(Circulation. 2000;101:2497.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
New Insights Into the Progression of Aortic Stenosis
Implications for Secondary Prevention
From Loma Linda VA Medical Center University and Loma Linda University, Loma Linda, Calif.
Correspondence to Ramdas G. Pai, MD, FRCP(E), FACC, Director of Echocardiography, Research and Fellowship Programs, Department of Cardiac Sciences, #1413, King Fahd National Guard Hospital, PO Box 22490, Riyadh 11246, Kingdom of Saudi Arabia. E-mail ramdaspai{at}pol.net
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Abstract |
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Background—The risk factors affecting aortic stenosis (AS) progression are not clearly defined. Insights into this may allow for its secondary prevention.
Methods and Results—We investigated predictors of AS progression
in 170 consecutive patients with AS who had paired echocardiograms 
3
months (23±11) apart. Various clinical,
echocardiographic, and biochemical variables were
related to the change in aortic valve area (AVA). The annual rate of
reduction in AVA was 0.10±0.27 cm2 or 7±18% per year.
The reduction in AVA per year was significantly related to initial AVA
(r=0.46, P<0.0001), the mean aortic
valve gradient (r=0.27, P=0.04),
left ventricular (LV) outflow tract velocity
(r=0.26, P=0.001), and LV
end-diastolic diameter (r=0.20,
P=0.04) and marginally to serum creatinine
level (r=0.15, P=0.08). Patients with a
rate of reduction in AVA faster than the mean had higher serum
creatinine (P=0.04) and calcium
(P=0.08) levels. Those with a serum
cholesterol level >200 mg/dL had a rate of AVA reduction
roughly twice that of those with a lower cholesterol level
(P=0.04). Stepwise multiple regression analysis
identified initial AVA, current smoking, and serum calcium level as the
independent predictors of amount of AVA reduction per year.
Conclusions—Absolute and percentage reduction in AVA per year in those with AS is greater in those with milder degrees of stenosis and is accelerated in the presence of smoking, hypercholesterolemia, and elevated serum creatinine and calcium levels. These findings may have important implications in gaining further insights into the mechanism of AS progression and in formulating strategies to retard this process.
Key Words: valves • heart diseases • prevention • echocardiography
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Introduction |
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Aortic stenosis (AS) is common with the aging population. Symptomatic AS is associated with a poor prognosis, and this is improved by aortic valve replacement. Though the risk factors for the development of AS are the same as that of coronary artery disease,1 the factors affecting its progression are not clearly defined.2 3 4 5 6 Identification of risk factors for AS progression may allow for its secondary prevention. The present study was undertaken to investigate the rate of AS progression and to determine clinical, echocardiographic, and biochemical characteristics that may have a bearing on the progression of this disease process.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patient Population
Subjects with any degree of AS seen in the echocardiographic laboratory and who had paired echocardiograms
3 (23±11) months apart were selected. Exclusion
criteria included the presence of a congenital heart disease, bicuspid
aortic valve, or previous valvular surgery. The study group
consisted of 170 consecutive patients meeting these criteria.
Clinical and Biochemical Data
Clinical data including age, sex, history of current smoking,
diabetes mellitus, hypertension, and end-stage kidney disease were
obtained. Laboratory data included the serum calcium, phosphate,
creatinine, uric acid, and cholesterol levels.
These data were obtained from a combination of chart review and
telephone interviews.
Echocardiographic and Doppler Data and
Measurements
Echocardiographic examinations were performed
with the use of standard techniques and commercially available
equipment. Anatomic measurements were made according to the American
Society of Echocardiography
guidelines.7 The aortic valve area (AVA) was calculated by
means of the continuity equation. The mean aortic valve gradient was
obtained by tracing the continuous wave flow velocity signal across the
aortic valve.
Statistics
Analysis was performed with the use of StatView version
4.5 (Abacus Concepts, Inc). Data are given as mean value±SD.
