Download Does Left Atrial Size Predict Mortality in Asymptomatic Patients with

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Journal compilation DOI: 10.1111/j.1540-8175.2009.01002.x
ORIGINAL INVESTIGATIONS
Does Left Atrial Size Predict Mortality in
Asymptomatic Patients with Severe Aortic Stenosis?
Grace Casaclang-Verzosa, M.D., Joseph F. Malouf, M.D., Christopher G. Scott, M.S.,
Eldyn Marcony Juracan, M.D., Rick A. Nishimura, M.D., and Patricia A. Pellikka, M.D.
Mayo Clinic, Rochester, Minnesota
Background: We assessed the hypothesis that diastolic function represented by left atrial size determines the rate of development of symptoms and the risk of all-cause mortality in asymptomatic
patients with severe aortic stenosis (AS). Methods: From a database of 622 asymptomatic patients
with isolated severe AS (velocity by Doppler ≥ 4 m/sec) followed for 5.4 ± 4 years, we reviewed
the echocardiograms and evaluated Doppler echocardiographic indices of diastolic function. Prediction of symptom development and mortality by left atrial diameter with and without adjusting for
clinical and echocardiographic parameters was performed using Cox proportional-hazards regression
analysis. Results: The age was 71 ± 11 years and 317 (62%) patients were males. The aortic valve
mean gradient was 46 ± 11 mmHg, and the Doppler-derived aortic valve area was 0.9 ± 0.2 cm2 .
During follow-up, symptoms developed in 233 (45%), valve surgery was performed in 290 (57%)
and 138 (27%) died. Left atrial enlargement was significantly correlated with symptom development
(P < 0.05) but the association diminished after adjusting for aortic valve area and peak velocity (P =
0.2). However, atrial diameter predicted death independent of age and gender (P = 0.007), comorbid
conditions (P = 0.03), and AS severity and Doppler parameters of diastolic function (P = 0.002). Conclusion: Diastolic function, represented as left atrial diameter, is related to mortality in asymptomatic
patients with severe AS. (Echocardiography 2010;27:105-109)
Key words: aortic stenosis, echocardiography, left atrium, valvular heart disease
In our previous study of asymptomatic adult
patients with peak aortic valve velocity of
≥4 m/sec followed for 5.4 ± 4 years, age, AV
velocity, chronic renal failure, and inactivity were
independently associated with all-cause mortality.1 However, no criteria or combination of these
accurately identified all asymptomatic patients at
risk of death. Impairment of diastolic function has
been observed to occur frequently as an adverse
consequence of severe aortic stenosis (AS).2–5
However, no large study has assessed the impact of diastolic function on the natural history of
asymptomatic patients with severe AS. The purpose of the present study was to evaluate the
role of echocardiographic parameters of diastolic
function on the rate of development of symptoms
and the risk of all-cause mortality in asymptomatic
patients with severe AS.
Address for correspondence and reprint requests: Patricia
A. Pellikka, M.D., Mayo Clinic, 200 First Street SW, Rochester,
MN 55905. Fax: 507-284-3968; E-mail: pellikka.patricia@
mayo.edu
Methods:
Two-Dimensional and Doppler
Echocardiography:
From our previously described cohort of 622 patients with severe, asymptomatic AS and peak
AV velocity of ≥4 m/sec,1 we identified patients in whom echo-Doppler parameters of
diastolic function, including left atrial size, E
and A velocities, E/A ratio, and E deceleration time, had been acquired at the time of
echocardiography performed between 1984 and
1995. Left atrial anteroposterior diameter was
measured in the parasternal long-axis view by
M-mode using the leading edge of the posterior aortic wall to the leading edge of the posterior atrial wall,6 or where M-mode was not feasible, by two-dimensional echocardiography in
the same view using the largest diameter during
left ventricular end systole. For patients in whom
left atrial diameter was not recorded in the
database, but had echocardiograms available for
the review, off-line measurements were made
by a single observer, blinded to the rest of the
data.
105
Casaclang-Verzosa, et al.
