IN
Is it Over?
The Journal Club ConferenceThe Journal Club ConferenceShadwan Alsafwah, MDShadwan Alsafwah, MD
Cardiology FellowCardiology FellowThe University of Tennessee at MemphisThe University of Tennessee at Memphis
In the Western world, calcific aortic stenosis is the In the Western world, calcific aortic stenosis is the most common form of valvular heart disease, and its most common form of valvular heart disease, and its incidence increases with age such that 3% of adults incidence increases with age such that 3% of adults over 75 years of age have aortic stenosis over 75 years of age have aortic stenosis
It is a progressive disease that leads to a need for It is a progressive disease that leads to a need for aortic-valve replacement when stenosis becomes aortic-valve replacement when stenosis becomes severe and symptoms developsevere and symptoms develop
Calcific aortic stenosis is now the leading indication Calcific aortic stenosis is now the leading indication for valve replacement in North America and Europefor valve replacement in North America and Europe
The growing number of aortic valve-replacement The growing number of aortic valve-replacement procedures (currently 50,000 cases annually in the procedures (currently 50,000 cases annually in the US) is a burden on the health care systemsUS) is a burden on the health care systems
However, there are currently no effective disease-However, there are currently no effective disease-modifying treatments, and the possibility of halting modifying treatments, and the possibility of halting the disease process would represent a therapeutic the disease process would represent a therapeutic advance advance
IntroductionIntroduction
Pathogenesis of Calcific Pathogenesis of Calcific AS AS
““Degenerative” calcific aortic valve disease was Degenerative” calcific aortic valve disease was thought for many years to be a passive thought for many years to be a passive accumulation of calcium binding to the aortic accumulation of calcium binding to the aortic surface of the valve leaflet surface of the valve leaflet
Now, convincing data indicate aortic stenosis is Now, convincing data indicate aortic stenosis is an active disease process with active an active disease process with active inflammatory component inflammatory component
At the tissue level, the valve leaflets show the At the tissue level, the valve leaflets show the following features:following features:
-Accumulation of LDL and Lp(a) with evidence -Accumulation of LDL and Lp(a) with evidence of of
oxidative modification oxidative modification
- An inflammatory cell infiltrate with activated T-lymphocytes and - An inflammatory cell infiltrate with activated T-lymphocytes and macrophagesmacrophages
- Activated macrophages and fibroblasts produce Osteopontin (a Activated macrophages and fibroblasts produce Osteopontin (a noncollagenous, glycosylated phosphoprotein that is a prominent noncollagenous, glycosylated phosphoprotein that is a prominent matrix component of mineralized bone) matrix component of mineralized bone)
- Osteopontin has several structural characteristics that lend Osteopontin has several structural characteristics that lend support to the potential roles it may play including: support to the potential roles it may play including:
1. Cellular adhesion via an Arg-Gly-Asp (RGD) motif 1. Cellular adhesion via an Arg-Gly-Asp (RGD) motif 2. Hydroxyapatite binding via a sequence of nine consecutive 2. Hydroxyapatite binding via a sequence of nine consecutive
aspartic acids aspartic acids 3. Calcium binding site3. Calcium binding site 4. Also, osteopontin has been identified as a substrate for 4. Also, osteopontin has been identified as a substrate for
transglutaminase transglutaminase and factor XIII, which may serve to covalently anchor the and factor XIII, which may serve to covalently anchor the
protein to protein to other extracellular matrix components. other extracellular matrix components. - The noncollagenous matrix proteins such as osteopontin, as well - The noncollagenous matrix proteins such as osteopontin, as well
as various enzymes and growth factors, control the calcific as various enzymes and growth factors, control the calcific process 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 -Production and activity of angiotensin converting enzyme and and
AT1 and AT2 receptors AT1 and AT2 receptors -Other inflammatory mediators such as interleukin-1-beta -Other inflammatory mediators such as interleukin-1-beta
and and transforming growth factor beta-1transforming growth factor beta-1 -Upregulation of adhesion molecules and alterations in -Upregulation of adhesion molecules and alterations in
matrix matrix metalloproteinase activity metalloproteinase activity - Hormones also influence the calcific process, as seen with - Hormones also influence the calcific process, as seen with
states states of altered calcium metabolism, such as of altered calcium metabolism, such as
hyperparathyroidism, hyperparathyroidism, Padget's disease, and renal failure, in which ectopic Padget's disease, and renal failure, in which ectopic calcification is not uncommon calcification is not uncommon
Rajamannan NM, Otto CM. Circulation. 2004;110:1180-82
AS and CADAS and CAD The active inflammatory component of calcific The active inflammatory component of calcific