Comparisons between groups were performed with the use of the
2 or unpaired t test. Linear
regression analysis was used to investigate the relation
between continuous variables. Stepwise multiple regression
analysis was used to identify the independent predictors of AS
progression. A value of P
0.05 was taken to be significant,
and a value between 0.05 and 0.10 was considered to be showing a trend
toward significance.
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Results |
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Baseline Patient Characteristics
Of the 170 subjects, 132 (78%) were men. Their age was 71±9 years. The initial AVA was 1.17±0.38 cm2 (range 0.5 to 2.5). The left ventricular (LV) ejection fraction was 55±14% (range 15% to 85%). Concomitant aortic regurgitation was seen in 89 patients, being mild in 66, moderate in 18, and severe in 5. Mitral regurgitation was present in 78 patients: mild in 54, moderate in 17, and severe in 7 patients. One hundred patients had systemic hypertension, 38 were diabetics, 62 were smokers, 12 were on dialysis, and 60 had a serum cholesterol level >200 mg%. Table 1
further characterizes the
study group.
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Changes Over Time
The mean time interval between the 2 studies was 23±11
months, ranging from 3 to 66 months. Over this period of time, the mean
AVA decreased from 1.17 to 1.01 cm2 and mean
systolic gradient increased from 20 to 27 mm Hg. The
annual rate of reduction in AVA was 0.10±0.27
cm2 or 7±18% per year when adjusted for the
baseline AVA, indicating a wide variability in AS progression.
Correlates of Decrease in AVA per Year
As shown in Table 2, the
absolute reduction in AVA per year was significantly related to initial
AVA (r=0.46, P<0.0001), peak aortic valve
velocity (r=-0.28, P=0.0002), the mean
aortic valve gradient (r=-0.27, P=0.04),
LV outflow tract velocity (r=0.26, P=0.001), and
LV end-diastolic diameter (r=0.20,
P=0.04) and marginally to the serum creatinine
level (r=0.15, P=0.08). There was no significant
correlation with age, ejection fraction, or serum
cholesterol level.
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Correlates of Percentage Decrease in AVA per
Year
The correlate of percentage decrease in AVA per year tends
to correct the decrement in area to its initial area and the duration
of follow-up (Table 2
). The percentage reduction in AVA per year
was significantly related to initial AVA (r=0.30,
P=0.0004), peak aortic valve velocity (r=-0.17,
P=0.03), the mean aortic valve gradient
(r=-0.28, P=0.04), LV outflow tract velocity
(r=0.17, P=0.03), and the serum calcium level
(r=0.21, P=0.008) and marginally to serum calcium
phosphate product (r=0.15, P=0.07).
Comparison of Rapid and Slow Progressors
At a percentage mean decrease in AVA per year of 7%, the
patients were dichotomously divided into rapid (AVA reduction 7% per
year) and slow progressors (AVA reduction <7% per year). As shown in
Table 3, the rapid progressors had larger
initial AVA (P=0.016), smaller mean transvalvular
gradient (P=0.01), and higher serum creatinine
levels (P=0.04). In this group, there was a trend toward a
higher preponderance of men (P=0.10), current smoking
(P=0.10), larger LV end-diastolic diameter
(P=0.10), larger LV end-systolic diameter
(P=0.07), and higher serum calcium level
(P=0.08).
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Rate of Progression With Selected Coronary
Risk Factors
In patients with a serum cholesterol level >200
mg/dL, the annual reduction in AVA was 0.14±0.35
cm2, compared with 0.07±0.19
cm2 in those with a level 200 mg/dL
(P=0.04). The corresponding values for percent reduction in
AVA per year were 10±21% versus 5±15%, respectively
(P=0.07). The absolute and percent reduction in AVA per year
in men compared with women were 0.12±0.28 cm2
versus 0.05±0.21 cm2 (P=0.19) and
8±18% versus 3±17% (P=0.11), respectively. Rates of
progression were not statistically different in those with or those
without hypertension or diabetes.