Patient’s clinical history and other Doppler
echocardiographic information, including ejection fraction, aortic valve (AV) area, AV mean
gradient, and AV peak velocity, were obtained
from the original database.1 Two-dimensional
and Doppler echocardiographic measurements
were obtained according to American Society of
Echocardiography recommendations.7 Patients
were classified as active or inactive according to
whether they required assistance with activities of
daily living. Follow-up was obtained as previously
described.1
Statistical Analysis:
The effects of left atrial diameter (considered separately as a continuous and categorical variable),
in addition to the clinical and echocardiographic
variables that have been previously tested on the
development of symptoms and on mortality, also
were analyzed using the same statistical model
(Cox proportional-hazards regression analysis) as
used in the previous study.1 Using methodology
similar to the previous study, follow-up until the
time of aortic valve surgery was considered for
both endpoints. Univariate and multivariate analysis in the subgroup of patients in whom left atrial
diameter was available was performed. The incremental value of left atrial diameter, as a surrogate
measure of diastolic function,8,9 on previously reported predictors (age, AV peak velocity, chronic
renal failure, and inactivity) on the development
of symptoms and death was determined adjusting for age and sex, clinical co-morbidities, and
severity of AS. Comparison between groups was
performed using 2-tailed Fisher’s test. The Contal
and O’Quigley test was used to estimate the optimal value for the single parameter being considered (left atrial diameter) associated with symptom development and death.10
Results:
The 513 patients in whom left atrial diameter was
measured were included. The mean age was 71 ±
11 years and 318 (62%) were males. The baseline
clinical and echocardiographic characteristics are
listed in Table I.
Development of Symptoms:
During the follow-up of 5.4 ± 4.0 years (maximum 15 years), 233 (45%) patients developed
symptoms of angina, dyspnea, and syncope. Univariate predictors of symptom development were
left atrial diameter, AV area, mean gradient, peak
velocity and peak velocity ≥ 4.5 (all P < 0.05).
A left atrial diameter of >40 mm was the optimal (P = 0.30) cutoff point for symptom development. Patients with left atrial diameter >40 mm
were 1.4 (95% CI, 1.1–1.9, P = 0.007) times more
likely to develop symptoms within 5 years than
106
TABLE I
Patient Characteristics
Age, years ± SD
Male sex, n (%)
Diabetes mellitus, n (%)
Hypertension, n (%)∗
Current/former smoker, n (%)
Chronic renal failure, n (%)
Inactivity, n (%)
Left ventricular hypertrophy, n (%)†
Ejection fraction, % ± SD
Aortic valve velocity ≥ 4.5, n (%)
Aortic valve velocity, m/sec ± SD
Aortic valve mean gradient, mmHg ± SD
Aortic valve area, cm2 ± SD
E-deceleration time, msec ± SD
E-deceleration time < 180 msec, n (%)
E, m/sec
A, m/sec
E/A
Left atrial diameter, mm ± SD
Left atrial diameter ≥ 45mm, n (%)
72 ± 11
317 (62)
621 (12)
220 (43)
193 (38)
20 (4)
37 (8)
85 (17)
64.3 ± 7.3
159 (31)
4.4 ± 0.4
46 ± 11
0.9 ± 0.2
253 ± 63
24 (8)
0.8 ± 0.3
1.0 ± 0.3
0.9 ± 0.3
42.3 ± 7.2
166 (32)
∗ Hypertension
was defined as blood pressure ≥ 140/90
mmHg or the use of antihypertensive medication.
†Left ventricular hypertrophy based on electrocardiographic
criteria.
those with smaller left atrial diameter. Patients
with left atrial diameter >40 mm had 83%, 66%,
and 27% chance of remaining asymptomatic at
1, 2, and 5 years, respectively. In comparison,
patients with left atrial diameter ≤40 mm had
84%, 71%, and 42% chance of remaining asymptomatic at 1, 2, and 5 years, respectively. Adjusting for age and sex alone, left atrial diameter was
significantly correlated with symptom development (P < 0.05) (Table II). When adjusted for clinical covariates (hypertension, diabetes mellitus,
coronary artery disease, chronic renal failure, inactivity, and electrocardiographically diagnosed
TABLE II
Prediction of Development of Symptoms until
Date of Surgery
Left Atrial Diameter > 40 mm
Unadjusted
Age and sex adjusted
Adjusted for age, sex, and
other clinical variables
Adjusted for age, sex, and
echo Doppler variables
Hazard Ratio
P Value
1.4
1.4
1.3
0.007
0.009
0.08
1.5
0.08
Clinical variables include hypertension, diabetes mellitus,
chronic renal failure, coronary artery disease, inactivity, and
left ventricular hypertrophy. Echo Doppler variables include
aortic valve area, peak velocity, mean gradient, ejection fraction, E velocity, E/A, and E deceleration time.