aortic-valve disease has been recognized, and aortic-valve disease has been recognized, and similarities with atherosclerotic disease have been similarities with atherosclerotic disease have been identified identified
Both calcific aortic-valve disease and atherosclerosis Both calcific aortic-valve disease and atherosclerosis are characterized by lipid infiltration, inflammation, are characterized by lipid infiltration, inflammation, neoangiogenesis, and calcification, and the two neoangiogenesis, and calcification, and the two diseases often coexist diseases often coexist
Patients with any degree of aortic-valve disease Patients with any degree of aortic-valve disease (e.g., aortic sclerosis, mild-to-moderate stenosis, or (e.g., aortic sclerosis, mild-to-moderate stenosis, or severe stenosis) have increased cardiovascular severe stenosis) have increased cardiovascular morbidity and mortalitymorbidity and mortality
Also, endothelial dysfunction is present in patients Also, endothelial dysfunction is present in patients with aortic stenosiswith aortic stenosis
AS and StatinsAS and Statins
From these observations, the hypothesis From these observations, the hypothesis has emerged that statins, which reduce the has emerged that statins, which reduce the progression of atherosclerotic disease and progression of atherosclerotic disease and significantly improve the clinical outcome significantly improve the clinical outcome among patients with coronary artery among patients with coronary artery disease, might also be beneficial in patients disease, might also be beneficial in patients with aortic stenosis with aortic stenosis
Since aortic stenosis, like atherosclerosis, is Since aortic stenosis, like atherosclerosis, is an active disease process, it seems an active disease process, it seems plausible that statins might slow its plausible that statins might slow its hemodynamic progression hemodynamic progression
AS and Statins in Animal AS and Statins in Animal Models 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 AS and Statins in HumansHumans
Until recently, the effects of statin therapy on Until recently, the effects of statin therapy on the progression of aortic stenosis have been the progression of aortic stenosis have been assessed only in retrospective studies. Four assessed only in retrospective studies. Four such studies used echocardiography to such studies used echocardiography to evaluate hemodynamic progression and evaluate hemodynamic progression and found a significantly lower rate of found a significantly lower rate of progression of aortic stenosis among patients progression of aortic stenosis among patients treated with statins treated with statins
Furthermore, an additional retrospective Furthermore, an additional retrospective study that used electron-beam computed study that used electron-beam computed tomography to determine the degree of tomography to determine the degree of valvular calcification identified a lesser valvular calcification identified a lesser degree of aortic-valve calcium accumulation degree of aortic-valve calcium accumulation among patients receiving statins among patients receiving statins
Each of these studies included between 65 and Each of these studies included between 65 and 211 patients, with a mean follow-up time between 211 patients, with a mean follow-up time between 21 and 44 months. 21 and 44 months.
Although these studies consistently described a Although these studies consistently described a lower rate of progression of aortic stenosis with lower rate of progression of aortic stenosis with statin therapy, they were all limited by their statin therapy, they were all limited by their nonrandomized, retrospective naturenonrandomized, retrospective nature
The slower rate of disease progression was The slower rate of disease progression was related to lowering of cholesterol levels in some of related to lowering of cholesterol levels in some of these studies but not others, suggesting that these studies but not others, suggesting that pleiotropic effects of statins may play a role pleiotropic effects of statins may play a role
These observations provided the rationale for the These observations provided the rationale for the first prospective randomized (SALTIRE) trial first prospective randomized (SALTIRE) trial
Scottish Aortic Stenosis and Lipid Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression Lowering Trial, Impact on Regression
(SALTIRE)(SALTIRE) The aim of the Scottish Aortic Stenosis and The aim of the Scottish Aortic Stenosis and
Lipid Lowering Trial, Impact on Regression Lipid Lowering Trial, Impact on Regression (SALTIRE) was to establish whether (SALTIRE) was to establish whether intensive lipid-lowering therapy with 80 mg intensive lipid-lowering therapy with 80 mg of atorvastatin daily would halt the of atorvastatin daily would halt the progression or induce regression of the progression or induce regression of the aortic-jet velocity on Doppler aortic-jet velocity on Doppler echocardiography, and of the aortic-valve echocardiography, and of the aortic-valve calcium score on computed tomography calcium score on computed tomography (CT), in patients with calcific aortic stenosis (CT), in patients with calcific aortic stenosis
Cowell, SJ, Newby DE, Prescott RJ et al. N Engl J Med 2005; 352:2389
MethodsMethods The Patients The Patients
