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2772
Systolic and Diastolic Dysfunction in
Patients With Clinical Diagnosis
of Dilated Cardiomyopathy
Relation to Symptoms and Prognosis
Charanjit S. Rihal, MD; Rick A. Nishimura, MD; Liv K. Hatle, MD;
Kent R. Bailey, PhD; A. Jamil Tajik, MD
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Background Dilated cardiomyopathy is an important cause
of morbidity and mortality among patients with congestive
heart failure. Hemodynamic and prognostic characterization
are critical in guiding selection of medical and surgical
therapies.
Methods and Results A cohort of 102 patients with the
clinical diagnosis of dilated cardiomyopathy who underwent
echocardiographic examination between 1986 and 1990 was
identified and followed up through July 1, 1991. Patients with
moderate or severe symptoms had lower indices of systolic
function and greater left atrial and right ventricular dilation.
Mitral inflow Doppler signals were characterized by a restrictive left ventricular filling pattern. In multivariate logistic
regression analysis, deceleration time, ejection fraction, and
peak E velocity were independently associated with symptom
status. Over a mean follow-up of 36 months, 35 patients died.
Kaplan-Meier estimated survival at 1, 2, and 4 years was 84%,
73%, and 61%, respectively, and was significantly poorer than
that of an age- and sex-matched population. The subgroup
with an ejection fraction <0.25 and deceleration time <130
milliseconds had a 2-year survival of only 35%. The subgroup
with ejection fraction <0.25 and deceleration time >130
milliseconds had an intermediate 2-year survival of 72%,
whereas patients with an ejection fraction .0.25 had 2-year
survivals 295% regardless of deceleration time. In multivariate analysis, ejection fraction and systolic blood pressure were
independently predictive of subsequent mortality. Mitral deceleration time was significant in univariate analysis.
Conclusions In patients with the clinical diagnosis of dilated cardiomyopathy, markers of diastolic dysfunction correlated strongly with congestive symptoms, whereas variables of
systolic function were the strongest predictors of survival.
Consideration of both ejection fraction and deceleration time
allowed identification of subgroups with divergent long-term
D ilated cardiomyopathy is a disease of idiopathic
origin characterized by reduced global left
ventricular systolic function. Adjusted prevalence rates range from 4.4 per 100 000 for women to 11
per 100 000 for men.' Case fatality rates approach 30%
at 3 years and 60% at 5 years after diagnosis.2 Whereas
the treatment of dilated cardiomyopathy is largely empiric, important advances in medical (angiotensin-converting enzyme inhibitors, new inotropic drugs) and
surgical therapy (heart transplantation) have occurred.
Besides diagnostic information, the comprehensive
evaluation of patients with dilated cardiomyopathy includes an assessment of prognosis. The conventionally
used prognostic variable has been left ventricular ejection fraction. However, as repeatedly demonstrated,
patients with dilated cardiomyopathy and ejection fractions in the midrange (20% to 30%) may have a highly
variable clinical course, and clinicians often face uncertainty in assessing the prognosis of a patient.
A wide range of diastolic transmitral flow velocity
patterns exists in various cardiac disease states, and
recent clinical and laboratory work has begun to shed
light on the hemodynamic significance and prognostic
implications of transmitral flow velocity profiles.3-5
However, little information is available about Doppler
echocardiographic hemodynamics and their relation to
the pathophysiology and long-term outcomes of dilated
cardiomyopathy.
The purpose of our study was to critically evaluate
various clinical and echocardiographic variables among
patients with the clinical diagnosis of dilated cardiomyopathy who underwent comprehensive echocardiographic examination at the Mayo Clinic Echocardiography Laboratory from 1986 to 1990. Follow-up data were
obtained through July 1, 1991. We hypothesized that left
ventricular ejection fraction would incompletely characterize hemodynamics and prognosis in this patient population and that diastolic Doppler echocardiographic
variables would add significantly to both of these
aspects.
Received June 2, 1994; revision accepted July 18, 1994.
From the Division of Cardiovascular Diseases and Internal
Medicine (C.S.R., R.A.N., A.J.T.) and the Section of Biostatistics
(K.R.B.), Mayo Clinic and Mayo Foundation, Rochester, Minn,
and the University of Trondheim (L.K.H.), Trondheim, Norway.