Left Atrial Size and Mortality in Aortic Stenosis
TABLE III
Predictors of Overall Mortality until Date of Surgery
Figure 1. Survival of patients according to left atrial diameter
(LAD) <45 mm and ≥45 mm. Time to death until date of
aortic valve surgery.
left ventricular hypertrophy) and echo Doppler
variables (AV area and AV peak velocity; E, E/A,
E deceleration time), left atrial diameter was not
a significant predictor of symptom development
(Table II). E, E/A, and E deceleration time were
also not predictive of symptom development (all
P > 0.05)
All-Cause Mortality:
During follow-up, 138 (27%) patients died; 51
(37%) of deaths were due to cardiac causes. Univariate predictors of death were age (P < 0.0001),
male gender (P = 0.01), diabetes mellitus (P =
0.04), coronary artery disease (P < 0.0001),
chronic renal failure (P = 0.005), inactivity
(P < 0.001), peak AV velocity (P = 0.04), peak AV
velocity ≥ 4.5 m/sec (P = 0.009), mean gradient
(P = 0.03), AV area (P = 0.02), left atrial diameter (P = 0.0005), left atrial diameter ≥ 4.5 m/sec
(P = 0.008), E velocity (P = 0.002), and E deceleration time (P = 0.004). Those who died had more
impaired diastolic function (mean left atrial diameter 44 mm vs. 41 mm, P < 0.001; mean EDT,
270 msec vs. 248 msec, P = 0.01) than those
who remained alive at 5 years. The relative risk of
death increased by 1.04 (95% CI, 1.00–1.08) per
one unit increase in the left atrial diameter. The
optimal cutoff value for left atrial diameter associated with increased risk of all-cause mortality was
≥45 mm (P = 0.02). All-cause mortality was significantly lower in patients with left atrial diameter
<45 mm (Fig. 1). The 1-, 2-, and 5-year probabilities of survival were 92%, 83%, and 51% for
those with left atrial diameter ≥45 mm compared
to 97%, 90%, and 66% for patients with left atrial
diameter <45 mm. In a multivariate analysis, left
atrial diameter demonstrated significant independent association with all-cause mortality when
adjusted for age and sex alone, and when adjusted for other clinical or echo Doppler variables
(Table III). When stratified according to age and
Left Atrial Diameter ≥ 45 mm
Hazard Ratio
P Value
Unadjusted
Age and sex adjusted
Adjusted for age, sex, and
other clinical variables
Adjusted for age, sex, and
echo Doppler variables
Left Atrial Diameter (per mm)
Unadjusted
Age and sex adjusted
Adjusted for age, sex and
other clinical variables
Adjusted for age, sex, and
echo Doppler variables
1.6
1.3
1.3
0.008
0.1
0.2
2.6
0.03
1.04
1.03
1.03
0.0005
0.007
0.03
1.1
0.01
Clinical variables include hypertension, diabetes mellitus,
coronary artery disease, chronic renal failure, inactivity, and
left ventricular hypertrophy. Echo Doppler variables include
aortic valve area, peak velocity, mean gradient, ejection fraction, E velocity, E/A, and E deceleration time.
inactivity, those who were older (≥ 70 years) and
were inactive had higher risk (Fig. 2). The presence of a larger left atrium (LAD ≥ 45 mm) augmented mortality risk across all groups (Fig. 2).