Patients older than 18 years of age with calcific aortic stenosis, an 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 aortic-jet velocity of at least 2.5 m per second, and aortic-valve calcification on echocardiography were eligible for inclusion calcification on echocardiography were eligible for inclusion
Exclusion criteria were:Exclusion criteria were: -Child-bearing potential without contraception -Child-bearing potential without contraception -Active or chronic liver disease -Active or chronic liver disease -History of alcohol or drug abuse -History of alcohol or drug abuse -Severe mitral-valve stenosis (mitral-valve area, <1 cm2), severe -Severe mitral-valve stenosis (mitral-valve area, <1 cm2), severe
mitral or mitral or aortic regurgitation, left ventricular dysfunction (ejection fraction aortic regurgitation, left ventricular dysfunction (ejection fraction
<35 <35 percent), a planned aortic-valve replacement percent), a planned aortic-valve replacement -Intolerance of statins, statin therapy or a potential benefit from -Intolerance of statins, statin therapy or a potential benefit from
statin statin therapy (according to the treating physician), a baseline serum therapy (according to the treating physician), a baseline serum
total total cholesterol concentration of less than 150 mg per deciliter cholesterol concentration of less than 150 mg per deciliter -Presence of a permanent pacemaker or defibrillator -Presence of a permanent pacemaker or defibrillator
Cowell, SJ, Newby DE, Prescott RJ et al. N Engl J Med 2005; 352:2389
MethodsMethodsStudy ProtocolStudy Protocol
Between March 2001 and April 2002, the Between March 2001 and April 2002, the blinded study coordinator randomly assigned blinded study coordinator randomly assigned eligible patients by the minimization eligible patients by the minimization technique with the use of a dedicated, locked technique with the use of a dedicated, locked computer program incorporating the computer program incorporating the following eight variables: age, sex, smoking following eight variables: age, sex, smoking habit, hypertension, diabetes mellitus, serum habit, hypertension, diabetes mellitus, serum cholesterol concentration, aortic-jet velocity, cholesterol concentration, aortic-jet velocity, and aortic-valve calcium score. Patients were and aortic-valve calcium score. Patients were assigned to either 80 mg of atorvastatin or assigned to either 80 mg of atorvastatin or matched placebo as a single daily dose matched placebo as a single daily dose
MethodsMethodsStudy ProtocolStudy Protocol
Patients were assessed at baseline, two months, Patients were assessed at baseline, two months, and six months and every six months thereafter and six months and every six months thereafter for a minimum of two years for a minimum of two years
Clinical evaluation included assessment of Clinical evaluation included assessment of functional status and adverse events, and the functional status and adverse events, and the biochemical analysis of blood biochemical analysis of blood
Echocardiography and CT were performed at Echocardiography and CT were performed at baseline, at each annual visit, and before baseline, at each annual visit, and before withdrawal from the study withdrawal from the study
Patients who underwent randomization and who Patients who underwent randomization and who were subsequently started on open-label statin were subsequently started on open-label statin therapy by their attending physician were therapy by their attending physician were immediately withdrawn from the study immediately withdrawn from the study
MethodsMethodsEnd PointsEnd Points
The two primary end points were:The two primary end points were: 1. Progression of stenosis, determined according to 1. Progression of stenosis, determined according to changes in aortic-jet velocity on Doppler echochanges in aortic-jet velocity on Doppler echo 2. Progression of valvular calcification, as measured 2. Progression of valvular calcification, as measured by CT by CT Secondary end points were:Secondary end points were: -A composite of clinical end points (death from -A composite of clinical end points (death from
cardiovascular causes, aortic-valve replacement, or cardiovascular causes, aortic-valve replacement, or hospitalization attributable to severe aortic stenosis) hospitalization attributable to severe aortic stenosis)
-Aortic-valve replacement -Aortic-valve replacement -Death from any cause-Death from any cause -Death from cardiovascular causes -Death from cardiovascular causes -Hospitalization for any cause-Hospitalization for any cause -Hospitalization for severe aortic stenosis-Hospitalization for severe aortic stenosis
The study was powered to detect a difference The study was powered to detect a difference in the primary end points of 0.15 m per second in the primary end points of 0.15 m per second per year in aortic-jet velocity and 500 agatston per year in aortic-jet velocity and 500 agatston units (AU) per year in aortic-valve calcium units (AU) per year in aortic-valve calcium score. These differences are equivalent to a score. These differences are equivalent to a reduction of more than 30 percent in the rate reduction of more than 30 percent in the rate of progression of aortic stenosis. This would of progression of aortic stenosis. This would exclude a clinically significant effect in the exclude a clinically significant effect in the majority of older patients with established majority of older patients with established disease, although a smaller effect may be disease, although a smaller effect may be clinically relevant in younger patients with mild clinically relevant in younger patients with mild aortic stenosisaortic stenosis
