectively
  (Plt0.001), and is in keeping with 97 adherence
  to the study treatment in both groups, which was
  confirmed by a pill count

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Effect of Atorvastatin on Disease Progression

• 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
  22.321.0 percent per year in the atorvastatin
  group, and 21.719.8 percent per year in the
  placebo group (P0.93 ratio of post-treatment
  aortic-valve calcium score, 0.998 95 percent
  confidence interval, 0.947 to 1.050)

26
Secondary End Points

• 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

27
Subgroup Analysis

• 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 (P0.04), 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 0.210.20 m per second per year in
  the atorvastatin group and 0.170.14 m per second
  per year in the placebo group. In those followed
  for 24 months or less, the increase in aortic-jet
  velocity was 0.190.22 m per second per year in
  the atorvastatin group and 0.230.25 m per second
  per year in the placebo group

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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, large-scale, 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 3522389
29
DiscussionResults

• In this randomized, double-blind,
  placebo-controlled, parallel-group 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

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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)

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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

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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 lt0.07 m per second per year for aortic-jet
  velocity and lt5 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

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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

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• 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

35
AS vs CAD

• At the tissue and cellular level
• in contrast to atherosclerosis, aortic stenosis
  is associated with a significantly less degree of
  smooth-muscle-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

36
AS vs CAD

• 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

37

• 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

38
Rajamannan NM, Otto CM. Circulation.
20041101180-82
39
So What is the Rest of the Story?
40
Other Proposed Mechanisms for the Development of
AS

• Abnormalities in Calcium Metabolism
• - Hyperparathyroidism
• Primary
• Secondary
• - Certain Vitamin D receptor genotype (allele
  B)
• ACE activity

41
AS and Hyperparathyroidism

• 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.
  197150744-55)

42
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
• 19811411663-5
• -McFalls EO, et al. Am Heart J 1990120206-8
• -Fujise K, et al. Br Heart J 199370282-4
  

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The vitamin D receptor genotype predisposes to
the development of calcific aortic valve stenosis

• 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 200185635-638
44

• 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 200185635-638
45
Rajamannan NM, Otto CM. Circulation.
20041101180-82
46
Angiotensin-Converting Enzyme Inhibitors and
Change in Aortic Valve Calcium

• 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. 2005165858-8
62.
47
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. 2005165858-8
62.
48
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. 2005165858-8
62.
49
Obrien, KD, et al. Arch Intern Med. 2005165858-8
62.
50
So, is this is the End of the Story for Statins
and AS?
51
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

• 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

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Thank You