Rates of Progression at Extremes of Biochemical
Values
To explore the possibility that extremes of biochemical
values may have markedly different effects on AS progression, patients
were also divided into tertiles based on serum cholesterol,
creatinine, and calcium levels, and the lowest and the
highest tertiles were compared. The absolute and percentage reduction
in AVA were 0.09±0.16 cm2 and 7.1±14.1%,
respectively, in patients at the lowest cholesterol tertile
(serum cholesterol 165 mg/dL, mean 133 mg/dL) compared
with 0.14±0.29 cm2 and 9.4±20.0% in the
highest tertile (serum cholesterol 207 mg/dL, mean 244).
However, the differences were not statistically significant. The
percentage reduction in AVA per year was not significantly different
for patients at the lowest and the highest tertiles of serum
creatinine (5.3+15.2% vs 9.2+19.2%) or calcium phosphate
product (3.4+15.8% vs 8.2+19.6%), though there was a greater
separation for absolute values. However, it was significantly greater
for those in the highest tertile for the serum calcium level compared
with those at the lowest tertile (11.4+22.0% vs 3.2+17.8%,
P=0.05).
Characteristics of Groups at Extremes of
Progression
Table 4 summarizes the
characteristics of groups at either end of progression, as judged by
the annual reduction in AVA. The rapid progressors (ie, top one third)
had a larger initial AVA (P<0.0001), larger LV
end-systolic diameter (P=0.05), higher
transvalvular velocity (P=0.001), higher LV outflow
tract velocity (P=0.002), and higher serum
creatinine level (P=0.04). A greater proportion
of these patients were on dialysis (11%) compared with the slow
progressors (3%), but this difference did not achieve statistical
significance (P=0.14).
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Valve Stenosis Behavior in Smokers and Its
Correlates
To explore the interaction between smoking and other risk
factors, analysis was performed in smokers alone. The effect of
various variables on the rate of progression was very similar to
that in the whole group except for the fact that thickness of the
ventricular septum correlated negatively with the annual
rate of AVA reduction (r=-0.34, P=0.05). These
data are summarized in Table 5.
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Multiple Regression Analysis for Predictors of
AS Progression
Stepwise multiple regression analysis was
carried out to identify the independent predictors of the absolute and
percent reductions in AVA per year. A univariate
probability value threshold of 0.10 was set for entry into the
equation; hence, the sex, smoking status, LV outflow tract velocity,
initial AVA, LV end-diastolic diameter, and serum
cholesterol, creatinine, and calcium levels
were entered as the independent variables. Absolute reduction in
AVA er year was independently influenced by initial AVA, smoking, and
serum calcium level (cumulative R=0.51), and the percent
reduction in AVA per year was independently correlated with LV
end-diastolic diameter and serum calcium level (cumulative
R=0.35). Sex and serum creatinine levels had a
trend toward significance for both and smoking for the latter.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study provides new insights into the factors affecting the rate of AS progression. It raises a strong possibility that smoking, male sex, and elevated serum creatinine, calcium, and cholesterol levels may catalyze AS progression. Many of these findings are new, and some confirm the findings of earlier smaller studies dealing with risk factors for AS progression.2 3 4 5 6 Studies addressing this issue are very limited, though there are elegant studies describing the natural history of AS progression.8 9
Clinical Correlates of AS Progression
In this study, only smoking and male sex were associated
with faster AS progression and hypertension; diabetes and age were not.
In a study of 120 patients with AS of rheumatic, congenital, or
degenerative causes, Mohler et al2 found only male sex and
smoking to be predictors of degenerative AS progression. In a smaller
study of 49 patients, Peter et al6 found older age and the
presence of coronary artery disease to be associated with a
more rapid increase in AS gradient. In their study of 112 patients,
Roger et al5 did not find age, sex, ejection fraction, or
the presence of coronary artery disease to be associated with
AS progression, as judged by an increase in the transvalvular
velocity obtained by Doppler
echocardiography.