77 patients were assigned to 77 patients were assigned to atorvastatin, and atorvastatin, and
78 to placebo 78 to placebo Median follow-up of 25 months Median follow-up of 25 months
(range: 7 to 36 months) (range: 7 to 36 months) Baseline characteristics were well Baseline characteristics were well
matched: matched:
Mean aortic-jet velocity was Mean aortic-jet velocity was 3.43±0.64 m/s (range, 2.5 to 5.0) 3.43±0.64 m/s (range, 2.5 to 5.0)
Median aortic-valve calcium score was Median aortic-valve calcium score was 5920 AU (range, 2485 to 14,231) 5920 AU (range, 2485 to 14,231)
Of the 155 patients, 119 had mild-to-Of the 155 patients, 119 had mild-to-moderate aortic stenosis (aortic-jet moderate aortic stenosis (aortic-jet velocity, 2.5 to 3.9 m/s), and 36 had velocity, 2.5 to 3.9 m/s), and 36 had severe stenosis (aortic-jet velocity, 4.0 severe stenosis (aortic-jet velocity, 4.0 m/s)m/s)
Results:Results:Serum Cholesterol ConcentrationsSerum Cholesterol Concentrations
The mean serum low-density lipoprotein (LDL) The mean serum low-density lipoprotein (LDL) cholesterol concentration remained at cholesterol concentration remained at 130±30 mg per deciliter in the placebo group 130±30 mg per deciliter in the placebo group and decreased by 53 percent to 63±23 mg per and decreased by 53 percent to 63±23 mg per deciliter in the atorvastatin group (P<0.001) deciliter in the atorvastatin group (P<0.001)
Serum total cholesterol was 209±35 mg per Serum total cholesterol was 209±35 mg per deciliter and 132±27 mg per deciliter in the deciliter and 132±27 mg per deciliter in the placebo and atorvastatin groups, respectively placebo and atorvastatin groups, respectively (P<0.001), and is in keeping with 97% (P<0.001), and is in keeping with 97% adherence to the study treatment in both adherence to the study treatment in both groups, which was confirmed by a pill count groups, which was confirmed by a pill count
Effect of Atorvastatin on Disease Effect of Atorvastatin on Disease
ProgressionProgression
Intensive lipid-lowering therapy with 80 mg of atorvastatin daily had Intensive lipid-lowering therapy with 80 mg of atorvastatin daily had no effect on the rate of change in aortic-jet velocity or valvular no effect on the rate of change in aortic-jet velocity or valvular calcification. calcification.
Progression in valvular calcification was 22.3±21.0 percent per year 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 in the atorvastatin group, and 21.7±19.8 percent per year in the placebo group (P=0.93; ratio of post-treatment aortic-valve calcium placebo group (P=0.93; ratio of post-treatment aortic-valve calcium score, 0.998; 95 percent confidence interval, 0.947 to 1.050) score, 0.998; 95 percent confidence interval, 0.947 to 1.050)
Secondary End PointsSecondary End Points
The proportion of patients reaching The proportion of patients reaching secondary clinical end points seemed to be secondary clinical end points seemed to be less in the atorvastatin group, but none of less in the atorvastatin group, but none of the comparisons achieved statistical the comparisons achieved statistical significance significance
Subgroup AnalysisSubgroup Analysis
Subgroup analysis of the primary end-point data was conducted in patients with mild-to-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 moderate aortic stenosis and severe aortic stenosis at baseline. As anticipated from earlier studies, patients with severe stenosis at baseline progressed more rapidly 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 (P=0.04), but the study findings were consistent regardless of the severity of stenosis at baseline baseline
Likewise, the length of follow-up did not influence outcome. In those followed for more 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 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 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 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 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 groupper year in the placebo group
ConclusionConclusion
“ “We conclude that intensive lipid-lowering therapy We conclude that intensive lipid-lowering therapy with 80 mg of atorvastatin daily does not halt the with 80 mg of atorvastatin daily does not halt the progression of calcific aortic stenosis or induce its progression of calcific aortic stenosis or induce its regression. Nevertheless, this trial does not rule out regression. Nevertheless, this trial does not rule out a small but potentially relevant reduction in the rate a small but potentially relevant reduction in the rate of disease progression or a significant reduction in of disease progression or a significant reduction in major clinical end points. Our study reinforces the major clinical end points. Our study reinforces the need for a long-term, large-scale, randomized, need for a long-term, large-scale, randomized, controlled trial of intensive lipid-lowering therapy in controlled trial of intensive lipid-lowering therapy in patients with calcific aortic stenosis, particularly in patients with calcific aortic stenosis, particularly in those with early, mild disease. In the meantime, we those with early, mild disease. In the meantime, we do not recommend statin therapy for patients with do not recommend statin therapy for patients with calcific aortic stenosis in the absence of coexisting calcific aortic stenosis in the absence of coexisting vascular disease” vascular disease”