Reprint requests to C.S. Rihal, MD, McMaster University,
Division of Cardiology, 237 Barton St E, Hamilton, Ontario,
Canada L8L 2X2.
C 1994.
prognoses. (Circulation. 1994;90:2772-2779.)
Key Words * cardiomyopathy * echocardiography .
diastole * prognosis
Methods
Research Design
The study was a retrospective cohort analysis that used the
resources of the Mayo Clinic Echocardiography Laboratory
and the Mayo Clinic medical records. All aspects of the study
Rihal et al Systolic and Diastolic Dysfunction
2773
were subject to review by the Mayo Institutional Review
Board; approval was given August 5, 1991.
TABLE 1. Echocardiographic Variables Recorded for
102 Patients With Dilated Cardiomyopathy
Subjects
Left ventricular end-diastolic dimension (EDD)
Left ventricular end-systolic dimension (ESD)
Mean left ventricular diastolic wall thickness (average of septal
and posterior wall thicknesses)
Mean left ventricular diastolic wall thickness/radius ratio
Left ventricular ejection fraction (EF): EF=(EDD2-ESD2)/EDD2
Peak left ventricular outflow tract (LVOT) velocity
Acceleration (a) to peak LVOT: a=LVOT velocity/acceleration
time
Isovolumic relaxation time (IVRT)
Filling velocity ratio (E/A)
Deceleration time of E (DT)
Peak tricuspid regurgitation velocity
(systolic blood pressure x radius)
Stress =
wall thickness
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By using the Mayo Echocardiography Laboratory database
(for the years 1986 to 1990), we identified all patients with the
diagnosis of dilated cardiomyopathy (n=686). Of these 686
patients, 442 had complete two-dimensional and Doppler
echocardiographic examinations performed. These patients
were stratified a priori into four groups according to ejection
fraction (dichotomized arbitrarily at 0.25) and deceleration
time (dichotomized at 130 milliseconds, which is -2 SD from
the mean normal for our laboratory).6 A random sample of
200 patients was chosen to obtain approximately equal samples
in each. Patient medical records were screened, and only
patients with the clinical diagnosis of idiopathic dilated cardiomyopathy were included in the study. Criteria for inclusion
included an ejection fraction <0.50 and the absence of a clear
etiology. Patients in whom a clear cause for cardiomyopathy
was identified or suspected (for example, coronary artery
disease, valvular heart disease, infiltrative processes) were
excluded. Coronary angiography and endomyocardial biopsy
were not considered mandatory for inclusion. Patients who
had incomplete or technically inadequate two-dimensional or
Doppler echocardiographic studies were excluded. In this
manner, a cohort of 102 patients was identified.
Echocardiographic Examination
Comprehensive two-dimensional and Doppler echocardiographic examinations were performed in all patients, as described previously,78 with commercially available echocardiographic instruments. The left atrial dimension was measured
in the parasternal long-axis view, and the right ventricular
dimension was measured in the parasternal short-axis view.
Transmitral flow velocity signals were obtained by placing a
pulsed-wave Doppler sample volume at the tips of the mitral
leaflets. Stroke volume was determined by measuring the left
ventricular outflow tract diameter, recording the pulsed-wave
Doppler signal at the level of the aortic annulus, and performing volumetric analysis with the time-velocity integral. Mitral
regurgitation was semiquantitatively assessed with color-flow
Doppler echocardiography.9.10
Data
Data recorded included age, sex, symptom status, and vital
status at the latest follow-up visit at the Mayo Clinic. All
echocardiograms were reviewed and digitally analyzed off line
(GTI Freeland Systems microprocessor). Ejection fraction was
calculated with a modification of the method of Quinones et
al.1" For the purposes of this analysis, left ventricular stress
was defined as (systolic blood pressure times left ventricular
radius) divided by left ventricular wall thickness in diastole.
Deceleration time was measured as the interval (in milliseconds) from peak early mitral filling (E velocity) to an extrapolation of the deceleration to 0 M/s.12 The mean of at least
three measurements for patients in sinus rhythm was used and
seven measurements for those with other rhythms. Interobserver variability has been documented for our laboratory.13
Additionally, we assessed variability by comparing 20 velocity
and interval measurements performed by two observers
independently.
The clinical and echocardiographic data recorded, including
both measured and derived variables, are listed in Table 1.