Discussion:
This study demonstrated that among asymptomatic patients with severe aortic stenosis,
those with enlarged left atria (left atrial diameter
>40 mm) were more likely to develop symptoms compared with patients who had smaller
atria (left atrial diameter ≤40 mm). By the second
and fifth year of follow-up, more patients with
left atrial diameter >40 mm developed symptoms
compared to those with smaller left atrial diameter (second year: 34% vs. 28%; fifth year: 73%
vs. 57%; P = 0.007). Left atrial diameter was a
strong independent predictor of all-cause mortality after adjusting for age, sex, clinical conditions,
AV area, peak AV velocity, and mean gradient.
Figure 2. Hazard ratio of all-cause death stratified by age,
inactivity, and left atrial diameter (LAD).
107
Casaclang-Verzosa, et al.
Furthermore, left atrial dilatation (LAD ≥ 45 mm)
augmented the risk of death in asymptomatic patients who were older (≥70 years) and not living
independently.
Our present study showed an important association between left atrial size and outcome in patients with severe but asymptomatic AS. Our findings are important for several reasons. The course
of these patients was not benign. At 5 years,
the probability of remaining symptom free for
asymptomatic patients with severe AS was only
33% and the probability of remaining free of cardiac events, including cardiac death or AV surgery
was only 25%.1 Standard clinical and echocardiographic characteristics are imperfect in identifying
patients at risk. For example, although risk was
increased in patients with chronic renal failure,
there were only 34 (4%) patients with chronic
renal failure. Estimates of activity level are approximate. Left ventricular hypertrophy may be
secondary to cardiovascular diseases other than
AS. Evaluation of diastolic function involves integration of hemodynamic data obtained from
Doppler echocardiography and can vary from
time to time depending on heart rate, volume status, and rate and depth of breathing.11–15 On the
other hand, left atrial diameter is an objective, accurate, and reproducible echocardiographic parameter that is easily obtained in most patients
and is relatively preload independent, does not
vary with heart rate and respiration, and reflects
the severity of diastolic dysfunction.8,9
Left atrial size has recently been identified as
a marker for cardiovascular events.9,16–21 Studies have also proven that its enlargement is a
marker of both severity and chronicity of diastolic dysfunction and magnitude of left atrial
pressure elevation.8,22–26 Left atrial enlargement
occurs because of increased wall tension from
prolonged elevation of filling pressures.23,27 Impairment of left ventricular diastolic function has
been well described in the presence of AS.5,28–30
It has been shown that the presence of diastolic
dysfunction increases risk of early and late mortality after AV surgery for severe AS.2,5,31 Early intervention is therefore advocated. However, determination of proper timing for aortic valve surgery
in the asymptomatic patient with severe AS remains challenging. The clinical spectrum of AS
is broad and patients with the same AV area
can differ considerably in New York Heart Association status. Indication for surgical intervention is clear for patients who present with clinical
symptoms of decreased cardiac output and concomitant coronary artery disease and other comorbidities.32 However, it is still unclear when to
intervene in a patient who has hemodynamically
significant AS but is asymptomatic.33,34 It is difficult to predict when the symptoms will occur.
108
Thus, there was a need for more accurate criteria
to identify those asymptomatic patients at risk of
death.
Our findings support the importance of diastolic function in the natural history of patients
with severe but asymptomatic AS. We believe that
monitoring progression of AS by mean gradient
and aortic valve area alone is insufficient. Comprehensive assessment of diastolic function including
left atrial size will guide physicians in the management of this high-risk group and evaluate the
optimal timing for intervention in asymptomatic
patients.
Our study contains limitations inherent in a
retrospective study. Left atrial diameter was not
available in all patients. We did not measure left
atrial volume, as it was not routine practice to
determine atrial volume during the period of the
study (1984–1995). The time period of the study
was broad, and Doppler measurements were less
often obtained during the earlier part of the study.
Detailed classification of diastolic function, including tissue Doppler assessment of the mitral annulus or a grading system of classification, was not
available.
Our study suggests that diastolic function, represented as left atrial diameter, is related to mortality and development of symptoms in asymptomatic patients with severe AS. Although further
prospective study is warranted, assessment of left
atrial size may be beneficial in the echocardiographic risk stratification of these patients.
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