Cowell, SJ, Newby DE, Prescott RJ et al. N Engl J Med 2005; 352:2389
Discussion:Discussion:ResultsResults
In this randomized, double-blind, placebo-controlled, parallel-In this randomized, double-blind, placebo-controlled, parallel-group trial of lipid-lowering therapy in patients with calcific aortic group trial of lipid-lowering therapy in patients with calcific aortic stenosis, a single coordinating center used a consistent and stenosis, a single coordinating center used a consistent and reproducible approach to assess the severity of aortic stenosis reproducible approach to assess the severity of aortic stenosis
It has clearly shown that high-dose atorvastatin reduces serum It has clearly shown that high-dose atorvastatin reduces serum LDL cholesterol concentrations as anticipated, but it does not halt LDL cholesterol concentrations as anticipated, but it does not halt the progression or induce regression of the valvular disease the progression or induce regression of the valvular disease process. This was shown with the use of two distinct measures of process. This was shown with the use of two distinct measures of disease severity — aortic-jet velocity assessed with Doppler disease severity — aortic-jet velocity assessed with Doppler echocardiography and valvular calcification assessed with helical echocardiography and valvular calcification assessed with helical CT CT
Moreover, there was no relationship between serum LDL Moreover, there was no relationship between serum LDL cholesterol concentrations and the progression of aortic stenosis, cholesterol concentrations and the progression of aortic stenosis, nor did high-dose atorvastatin have a demonstrable effect on nor did high-dose atorvastatin have a demonstrable effect on clinical end pointsclinical end points
StrengthsStrengths 1. The first prospective, randomized study assessing the effect of 1. The first prospective, randomized study assessing the effect of statins in aortic stenosis statins in aortic stenosis 2. Although the characteristics of the patients in this study and in 2. Although the characteristics of the patients in this study and in the retrospective studies were similar, the present study the retrospective studies were similar, the present study
differs differs not only because of its prospective design but also because the not only because of its prospective design but also because the indications for therapy were different. In the retrospective indications for therapy were different. In the retrospective trials, statin therapy was indicated for the treatment of trials, statin therapy was indicated for the treatment of hyperlipidemia, whereas in the prospective trial, patients in hyperlipidemia, whereas in the prospective trial, patients in whom statins were indicated for the treatment of whom statins were indicated for the treatment of hyperlipidemia were excluded hyperlipidemia were excluded 3. In this study statins were prescribed at a high dose (80 mg of 3. In this study statins were prescribed at a high dose (80 mg of atorvastatin per day). In the retrospective studies, the doses atorvastatin per day). In the retrospective studies, the doses were lower 10-20 mg per day of atorvastatin)were lower 10-20 mg per day of atorvastatin)
Weaknesses Weaknesses 1. The study excluded patients with an aortic-1. The study excluded patients with an aortic-
jet jet velocity of less than 2.5 m per second, velocity of less than 2.5 m per second, although it acknowledged that intervening at although it acknowledged that intervening at this earlier stage of the disease process may this earlier stage of the disease process may have been more beneficial have been more beneficial 2. The study was designed to detect a 2. The study was designed to detect a
substantial substantial delay in disease progression and was not delay in disease progression and was not powered to assess meaningful effects on powered to assess meaningful effects on clinical end points, such as valve clinical end points, such as valve
replacement replacement and cardiovascular death and cardiovascular death
WeaknessesWeaknesses
3. Although the study can exclude a treatment 3. Although the study can exclude a treatment benefit of the magnitude previously reported in benefit of the magnitude previously reported in retrospective observational studies (a reduction retrospective observational studies (a reduction in the aortic-jet velocity of 0.30 m per second per in the aortic-jet velocity of 0.30 m per second per year and valvular calcification of 30 percent per year and valvular calcification of 30 percent per year), the 95 percent confidence intervals year), the 95 percent confidence intervals indicate that the study may have missed a indicate that the study may have missed a modest treatment benefit (a delay in disease modest treatment benefit (a delay in disease progression of <0.07 m per second per year for progression of <0.07 m per second per year for aortic-jet velocity and <5 percent per year for aortic-jet velocity and <5 percent per year for valvular calcification). Although such modest valvular calcification). Although such modest reductions are unlikely to be meaningful in the reductions are unlikely to be meaningful in the majority of older patients, a small decrease in majority of older patients, a small decrease in disease progression may be clinically important disease progression may be clinically important in younger patients with mild disease that may in younger patients with mild disease that may progress over many years progress over many years