Blood pressure was measured by auscultation by the patient's
physician and recorded in the medical record. A blood pressure measurement obtained as close as possible temporally to
the index echocardiogram was used for data analysis. Follow-up data were gathered through scrutiny of the Mayo Clinic
records, supplemented by direct mail or telephone contact,
and were complete through July 1, 1991.
Statistical Analysis
Descriptive group data are presented as mean +±SD unless
otherwise stated. To assess correlates of symptomatic status,
patients were grouped into those with mild (New York Heart
Association [NYHA] functional class I or II) or moderate-tosevere (class III or IV) symptoms, and group differences in
demographic, clinical, and echocardiographic variables were
assessed by Student's t test or by x2 test for proportions.
Multiple logistic regression analysis was used to determine
independent correlates of symptom status. Results are reported as odds ratios associated with specific contrasts in
predictor variables.
Survival was estimated by the Kaplan-Meier product-limit
method, with the follow-up period starting at the index
echocardiogram, and group differences were assessed with the
log rank test. Of particular interest was the stratified comparison based on ejection fraction and deceleration time. Univariate and multivariate Cox proportional hazards models were
constructed to assess univariate as well as independent associations with survival. Results of these models were reported
as hazard ratios associated with specific contrasts in the
predictor variables.
Statistical significance was judged at the two-sided .05 level.
With 102 patients and 35 fatal events occurring during followup, the study had 80% power to detect a standardized Cox
regression coefficient of .45, equivalent to a 1 SD shift (decrease) in deceleration time being associated with a relative
hazard of 1.57.
Results
Baseline Characteristics
The clinical characteristics of the cohort of 102 patients (65 men and 37 women; mean age, 61±+ 14 years),
determined at the time of the index echocardiographic
examination, are listed in Table 2. Mean systolic blood
pressure was 124±19 mm Hg, and mean diastolic blood
pressure was 80±11 mm Hg. All patients were white,
and no patient had had a documented myocardial
infarction, coronary angioplasty, or coronary bypass
operation. At the time of the index echocardiogram, a
history of hypertension was present in 21 of the patients
and diabetes mellitus in 13; 47 were current or former
smokers. The patients were taking the following medi-
2774
Circulation Vol 90, No 6 December 1994
TABLE 2. Baseline Clinical and Two-dimensional and
Doppler Echocardiographic Characteristics of 102*
Patients With Dilated Cardiomyopathy
New York Heart Association
No.
Functional Class
11
IV
Not determined
Sinus rhythm
Atrial fibrillation
Moderate or severe mitral regurgitation
30
28
34
9
1
75
19
44
Mean+SD
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Systolic blood pressure, mm Hg (n=99)
End-diastolic dimension, mm (n=101)
End-systolic dimension, mm (n= 101)
Fractional shortening, % (n=101)
Left ventricular ejection fraction, %
(n=101)
End-diastolic wall thickness, mm
(n=76)
End-systolic wall thickness, mm (n=67)
Thickness-radius ratio (n=87)
Peak LVOT velocity, m/s (n=98)
LVOT acceleration, m/s2 (n=90)
Stroke volume, mL (n=87)
Tricuspid regurgitation velocity, m/s
(n=66)
Peak E velocity, m/s (n=97)
Peak A velocity, m/s (n=74)
E/A ratio (n=74)
Deceleration time, ms (n=98)
LVOT indicates left ventricular outflow tract.
*Mean age±SD, 61±14 years; 65 men.
124±+19
69+9
60±9
13±5
23±8
10±2
12±2
0.29±0.07
0.76±0.19
8.9±3.2
41±16
2.9±0.5
0.77±0.26
0.58±0.28
1.68±1.21
172±66
cations: 68, diuretic medications; 69, a digitalis preparation; 52, an angiotensin-converting enzyme inhibitor;
14, nitrates; 11, a calcium channel blocker; and 3,
,-adrenoreceptor blockers. Furthermore, 75 patients
were in sinus rhythm, and 27 had other chronic rhythms
(atrial fibrillation or paced). Nine patients were taking
antiarrhythmic agents and 7 were taking warfarin sodium. ECG evidence of left ventricular hypertrophy was
present in 13 and bundle-branch block in 38. Cardiomegaly (cardiothoracic ratio >0.50) was present on
chest roentgenography in 69 patients.