Echocardiographic Correlates
In our study, AS progression was slower in severe
stenosis, which is also associated with a larger
transvalvular gradient. This finding is not new and has been
reported by Otto et al9 and Brener et al.4 It
is tempting to speculate that the stretching effect of a larger
gradient in patients with more severe AS retards progression. Higher LV
outflow tract velocity, which reflects greater cardiac output,
accelerated AS progression, raising the potential importance of
mechanical factors. A higher cardiac output can potentially cause
greater trauma to the valve, thus accelerating the inflammatory or
degenerative processes in the valve. Also, rapid progressors had larger
LV size but similar wall thickness and ejection fraction. Clearly, the
effect of LV size, function, and mechanical influences on the aortic
valve need further evaluation.
Biochemical Factors
Although AS is seen more often in dialysis patients and
seems to be characterized by a more rapid progression,3
the effect of creatinine and calcium in normal patients has
not been reported previously. Even after excluding the dialysis
patients, these biochemical factors, in a relatively normal range,
appeared to affect AS progression. The mechanism of this is unclear.
Accelerated AS has also been reported in primary
hyperparathyroidism,10 pointing to the importance of the
calcium phosphate product, which is also increased in kidney
failure. The effect of serum creatinine within the normal
range is intriguing and could be either a direct effect on the aortic
valve or an indirect effect through other biochemical mediators. The
effect of hypercholesterolemia is new, though
aortic valve disease occurs in familial
hypercholesterolemia and serum
triglycerides are associated with AS progression in the
bicuspid valve.2 11
Rate of AS Progression
In our study, the mean rate of AS progression was 0.10±0.27
cm2 or 7+18% per year and had a very large
confidence interval. A wide confidence interval makes prediction of
progression in a given patient practically impossible. For example, in
a given patient, the reduction in valve area in a year could be as much
as 0.64 cm2 or 43% of its initial area. This
finding is identical to prior published studies.4 5 6 9
Clinical Implications
This study indicates that the rate of AS progression is
unpredictable in a given patient. It can be speculated that modifying
the risk factors such as smoking and cholesterol and
managing creatinine and calcium phosphate product may
be important in AS patients for its secondary prevention. The
biochemical and cellular bases of these modifiable risk factors on the
progression of AS need further investigation. The relation between
degenerative changes in the aortic valve and
cardiovascular morbidity and mortality rates also may
indicate some common risk factors for both AS and coronary
artery disease.12
Study Limitations
This is a retrospective study. The study population is not
large enough to exclude the contribution of other risk factors to AS
progression. Though the study points to several new risk factors, the
mechanisms by which they operate are not clear.
Conclusions
Absolute and percentage reduction in AVA per year in those
with AS is greater in those with milder degrees of stenosis and
is accelerated in the presence of smoking,
hypercholesterolemia, and elevated serum
creatinine and calcium levels. These findings may have
important implications in gaining further insights into the mechanism
of AS progression and in formulating strategies to retard its
progression.
Received June 11, 1999; revision received November 30, 1999; accepted December 22, 1999.
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L Wallby, B Janerot-Sjoberg, T Steffensen, and M Broqvist T lymphocyte infiltration in non-rheumatic aortic stenosis: a comparative descriptive study between tricuspid and bicuspid aortic valves Heart, October 1, 2002; 88(4): 348 - 351. [Abstract] [Full Text] [PDF]
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N A Boon and P Bloomfield The medical management of valvar heart disease Heart, April 1, 2002; 87(4): 395 - 400. [Full Text] [PDF]
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K. Pohle, R. Maffert, D. Ropers, W. Moshage, N. Stilianakis, W. G. Daniel, and S. Achenbach Progression of Aortic Valve Calcification: Association With Coronary Atherosclerosis and Cardiovascular Risk Factors Circulation, October 16, 2001; 104(16): 1927 - 1932. [Abstract] [Full Text] [PDF]
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R. P. Choudhury, F. Leyva, R. G. Pai, S. Palta, A. M. Pai, and K. S. Gill New Insights Into the Progression of Aortic Stenosis: Implications for Secondary Prevention Response Circulation, March 27, 2001; 103 (12): e67 - e67. [Full Text] [PDF]
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