WeaknessesWeaknesses
4. Although the observation periods in this 4. Although the observation periods in this study in comparison to the prior retrospective study in comparison to the prior retrospective studies were similar. However, in the studies were similar. However, in the retrospective studies, the patients were retrospective studies, the patients were already receiving therapy at the time of already receiving therapy at the time of inclusion in the study and many of them were inclusion in the study and many of them were started therapy long before the study. Thus, started therapy long before the study. Thus, one cannot rule out the need for longer one cannot rule out the need for longer overall treatment periods to observe an effect overall treatment periods to observe an effect of statin therapyof statin therapy
5. Although all the studies were similar in size, 5. Although all the studies were similar in size, they were all relatively small, and it is too they were all relatively small, and it is too early to draw conclusions on the value of early to draw conclusions on the value of statin therapy in aortic stenosis statin therapy in aortic stenosis
Given the strength of the data linking Given the strength of the data linking aortic stenosis with atherosclerosis aortic stenosis with atherosclerosis and hypercholesterolemia, this study and hypercholesterolemia, this study failed to halt the progression of failed to halt the progression of calcific aortic stenosis?calcific aortic stenosis?
One potential explanation is that, although One potential explanation is that, although these features may drive the these features may drive the initiationinitiation of aortic of aortic stenosis, the disease stenosis, the disease progressionprogression may depend may depend on other factors on other factors
AS vs CADAS vs CAD
At the tissue and cellular level: At the tissue and cellular level: in contrast to atherosclerosis, aortic stenosis is in contrast to atherosclerosis, aortic stenosis is
associated with a significantly less degree of associated with a significantly less degree of smooth-muscle-cell proliferation and lipid-laden smooth-muscle-cell proliferation and lipid-laden macrophages. On the other hand, it is macrophages. On the other hand, it is dominated by earlier and more extensive dominated by earlier and more extensive mineralization mineralization
Hence, decreasing the lipid pool and Hence, decreasing the lipid pool and strengthening the fibrous cap may be less strengthening the fibrous cap may be less relevant to the progression of aortic stenosis relevant to the progression of aortic stenosis than they are for the reduction in than they are for the reduction in atherosclerotic-plaque rupture with statin atherosclerotic-plaque rupture with statin therapy in patients with coronary heart disease therapy in patients with coronary heart disease
AS vs CADAS vs CAD
However, perhaps the most important However, perhaps the most important difference is the mechanism of clinical events:difference is the mechanism of clinical events:
In atherosclerosis, plaque instability is key; in In atherosclerosis, plaque instability is key; in aortic stenosis, the shear bulk of the lesion is aortic stenosis, the shear bulk of the lesion is the problem. Early in the disease process, small the problem. Early in the disease process, small areas of inflammation and lipid infiltration are areas of inflammation and lipid infiltration are interspersed with areas of normal leaflet so interspersed with areas of normal leaflet so that the valve leaflets remain flexible and open that the valve leaflets remain flexible and open normally in systole. Late in the disease process, normally in systole. Late in the disease process, the abnormal areas become confluent with the abnormal areas become confluent with prominent calcification and increased fibrosis, prominent calcification and increased fibrosis, resulting in increased leaflet stiffness and resulting in increased leaflet stiffness and obstruction to left ventricular outflow obstruction to left ventricular outflow
Inhibition of lipid accumulation in the valve Inhibition of lipid accumulation in the valve tissue is the first pathway to be studied; tissue is the first pathway to be studied; however, other more specific therapies however, other more specific therapies targeting endothelial disruption, inflammation, targeting endothelial disruption, inflammation, or tissue calcification may be more effective or tissue calcification may be more effective
Hence, therapy may need to be tailored to the Hence, therapy may need to be tailored to the stage of the disease process; some may stage of the disease process; some may prevent initiation of disease process, whereas prevent initiation of disease process, whereas others may be more effective in slowing others may be more effective in slowing calcium accumulation in end-stage diseasecalcium accumulation in end-stage disease
Rajamannan NM, Otto CM. Circulation. 2004;110:1180-82
So What is the Rest of So What is the Rest of the Story?the Story?