Coronary angiography was performed in 57 patients
(36 men; mean age, 59±14 years). Of these patients, the
coronary arteries were normal in 75%, but insignificant
disease (all lesions <50%) was present in 14%. Singlevessel disease was present in 9%. In all patients, the
degree of left ventricular dysfunction was thought to be
incongruent with the degree of coronary artery atherosclerosis, consistent with a primary myocardial process.
400
300
E
0
C
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*,
0
..
'M
-*
,
0
0
0.1
0
0
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0
.
0
.
0
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% .
.
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S
11oo
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*Y _. * :
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0
0.2
0.3
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Ejection fraction
FIG 1. Plot shows distribution of left ventricular ejection fraction
by mitral deceleration time.
Right ventricular endomyocardial biopsy was performed in 28 patients (22 men; mean age, 57±+16 years)
and revealed nonspecific cellular hypertrophy and interstitial fibrosis in all of them (patients with specific
biopsy-proven diagnoses were excluded a priori). Echocardiographic variables measured at the index examination are listed in Table 2. Mean left ventricular end-diastolic dimension was increased at 69±9 mm, and
eccentric hypertrophy was present (mean diastolic wall
thickness, 10+2 mm). Significant left ventricular systolic
dysfunction was present, with a mean ejection fraction
of 0.23±0.08 and a mean stroke volume of 41±16 mL.
The mitral inflow deceleration time was <130 milliseconds in 37 patients, 131 to 250 milliseconds in 50, and
>250 milliseconds in 11. The distribution of mitral
deceleration time and left ventricular ejection fraction is
shown in Fig 1. Mean tricuspid regurgitation velocity
was elevated at 2.9±0.5 m/s, reflecting increased pulmonary arterial systolic pressures.
Symptom Status
Fifty-eight patients had mild or no symptoms (NYHA
class I or II) and 43 had moderate or severe symptoms
(NYHA class III or IV). In one patient, functional class
could not be determined from the medical record. As
shown in Table 3, patients with severe symptoms had
higher heart rates and larger left atria and right ventricles but equal degrees of left ventricular dilation. Measures of systolic function such as left ventricular ejection
fraction (median, 0.18 in the severe group compared
with 0.24 in the mild group; P=.0001) and stroke
volume (median, 34 mL compared with 45 mL; P=.02)
were significantly lower among those with severe symptoms. Left ventricular outflow acceleration was not
significantly different (median, 8.7 m/s2 compared with
8.5 m/s2). Among the severely symptomatic, median
peak mitral E velocity was significantly higher (0.90 m/s
compared with 0.70 m/s; P<.0001) and median peak A
velocity was significantly lower (0.40 m/s compared with
0.60 m/s; P=.02). The E/A ratio was markedly different
between the two groups (median, 1.0 compared with
3.0; P=.0004). Deceleration time was markedly shortened among the severely symptomatic (median, 120
milliseconds compared with 200 milliseconds; P<.0001).
Logistic regression analysis was performed to determine correlates of symptom status (Table 4). In the
univariate model, indices of diastolic filling were the
important correlates, especially deceleration time
(P<.0001; odds ratio, 0.68 for a 20-millisecond differ-
Rihal et al Systolic and Diastolic Dysfunction
2775
TABLE 3. Symptom Status of 101 Patients With Dilated Cardiomyopathy
Mild or No Symptoms
(n=58)
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Variable
Age, y
Systolic blood pressure, mm Hg
Diastolic blood pressure, mm Hg
Heart rate, beats per minute
Right ventricular dimension, mm
Left atrial dimension, mm
EDD, mm
Left ventricular ejection fraction
Stroke volume, mL
LVOT acceleration, m/s2
Thickness-radius ratio
Tricuspid regurgitation velocity, m/s
Peak E velocity, m/s
Peak A velocity, m/s
E/A ratio
Deceleration time, ms
Moderate or severe mitral
Median
62.3
128
80
71
28
45
67
0.24
45
8.5
0.23
2.7
0.70
0.60
1.0
200
Range
18.1-86.7
80-175
40-100
52-118
8-54
34-63
52-91
0.13-0.47
16-80
3.5-17
0.18-0.54
1.9-5.0
0.35-1.35
0.10-1.14
0.42-6.0
80-350
Moderate or Severe
Symptoms (n=43)
Median
62.2
120
80
90
34
50
70
0.18
34
8.7
0.28
3.0
0.90
0.40
3.0
120
No. (%)
19 (33)
24 (56)
EDD indicates left ventricular end-diastolic dimension; LVOT, left ventricular outflow tract.
regurgitation,
ence), peak E velocity (P=.0001; odds ratio, 7.26 for a
0.5-m/s difference), and E/A ratio (P=.0011; odds ratio,
2.63 for a 1 SD difference). Ejection fraction and stroke
volume were also correlated with symptom status with
high degrees of significance.
Multivariate models were also constructed to determine independent predictors of functional class; the
best-fit main effects model is depicted in Table 4. Two
of three independent variables reflected diastolic rather
than systolic variables. Peak E velocity (odds ratio, 4.49
for a 0.5-m/s difference; P=.018), ejection fraction
(odds ratio, 0.27 for a 10-U contrast; P=.0039), and
deceleration time (odds ratio, 0.81 for a 20-millisecond
difference; P=.08) were included in the final model.
Although E/A ratio is a widely used variable, it was not
significant in multivariate analysis and did not enter the
final model.
Long-term Outcome
Median follow-up time was 36 months (range, 1 to 54
months); 35 patients died during the follow-up period:
34 of cardiac causes (congestive heart failure or sudden
death) and 1 of a noncardiac cause. The Kaplan-Meier
life table probability of survival was 83.5%, 72.9%,
64.2%, and 61.1% at 1, 2, 3, and 4 years, respectively,
after the index echocardiogram (Fig 2). This is significantly poorer than the expected 97.7%, 95.4%, 93.0%,
and 90.5% yearly survival, respectively, for the age- and
sex-matched 1980, white, north central US population
(one-sample log rank x2=174.8; P<.0001).
To gain further perspective on the usefulness of
echocardiographic prognostic indicators, subgroups
stratified according to ejection fraction (at 0.25) and
Range
18.8-84.1
86-160
55-110
50-130
20-57
29-64
55-98
0.09-0.36
13-59
4.6-20.8
0.14-0.46
2.3-4.0
0.40-1.6
0.14-1.20
0.7-5.0
80-333
P
.99
.18
.28
.001
.008
.04
.64
.0001
.02
.77
.59
.059
<.0001
.02
.0004
<.0001
.02
deceleration time (at 130 milliseconds) were identified
(Fig 3). At 2 years after the index echocardiographic
examination, life table-estimated probabilities of survival were: ejection fraction .0.25 and deceleration
time .130 milliseconds (n=26), 95%; ejection fraction
.0.25 and deceleration time <130 milliseconds (n=29),
100%; ejection fraction <0.25 and a deceleration time
.130 milliseconds (n=37), 71.6%; and for the subgroup
with an ejection fraction <0.25 and deceleration time
<130 milliseconds, only 34.8% (four-group log rank
X2=22.3 on 3 degrees of freedom [dfl, P<.0001).
Because on inspection of the data (Fig 3) the low
ejection fraction-low deceleration time subgroup
seemed to do significantly worse, an internal comparison of this subgroup with the three others yielded a x2
of 18.43 (1 df, P<.0001). When compared with the two
ejection fraction >0.25 subgroups, survival of the subgroup with a low ejection fraction and higher deceleration time was significantly worse (x2, 6.16 on 1 df;
P=.013). No significant difference was found between
the two ejection fraction >0.25 subgroups. Thus, the
original four-group x2 of 22.3 was largely due to the
poor survival of the low ejection fraction-low deceleration time subgroup, with a smaller contribution from
the subgroup with a low ejection fraction but higher
deceleration time with an intermediate prognosis. Subgroups with ejection fraction >0.25 had a relatively
good survival regardless of the deceleration time.