Other Proposed Mechanisms Other Proposed Mechanisms for the Development of ASfor the Development of AS
Abnormalities in Calcium Abnormalities in Calcium Metabolism:Metabolism:
- Hyperparathyroidism - Hyperparathyroidism
PrimaryPrimary
SecondarySecondary - Certain Vitamin D receptor - Certain Vitamin D receptor
genotype genotype (allele B) (allele B)
ACE activityACE activity
AS and AS and Hyperparathyroidism Hyperparathyroidism
Multiorgan soft tissue calcification commonly occurs in Multiorgan soft tissue calcification commonly occurs in patients with chronic renal failure; secondary patients with chronic renal failure; secondary hyperparathyroidism is thought to be the major causative hyperparathyroidism is thought to be the major causative factorfactor
-Asymptomatic calcification of heart valves has been -Asymptomatic calcification of heart valves has been reported in reported in
up to a third of such patientsup to a third of such patients -Hemodynamically significant AS is found in 3% in those -Hemodynamically significant AS is found in 3% in those patients patients In a postmortem study, parathyroid hyperplasia was In a postmortem study, parathyroid hyperplasia was
found in all six patients with chronic renal failure, who found in all six patients with chronic renal failure, who were shown to have extensive cardiac calcification. (were shown to have extensive cardiac calcification. (Terman Terman D, et al. Cardiac calcification in uremia. Am J Med. 1971;50:744-55) D, et al. Cardiac calcification in uremia. Am J Med. 1971;50:744-55)
AS and AS and HyperparathyroidismHyperparathyroidism
Although up till recently enhanced Although up till recently enhanced progression of valve stenosis in the presence progression of valve stenosis in the presence of secondary hyperparathyroidism has not of secondary hyperparathyroidism has not been studied systematically, but there are been studied systematically, but there are many case reports in the literature to many case reports in the literature to support that:support that:
-Depace NL, et al. Arch Intern Med -Depace NL, et al. Arch Intern Med 1981;141:1663-51981;141:1663-5 -McFalls EO, et al. Am Heart J -McFalls EO, et al. Am Heart J
1990;120:206-81990;120:206-8 -Fujise K, et al. Br Heart J 1993;70:282-4 -Fujise K, et al. Br Heart J 1993;70:282-4
The vitamin D receptor genotype The vitamin D receptor genotype predisposes to the development of predisposes to the development of
calcific aortic valve stenosiscalcific aortic valve stenosis The distribution of one polymorphism of the vitamin The distribution of one polymorphism of the vitamin
D receptor (BsmI B/b) was examined in D receptor (BsmI B/b) was examined in 100 consecutive patients with calcific valvar aortic 100 consecutive patients with calcific valvar aortic stenosis and compared with a control group of stenosis and compared with a control group of 100 patients (paired match for age, sex, and the 100 patients (paired match for age, sex, and the presence of coronary artery disease from a total of presence of coronary artery disease from a total of 630 patients without calcified aortic valves) 630 patients without calcified aortic valves)
RESULTS:RESULTS: There was a significant difference in There was a significant difference in vitamin D receptor allele and genotype frequencies vitamin D receptor allele and genotype frequencies between the two groups. The allele B had a higher between the two groups. The allele B had a higher prevalence in patients with calcific aortic stenosis prevalence in patients with calcific aortic stenosis (B = 0.56, b = 0.44) than in the control cohort (B = 0.56, b = 0.44) than in the control cohort (B = 0.40, b = 0.60) (p = 0.001)(B = 0.40, b = 0.60) (p = 0.001)
Ortlepp, Jr, et al. Heart 2001;85:635-638
This study found an association between the B allele This study found an association between the B allele which seems to predispose gene carriers to blunted which seems to predispose gene carriers to blunted calcium absorption, more rapid bone loss, reduced calcium absorption, more rapid bone loss, reduced bone mineral density, and raised parathormone bone mineral density, and raised parathormone secretion and the prevalence of calcific aortic valve secretion and the prevalence of calcific aortic valve stenosis stenosis
There might be several hypotheses to explain the There might be several hypotheses to explain the relation between genotype and the development of relation between genotype and the development of aortic stenosis. Individuals with a slightly unfavorable aortic stenosis. Individuals with a slightly unfavorable bone mineral density might develop mechanisms to bone mineral density might develop mechanisms to overcome this alteration of calcium homeostasis. Like overcome this alteration of calcium homeostasis. Like parathormone, other hormones, proteins, or second parathormone, other hormones, proteins, or second messengers might trigger calcification of extraosseous messengers might trigger calcification of extraosseous structures like the aortic valve. The aortic valve is structures like the aortic valve. The aortic valve is likely to be one of the first extraosseous structures likely to be one of the first extraosseous structures involved because of the high level of mechanical involved because of the high level of mechanical stress to which it is subjected 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 Angiotensin-Converting Enzyme Inhibitors and Change in Aortic Inhibitors and Change in Aortic