Next, predictors of long-term survival were assessed
by Cox proportional hazards analysis (Table 5). In
contrast to symptoms, the most important correlates of
survivorship were indices of left ventricular systolic
function. Ejection fraction and systolic blood pressure
Circulation Vol 90, No 6 December 1994
2776
TABLE 4. Logistic Regression Models of Symptom Status
Variable
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
-0.0194
3.9634
-0.1241
0.7982
-0.0382
0.9527
0.8112
0.7647
-0.0156
0.0245
-3.3531
0.0695
0.2358
0.0006
DT
Peak E velocity
Left ventricular ejection fraction
E/A ratio
Stroke volume
Moderate or severe MR
TR velocity
Atrial fibrillation
Systolic blood pressure
EDD
Thickness-radius
LVOT acceleration
Male sex
Age
SE
P
Univariate Model
0.0048
1.0416
0.0341
0.2453
0.0155
0.4154
0.5176
0.5169
0.0110
0.0235
0.3861
0.0711
0.4233
0.0140
<.0001
.0001
.0003
.0011
.0140
.0218
.1170
.1390
.1583
.2978
.3221
.3285
.5775
.9674
Odds
Ratio
95% Cl
0.56, 0.82
2.61, 20.1
0.15, 0.56
1.47, 4.70
0.50, 0.92
1.15, 5.85
0.82, 6.21
0.68*
7.26t
0.29t
2.63§
0.68t
2.59
2.25
2.15
0.86t
0.78, 5.92
0.69,1.06
0.90,1.42
0.75, 0.83
0.80,1.95
0.55, 2.90
0.76,1.32
1.1311
0.79§
1.25§
1.27
1.01t
Multivariate Main Effects Model
1.29, 15.61
.0180
4.49t
1.2707
3.0049
Peak E velocity
0.11, 0.66
0.27t
.0039
0.0456
-0.1316
Left ventricular ejection fraction
0.64,1.02
.081*
.0764
0.0059
-0.0104
DT
Cl indicates confidence interval; DT, mitral deceleration time; EDD, left ventricular end-diastolic dimension; LVOT, left ventricular
outflow tract; MR, mitral regurgitation; SE, standard error; and TR, tricuspid regurgitation.
*Computed for 20-ms difference.
tComputed for 0.5-m/s difference.
tComputed for 10-U difference.
§Computed for 1 SD difference.
IlComputed for 5-mm difference.
were the most powerful predictors; heart rate, NYHA
functional class, stroke volume, and age were also
significant in univariate analysis. Two variables of diastolic dysfunction, the mitral deceleration time and the
E/A ratio, were correlated with long-term survival in
univariate analysis.
Multivariate proportional hazards models were constructed, and the strongest model is depicted in Table 5.
Ejection fraction (/3=-0.0989; P=.0006; and hazard
ratio, 0.37 for a 10% difference) and systolic blood
pressure (/3= -0.0315; P=.0064; hazard ratio, 0.73 for a
10 mm Hg difference) were the only independent predictors of survivorship. The linear main effects model is
illustrated in Fig 4. Interaction and nonlinear quadratic
models did not add clinically important information.
Interobserver Variability
For Doppler velocity measurements, interobserver
variability was low, with r=.97 and SE of 0.05 m/s. For
100
EF a2Q25 and DT < 130
1W ,,
-
----
EF 2Q25 and
80
S0
.
-
60
!*
DT k130 -----
____
EF <0.25 andD1 130
t
60
2
cn
40
E
-
-------
Observed
CO)
Expected
<0 25
EFand
40
DT < 130
20
20
v
U
0
N-102
1
80
2
65
3
43
4
19
Years
FIG 2. Kaplan-Meier life table-estimated probability of survival
after index echocardiogram compared with that for age- and
sex-matched 1980 north central US population. X 2=174.8;
P<.0001 by log rank test. Bars indicate 2 SE.
0
2
1
3
Years
FIG 3. Kaplan-Meier life table-estimated probability of survival
after index echocardiogram of subgroups stratified by ejection
fraction (EF) and mitral deceleration time (DT). x 2=257;
P<.0001 by log rank test.
Rihal et al Systolic and Diastolic Dysfunction
TABLE 5. Proportional Hazards Model of Long-term Survival
(3
SE
Variable
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Left ventricular ejection fraction
Systolic blood pressure
Heart rate
NYHA Ill or IV
Stroke volume
Age
DT
E/A ratio
EDD
Male sex
Atrial fibrillation
Thickness-radius
E velocity
Moderate or severe MR
TR velocity
LVOT acceleration
Stress
0.0302
0.0102
0.0101
0.3436
0.0131
0.0143
0.0030
0.1685
0.0183
0.3872
0.3873
2.6796
0.6767
0.3395
0.3548
0.0639
0.0013
-0.1145
-0.0339
0.0275
0.8034
-0.0288
0.0296
-0.0059
0.3198
0.0334
0.5468
0.5429
-2.8814
0.6152
0.2636
0.2366
-0.0161
-0.0003
P
Hazard Ratio
Univariate Model
.0002
.0009
.0062
.0194
.0282
.0386
.0487
.0578
.0669
.1578
.1610
.2822
.3633
.4375
.5048
.8011
.8052
0.32*
0.71 *
1.32t
2.23
0.75*
1.34*
0.89*
1.47§
1.1811
1.73
1.72
0.82§
1 .36¶
1.30
1.27
0.95§
0.76#
2777
95% Cl
0.18, 0.58
0.58, 0.87
1.08, 1.61
1.14, 4.38
0.58, 0.97
1.02, 1.78
0.79,1.00
0.99, 2.20
0.99,1.41
0.81, 3.69
0.81, 3.68
0.57,1.18
0.70, 2.64
0.67, 2.53
0.63, 2.54
0.64,1.42
0.57, 1.06
Multivariate Main Effects Model
.0006
0.37*
-0.0989
0.0291
Left ventricular ejection fraction
0.21, 0.66
0.0110
.0064
-0.0315
0.73*
0.59, 0.91
Systolic blood pressure
Cl indicates confidence interval; DT, mitral deceleration time; EDD, left ventricular end-diastolic dimension; LVOT, left ventricular
outflow tract; NYHA, New York Heart Association functional class; MR, mitral regurgitation; and TR, tricuspid regurgitation.
*Computed for 10-U difference.
tComputed for 10-beat-per-minute difference.
tComputed for 20-ms difference.
§Computed for 1 SD difference.
IlComputed for 5-mm difference.
¶Computed for 0.5-m/s difference.
#Computed for 100-U increase.
all time interval measurements, interobserver variability was also low, with r=.99 and SE of 15 milliseconds.
Discussion
Summary of the Current Study
Dilated cardiomyopathy is a primary disorder of the
myocardium of unknown cause characterized by pro180
E
LD
140
120
mQ100Q4Q8Q XQ XQ
_100
~~~~~~~~~~~841%
o
q~
bn
FIG 4. Contour plot of Cox proportional hazards model of
survival. Log hazard=-0.8901 times ejection fraction minus
0.0315 times systolic blood pressure. Percentages are 3-year
predicted survival based on baseline ejection fraction and systolic blood pressure.
gressive left ventricular dilation, severely decreased
global systolic function, and the activation of major
neurohormonal systems.14-18
The purpose of this study was to examine the clinical
and echocardiographic characteristics of a random cross
section of patients with the clinical diagnosis of dilated
cardiomyopathy and to determine the prognostic impli-
cations of these characteristics. On average, patients
with severe congestive heart failure had lower indices of
systolic function and were more likely to have significant
mitral regurgitation and greater left atrial and right
ventricular dilation. Left ventricular diastolic filling
abnormalities were prominent, with a restrictive-type
filling pattern (that is, high E, low A, short deceleration
time) being common. As previously pointed out,13 this
filling pattern probably reflects higher early diastolic left
atrial-left ventricular gradients and higher left atrial
pressures. In multivariate analysis, variables of diastolic
filling were independently associated with severe symptoms. This finding suggests that mitral inflow Doppler
echocardiographic patterns add important information
to the full hemodynamic characterization of patients
with congestive heart failure and is congruent with
previous work.3-5,12
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Circulation Vol 90, No 6 December 1994
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With regard to survival, long-term outcome was best
modeled by a multivariate model using two variables of
systolic function: left ventricular ejection fraction and
systolic blood pressure. The mitral deceleration time
was significant only in univariate analysis. Nonetheless,
consideration of this variable may still be useful clinically and may enhance patient management. It is evident (Fig 3) that subgroups with divergent prognoses
may be identified on the basis of stratification by
ejection fraction and deceleration time. Patients with an
extremely short deceleration time and severe systolic
dysfunction experienced rapid short-term attrition.