Valve CalciumValve Calcium Background: Background: Because lipoproteins, angiotensin- Because lipoproteins, angiotensin-
converting enzyme, and angiotensin II colocalize with converting enzyme, and angiotensin II colocalize with calcium in aortic valve lesions, the study hypothesized calcium in aortic valve lesions, the study hypothesized an association between ACEI use and lowered aortic an association between ACEI use and lowered aortic valve calcium (AVC) accumulation, as measured by valve calcium (AVC) accumulation, as measured by electron beam computed tomographyelectron beam computed tomography
Rates of change in volumetric AVC scores were Rates of change in volumetric AVC scores were determined retrospectively for 123 patients who had determined retrospectively for 123 patients who had undergone 2 serial electron beam computed undergone 2 serial electron beam computed tomographic scans. The mean (±SD) interscan interval tomographic scans. The mean (±SD) interscan interval was 2.5 (±1.7) years; 80 patients did not receive ACEIs was 2.5 (±1.7) years; 80 patients did not receive ACEIs and 43 received ACEIs. The relationship of ACEI use to and 43 received ACEIs. The relationship of ACEI use to median rates of AVC score change (both unadjusted and median rates of AVC score change (both unadjusted and adjusted for baseline AVC scores and coronary heart adjusted for baseline AVC scores and coronary heart disease risk factors) was determined 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 So, is this is the End of the Story the Story
for Statins and AS? for Statins and AS?
In The HorizonIn The Horizon At least 2 prospective, randomized, placebo-controlled At least 2 prospective, randomized, placebo-controlled
multicenter studies of lipid-lowering therapy to prevent multicenter studies of lipid-lowering therapy to prevent disease progression in aortic stenosis are in progress: disease progression in aortic stenosis are in progress:
-The Aortic Stenosis Progression Observation -The Aortic Stenosis Progression Observation
Measuring Effect of Rosuvastatin (ASTRONOMER) Measuring Effect of Rosuvastatin (ASTRONOMER)
study in Canada study in Canada
-Simvastatin and Ezetimide in Aortic Stenosis (SEAS) -Simvastatin and Ezetimide in Aortic Stenosis (SEAS)
study in Europe study in Europe We should await the results of these trials to determine We should await the results of these trials to determine
whether it will become appropriate to prescribe statin whether it will become appropriate to prescribe statin therapy routinely in patients with calcific valve disease.therapy routinely in patients with calcific valve disease.
SummarySummary Calcific aortic stenosis is an active disease process with Calcific aortic stenosis is an active disease process with
active inflammatory componentactive inflammatory component There is evidence in the literature (animal models and There is evidence in the literature (animal models and
retrospective studies) that statins may be beneficial in retrospective studies) that statins may be beneficial in slowing down the progression of ASslowing down the progression of AS
SALTIRE trial, the first randomized prospective trial, failed SALTIRE trial, the first randomized prospective trial, failed to show a beneficial effect of atorvastatin on AS progression.to show a beneficial effect of atorvastatin on AS progression.
However, SALTIRE trial had many limitations and final However, SALTIRE trial had many limitations and final conclusions about the benefits of statins on the progression conclusions about the benefits of statins on the progression of AS should wait further studiesof AS should wait further studies
Interfering with lipid metabolism in the valve tissue was the Interfering with lipid metabolism in the valve tissue was the first pathway to be studied prospectively; however, further first pathway to be studied prospectively; however, further studies are needed to address the other pathways involved studies are needed to address the other pathways involved in the pathogenesis of AS including endothelial disruption, in the pathogenesis of AS including endothelial disruption, inflammation, tissue ACE system, and tissue calcificationinflammation, tissue ACE system, and tissue calcification
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