Consideration of such variables may enhance the ability
of clinicians to plan management, especially if orthotopic cardiac transplantation is being considered. Because approximately 50% of deaths in patients with
dilated cardiomyopathy occur suddenly,219-22 it is not
surprising that hemodynamic variables such as deceleration time do not completely predict prognosis.
Comparison With Previous Work
Multiple clinical predictors of survival among patients with dilated cardiomyopathy have been determined, including the cardiothoracic ratio, left ventricular ejection fraction and end-diastolic pressure,
ventricular arrhythmias, conduction delays, left ventricular wall thickness, and the presence of the third heart
sound.23-30 In our study, left ventricular wall thicknessradius ratio and crude stress calculations were postulated to be markers of late outcome, but this was found
not to be the case, consistent with some27 but not a1128-30
previous studies.
Two recently published European series4,5 examined
left ventricular diastolic filling variables among patients
with dilated cardiomyopathy. As in the current study,
restrictive filling was highly associated with severe symptoms. Unlike the current study, however, restrictive
filling was the most powerful predictor of future cardiac
events and mortality. Because all retrospective case
control and cohort studies are unavoidably affected by
selection and referral biases, many important differences in the patient populations studied are apparent.
We used a stratified random sample for case selection in
an attempt to ensure a broad range of deceleration
times and ejection fractions, whereas the other studies
used consecutive case series. Regional variability may
have had a role in determining differences in patient
cohorts; for example, in one study4 the mean age of the
cohort was 39 years, significantly less than that in the
current study. Significant variability in a priori selection
criteria existed as well; for example, minimally symptomatic patients and those with atrial fibrillation or
severe mitral regurgitation were excluded but those with
ischemic cardiomyopathy were included in one study.5
Important differences in construction of multivariable
models also exist: in one study,4 neither fractional
shortening nor ejection fraction were included in the
multivariate analysis, and in another study,5 blood pressure was excluded. Thus, direct comparison of results is
difficult.
Strengths and Limitations
All echocardiographic examinations were performed
in an experienced laboratory and the data were recorded prospectively. To obtain clinically useful long-
term follow-up information, patients examined when
Doppler interrogation became routine in our laboratory
(1986) were included. However, our study was a retrospective cohort analysis and has the inherent limitations
of this design. Whereas the extremely short deceleration
times in the severely symptomatic group are consistent
with a rapidly decreasing early diastolic filling gradient
with increasing left ventricular diastolic pressure (rapid
filling wave), we were unable to assess the independent
effect of mitral regurgitation on the mitral flow velocity
profile, in particular, the E velocity. It is possible that
the observed higher peak E velocities in the severely
symptomatic group were partly due to the higher prevalence of moderate or severe mitral regurgitation
among this group.
In the early application of Doppler echocardiography, some variables (isovolumic relaxation times, dP/
dT,31 and pulmonary and systemic venous flow patterns)
that may have provided additional information were not
measured with sufficient frequency to warrant inclusion.
Because simultaneous invasive monitoring was not performed, the ability to separate diastolic filling abnormalities due to fluid overload from those due to intrinsic
myocardial processes and to rule out pseudonormalization was limited. Because not all patients returned to
the Mayo Clinic for their follow-up examinations, the
evolution of mitral inflow patterns and their modification by medical therapy were not considered. The
retrospective nature of our study did not allow us to
characterize accurately patient deaths as due to congestive heart failure or sudden (presumably arrhythmic)
cardiac death. Thus, we did not use recurrent hospitalization as a clinical end point to avoid misclassification
and incomplete data. However, these limitations do not
detract from the value of the prognostic data determined in this manner.
Conclusions
In patients with the clinical diagnosis of dilated cardiomyopathy, variables of systolic dysfunction are the most
important independent predictors of outcome; variables of
diastolic filling add significantly to acute hemodynamic
characterization and allow further identification of subgroups with divergent long-term prognoses. Two-dimensional and Doppler echocardiographic examinations are
noninvasive methods for achieving these ends and should
be considered in all patients with suspected or known
dilated cardiomyopathy.
Acknowledgment
The authors thank Cynthia Crowson for computer programming and data analysis.
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Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated
cardiomyopathy. Relation to symptoms and prognosis.
C S Rihal, R A Nishimura, L K Hatle, K R Bailey and A J Tajik
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Circulation. 1994;90:2772-2779
doi: 10.1161/01.CIR.90.6.2772
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